5) Neurosience

Neuroscience
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Contents
Articles
Societies
American Society for Neurochemistry
General Neuroscience
1
1
5
Central nervous system
Neurochemistry
Neurotransmitter
Dopamine
Astrocytes
Astrocyte
Oligodendrocytes
16
28
28
38
Oligodendrocyte
38
Myelin
42
Myelin basic protein
45
Demyelinating disease
52
Neurons
56
Axon
56
Neuron
62
Action potential
75
Diseases
Multiple sclerosis
Anatomy
97
97
112
Spinal cord
112
Cerebellum
121
Brain
135
References
Article Sources and Contributors
155
Image Sources, Licenses and Contributors
159
Article Licenses
License
162
Societies
The American Society for Neurochemistry (ASN) is a professional society for neurochemists and neuroscientists
from North, Central, and South America and the Caribbean, whose research concerns the role and interactions of
small molecules (proteins, peptides, nucleic acids, lipids, sugars) in the development, growth, function and pathology
of the nervous system.
History
The ASN was founded in 1969. The organizing committee that founded the ASN consisted of 12 scientists, namely
Jordi Folch-Pi, Guy McKhann, Francis LeBaron, Bernard Agranoff, Donald B. Tower, E. Martin Gal, Semour S.
Kety, Abel Lajtha, Henry S. Mahler, Eugene Roberts, Wallace W. Tourtellotte, and Frederick J. Wolfgram. The first
President of ASN was Dr Tower; Dr Folch-Pi was the 2nd President. The current president (20132015) is Etty
(Tika) Benveniste at the University of Alabama at Birmingham; and the current president elect is Babette Fuss in
Virginia.
The ASN was incorporated August 5, 1969,[1] and is guided by a set of Bylaws and Standing Rules which
incorporate amendments to the bylaws.[2] These guidelines, and other aspects of running and maintaining the society
are carried out by the officers and council members;[3] who are assisted by a number of Standing Committees.[4] The
history and archives of ASN have been organized by several current and former ASN members,[5] as well as the list
of past and current officers and council members [6]
The roots of neurochemistry are being documented by several current ASN members. A brief biography of
Nicolas-Louis Vauquelin was recently published in the newsletter of the International Society for Neurochemistry, a
sister society of ASN; future articles will cover the lives of the founders of neurochemistry, including Thudicum,
Magendie, and others.
Mission statement
1. To advance and promote cellular and molecular neuroscience knowledge.
2. To advance, promote, support, encourage and facilitate communication among investigators in neurochemistry
and related neurosciences.
3. To promote, support, encourage and facilitate the dissemination of information concerning neurochemical
research through scientific meetings, seminars, publications and related activities.
4. To promote, support and encourage the research of individual cellular and molecular neuroscientists and to
engage in any and all other activities for the advancement of the science of neurochemistry which may be deemed
advisable.
5. To insure that all of its activities remain open to the full participation of scholars of all backgrounds and
nationalities.
Annual meeting
Annual meetings[7] include plenary lectures, symposia, colloquia and workshops over the course of 4 days. The
scientific program of the meetings are designed to address the four major themes of the Society:
1. Building the Nervous System.
2. Glial Cell Biology.
3. Metabolism and Cell & Molecular Neurobiology
4. Neurodegeneration and Disease.
Substantial time is allotted throughout the meeting for scientific
discussions both formally and informally. Short oral presentations are
selected from the submitted abstracts, along with daily poster sessions.
Special efforts are taken to encourage young investigator participation.
For instance, the Society sponsors a dinner for pre-doctoral and
post-doctoral students to enable them to establish stronger relationships
with their peers. The Society also subsidizes lunches with the plenary
speakers. Numerous travel awards are available for fellows and junior
faculty, and young investigators are encouraged to submit and chair or
co-chair scientific sessions for the annual meeting.
The first annual ASN meeting was held March 1618, 1970 in
Albuquerque, NM. The 43rd meeting took place in Baltimore, MD
from March 3-7th, 2012.[8] The next ASN meeting is schedule to take
place in March 2014 in Long Beach, California.
Activated Astrocytes in Cortex of TgAPP mouse
Cultured Astrocyte. Green

shows staining for GFAP
In addition to the scientific content, there are several events that reach
out to local students and public. This includes a visit from local high school students to introduce them to
neuroscience research; and a Public Forum that is open to the general public and addresses a current health concern.
The ASN also hosts an image competition "Science in Nature" where attendees submit representative art of their
research interests. Images are judged for scientific as well as artistic merit, and winning images incorporated into a
calendar.
Every 6 years the ASN helps organize a joint meeting with the International Society for Neurochemistry; in 2007 the
joint meeting was scheduled to take place in Cancun, Mexico but was canceled due to Hurricane Dean. However,
Cancun was selected as the venue for the 2013 joint meeting [9] which was highly successful. The next joint
ISN-ASN meeting will take place in 2019 with the exact venue still to be determined.
Publications
The ASN publishes the textbook Basic Neurochemistry used
worldwide by undergraduate, graduate, and post graduate students and
instructors. The founding editor was George Siegel, and the current
chief editor is Scott Brady. Basic Neurochemistry in currently in its 7th
edition, and the 8th edition is scheduled for release in November 2011.
The ASN launched a new Open Access online journal titled ASN
NEURO [10] at the 40th annual meeting which took place in March
2009. ASN NEURO is published by Portland Press, and furthers the
ASN missions to advance, promote, support, encourage and facilitate
communication among cellular and molecular neuroscientists. The
founding editor was Anthony Campagnoni, at the University of
Primary neurons isolated from the Substantia
California in Los Angeles (UCLA), who served for 4.5 years. The
Nigra stained for Tyrosine Hydroxylase (green),
position of Editor in Chief is now held by Monica Carson from the
nuclei (blue), and doublecortin (red)
University of California in Riverside. After 2 years the journal did
extremely well having been accepted for indexing into PubMed after 2
issues, and with several papers receiving special recognition in Faculty1000 as well as in local and national news
reports. ASN NEURO received an initial impact factor from the Institute for Scientific Information(ISI) of 3.8 in
June 2011 which reflects citations in 2009 and 2010 to papers published in 2009. In June 2012 the first 2 year impact
factor was 3.75.
Awards
The Jordi Folch-Pi Award is given to an outstanding young investigator who has demonstrated a high level of
research competence and originality, who has significantly advanced our knowledge of neurochemistry and who
shows a high degree of potential for future accomplishments. Dr Jordi Folch-Pi,[11] one of the founders of ASN, is
known for his discovery of mild methods to extract biological lipids and for the discovery of myelin proteolipid
protein. A full list of past awardees can be found here [12]
The Marian Kies Memorial Award is given to a junior scientist for outstanding research conducted during graduate
training. Dr Kies[13] devoted energy and enthusiasm to the development of young scientists, and is known for her
work on myelin basic protein and studies in animal models of multiple sclerosis. A full list of past awardees can be
found here [14]
The Bernard Haber Award recognizes an individual whose leadership skills have fostered collaborations among
the world's neuroscientists. Dr Haber[15] was editor-in-chief of the Journal of Neuroscience Research, and developed
strong relationships between ASN and the International Society for Neurochemistry.
The ASN offers Young Investigator Educational Enhancement (YIEE) awards for graduate students in their last
year of studies and who reside in the Americas to travel to the annual meeting. Beginning at the 2010 meeting, one
YIEE awardee is selected to receive the prestigious ASN NEURO travel award.
ASN also offers Young Latin American Award scholarships for young neuroscientists from Latin American
countries. These awards subsidize travel expenses to attend the Annual Meeting, along with a short visit to an
established neuroscience laboratory in North America.
References
[1] ASN Articles of Incorporation (http:/ / www. asneurochem. org/ library/ articles. htm)
[2] ASN Bylaws and Standing Rule (http:/ / www. asneurochem. org/ library/ structure. htm)
[3] Current ASN Officers and Council Members (http:/ / www. asneurochem. org/ library/ council. htm)
[4] ASN Standing Committees (http:/ / www. asneurochem. org/ library/ committees. htm)
[5] ASN History and Archives page (http:/ / www. asneurochem. org/ library/ History. htm)
[6] Past ASN officers and council members (http:/ / www. asneurochem. org/ History/ ASNPastOfficers. htm)
[7] List of ASN annual meetings (http:/ / asneurochem. org/ History/ PastASNMeetings. htm)
[8] Baltimore Meeting 2012 (http:/ / asneurochem. org/ 2012Meeting/ ASN2012. htm)
[9] ISN-ASN joint meeting 2013 (http:/ / www. isn-asncancun2013. org/ )
[10] ASN Neuro home page (http:/ / www. asnneuro. org/ an/ default. htm)
[11] Jordi Folch-Pi Biography (http:/ / www. cyberlipid. org/ phlip/ folch3. htm)
[12] Jordi Folch-Pi Awardees (http:/ / www. asneurochem. org/ History/ PastAwardeesoftheJordiFolch-PiAward. htm)
[13] Marian Kies Biography (http:/ / www. asneurochem. org/ History/ MarianKies. htm)
[14] Marian Kies Awardees (http:/ / www. asneurochem. org/ History/ PastAwardeesoftheMarionKiesAward. htm)
[15] Bernard Haber Biography (http:/ / www. asneurochem. org/ library/ BernardHaberAward. htm)
External links
American Society for Neurochemistry home page (http://asneurochem.org/)
ASN NEURO, the ASN journal home page (http://www.asnneuro.org/)

An Informal Oral History of the ASN by Claude F. Baxter (http://asneurochem.org/History/Contents.htm)
Basic Neurochemistry textbook (http://asneurochem.org/library/BasicNeurochemText.htm)
ASN Awards home page (http://asneurochem.org/library/awards.htm)
Other Neurochemistry Societies

International Society for Neurochemistry home page (http://www.neurochemistry.org/)
Home page for Journal of Neurochemistry (http://www.jneurochemistry.org/)
Asian Pacific Society for Neurochemistry home page (http://www.apsneurochem.org/)
European Society for Neurochemistry home page (http://www.neurochemsoc.eu/)
Society for Neuroscience homepage (http://www.sfn.org/)
Agencies and Funding Sites for Neurochemistry
NIH main grants page (http://grants.nih.gov/grants/oer.htm)
National Multiple Sclerosis Society main page (http://www.nationalmssociety.org/index.aspx)
General Neuroscience
The central nervous system (CNS) is the part of the nervous system that integrates the information that it receives
from, and coordinates the activity of, all parts of the bodies of bilaterian animalsthat is, all multicellular animals
except radially symmetric animals such as sponges and jellyfish. It contains the majority of the nervous system and
consists of the brain and the spinal cord. Some classifications also include the retina and the cranial nerves in the
CNS. Together with the peripheral nervous system, it has a fundamental role in the control of behavior. The CNS is
contained within the dorsal cavity, with the brain in the cranial cavity and the spinal cord in the spinal cavity. In
vertebrates, the brain is protected by the skull, while the spinal cord is protected by the vertebrae, and both are
enclosed in the meninges.[1]
Development
During early development of the vertebrate embryo, a longitudinal
groove on the neural plate gradually deepens and the ridges on either
side of the groove (the neural folds) become elevated, and ultimately
meet, transforming the groove into a closed tube, the ectodermal wall
of which forms the rudiment of the nervous system. This tube initially
differentiates into three vesicles (pockets): the prosencephalon at the
front, the mesencephalon, and, between the mesencephalon and the
spinal cord, the rhombencephalon. (By six weeks in the human
Development of the neural tube
embryo) the prosencephalon then divides further into the telencephalon
and diencephalon; and the rhombencephalon divides into the metencephalon and myelencephalon.
As the vertebrate grows, these vesicles differentiate further still. The telencephalon differentiates into, among other
things, the striatum, the hippocampus and the neocortex, and its cavity becomes the first and second ventricles.
Diencephalon elaborations include the subthalamus, hypothalamus, thalamus and epithalamus, and its cavity forms
the third ventricle. The tectum, pretectum, cerebral peduncle and other structures develop out of the mesencephalon,
and its cavity grows into the mesencephalic duct (cerebral aqueduct). The metencephalon becomes, among other
things, the pons and the cerebellum, the myelencephalon forms the medulla oblongata, and their cavities develop into
the fourth ventricle.
Brain regions of a 4 week old human embryo
Central Brain Prosencephalon Telencephalon

nervous
Diencephalon
system
Brain stem
Mesencephalon
Rhinencephalon, Amygdala, Hippocampus, Neocortex, Basal ganglia, Lateral ventricles

Epithalamus, Thalamus, Hypothalamus, Subthalamus, Pituitary gland, Pineal gland, Third
ventricle
Tectum, Cerebral peduncle, Pretectum, Mesencephalic duct
Rhombencephalon Metencephalon
Myelencephalon
Pons, Cerebellum
Medulla oblongata
Spinal cord
Evolution
Planarians, members of the phylum Platyhelminthes (flatworms), have
the simplest, clearly defined delineation of a nervous system into a
central nervous system (CNS) and a peripheral nervous system
(PNS).[2] [3] Their primitive brain, consisting of two fused anterior
ganglia, and longitudinal nerve cords form the CNS; the laterally
projecting nerves form the PNS. A molecular study found that more
than 95% of the 116 genes involved in the nervous system of
planarians, which includes genes related to the CNS, also exist in
humans.[4] Like planarians, vertebrates have a distinct CNS and PNS,
though more complex than those of planarians.
The CNS of chordates differs from that of other animals in being
placed dorsally in the body, above the gut and notochord/spine.[5] The
basic pattern of the CNS is highly conserved throughout the different
species of vertebrates and during evolution. The major trend that can
be observed is towards a progressive telencephalisation: the
telencephalon of reptiles is only an appendix to the large olfactory
bulb, while in mammals it makes up most of the volume of the CNS. In
The central nervous system (2) is a combination
the human brain, the telencephalon covers most of the diencephalon
of the brain (1) and the spinal cord (3).
and the mesencephalon. Indeed, the allometric study of brain size
among different species shows a striking continuity from rats to
whales, and allows us to complete the knowledge about the evolution of the CNS obtained through cranial endocasts.

Mammals which appear in the fossil record after the first fishes, amphibians, and reptiles are the only vertebrates
to possess the evolutionarily recent, outermost part of the cerebral cortex known as the neocortex.[6] The neocortex
of monotremes (the duck-billed platypus and several species of spiny anteaters) and of marsupials (such as
kangaroos, koalas, opossums, wombats, and Tasmanian devils) lack the convolutions gyri and sulci found in the
neocortex of most placental mammals (eutherians).[] Within placental mammals, the size and complexity of the
neocortex increased over time. The area of the neocortex of mice is only about 1/100 that of monkeys, and that of
monkeys is only about 1/10 that of humans.[6] In addition, rats lack convolutions in their neocortex (possibly also
because rats are small mammals), whereas cats have a moderate degree of convolutions, and humans have quite
extensive convolutions.[6] Extreme convolution of the neocortex is found in dolphins, possibly related to their
complex echolocation.
Diseases of the central nervous system

There are many central nervous system diseases, including infections of the central nervous system such as
encephalitis and poliomyelitis, neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral
sclerosis, autoimmune and inflammatory diseases such as multiple sclerosis or acute disseminated
encephalomyelitis, and genetic disorders such as Krabbe's disease, Huntington's disease, or adrenoleukodystrophy.
Lastly, cancers of the central nervous system can cause severe illness and, when malignant, can have very high
mortality rates.
Specialty professional organizations recommend that neurological imaging of the brain be done only to answer a
specific clinical question and not as routine screening.[]
References
[5] Romer, A.S. (1949): The Vertebrate Body. W.B. Saunders, Philadelphia. (2nd ed. 1955; 3rd ed. 1962; 4th ed. 1970)
[6] 198
External links
Sylvius: 400+ structure neuroanatomical visual glossary (http://www.sylvius.com)

High-Resolution Cytoarchitectural Primate Brain Atlases (http://primate-brain.org)
Human Brains: A Learning Tool (http://www.marymt.edu/~psychol/brain.html).
Explaining the human nervous system (http://www.humannervoussystem.info).
Nervous System Back Pain Anatomy (info on nerve pairs) (http://www.backrack.co.uk/nervous_index.
shtml).
Textbook in Medical Physiology And Pathophysiology, many links (http://www.mfi.ku.dk/ppaulev/content.
htm)
Brain and Cranial Nerves, Anatomy and Physiology Lecture, Northland Community College (http://www.
northland.cc.mn.us/biology/AP2Online/Fall2002/AP2PowerPoint/AP2Brainlecture_files/v3_document.
htm)
Latest Research on the Brain and Central Nervous System (http://www.sciencedaily.com/news/mind_brain/)
From ScienceDaily (http://www.sciencedaily.com/)
The Department of Neuroscience at Wikiversity
Overview of the Central Nervous System (http://nba.uth.tmc.edu/neuroscience/s2/chapter01.html),
Neuroscience Online (electronic neuroscience textbook)
Neurochemistry
Neurochemistry
Neurochemistry is the specific study of neurochemicals, including neurotransmitters and other molecules (such as
psychopharmaceuticals) that influence the function of neurons. This field closely examines how these
neurochemicals influence the network of neural operation. This evolving area of neuroscience offers a neurochemist
a micro-macro connection between the analysis of organic compounds active in the nervous system and neural
processes such as cortical plasticity, neurogenesis and neural differentiation.
History
The founding of neurochemistry as a discipline traces it origins to a series of "International Neurochemical
Symposia", of which the first symposium volume published in 1954 was titled Biochemistry of the Developing
Nervous System.[1] These meetings led to the formation of the International Society for Neurochemistry and the
American Society for Neurochemistry. These early gatherings discussed the tentative nature of possible
neurotransmitter substances such as acetylcholine, histamine, substance P, and serotonin. By 1972, ideas were more
concrete. Neurochemicals such as norepinephrine, dopamine, and serotonin were classified as "putative
neurotransmitters in certain neuronal tracts in the brain."
References
External links
Basic Neurochemistry (http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?call=bv.View..ShowTOC&
rid=bnchm.TOC) online, searchable textbook.
American Society for Neurochemistry (http://www.asneurochem.org)
Neurotransmitter
Neurotransmitter
Structure of a typical chemical synapse
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse.[1]
Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane in the axon terminal, on the
presynaptic side of a synapse. They are released into and diffuse across the synaptic cleft, where they bind to specific
receptors in the membrane on the postsynaptic side of the synapse.[2] Release of neurotransmitters usually follows
arrival of an action potential at the synapse, but may also follow graded electrical potentials. Low level "baseline"
release also occurs without electrical stimulation. Many neurotransmitters are synthesized from plentiful and simple
precursors, such as amino acids, which are readily available from the diet and which require only a small number of
biosynthetic steps to convert.[]
Discovery
Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was
electrical. However, through the careful histological examinations of Ramn y Cajal (18521934), a 20 to 40nm gap
between neurons, known today as the synaptic cleft, was discovered. The presence of such a gap suggested
communication via chemical messengers traversing the synaptic cleft, and in 1921 German pharmacologist Otto
Loewi (18731961) confirmed that neurons can communicate by releasing chemicals. Through a series of
experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by
controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment,
Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical
concentrations. Furthermore, Otto Loewi is accredited with discovering acetylcholine (ACh)the first known
neurotransmitter.[3] Some neurons do, however, communicate via electrical synapses through the use of gap
junctions, which allow specific ions to pass directly from one cell to another.[]
Identifying neurotransmitters
The chemical identity of neurotransmitters is often difficult to determine experimentally. For example, it is easy
using an electron microscope to recognize vesicles on the presynaptic side of a synapse, but it may not be easy to
determine directly what chemical is packed into them. The difficulties led to many historical controversies over
whether a given chemical was or was not clearly established as a transmitter. In an effort to give some structure to
the arguments, neurochemists worked out a set of experimentally tractable rules. According to the prevailing beliefs
of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following conditions:
Neurotransmitter
There are precursors and/or synthesis enzymes located in the presynaptic side of the synapse.
The chemical is present in the presynaptic element.
It is available in sufficient quantity in the presynaptic neuron to affect the postsynaptic neuron.
There are postsynaptic receptors and the chemical is able to bind to them.
A biochemical mechanism for inactivation is present.
Modern advances in pharmacology, genetics, and chemical neuroanatomy have greatly reduced the importance of
these rules. A series of experiments that may have taken several years in the 1960s can now be done, with much
better precision, in a few months. Thus, it is unusual nowadays for the identification of a chemical as a
neurotransmitter to remain controversial for very long periods of time.
Types of neurotransmitters
There are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides, and
monoamines is sufficient for some classification purposes.
Major neurotransmitters:
Amino acids: glutamate,[] aspartate, D-serine, -aminobutyric acid (GABA), glycine
Monoamines and other biogenic amines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine
(adrenaline), histamine, serotonin (SE, 5-HT)
Peptides: somatostatin, substance P, opioid peptides[4]
Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, etc.
In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly. Many of these are
"co-released" along with a small-molecule transmitter, but in some cases a peptide is the primary transmitter at a
synapse. -endorphin is a relatively well known example of a peptide neurotransmitter; it engages in highly specific
interactions with opioid receptors in the central nervous system.
Single ions, such as synaptically released zinc, are also considered neurotransmitters by some,[5] as are some gaseous
molecules such as nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO).[6] Because they are not
packaged into vesicles they are not classical neurotransmitters by the strictest definition, however they have all been
shown experimentally to be released by presynaptic terminals in an activity-dependent way.
By far the most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human
brain.[] The next most prevalent is GABA, which is inhibitory at more than 90% of the synapses that do not use
glutamate. Even though other transmitters are used in far fewer synapses, they may be very important
functionallythe great majority of psychoactive drugs exert their effects by altering the actions of some
neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as
cocaine and amphetamine exert their effects primarily on the dopamine system. The addictive opiate drugs exert
their effects primarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.
Excitatory and inhibitory

Some neurotransmitters are commonly described as "excitatory" or "inhibitory". The only direct effect of a
neurotransmitter is to activate one or more types of receptors. The effect on the postsynaptic cell depends, therefore,
entirely on the properties of those receptors. It happens that for some neurotransmitters (for example, glutamate), the
most important receptors all have excitatory effects: that is, they increase the probability that the target cell will fire
an action potential. For other neurotransmitters, such as GABA, the most important receptors all have inhibitory
effects (although there is evidence that GABA is excitatory during early brain development). There are, however,
other neurotransmitters, such as acetylcholine, for which both excitatory and inhibitory receptors exist; and there are
some types of receptors that activate complex metabolic pathways in the postsynaptic cell to produce effects that
cannot appropriately be called either excitatory or inhibitory. Thus, it is an oversimplification to call a
10
Neurotransmitter
neurotransmitter excitatory or inhibitorynevertheless it is convenient to call glutamate excitatory and GABA
inhibitory so this usage is seen frequently.
Actions
As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a
neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical
properties of the receptors that the transmitter binds to.
Here are a few examples of important neurotransmitter actions:
Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at
most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Excess glutamate can
overstimulate the brain and causes seizures.[citation needed] Modifiable synapses are thought to be the main
memory-storage elements in the brain. Excessive glutamate release can lead to excitotoxicity causing cell death.
GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many
sedative/tranquilizing drugs act by enhancing the effects of GABA. Correspondingly glycine is the inhibitory
transmitter in the spinal cord.
Acetylcholine is distinguished as the transmitter at the neuromuscular junction connecting motor nerves to
muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses. Acetylcholine also
operates in many regions of the brain, but using different types of receptors, including nicotinic and muscarinic
receptors.[7]
Dopamine has a number of important functions in the brain; this includes regulation of motor behavior, pleasures
related to motivation and also emotional arousal. It plays a critical role in the reward system; people with
Parkinson's disease have been linked to low levels of dopamine and people with schizophrenia have been linked
to high levels of dopamine.[8]
Serotonin is a monoamine neurotransmitter. Most is produced by and found in the intestine (approximately 90%),
and the remainder in central nervous system neurons. It functions to regulate appetite, sleep, memory and
learning, temperature, mood, behaviour, muscle contraction, and function of the cardiovascular system and
endocrine system. It is speculated to have a role in depression, as some depressed patients are seen to have lower
concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.[]
Substance P is an undecapeptide responsible for transmission of pain from certain sensory neurons to the central
nervous system. It also aids in controlling relaxation of the vasculature and lowering blood pressure through the
release of nitric oxide.[9]
Opioid peptides are neurotransmitters that act within pain pathways and the emotional centers of the brain; some
of them are analgesics and elicit pleasure or euphoria.[10]
Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of the
system affects large volumes of the brain, called volume transmission. Major neurotransmitter systems include the
noradrenaline (norepinephrine) system, the dopamine system, the serotonin system and the cholinergic system.
Drugs targeting the neurotransmitter of such systems affect the whole system; this fact explains the complexity of
action of some drugs. Cocaine, for example, blocks the reuptake of dopamine back into the presynaptic neuron,
leaving the neurotransmitter molecules in the synaptic gap longer. Since the dopamine remains in the synapse longer,
the neurotransmitter continues to bind to the receptors on the postsynaptic neuron, eliciting a pleasurable emotional
response. Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses,
which leads to the downregulation of some postsynaptic receptors. After the effects of the drug wear off, one might
feel depressed because of the decreased probability of the neurotransmitter binding to a receptor. Prozac is a
selective serotonin reuptake inhibitor (SSRI), which blocks re-uptake of serotonin by the presynaptic cell. This
increases the amount of serotonin present at the synapse and allows it to remain there longer, hence potentiating the
effect of naturally released serotonin.[] AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to
11
Neurotransmitter
12
dopamine; reserpine prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B
and thus increases dopamine levels.
Diseases may affect specific neurotransmitter systems. For example, Parkinson's disease is at least in part related to
failure of dopaminergic cells in deep-brain nuclei, for example the substantia nigra. Levodopa is a precursor of
dopamine, and is the most widely used drug to treat Parkinson's disease.
A brief comparison of the major neurotransmitter systems follows:
Neurotransmitter systems
System
Noradrenaline
system
Dopamine system
Origin
locus coeruleus
Lateral tegmental field

dopamine pathways:
Serotonin system
[]
arousal
reward
motor system, reward, cognition, endocrine, nausea
mesocortical pathway
mesolimbic pathway
nigrostriatal pathway
tuberoinfundibular pathway
caudal dorsal raphe nucleus

rostral dorsal raphe nucleus
Cholinergic system
[]
Effects
pontomesencephalotegmental
complex
basal optic nucleus of Meynert
Increase (introversion), mood, satiety, body temperature and sleep, while decreasing
nociception.
learning
short-term memory
arousal
reward
medial septal nucleus
Common neurotransmitters
Category
Name
Small: Amino acids
Aspartate
Neuropeptides
N-Acetylaspartylglutamate
Small: Amino acids
Abbreviation Metabotropic
Ionotropic
NAAG
Metabotropic glutamate receptors;

selective agonist of mGluR3
Glutamate (glutamic acid)
Glu
Metabotropic glutamate receptor
NMDA receptor, Kainate

receptor, AMPA receptor
Small: Amino acids
Gamma-aminobutyric acid
GABA
GABAB receptor
GABAA, GABAA- receptor
Small: Amino acids
Glycine
Gly
Glycine receptor
Small: Acetylcholine
Acetylcholine
Ach
Muscarinic acetylcholine receptor
Nicotinic acetylcholine
receptor
Small: Monoamine
(Phe/Tyr)
Dopamine
DA
Dopamine receptor
Small: Monoamine
(Phe/Tyr)
Norepinephrine (noradrenaline)
NE
Adrenergic receptor
Small: Monoamine
(Phe/Tyr)
Epinephrine (adrenaline)
Epi
Adrenergic receptor
Small: Monoamine
(Phe/Tyr)
Octopamine
Neurotransmitter
13
Small: Monoamine
(Phe/Tyr)
Tyramine
Small: Monoamine
(Trp)
Serotonin (5-hydroxytryptamine)
5-HT
Serotonin receptor, all but 5-HT3
5-HT3
Small: Monoamine
(Trp)
Melatonin
Mel
Melatonin receptor
Small: Diamine (His)
Histamine
Histamine receptor
PP: Gastrins
Gastrin
PP: Gastrins
Cholecystokinin
CCK
Cholecystokinin receptor
PP: Neurohypophyseals Vasopressin
AVP
Vasopressin receptor
PP: Neurohypophyseals Oxytocin
OT
Oxytocin receptor
PP: Neurohypophyseals Neurophysin I
PP: Neurohypophyseals Neurophysin II
PP: Neuropeptide Y
Neuropeptide Y
NY
Neuropeptide Y receptor
PP: Neuropeptide Y
Pancreatic polypeptide
PP
PP: Neuropeptide Y
Peptide YY
PYY
PP: Opioids
Corticotropin (adrenocorticotropic ACTH

hormone)
Corticotropin receptor
PP: Opioids
Dynorphin
PP: Opioids
Endorphin
PP: Opioids
Enkephaline
PP: Secretins
Secretin
Secretin receptor
PP: Secretins
Motilin
Motilin receptor
PP: Secretins
Glucagon
Glucagon receptor
PP: Secretins
Vasoactive intestinal peptide
VIP
Vasoactive intestinal peptide

receptor
PP: Secretins
Growth hormone-releasing factor
GRF
PP: Somatostatins
Somatostatin
Somatostatin receptor
SS: Tachykinins
Neurokinin A
SS: Tachykinins
Neurokinin B
SS: Tachykinins
Substance P
PP: Other
Bombesin
PP: Other
Gastrin releasing peptide
GRP
Gas
Nitric oxide
NO
Soluble guanylyl cyclase
Gas
Carbon monoxide
CO
Heme bound to potassium

channels
Other
Anandamide
AEA
Cannabinoid receptor
Other
Adenosine triphosphate
ATP
P2Y12
P2X receptor
Neurotransmitter
Precursors of neurotransmitters
While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence is mixed as to
whether neurotransmitter release (firing) is increased. Even with increased neurotransmitter release, it is unclear
whether this will result in a long-term increase in neurotransmitter signal strength, since the nervous system can
adapt to changes such as increased neurotransmitter synthesis and may therefore maintain constant firing.[] Some
neurotransmitters may have a role in depression, and there is some evidence to suggest that intake of precursors of
these neurotransmitters may be useful in the treatment of mild and moderate depression.[][]
Dopamine precursors
L-DOPA,
a precursor of dopamine that crosses the bloodbrain barrier, is used in the treatment of Parkinson's
disease.
Norepinephrine precursors
For depressed patients where low activity of the neurotransmitter norepinephrine is implicated, there is only little
evidence for benefit of neurotransmitter precursor administration. L-phenylalanine and L-tyrosine are both
precursors for dopamine, norepinephrine, and epinephrine. These conversions require vitamin B6, vitamin C, and
S-adenosylmethionine. A few studies suggest potential antidepressant effects of L-phenylalanine and L-tyrosine, but
there is much room for further research in this area.[]
Serotonin precursors
Administration of L-tryptophan, a precursor for serotonin, is seen to double the production of serotonin in the brain.
It is significantly more effective than a placebo in the treatment of mild and moderate depression.[] This conversion
requires vitamin C.[] 5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is also more effective than a
placebo.[]
Degradation and elimination

A neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent further excitatory or
inhibitory signal transduction. For example, acetylcholine (ACh), an excitatory neurotransmitter, is broken down by
acetylcholinesterase (AChE). Choline is taken up and recycled by the pre-synaptic neuron to synthesize more ACh.
Other neurotransmitters such as dopamine are able to diffuse away from their targeted synaptic junctions and are
eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific
degradation pathways at regulatory points, which may be the target of the body's own regulatory system or
recreational drugs.
References
[2]
[3]
[4]
[5]
Elias, L. J, & Saucier, D. M. (2005). Neuropsychology: Clinical and Experimental Foundations. Boston: Pearson
Saladin, Kenneth S. Anatomy and Physiology: The Unity of Form and Function. McGraw Hill. 2009 ISBN 0-07-727620-5
http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 38738
Kodirov,Sodikdjon A., Shuichi Takizawa, Jamie Joseph, Eric R. Kandel, Gleb P. Shumyatsky, and Vadim Y. Bolshakov. Synaptically
released zinc gates long-term potentiation in fear conditioning pathways. PNAS, October 10, 2006. 103(41): 15218-23.
[6] Nitric oxide and other gaseous neurotransmitters (http:/ / www. marsdd. com/ events/ details/
international-symposium-on-nitric-oxide-and-other-gaseous-neurotransmitters/ )
[7] http:/ / www. ebi. ac. uk/ interpro/ potm/ 2005_11/ Page2. htm
[8] Schacter, Gilbert and Weger. Psychology.United States of America.2009.Print.
[9] http:/ / www. wellnessresources. com/ health_topics/ sleep/ substance_p. php
[10] Schacter, Gilbert and Weger. Psychology. 2009.Print.
14
Neurotransmitter
External links
Molecular Expressions Photo Gallery: The Neurotransmitter Collection (http://micro.magnet.fsu.edu/micro/
gallery/neurotrans/neurotrans.html)
Brain Neurotransmitters (http://www.benbest.com/science/anatmind/anatmd10.html)
Endogenous Neuroactive Extracellular Signal Transducers (http://www.neurotransmitter.net/neurosignaling.
html)
Neurotransmitter (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Neurotransmitter) at the
US National Library of Medicine Medical Subject Headings (MeSH)
neuroscience for kids website (http://faculty.washington.edu/chudler/chnt1.html)
brain explorer website (http://www.brainexplorer.org/neurological_control/Neurological_Neurotransmitters.
shtml)
wikibooks cellular neurobiology (http://en.wikibooks.org/wiki/Neuroscience/Cellular_Neurobiology/
Neurotransmitters)
15
Dopamine
16
Dopamine
Dopamine
Identifiers
[1]
CAS number
51-61-6
PubChem
681
ChemSpider
661
UNII
VTD58H1Z2X
DrugBank
DB00988
KEGG
D07870
ChEBI
CHEBI:18243
ChEMBL
CHEMBL59
ATC code
C01 CA04
Jmol-3D images
Image 1
, 62-31-7
[2]
(hydrochloride)
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
Properties
Molecular formula
C H NO
Molar mass
153.18 g/mol
Appearance
colorless solid
Density
1.26 g/cm3
Melting point
128C, 401K, 262F
Boiling point
decomposes
Solubility in water
60.0 g/100 ml
8 11
(verify)
[12]
(what is: / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25C, 100kPa)
Infobox references
Dopamine is a simple organic chemical in the catecholamine family that plays a number of important roles in the
brains and bodies of animals. Its name derives from its chemical structure, which consists of an amine group (NH2)
Dopamine
17
linked to a catechol structure called dihydroxyphenethylamine, the decarboxylated form of dihydroxyphenylalanine

(known as L-DOPA).
In the brain, dopamine functions as a neurotransmittera chemical released by nerve cells to send signals to other
nerve cells. It plays a major role in the brain system that is responsible for reward-motivated behavior. Every type of
reward that has been studied increases the level of dopamine in the brain, and a variety of addictive drugs, including
stimulants such as cocaine, amphetamine, and methamphetamine, act by amplifying the effects of dopamine.
Personality traits such as extraversion and reward seeking have been linked to higher sensitivity to rewarding stimuli
in the dopamine system.
Several important diseases of the nervous system are associated with dysfunctions of the dopamine system.
Parkinson's disease, an age-related degenerative condition causing tremor and motor impairment, is caused by loss of
dopamine-secreting neurons in a small brainstem area called the substantia nigra. There is evidence that
schizophrenia involves altered levels of dopamine activity, and the antipsychotic drugs that are frequently used to
treat it have a primary effect of attenuating dopamine activity. Attention deficit hyperactivity disorder (ADHD) and
restless legs syndrome (RLS) are also believed to be associated with decreased dopamine activity.
Outside the central nervous system dopamine acts as a hormone, released by the adrenal gland into the bloodstream,
where it circulates to every part of the body. This peripheral dopamine has significant effects on the kidneys, heart,
immune system, and sympathetic nervous system.
Dopamine is available as an intravenous medication, producing effects such as increased heart rate and blood
pressure. However, because dopamine cannot cross the bloodbrain barrier, dopamine given as a drug does not
directly affect the central nervous system. To increase the amount of dopamine in the brains of patients with diseases
such as Parkinson's disease, L-DOPA (the precursor of dopamine) is often given because it crosses the bloodbrain
barrier relatively easily.
Anatomy
Inside the brain, dopamine plays important roles in motor control,
motivation, arousal, and reward, as well as a number of lower-level
functions including lactation, sexual gratification, and nausea.
Dopaminergic neurons (i.e., neurons whose primary neurotransmitter is
dopamine) are comparatively few in number, and their cell bodies are
confined to a few relatively small brain areas, but they send projections
to many other brain areas and exert powerful effects on their targets.
These dopaminergic cell groups were first mapped in 1964 by Annica
Dahlstrm and Kjell Fuxe, who assigned them labels starting with the
letter "A" (for "aminergic").[13] In their scheme, areas A1 through A7
contain the neurotransmitter norepinephrine, whereas A8 through A14
contain dopamine. Here is a list of the dopaminergic areas they
identified:
Major dopamine pathways. As part of the reward

pathway, dopamine is manufactured in nerve cell
bodies located within the ventral tegmental area
(VTA) and is released in the nucleus accumbens
and the prefrontal cortex. The motor functions of
dopamine are linked to a separate pathway, with
cell bodies in the substantia nigra that
manufacture and release dopamine into the
striatum.
The substantia nigra, a small midbrain area that forms a component

of the basal ganglia. The dopamine neurons are found mainly in a
part of this structure called the pars compacta (cell group A8) and
nearby (group A9). Their most important projections go to the striatum, globus pallidus, and subthalamic nucleus,
all of which also belong to the basal ganglia, and play important roles in motor control. The name substantia
nigra is Latin for "dark substance", and refers to the fact that the dopaminergic neurons there are darkly
pigmented. These neurons are especially vulnerable to damage. When a large fraction of them die, the result is a
Parkinsonian syndrome.
Dopamine
18
The ventral tegmental area (VTA), another midbrain area. This cell group (A10) is the largest group of
dopaminergic cells in the human brain, though still quite small in absolute terms. Projections from these
dopaminergic neurons go to the nucleus accumbens and the prefrontal cortex as well as several other areas. These
neurons play a central role in reward and other aspects of motivation. The nucleus accumbens is often considered
to the "limbic" part of the striatum. As such, it is the part of the striatum involved in the highest level aspects of
motor control, which include motivation and decision-making. Thus, the role of the VTA in motivation and
decision-making is structurally analogous to the role of the substantia nigra in low-level motor control.
The posterior hypothalamus. These dopaminergic cells (group A11) project to the spinal cord, and their function
is not well established. These is some evidence that pathology in this area plays a role in restless legs syndrome, a
condition in which people have difficulty sleeping due to persistent uncontrollable movements, especially in the
legs.[14]
The arcuate nucleus of the hypothalamus. An important projection from these dopaminergic neurons (cell group
A12) goes to the pituitary gland, where it influences the section of the hormone prolactin.[]
The zona incerta. These cells (group A13) project to several areas of the hypothalamus, and participate in the
control of gonadotropin-releasing hormone, which is necessary to activate the development of reproductive
systems that occurs following puberty, both in males and females.[]
The periventricular nucleus of the hypothalamus, and its immediate vicinity (group A14). These dopamine cells,
like those in the arcuate nucleus, project to the pituitary region (but a different part), and play a role in prolactin
regulation.[]
Cellular effects
Dopamine receptors in the mammal brain
Family Receptor
D1-like
D2-like
Gene
D1
DRD1
D5
DRD5
D2
DRD2
D3
DRD3
D4
DRD4
[15]
Type
Mechanism
Gs-coupled.
Increase intracellular levels of cAMP

by activating adenylate cyclase.
[16]
[17] G /G -coupled.
i o
[18]
Decrease intracellular levels of

cAMP
by inhibiting adenylate cyclase.
[19]
Like many other biologically active substances, dopamine exerts its effects by binding to and activating receptors
located on the surface of cells. In mammals, five subtypes of dopamine receptors have been identified, labeled D1
through D5. All of them function as G protein-coupled receptors, meaning that they exert their effects via a complex
second messenger system. Glossing over the details, dopamine receptors in mammals can be divided into two
families, known as D1-like and D2-like. The ultimate effect of D1-like receptors (D1 and D5) can be excitation (via
opening of sodium channels) or inhibition (via opening of potassium channels); the ultimate effect of D2-like
receptors (D2, D3, and D4) is usually inhibition of the target neuron. Consequently, it is incorrect to describe
dopamine itself as either excitatory or inhibitory. Its effect on a target neuron depends on which types of receptors
are present on the membrane of that neuron and on the internal responses of that neuron to cyclic AMP. D1 receptors
are the most numerous dopamine receptors in the central nervous system; D2 receptors are next; D3, D4, and D5
receptors are present at significantly lower levels.
The level of extracellular dopamine is modulated by two mechanisms: tonic and phasic dopamine transmission.
Tonic dopamine transmission occurs when small amounts of dopamine are released independently of neuronal
Dopamine
activity, and is regulated by the activity of other neurons and neurotransmitter reuptake.[20] Phasic dopamine release
results from the activity of the dopamine-containing cells themselves. This activity is characterized by irregular
pacemaking activity of single spikes, and rapid bursts of typically 2-6 spikes in quick succession.[21][22]
The substantia nigra dopamine system and motor control

The basal ganglia play an essential role in the control of movement, a role that can be described as response
selection. When a person or animal is in a situation where several behaviors are possible, activity in the basal ganglia
determines which of them is executed, by releasing that response from inhibition while increasing inhibition of other,
suppressed, responses. Dopamine in the substantia nigrabasal ganglia circuit modulates this decision-making
process in at least two important ways.
First, dopamine sets the effort threshold for executing behaviors. The higher the level of dopamine activity, the lower
the impetus required to evoke a given behavior. As a consequence, high levels of dopamine lead to high levels of
motor activity and "impulsive" behavior; conversely, low levels of dopamine lead to torpor and slowed reactions.
Parkinson's disease, in which dopamine levels in the substantia nigra circuit are greatly reduced, is characterized by
stiffness and greatly reduced movementhowever, when people with the disease are confronted with strong stimuli
such as a serious threat, their reactions can be as vigorous as those of a healthy person. In the opposite direction,
drugs that increase the effects of dopamine, such as cocaine or amphetamine, produce heightened levels of activity,
including at the highest levels psychomotor agitation and stereotyped movements.
Second, dopamine functions as a "teaching" signal. When a motor response is followed by an increase in dopamine
activity, the basal ganglia circuit is altered in a way that makes the same response easier to evoke when similar
situations arise in the future. Many theoreticians believe that the mechanism underlying this type of learning involves
a form of long-term potentiation that occurs in the striatum and is strongly modulated by dopaminein other words,
a mechanism by which dopamine activity induces strengthening or weakening of synaptic connections inside the
striatum.[23]
The basal ganglia form one of the most complicated systems in the brain, and dopamine acts on this system at
several levels. Consequently, the mechanisms by which dopamine affects response selection and learning are only
understood to a limited degree. This is currently a very active topic of neuroscience research.
The ventral tegmental area, reward, and cognition

The ventral tegmental area (VTA) contains the largest group of dopamine neurons in the human brain. They project
to numerous brain areas, but the two largest projections are the mesolimbic pathway, which targets the nucleus
accumbens and other limbic structures, and the mesocortical pathway, which targets the prefrontal and insular parts
of the cerebral cortex.
There is a strong functional analogy between the VTA dopamine system and the substantia nigra dopamine system.
The basal ganglia consist of a set of parallel circuits, which all have similar architecture but control different aspects
of behavior. Most of these circuits run through the striatum, which receives dopamine from the substantia nigra. The
striatal circuits control low-level forms of response selection, that is, behaviors that use particular muscle groups or
specific action patterns. The "limbic" circuit, however, runs through the nucleus accumbens (also known as the
"limbic striatum"), which receives dopamine from the VTA. The limbic circuit controls the highest-level aspects of
response selection, such as planning and decision-making. The low-level striatal circuits are connected to the
primary motor and premotor parts of the cerebral cortex; the limbic circuit is connected to the prefrontal cortex.
Thus, the effect of VTA dopamine on high-level decision-making is functionally analogous to the effect of substantia
nigra dopamine on the execution of simple movements.
19
Dopamine
Reinforcement and reward-seeking behavior

Dopamine is strongly associated with the reward system of the brain. Dopamine is released in areas such as the
nucleus accumbens and prefrontal cortex as a result of rewarding experiences such as food, sex, and neutral stimuli
that become associated with them.[] The source of this dopamine is the VTA. Electrical stimulation of the VTA or its
output pathways can itself serve as a potent reward: animals will quickly learn to press a lever if it results in
stimulation of dopamine release, and often will continue pressing the lever for a long time, at steadily increasing
rates. A variety of drugs that increase dopamine levels are intrinsically rewarding and increase the effects of other
types of reward.
In spite of the overwhelming evidence showing a strong association between dopamine and reward, there has been a
great deal of dispute about whether the function of dopamine should be described as reward per se, or as some more
complex construct that relates strongly to reward. The difficulty arises mainly from two observations: (1) in addition
to being rewarding, dopamine is also arousing it produces a general increase in movement of all sorts; (2)
dopamine release can be caused by events that do not seem to have anything to do with reward, most notably pain.
One of the most popular alternatives to the reward theory is the "incentive salience" theory, which argues that the
function of dopamine is to increase the effects of motivators of all sorts, both positive and negative.[24]
A substantial body of evidence suggests that dopamine encodes not reward itself, but rather reward prediction error,
that is, the degree to which reward is surprising. According to this hypothesis, which derives initially from
recordings made by Wolfram Schultz, rewards that are expected do not produce any activation of dopamine cells, but
rewards that are greater than expected produce a short-lasting increase in dopamine, whereas the omission of an
expected reward actually causes dopamine release to drop below its ordinary background level. The "prediction
error" hypothesis has drawn particular interest from computational neuroscientists, because an influential
computational-learning method known as temporal difference learning makes heavy use of a signal that encodes
prediction error. This confluence of theory and data has led to a fertile interaction between theoretical and empirical
neuroscientists.
Recent research finds that while some dopaminergic neurons react in the way expected of reward neurons, others do
not and seem to respond in regard to unpredictability.[] This research finds the reward neurons predominate in the
ventromedial region in the substantia nigra pars compacta as well as the ventral tegmental area. Neurons in these
areas project mainly to the ventral striatum and thus might transmit value-related information in regard to reward
values.[] The nonreward neurons are predominate in the dorsolateral area of the substantia nigra pars compacta
which projects to the dorsal striatum and may relate to orienting behaviour.[] It has been suggested that the difference
between these two types of dopaminergic neurons arises from their input: reward-linked ones have input from the
basal forebrain, while the nonreward-related ones from the lateral habenula.[]
Animal studies
Clues to dopamine's role in motivation, desire, and pleasure have come from studies performed on animals. In one
such study, rats were depleted of dopamine by up to 99 percent in the nucleus accumbens and neostriatum using
6-hydroxydopamine.[] With this large reduction in dopamine, the rats would no longer eat of their own volition. The
researchers then force-fed the rats food and noted whether they had the proper facial expressions indicating whether
they liked or disliked it. The researchers of this study concluded that the reduction in dopamine did not reduce the
rat's consummatory pleasure, only the desire to eat. In another study, mutant hyperdopaminergic (increased
dopamine) mice show higher "wanting" but not "liking" of sweet rewards.[] Mice who cannot synthesize dopamine
are unable to feed sufficiently to survive more than a few weeks after birth, but will feed normally and survive if
administered L-DOPA.[]
Dopamine modulates foraging behavior in animals, by activating brain systems registering reward when food
sources are found.[25] When monkeys are given a highly palatable food, dopamine levels rise, but levels then decline
when the palatable food is available for prolonged periods of time and is no longer novel.[26]
20
Dopamine
Processing of pain
Dopamine has been demonstrated to play a role in pain processing in multiple levels of the central nervous system
including the spinal cord, periaqueductal gray (PAG), thalamus, basal ganglia, and cingulate cortex. Accordingly,
decreased levels of dopamine have been associated with painful symptoms that frequently occur in Parkinson's
disease. Abnormalities in dopaminergic neurotransmission have also been demonstrated in painful clinical
conditions, including burning mouth syndrome,[27] fibromyalgia, and restless legs syndrome. In general, the
analgesic capacity of dopamine occurs as a result of dopamine D2 receptor activation; however, exceptions to this
exist in the PAG, in which dopamine D1 receptor activation attenuates pain presumably via activation of neurons
involved in descending inhibition.[28] In addition, D1 receptor activation in the insular cortex appears to attenuate
subsequent pain-related behavior.
Behavior disorders
Altered dopamine neurotransmission is implicated in attention-deficit hyperactivity disorder, and stimulant
medications that are used to treat its symptoms increase dopamine neurotransmission.[29] Consistent with this
hypothesis, dopaminergic pathways have a role in inhibitory action control and the inhibition of the tendency to
make unwanted actions.[30]
The long-term use of levodopa in Parkinson's disease has been linked to dopamine dysregulation syndrome.[]
Other brain functions

Regulation of prolactin secretion
Dopamine is the primary neuroendocrine inhibitor of the secretion of prolactin from the anterior pituitary gland.[]
Dopamine produced by neurons in the arcuate nucleus of the hypothalamus is secreted into the
hypothalamo-hypophysial blood vessels of the median eminence, which supply the pituitary gland. The lactotrope
cells that produce prolactin, in the absence of dopamine, secrete prolactin continuously; dopamine inhibits this
secretion. Thus, in the context of regulating prolactin secretion, dopamine is occasionally called prolactin-inhibiting
factor (PIF), prolactin-inhibiting hormone (PIH), or prolactostatin.
Nausea
Nausea and vomiting are largely determined by activity in a brainstem area known as the chemoreceptor trigger
zone. This area contains a large population of type D2 dopamine receptors. Consequently, drugs that activate D2
receptors have a high potential to cause nausea. This group includes some medications that are administered for
Parkinson's disease, as well as other dopamine agonists such as apomorphine. In many cases, D2-receptor
antagonists such as metoclopramide are useful as anti-nausea drugs.
Evolution and cross-species comparisons

The reward system in insects uses octopamine, which is the presumed arthropod homolog of norepinephrine,[] rather
than dopamine. In insects, dopamine acts instead as a punishment signal and is necessary to form aversive
memories.[][]
Links to psychosis
Abnormally high dopaminergic transmission has been linked to psychosis and schizophrenia.[31] However, clinical
studies relating schizophrenia to brain dopamine metabolism have ranged from controversial to negative, with HVA
levels in the CSF the same for schizophrenics and controls.[32] Increased dopaminergic functional activity,
specifically in the mesolimbic pathway, is found in schizophrenic individuals. However, decreased activity in
21
Dopamine
another dopaminergic pathway, the mesocortical pathway, may also be involved. The two pathways are thought to be
responsible for differing sets of symptoms seen in schizophrenia.[citation needed]
Antipsychotic medications act largely as dopamine antagonists, inhibiting dopamine at the receptor level, and
thereby blocking the effects of the neurochemical in a dose-dependent manner. The older, so-called typical
antipsychotics most commonly act on D2 receptors,[33] while the atypical drugs also act on D1, D3 and D4 receptors,
though they have a lower affinity for dopamine receptors in general.[34][35] The finding that drugs such as
amphetamines, methamphetamine and cocaine, which can increase dopamine levels by more than tenfold,[36] can
temporarily cause psychosis, provides further evidence for this link.[37] However, many non-dopaminergic drugs can
induce acute and chronic psychosis.[38] The NMDA antagonists Ketamine and PCP both are used in research to
reproduce the positive and negative symptoms commonly associated with schizophrenia.[39][40]
Dopaminergic dysregulation has also been linked to depressive disorders.[41] Early research in humans used various
methods of analyzing dopamine levels and function in depressed patients. Studies have reported that there is
decreased concentration of tyrosine, a precursor to dopamine, in the blood plasma, ventricular spinal fluid, and
lumbar spinal fluid of depressed patients compared to control subjects.[42] [43] One study measured the amount of
homovanillic acid, the major metabolite of dopamine in the CSF, as a marker for the dopamine pathway turnover
rate, and found decreased concentrations of homovanillic acid in the CSF of depressed patients.[44] Postmordem real
time reverse transcriptase-polymerase chain reaction (RT-PCR) has also been used to find that gene expression of a
specific subtype of dopamine receptor was elevated in the amygdale of people suffering from depression as
compared to control subjects.[45]
The action of commonly used antidepressant drugs also has yielded information about possible alterations of the
dopaminergic pathway in treating depression. It has been reported that many antidepressant drugs increase
extracellular dopamine concentrations in the rat prefrontal cortex[46], but vary greatly in their affects on the striatum
and nucleus accumbens.[47] [48] This can be compared to electro convulsive shock treatment (ECT), which has been
shown to have a multiple fold increase in striatal dopamine levels in rats.[49]
More recent research studies with rodents have found that depression-related behaviors are associated with
dopaminergic system dysregulation.[50] In rodents exposed to chronic mild stress, decreased escape behavior and
decreased forced swimming is reversed with activation of the dopaminergic mesolimbic pathway.[51] Also, rodents
that are susceptible to depression-related behavior after social defeat can have their behavior reversed with dopamine
pathway activation.[52] Depletion of dopamine in the caudate nucleus and nucleus accumbens has also been reported
in cases of learned helplessness in animals. These symptoms can be reversed with dopamine agonists and
antidepressant administration prior to the learned helplessness protocol.[53]
Pharmacology
Under the trade names Intropan, Inovan, Revivan, Rivimine, Dopastat, and Dynatra, dopamine, as well as
norepinephrine and epinephrine, are also used as pharmaceutical drugs in injectable forms in the emergency clinical
treatment of severe hypotension and/or bradycardia, circulatory shock, and cardiac arrest, the latter of which for the
purpose of cardiopulmonary resuscitation.[citation needed]
Levodopa is a dopamine precursor used in various forms to treat Parkinson's disease and dopa-responsive dystonia. It
is typically co-administered with an inhibitor of peripheral decarboxylation (DDC, dopa decarboxylase), such as
carbidopa or benserazide. Inhibitors of alternative metabolic route for dopamine by catechol-O-methyl transferase
are also used. These include entacapone and tolcapone.
22
Dopamine
Psychomotor stimulants
Cocaine and amphetamines inhibit the re-uptake of dopamine; however, they influence separate mechanisms of
action. Cocaine is a dopamine transporter and norepinephrine transporter blocker that competitively inhibits
dopamine uptake to increase the lifetime of dopamine and augments an overabundance of dopamine (an increase of
up to 150 percent) within the parameters of the dopamine neurotransmitters. Like cocaine, amphetamines increase
the concentration of dopamine in the synaptic gap, but by a different mechanism. Amphetamines and
methamphetamine are similar in structure to dopamine, and so can enter the terminal bouton of the presynaptic
neuron via its dopamine transporters as well as by diffusing through the neural membrane directly.[citation needed] By
entering the presynaptic neuron, amphetamines force dopamine molecules out of their storage vesicles and expel
them into the synaptic gap by making the dopamine transporters work in reverse.
Effects of drugs that reduce dopamine activity

In humans, drugs that reduce dopamine activity (neuroleptics, e.g. antipsychotics) have been shown to impair
concentration, reduce motivation, cause anhedonia (inability to experience pleasure), and long-term use has been
associated with tardive dyskinesia, an irreversible movement disorder.[] Antipsychotics have significant effects on
gonadal hormones including significantly lower levels of estradiol and progesterone in women, whereas men display
significantly lower levels of testosterone and DHEA when undergoing antipsychotic drug treatment compared to
controls. Antipsychotics are known to cause hyperprolactinaemia leading to amenorrhea, cessation of normal cyclic
ovarian function, loss of libido, occasional hirsutism, false positive pregnancy tests, and long-term risk of
osteoporosis in women. The effects of hyperprolactinemia in men are gynaecomastia, lactation, impotence, loss of
libido, and hypospermatogenesis.[] Furthermore, antipsychotic drugs are associated with weight gain, diabetes,
drooling, dysphoria (abnormal depression and discontent), fatigue, sexual dysfunction, heart rhythm problems, stroke
and heart attack.
Selective D2/D3 agonists pramipexole and ropinirole, used to treat restless legs syndrome (RLS), have limited
anti-anhedonic properties as measured by the Snaith-Hamilton Pleasure Scale (SHAPS).[]
Nonneural functions
Renal and cardiovascular
Dopamine (brand name Intropin or Giludop) also has effects when administered through an IV line outside the
central nervous system. The effects in this form are dose dependent.
Dopamine induces natriuresis (sodium loss) in the kidneys, and has a diuretic effect, potentially increasing urine
output from 5 ml/kg/hr to 10 ml/kg/hr.[54][55] Dosages from 2 to 5 g/kg/min are considered the "renal dose".[56]
It was once thought that at this low dosage provided increased renal perfusion in critically ill patients. The
mechanism was thought to involve dopamine binding D1 receptors, dilating blood vessels, increasing blood flow
to renal, mesenteric, and coronary arteries, which would thus increase overall renal perfusion.[] However, recent
multi-center, randomized trials have shown that this is not clinically effective.[] Thus, "renal dose" dopamine is
largely considered a myth that has been propagated in medicine for the past 30 years.
Intermediate dosages from 5 to 10 g/kg/min, known as the "cardiac dose", additionally have a positive inotropic
and chronotropic effect through increased 1 receptor activation. Dopamine is used in patients with shock or heart
failure to increase cardiac output and blood pressure.[] Dopamine begins to affect the heart at lower doses, from
about 3 g/kg/min IV.[57]
High doses from 10 to 20 g/kg/min are the "pressor dose".[] This dose causes vasoconstriction, increases
systemic vascular resistance, and increases blood pressure through 1 receptor activation,[] but can cause the
vessels in the kidneys to constrict to the point that urine output is reduced.[]
23
Dopamine
Immunoregulatory
Dopamine acts upon receptors present on immune cells, with all subtypes of dopamine receptors found on
leukocytes. There is low expression of receptors on T lymphocytes and monocytes, moderate expression on
neutrophils and eosinophils, and high expression on B cells and natural killer cells.[58] The sympathetic innervation
of lymphoid tissues is dopaminergic, and increases during stress.[59] Dopamine can also affect immune cells in the
spleen, bone marrow, and blood circulation.[60] In addition, dopamine can be synthesized and released by the
immune cells themselves.[61][62]
The effects of dopamine on immune cells depend upon their physiological state. While dopamine activates resting T
cells, it inhibits them when they are activated. Disorders such as schizophrenia and Parkinson's disease, in which
there are changes in brain dopamine receptors and dopamine signaling pathways, are also associated with altered
immune functioning.[63]
Toxicity
The LD50, or dose which is expected to be lethal in 50% of the population, has been found to be: 59mg/kg (mouse;
administered i.v.); 950mg/kg (mouse; administered i.p.); 163mg/kg (rat; administered i.p.); 79mg/kg (dog;
administered i.v.)[64]Wikipedia:Please clarify
In plants
Fruit browning
Polyphenol oxidases (PPOs) are a family of enzymes responsible for the browning of fresh fruits and vegetables
when they are cut or bruised. These enzymes use molecular oxygen (O2) to oxidise various 1,2-diphenols to their
corresponding quinones. The natural substrate for PPOs in bananas is dopamine. The product of their oxidation,
dopamine quinone, spontaneously oxidises to other quinones. The quinones then polymerise and condense with
amino acids and proteins to form brown pigments known as melanins. The quinones and melanins derived from
dopamine may help protect damaged fruit and vegetables against growth of bacteria and fungi.[]
Anti-herbivore
Dopamine is released by the marine alga Ulvaria obscura as an anti-herbivore defense mechanism.[65]
Biochemical mechanisms
Structurally, dopamine belongs to the catecholamine and phenethylamine classes. In biological systems, dopamine is
synthesized in brain cells and adrenal cells from the precursor L-DOPA. In brain cells, it is transported to synaptic
sites and packaged into vesicles for release, which occurs during synaptic transmission. After release, free dopamine
is either reabsorbed into the presynaptic terminal for reuse, or broken down by the enzymes monoamine oxidase or
COMT, producing a variety of degradation metabolites.
24
Dopamine
25
Biosynthesis
Dopamine is synthesized in a restricted set of cell types, mainly neurons
and cells in the medulla of the adrenal glands. This is the metabolic
pathway:
L-Phenylalanine
L-Tyrosine L-DOPA Dopamine
Thus the direct precursor of dopamine is L-DOPA, but this itself can be
synthesized from the essential amino acids phenylalanine or tyrosine.
These amino acids are found in nearly every protein and as such are
provided from ingestion of protein-containing food, with tyrosine being the
most common. Although dopamine itself is also found in many types of
food, it is incapable of crossing the bloodbrain barrier that surrounds and
protects the brain. It must therefore be synthesized inside the brain in order
to perform its neural actions.
L-Phenylalanine
is converted into L-tyrosine by the enzyme phenylalanine

hydroxylase (PAH), with molecular oxygen (O2) and tetrahydrobiopterin
(THB) as cofactors. L-Tyrosine is converted into L-DOPA by the enzyme
tyrosine hydroxylase (TH), with tetrahydrobiopterin (THB), O2, and
ferrous iron (Fe2+) as cofactors. L-DOPA is converted into dopamine by
the enzyme aromatic L-amino acid decarboxylase (AAAD; also known as
DOPA decarboxylase (DDC)), with pyridoxal phosphate (PLP) as the
cofactor.
Dopamine itself is also used as precursor in the synthesis of the
neurotransmitters norepinephrine and epinephrine. Dopamine is converted
Catecholamine biosynthesis
into norepinephrine by the enzyme dopamine -hydroxylase (DBH), with
O2 and L-ascorbic acid as cofactors. Norepinephrine is converted into epinephrine by the enzyme
phenylethanolamine N-methyltransferase (PNMT) with S-adenosyl-L-methionine (SAMe) as the cofactor.
It should be noted that some of the cofactors also require their own synthesis. Deficiency in any required amino acid
or cofactor will result in subsequent dopamine, norepinephrine, and epinephrine biosynthesis impairment and
deficiency.
Storage, release, and reuptake

Inside the brain dopamine functions as a neurotransmitter, and is controlled by a set of mechanisms that are common
to all neurotransmitters. After synthesis, dopamine is transported from the cytosol into synaptic vesicles by the
vesicular monoamine transporter 2 (VMAT2). Dopamine is stored in and remains in these vesicles until an action
potential occurs and causes the contents of the vesicles to be ejected into the synaptic cleft.
Once in the synapse, dopamine binds to and activates dopamine receptors, which can be located either on
postsynaptic target cells or on the membrane of the dopamine-releasing cell itself (i.e., autoreceptors).
After an action potential, the dopamine molecules quickly become unbound from their receptors. They are then
absorbed back into the presynaptic cell, via reuptake mediated either by the high-affinity dopamine transporter
(DAT) or by the low-affinity plasma membrane monoamine transporter (PMAT). Once back in the cytosol,
dopamine is subsequently repackaged into vesicles by VMAT2, making it available for future release.
Dopamine
26
Degradation
Dopamine is broken down into inactive
metabolites by a set of enzymes,
monoamine oxidase (MAO), aldehyde
dehydrogenase
(ALDH),
and
catechol-O-methyl
transferase
(COMT), acting in sequence. Both
isoforms of MAO, MAO-A and
MAO-B, are equally effective.
The metabolites produced by these
processes are:
DOPAL
(3,4-Dihydroxyphenylacetaldehyde)
DOPAC
(3,4-Dihydroxyphenylacetic acid)
DOPET
(3,4-dihydroxyphenylethanol, also
known as Hydroxytyrosol)
MOPET
(3-methoxy-4-hydroxyphenylethanol,
also known as Homovanillyl
alcohol)
Dopamine degradation
3-MT (3-Methoxytyramine)
HVA (Homovanillic acid)
All of these are intermediate metabolites except MOPET and HVA, which are filtered from the bloodstream by the
kidneys and then excreted in the urine.
The specific reactions that make up these pathways are:
Dopamine DOPAL, mediated by MAO

DOPAL DOPAC, mediated by ALDH
DOPAL DOPET, mediated by aldose reductase (minor pathway)
DOPAC HVA, mediated by COMT
DOPET MOPET, mediated by COMT
Dopamine 3-MT, mediated by COMT
3-MT HVA, mediated by MOA
In most areas of the brain, including the striatum and basal ganglia, dopamine is inactivated by reuptake via the
DAT, then enzymatic breakdown by MAO into DOPAC. In the prefrontal cortex, however, there are very few DAT
proteins, and dopamine is inactivated instead by reuptake via the norepinephrine transporter (NET), presumably on
neighboring norepinephrine neurons, then enzymatic breakdown by COMT into 3-MT.[66] The DAT pathway is
roughly an order of magnitude faster than the NET pathway: in mice, dopamine concentrations decay with a half-life
of 200 milliseconds in the caudate nucleus (which uses the DAT pathway) versus 2,000 milliseconds in the
prefrontal cortex.[67] Dopamine that is not broken down by enzymes is repackaged into vesicles for.
Dopamine
History
Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in London,
England.[68] It was named dopamine because it is a monoamine whose precursor in the Barger-Ewens synthesis is
3,4-dihydroxyphenylalanine (levodopamine or L-DOPA). Dopamine's function as a neurotransmitter was first
recognized in 1958 by Arvid Carlsson and Nils-ke Hillarp at the Laboratory for Chemical Pharmacology of the
National Heart Institute of Sweden.[69] Carlsson was awarded the 2000 Nobel Prize in Physiology or Medicine for
showing that dopamine is not only a precursor of norepinephrine (noradrenaline) and epinephrine (adrenaline), but
also a neurotransmitter.
References
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=51-61-6

http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=62-31-7
http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=681
http:/ / www. chemspider. com/ 661
http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=VTD58H1Z2X
http:/ / www. drugbank. ca/ drugs/ DB00988
http:/ / www. kegg. jp/ entry/ D07870
https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=18243
[9] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL59
[10] http:/ / www. whocc. no/ atc_ddd_index/ ?code=C01CA04
[11] http:/ / chemapps. stolaf. edu/ jmol/ jmol. php?model=c1cc%28c%28cc1CCN%29O%29O
[12] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=464188976& page2=Dopamine
[15] http:/ / www. genenames. org/ data/ hgnc_data. php?match=DRD1
[25] http:/ / onlinelibrary. wiley. com/ doi/ 10. 1207/ s15516709cog0000_50/ abstract
[26] http:/ / www. jneurosci. org/ content/ 13/ 3/ 900. full. pdf
[33] http:/ / www. williams. edu/ imput/ synapse/ pages/ IIIB5. htm
[34] http:/ / bjp. rcpsych. org/ cgi/ content/ full/ 181/ 4/ 271
[36] Methamphetamine 101 (http:/ / 74. 125. 153. 132/ search?q=cache:b3pkrTPLeT0J:www. stopmethinflorida. org/ documents/
Methamphetamine101. ppt+ www. stopmethinflorida. org/ documents/ Methamphetamine101. ppt& cd=1& hl=en& ct=clnk& gl)
[38] Cardinal, R.N. & Bullmore, E.T., The Diagnosis of Psychosis, Cambridge University Press, 2011, ISBN 978-0-521-16484-9
[39] The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia (http:/
/ www. sciencedirect. com/ science/ article/ pii/ S0893133X98000608)
[64] R. J. Lewis (Ed.) (2004), Sax's Dangerous Properties of Industrial Materials, 11th Ed., p. 1552, Wiley & Sons, Hoboken, NJ.
[68] Fahn, Stanley, "The History of Levodopa as it Pertains to Parkinson's disease," Movement Disorder Society's 10th International Congress of
Parkinson's Disease and Movement Disorders on November 1, 2006, in Kyoto, Japan. (http:/ / movementdisorders. org/ education/ onlinecme/
levodopa/ print. pdf)
External links
DrugBank APRD00085 (http://www.drugbank.ca/drugs/APRD00085)
U.S. National Library of Medicine: Drug Information Portal - Dopamine (http://druginfo.nlm.nih.gov/
drugportal/dpdirect.jsp?name=Dopamine)
27
28
Astrocytes
Astrocyte
For the cell in the gastrointestinal tract, see Interstitial cell of Cajal.
Neuron: Astrocyte
Immunocytochemical staining of Astrocytes in culture using an antibody against glial fibrillary acidic protein.
NeuroLex ID
sao1394521419
Dorlands/Elsevier
12165688
[1]
[2]
Astrocytes (etymology: astron gk. star, cyte gk. cell), also known collectively as astroglia, are characteristic
star-shaped glial cells in the brain and spinal cord. They are the most abundant cell of the human brain. They
perform many functions, including biochemical support of endothelial cells that form the bloodbrain barrier,
provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a role in the repair and
scarring process of the brain and spinal cord following traumatic injuries.
Research since the mid-1990s has shown that astrocytes propagate intercellular Ca2+ waves over long distances in
response to stimulation, and, similar to neurons, release transmitters (called gliotransmitters) in a Ca2+-dependent
manner. Data suggest that astrocytes also signal to neurons through Ca2+-dependent release of glutamate.[] Such
discoveries have made astrocytes an important area of research within the field of neuroscience.
Astrocyte
29
Description
Astrocytes are a sub-type of glial cells in the central
nervous system. They are also known as astrocytic
glial cells. Star-shaped, their many processes envelope
synapses made by neurons. Astrocytes are classically
identified using histological analysis; many of these
cells express the intermediate filament glial fibrillary
acidic protein (GFAP). Several forms of astrocytes
exist in the Central Nervous System including fibrous
(in white matter), protoplasmic (in grey matter), and
radial. The fibrous glia are usually located within white
matter, have relatively few organelles, and exhibit long
unbranched cellular processes. This type often has
"vascular feet" that physically connect the cells to the
outside of capillary walls when they are in close
proximity to them. The protoplasmic glia are the most
prevalent and are found in grey matter tissue, possess a
larger quantity of organelles, and exhibit short and
highly branched tertiary processes. The radial glia are
disposed in a plane perpendicular to axis of ventricles.
One of their processes about the pia mater, while the
other is deeply buried in gray matter. Radial glia are
mostly present during development, playing a role in
neuron migration. Mueller cells of retina and Bergmann
glia cells of cerebellar cortex represent an exception,
being present still during adulthood. When in proximity
to the pia mater, all three forms of astrocytes send out
processes to form the pia-glial membrane.
Isolated Astrocyte shown with confocal microscopy. Image: Nathan

S. Ivey and Andrew G. MacLean
Astrocyte - rodent cell culture stained for GFAP (red)
23 weeks fetal brain culture human astrocyte
Astrocyte
30
Astrocytes - rat spinal cord stained for GFAP (green)
Astrocytes (red) among neurons in the living

cerebral cortex
Functions
Previously in medical science, the neuronal
network was considered the only important
one, and astrocytes were looked upon as gap
fillers. More recently, the function of
astrocytes has been reconsidered,[3] and are
now thought to play a number of active roles
in the brain, including the secretion or
absorption of neural transmitters and
maintenance of the bloodbrain barrier.[4]
Following on this idea the concept of a
"tripartite synapse" has been proposed,
referring to the tight relationship occurring
at synapses among a presynaptic element, a
postsynaptic element and a glial element.[5]
Metabolic interactions between astrocytes and neurons. From a computational

study by akr et al., 2007.
Structural: They are involved in the

physical structuring of the brain. Astrocytes get their name because they are "star-shaped". They are the most
abundant glial cells in the brain that are closely associated with neuronal synapses. They regulate the transmission
of electrical impulses within the brain.
Glycogen fuel reserve buffer: Astrocytes contain glycogen and are capable of glycogenesis. The astrocytes next
to neurons in the frontal cortex and hippocampus store and release glycogen. Thus, Astrocytes can fuel neurons
with glucose during periods of high rate of glucose consumption and glucose shortage. Recent research suggests
there may be a connection between this activity and exercise. [6]
Astrocyte
Metabolic support: They provide neurons with nutrients such as lactate.
Bloodbrain barrier: The astrocyte end-feet encircling endothelial cells were thought to aid in the maintenance
of the bloodbrain barrier, but recent research indicates that they do not play a substantial role; instead, it is the
tight junctions and basal lamina of the cerebral endothelial cells that play the most substantial role in maintaining
the barrier.[7] However, it has recently been shown that astrocyte activity is linked to blood flow in the brain, and
that this is what is actually being measured in fMRI.[8] [9]
Transmitter uptake and release: Astrocytes express plasma membrane transporters such as glutamate
transporters for several neurotransmitters, including glutamate, ATP, and GABA. More recently, astrocytes were
shown to release glutamate or ATP in a vesicular, Ca2+-dependent manner.[10] (This has been disputed for
hippocampal astrocytes.)[11]
Regulation of ion concentration in the extracellular space: Astrocytes express potassium channels at a high
density. When neurons are active, they release potassium, increasing the local extracellular concentration.
Because astrocytes are highly permeable to potassium, they rapidly clear the excess accumulation in the
extracellular space.[12] If this function is interfered with, the extracellular concentration of potassium will rise,
leading to neuronal depolarization by the Goldman equation. Abnormal accumulation of extracellular potassium
is well known to result in epileptic neuronal activity.[13]
Modulation of synaptic transmission: In the supraoptic nucleus of the hypothalamus, rapid changes in astrocyte
morphology have been shown to affect heterosynaptic transmission between neurons.[14] In the hippocampus,
astrocytes suppress synaptic transmission by releasing ATP, which is hydrolyzed by ectonucliotidases to yield
adenosine. Adenosine acts on neuronal adenosine receptors to inhibit synaptic transmission, thereby increasing
the dynamic range available for LTP.[15]
Vasomodulation: Astrocytes may serve as intermediaries in neuronal regulation of blood flow.[16]
Promotion of the myelinating activity of oligodendrocytes: Electrical activity in neurons causes them to release
ATP, which serves as an important stimulus for myelin to form. However, the ATP does not act directly on
oligodendrocytes. Instead, it causes astrocytes to secrete cytokine leukemia inhibitory factor (LIF), a regulatory
protein that promotes the myelinating activity of oligodendrocytes. This suggest that astrocytes have an
executive-coordinating role in the brain.[17]
Nervous system repair: Upon injury to nerve cells within the central nervous system, astrocytes fill up the space
to form a glial scar, repairing the area and replacing the CNS cells that cannot regenerate.[citation needed]
Long-term potentiation: Scientists continue to argue back and forth as to whether or not astrocytes integrate
learning and memory in the hippocampus. It is known that glial cells are included in neuronal synapses, but many
of the LTP studies are performed on slices, so scientists disagree on whether or not astrocytes have a direct role of
modulating synaptic plasticity.
Recent studies
A recent study, done in November 2010 and published March 2011, was done by a team of scientists from the
University of Rochester and University of Colorado School of Medicine They did an experiment to attempt to repair
trauma to the Central Nervous System of an adult rat by replacing the glial cells. When the glial cells were injected
into the injury of the adult rats spinal cord, astrocytes were generated by exposing human glial precursor cells to
bone morphogenetic protein (Bone morphogenetic protein is important because it is considered to create tissue
architecture throughout the body). So, with the bone protein and human glial cells combined, they promoted
significant recovery of conscious foot placement, axonal growth, and obvious increases in neuronal survival in the
spinal cord laminae. On the other hand, human glial precursor cells and astrocytes generated from these cells by
being in contact with ciliary neurotrophic factors, failed to promote neuronal survival and support of axonal growth
at the spot of the injury.[]
One study done in Shanghai had two types of hippocampal neuronal cultures: In one culture, the neuron was grown
from a layer of astrocytes and the other culture was not in contact with any astrocytes, but they were instead fed a
31
Astrocyte
Glial Conditioned Medium (GCM), which inhibits the rapid growth of cultured astrocytes in the brains of rats in
most cases. In their results they were able to see that astrocytes had a direct role in Long-term potentiation with the
mixed culture (which is the culture that was grown from a layer of astrocytes) but not in GCM cultures.[]
Recent studies have shown that astrocytes play an important function in the regulation of neural stem cells. Research
from the Schepens Eye Research Institute at Harvard shows the human brain to abound in neural stem cells, which
are kept in a dormant state by chemical signals (ephrin-A2 and ephrin-A3) from the astrocytes. The astrocytes are
able to activate the stem cells to transform into working neurons by dampening the release of ephrin-A2 and
ephrin-A3.[citation needed]
Furthermore, studies are underway to determine whether astroglia play an instrumental role in depression, based on
the link between diabetes and depression. Altered CNS glucose metabolism is seen in both these conditions, and the
astroglial cells are the only cells with insulin receptors in the brain.
In a study published in a 2011 issue of Nature Biotechnology[18] and reported in lay science article,[19] a group of
researchers from the University of Wisconsin reports that it has been able to direct embryonic and induced human
stem cells to become astrocytes.
A 2012 study[20] of the effects of marijuana on short term memories found that THC activates CB1 receptors of
astrocytes which cause receptors for AMPA to be removed from the membranes of associated neurons.
Calcium waves
Astrocytes are linked by gap junctions, creating an electrically coupled (functional) syncytium.[21] Because of this
ability of astrocytes to communicate with their neighbors, changes in the activity of one astrocyte can have
repercussions on the activities of others that are quite distant from the original astrocyte.
An influx of Ca2+ ions into astrocytes is the essential change that ultimately generates calcium waves. Because this
influx is directly caused by an increase in blood flow to the brain, calcium waves are said to be a kind of
hemodynamic response function. An increase in intracellular calcium concentration can propagate outwards through
this functional syncytium. Mechanisms of calcium wave propagation include diffusion of calcium ions and IP3
through gap junctions and extracellular ATP signalling.[22] Calcium elevations are the primary known axis of
activation in astrocytes, and are necessary and sufficient for some types of astrocytic glutamate release.[23]
Development
Astrocytes are macroglial cells in the central nervous system. Astrocytes are derived from heterogeneous populations
of progenitor cells in the neuroepithelium of the developing central nervous system. Recent works, summarized in a
review by Rowitch and Kriegstein,[24] indicate that there is remarkable similarity between the well known genetic
mechanisms that specify the lineage of diverse neuron subtypes and that of macroglial cells. Just as with neuronal
cell specification, canonical signaling factors like Sonic hedgehog (SHH), Fibroblast growth factor (FGFs), WNTs
and bone morphogenetic proteins (BMPs), provide positional information to developing macroglial cells through
morphogen gradients along the dorsalventral, anteriorposterior and mediallateral axes. The resultant patterning
along the neuraxis leads to segmentation of the neuroepithelium into progenitor domains (p0, p1 p2, p3 and pMN)
for distinct neuron types in the developing spinal cord. On the basis of several studies it is now believed that that this
model also applies to macroglial cell specification. Studies carried out by Hochstim and colleagues have
demonstrated that three distinct populations of astrocytes arise from the p1, p2 and p3 domains.[25] These subtypes of
astrocytes can be identified on the basis of their expression of different transcription factors (PAX6, NKX6.1) and
cell surface markers (reelin and SLIT1). The three populations of astrocyte subtypes which have been identified are
1) dorsally located VA1 astrocytes, derived from p1 domain, express PAX6 and reelin 2) ventrally located VA3
astrocytes, derived from p3, express NKX6.1 and SLIT1 and 3) and intermediate white-matter located VA2
astrocyte, derived from the p2 domain, which express PAX6, NKX6.1, reelin and SLIT1.[26] After astrocyte
32
Astrocyte
specification has occurred in the developing CNS, it is believed that astrocyte precursors migrate to their final
positions within the nervous system before the process of terminal differentiation occurs.
Classification
There are several different ways to classify astrocytes.
Lineage and antigenic phenotype

These have been established by classic work by Raff et al. in early 1980s on Rat optic nerves.
Type 1: Antigenically Ran2+, GFAP+, FGFR3+, A2B5-, thus resembling the "type 1 astrocyte" of the postnatal
day 7 rat optic nerve. These can arise from the tripotential glial restricted precursor cells (GRP), but not from the
bipotential O2A/OPC (oligodendrocyte, type 2 astrocyte precursor, also called Oligodendrocyte progenitor cell)
cells.
Type 2: Antigenically A2B5+, GFAP+, FGFR3-, Ran 2-. These cells can develop in vitro from the either
tripotential GRP (probably via O2A stage) or from bipotential O2A cells (which some peopleWikipedia:Avoid
weasel words think may in turn have been derived from the GRP) or in vivo when these progenitor cells are
transplanted into lesion sites (but probably not in normal development, at least not in the rat optic nerve).
Type-2 astrocytes are the major astrocytic component in postnatal optic nerve cultures that are generated by O2A
cells grown in the presence of fetal calf serum but are not thought to exist in vivo (Fulton et al., 1992).
Anatomical classification
Protoplasmic: found in grey matter and have many branching processes whose end-feet envelop synapses. Some
protoplasmic astrocytes are generated by multipotent subventricular zone progenitor cells.[][]
Gmri-positive astrocytes. These are a subset of protoplasmic astrocytes that contain numerous cytoplasmic
inclusions, or granules, that stain positively with Gmri's chrome-alum hematoxylin stain. It is now known that
these granules are formed from the remnants of degenerating mitochondria engulfed within lysosomes,[27] Some
type of oxidative stress appears to be responsible for the mitochondrial damage within these specialized
astrocytes. Gmri-positive astrocytes are much more abundant within the arcuate nucleus of the hypothalamus
and in the hippocampus than in other brain regions. They may have a role in regulating the response of the
hypothalamus to glucose.[28][29]
Fibrous: found in white matter and have long thin unbranched processes whose end-feet envelop nodes of
Ranvier.[30] Some fibrous astrocytes are generated by radial glia.[][][][][]
33
Astrocyte
34
Transporter/receptor classification
GluT type: express glutamate transporters (EAAT1/ SLC1A3 [31] and EAAT2/ SLC1A2 [32]) and respond to
synaptic release of glutamate by transporter currents
GluR type: express glutamate receptors (mostly mGluR and AMPA type) and respond to synaptic release of
glutamate by channel-mediated currents and IP3-dependent Ca2+ transients
Bergmann glia
Bergmann glia, a type of glia[33][34] also known as radial epithelial
cells (as named by Camillo Golgi) or Golgi epithelial cells (GCEs;
not to be mixed up with Golgi cells), are astrocytes in the
cerebellum that have their cell bodies in the Purkinje cell layer and
processes that extend into the molecular layer, terminating with
bulbous endfeet at the pial surface. Bergmann glia express high
densities of glutamate transporters that limit diffusion of the
neurotransmitter glutamate during its release from synaptic
terminals. Besides their role in early development of the
cerebellum, Bergmann glia are also required for the pruning or
addition of synapses.[citation needed]
Pathology
SLC1A3 expression highlights Bergmann glia in the

brain of a mouse at 7th postnatal day, sagittal section.
Astrocytomas are primary intracranial tumors derived from

astrocytes cells of the brain. It is also possible that glial progenitors or neural stem cells give rise to astrocytomas.
Astrocytomas are brain tumors that develop from astrocytes. They may occur in many parts of the brain and
sometimes in the spinal cord. They can occur at any age but they primarily occur in males. Astrocytomas are divided
into two categories: Low grade (I and II) and High Grade (III and IV). Low grade tumors are more common in
children and high grade tumors are more common in adults.[35]
Pilocytic Astrocytoma are Grade I tumors. They are considered benign and slow growing tumors. Pilocytic
Astrocytomas frequently have cystic portions filled with fluid and a nodule, which is the solid portion. Most are
located in the cerebellum. Therefore, most symptoms are related to balance or coordination difficulties.[35] They also
occur more frequently in children and teens.[36]
Grade II Tumors grow relatively slow but invade surrounding healthy tissue. Usually considered benign but can
grow into malignant tumors. Other names that are used are Fibrillary or Protoplasmic astrocytomas. They are
prevalent in younger people who are often present with seizures.[36]
Anaplastic astrocytoma is classified as grade III and are malignant tumors. They grow more rapidly than lower grade
tumors and tend to invade nearby healthy tissue. Anaplastic astrocytomas recur more frequently than lower grade
tumors because of their tendency to spread into surrounding tissue makes them difficult to completely remove
surgically.[35]
Glioblastoma Multiforme is also a malignant tumor and classified as a grade IV. Glioblastomas can contain more
than one cell type (i.e., astrocytes, oligondroctyes). Also, while one cell type may die off in response to a particular
treatment, the other cell types may continue to multiply. Glioblastomas are the most invasive type of glial tumors.
Grows rapidly and spreads to nearby tissue. Approximately 50% of astrocytomas are glioblastomas and are very
difficult to treat.[35]
Astrocyte
Tripartite synapse
Within the dorsal horn of the spinal cord, activated astrocytes have the ability to respond to almost all
neurotransmitters (Haydon, 2001) and, upon activation, release a multitude of neuroactive molecules such as
glutamate, ATP, nitric oxide (NO), prostaglandins (PG), and D-serine, which in turn influences neuronal excitability.
The close association between astrocytes and presynaptic and postsynaptic terminals as well as their ability to
integrate synaptic activity and release neuromodulators has been termed the "tripartite synapse" (Araque et al.,
1999). Synaptic modulation by astrocytes takes place because of this 3-part association.
Astrocytes in chronic pain sensitization

Under normal conditions, pain conduction begins with some noxious signal followed by an action potential carried
by nociceptive (pain sensing) afferent neurons, which elicit excitatory postsynaptic potentials (EPSP) in the dorsal
horn of the spinal cord. That message is then relayed to the cerebral cortex, where we translate those EPSPs into
"pain". Since the discovery of astrocytic influence, our understanding of the conduction of pain has been
dramatically complicated. Pain processing is no longer seen as a repetitive relay of signals from body to brain, but as
a complex system that can be up- and down-regulated by a number of different factors. One factor at the forefront of
recent research is in the pain-potentiating synapse located in the dorsal horn of the spinal cord and the role of
astrocytes in encapsulating these synapses. Garrison and co-workers (Garrison, 1991)Wikipedia:Citing
sources#What information to include were the first to suggest association when they found a correlation between
astrocyte hypertrophy in the dorsal horn of the spinal cord and hypersensitivity to pain after peripheral nerve injury,
typically considered an indicator of glial activation after injury. Astrocytes detect neuronal activity and can release
chemical transmitters, which in turn control synaptic activity (Volters and Meldolesi, 2005; Haydon, 2001; Fellin, et
al., 2006). In the past, hyperalgesia was thought to be modulated by the release of substance P and excitatory amino
acids (EAA), such as glutamate, from the presynaptic afferent nerve terminals in the spinal cord dorsal horn.
Subsequent activation of AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid), NMDA
(N-methyl-D-aspartate) and kainate subtypes of ionotropic glutamate receptors follows. It is the activation of these
receptors that potentiates the pain signal up the spinal cord. This idea, although true, is an oversimplification of pain
transduction. A litany of other neurotransmitter and neuromodulators, such as calcitonin gene-related peptide
(CGRP), adenosine triphosphate (ATP), brain-derived neurotrophic factor (BDNF), somatostatin, vasoactive
intestinal peptide (VIP), galanin, and vasopressin are all synthesized and released in response to noxious stimuli. In
addition to each of these regulatory factors, several other interactions between pain-transmitting neurons and other
neurons in the dorsal horn have added impact on pain pathways.
Two states of persistent pain

After persistent peripheral tissue damage there is a release of several factors from the injured tissue as well as in the
spinal dorsal horn. These factors increase the responsiveness of the dorsal horn pain-projection neurons to ensuing
stimuli, termed "spinal sensitization," thus amplifying the pain impulse to the brain. Release of glutamate, substance
P, and calcitonin gene-related peptide (CGRP) mediates NMDAR activation (originally silent because it is plugged
by Mg2+), thus aiding in depolarization of the postsynaptic pain-transmitting neurons (PTN). In addition, activation
of IP3 signaling and MAPKs (mitogen-activated protein kinases) such as ERK and JNK, bring about an increase in
the synthesis of inflammatory factors that alter glutamate transporter function. ERK also further activates AMPARs
and NMDARs in neurons. Nociception is further sensitized by the association of ATP and substance P with their
respective receptors, P<sub>2</sub>X<sub>3</sub>, and neurokinin 1 receptor (NK1R), as well as activation of
metabotropic glutamate receptors and release of BDNF. Persistent presence of glutamate in the synapse eventually
results in dysregulation of GLT1 and GLAST, crucial transporters of glutamate into astrocytes. Ongoing excitation
can also induce ERK and JNK activation, resulting in release of several inflammatory factors.
35
Astrocyte
As noxious pain is sustained, spinal sensitization creates transcriptional changes in the neurons of the dorsal horn
that lead to altered function for extended periods. Mobilization of Ca2+ from internal stores results from persistent
synaptic activity and leads to the release of glutamate, ATP, tumor necrosis factor- (TNF-), interleukin 1
(IL-1), IL-6, nitric oxide (NO), and prostaglandin E2 (PGE2). Activated astrocytes are also a source of matrix
metalloproteinase 2 (MMP2), which induces pro-IL-1 cleavage and sustains astrocyte activation. In this chronic
signaling pathway, p38 is activated as a result of IL-1 signaling, and there is a presence of chemokines that trigger
their receptors to become active. In response to nerve damage, heat shock proteins (HSP) are released and can bind
to their respective TLRs, leading to further activation.
References
[1] http:/ / www. neurolex. org/ wiki/ sao1394521419
[2] http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split. jsp?pg=/ ppdocs/ us/ common/ dorlands/ dorland/ a_68. htm
[4] Kolb & Whishaw: Fundamentals of Human Neuropsychology, 2008
[18] http:/ / www. nature. com/ nbt/ journal/ vaop/ ncurrent/ abs/ nbt. 1877. html
[19] http:/ / www. sciencedebate. com/ science-blog/ human-astrocytes-cultivated-stem-cells-lab-dish-u-wisconsin-researchers
[22] Newman, EA.(2001) "Propagation of intercellular calcium waves in retinal astrocytes and Mller cells." (http:/ / www. pubmedcentral. nih.
gov/ articlerender. fcgi?tool=pubmed& pubmedid=11264297)J Neurosci. 21(7):2215-23
[28] Young JK, McKenzie JC (2004) " GLUT2 immunoreactivity in Gmri-positive astrocytes of the hypothalamus (http:/ / www. jhc. org/ cgi/
content/ full/ 52/ 11/ 1519)."J. Histochemistry & Cytochemistry 52: 1519-1524 PMID
[31] http:/ / www. genenames. org/ data/ hgnc_data. php?match=SLC1A3
[32] http:/ / www. genenames. org/ data/ hgnc_data. php?match=SLC1A2
[35] Astrocytomas. (2010). Retrieved 2011, from IRSA: http:/ / www. irsa. org/ astrocytoma. html
[36] Astrocytoma Tumors (2005, August). Retrieved 2011, from American Association of Neurological Surgeons: http:/ / www. aans. org/
Patient%20Information/ Conditions%20and%20Treatments/ Astrocytoma%20Tumors. aspx.
Halassa, M.M., Fellin, T., and Haydon, P.G. (2006). "The tripartite synapse: roles for gliotransmission in health
and disease". Trends in Mol. Sci 13 (2): 5463. doi: 10.1016/j.molmed.2006.12.005 (http://dx.doi.org/10.
1016/j.molmed.2006.12.005). PMID 17207662 (http://www.ncbi.nlm.nih.gov/pubmed/17207662).
White, F.A., Jung, H. and Miller, R.J. (2007). "Chemokines and the pathophysiology of neuropathic pain" (http://
www.ncbi.nlm.nih.gov/pmc/articles/PMC2154400). Proc. Natl Acad. Sci. USA 104 (51): 2015120158. doi:
10.1073/pnas.0709250104 (http://dx.doi.org/10.1073/pnas.0709250104). PMC 2154400 (http://www.ncbi.
nlm.nih.gov/pmc/articles/PMC2154400). PMID 18083844 (http://www.ncbi.nlm.nih.gov/pubmed/
18083844).
Milligan, E.D. and Watson, L.R. (2009). "Pathological and protective roles of glia in chronic pain". Neuron-Glia
Interactions 10: 2336.
Watkins, L.R., Milligan, E.D. and Maier, S.F. (2001). "Glial activation: a driving force for pathological pain".
Trends in Neurosci. 24 (8): 450455. doi: 10.1016/S0166-2236(00)01854-3 (http://dx.doi.org/10.1016/
S0166-2236(00)01854-3).
Volterra, A. and Meldolesi, J. (2005). "Astrocytes, from brain glue to communication elements: the revolution
continues". Nat. Rev Neurosci. 6 (8): 626640. doi: 10.1038/nrn1722 (http://dx.doi.org/10.1038/nrn1722).
PMID 16025096 (http://www.ncbi.nlm.nih.gov/pubmed/16025096).
Freeman, M. R. (2010). "Specification and Morphogenesis of Astrocytes". Science 330 (6005): 7748. doi:
10.1126/science.1190928 (http://dx.doi.org/10.1126/science.1190928). PMID 21051628 (http://www.ncbi.
nlm.nih.gov/pubmed/21051628).
36
Astrocyte
External links
Cell Centered Database - Astrocyte (http://ccdb.ucsd.edu/sand/main?stype=lite&keyword=protoplasmic
astrocyte&Submit=Go&event=display&start=1)
UIUC Histology Subject 57 (https://histo.life.illinois.edu/histo/atlas/oimages.php?oid=57)
"Astrocytes" (http://www.sfn.org/index.cfm?pagename=brainBriefings_astrocytes) at Society for
Neuroscience
NIF Search - Astrocyte (https://www.neuinfo.org/mynif/search.php?q=Astrocyte&t=data&s=cover&b=0&
r=20) via the Neuroscience Information Framework
37
38
Oligodendrocytes
Oligodendrocyte
Oligodendrocyte
Oligodendrocyte
Oligodendrocytes form the electrical insulation around the axons of CNS nerve cells.
Latin
oligodendrocytus
Code
TH H2.00.06.2.01018
[1]
Oligodendrocytes (from Greek, meaning cells with a few branches), or oligodendroglia (Greek, few tree glue),[2]
are a type of brain cell. They are a variety of neuroglia. Their main functions are to provide support and to insulate
the axons (the long projection of nerve cells) in the central nervous system (the brain and spinal cord) of some
vertebrates. (The same function is performed by Schwann cells in the peripheral nervous system.) Oligodendrocytes
do this by creating the myelin sheath, which is 80% lipid and 20% protein.[3] A single oligodendrocyte can extend its
processes to 50 axons, wrapping approximately 1m of myelin sheath around each axon; Schwann cells, on the
other hand, can wrap around only 1 axon. Each oligodendrocyte forms one segment of myelin for several adjacent
axons.[3]
Oligodendrocyte
Origin
Oligodendroglia, types of glial cells, arise during development from oligodendrocyte precursor cells, which can be
identified by their expression of a number of antigens, including the ganglioside GD3,[4] the NG2 chondroitin sulfate
proteoglycan,[5] and the platelet-derived growth factor-alpha receptor subunit PDGF-alphaR.[6] Most
oligodendrocytes develop during embryogenesis and early postnatal life from restricted periventricular germinal
regions.[7]Oligodendroctyes are found only in the central nervous system which comprises the brain and spinal cord.
These cells were originally thought to have been produced in the ventral neural tube; however, research now shows
oligodendrocytes originate from the ventral ventricular zone of the embryonic spinal cord and possibly have some
concentrations in the forebrain.[8] They are the last cell type to be generated in the CNS.[9] Myelination is only
prevalent in a few brain regions at birth and continues into adulthood. The entire process is not complete until about
2530 years of age.[10] Oligodendrocyte formation in the adult brain is associated with glial-restricted progenitors
cells, known as oligodendrocyte progenitor cells (OPCs).[11] SVZ cells migrate away from germinal[12] zones to
populate both developing white and gray matter, where they differentiate and mature into myelin-forming
oligodendroglia.[13] However, it is not clear whether all oligodendroglial progenitors undergo this sequence of
events. It has been suggested that some undergo apoptosis [14] and others fail to differentiate into mature
oligodendroglia but persist as adult oligodendroglial progenitors.[15]
Function
As part of the nervous system, oligodendrocytes are closely related to
nerve cells, and, like all other glial cells, oligodendrocytes provide a
supporting role for neurons. In addition, the nervous system of
mammals depends crucially on myelin sheaths, which reduce ion
leakage and decrease the capacitance of the cell membrane.[16] Myelin
also increases impulse speed, as saltatory propagation of action
potentials occurs at the nodes of Ranvier in between Schwann cells (of
the PNS) and oligodendrocytes (of the CNS). Oligodendrocytes
provide the same functionality as the insulation on a household
electrical wire (with the rather large difference that, while household
An oligodendrocyte seen myelinating several
axons.
electrical wires are in a non-conducting medium - air - the axons run in
a solution of water and ions, which conducts electrical current well).
Furthermore, impulse speed of myelinated axons increases linearly with the axon diameter, whereas the impulse
speed of unmyelinated cells increases only with the square root of the diameter. The insulation must be proportional
to the diameter of the fiber inside. The optimal ratio of axon diameter divided by the total fiber diameter (which
includes the myelin) is 0.6.[10] In contrast, Satellite oligodendrocytes are functionally distinct from most
oligodendrocytes. They are not attached to neurons and, therefore, do not serve an insulating role. They remain
apposed to neurons and regulate the extracellular fluid.[17] Satellite oligodendrocytes are considered to be a part of
the gray matter whereas myelinating oligodendrocytes are a part of the white matter.
Myelination is an important component of intelligence. Neuroscientist Vincent J. Schmithorst found that there is a
correlation with white matter and intelligence. People with greater white matter had higher IQ's.[10] A study done
with rats by Janice M Juraska showed that rats that were raised in an enriched environment had more myelination in
their corpus callosum.[18]
39
Oligodendrocyte
Pathology
Diseases that result in injury to the oligodendroglial cells include demyelinating diseases such as multiple sclerosis
and leukodystrophies. Trauma to the body, e.g. spinal cord injury, can also cause demyelination. Cerebral palsy
(periventricular leukomalacia) is caused by damage to developing oligodendrocytes in the brain areas around the
cerebral ventricles. In cerebral palsy, spinal cord injury, stroke and possibly multiple sclerosis, oligodendrocytes are
thought to be damaged by excessive release of the neurotransmitter glutamate.[19] Damage has also been shown to be
mediated by N-methyl-d-aspartate receptors.[19] Oligodendrocyte dysfunction may also be implicated in the
pathophysiology of schizophrenia and bipolar disorder.[20]
Oligodendroglia are also susceptible to infection by the JC virus, which causes progressive multifocal
leukoencephalopathy (PML), a condition that specifically affects white matter, typically in immunocompromised
patients. Tumors of oligodendroglia are called oligodendrogliomas. The chemotherapy agent Fluorouracil (5-FU)
causes damage to the oligodendrocytes in mice, leading to both acute central nervous system (CNS) damage and
progressively worsening delayed degeneration of the CNS.[21]
Notes
[1] http:/ / www. unifr. ch/ ifaa/ Public/ EntryPage/ ViewTH/ THh200. html
[2] .
[3] Carlson, Physiology of Behavior, 2010
[4] Curtis et al., 1988; LeVine and Goldman, 1988; Hardy and Reynolds, 1991; Levine et al., 1993
[5] Levine et al., 1993
[6] Pringle et al., 1992
[7] Vallstedt et al., 2004
[8] Richardson, W; D., Kessaris, Pringle, N (2006). "Oligodendrocyte wars". Nature Neuroscience Reviews. 1 7: 11-18
[9] Thomas et al., Spatiotemporal development of oligodendrocytes in the embryonic brain., 2000
[10] Fields, 2008
[11] Menn, et al., Origin of Oligodendrocytes in the Subventricular Zone of the Adult Brain, 2006
[12] Menn, et al., 2006
[13] Hardy and Reynolds, 1991; Levison and Goldman, 1993
[14] Barres et al., 1992
[15] Wren et al., 1992
[16] Sokol, 2009
[17] Baumann and Pham-Dinh, 2001
[19] Kradttir et al., 2007
[20] Tkachev et al., 2003
[21] "Chemotherapy-induced Damage to the CNS as a Precursor Cell Disease" (http:/ / www. urmc. rochester. edu/ biomedical-genetics/ faculty/
chemotherapy-induced-damage-to-cns. cfm) by Dr. Mark D. Noble, University of Rochester
References
Baumann, N; Pham-Dinh, D (2001). "Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous
System" (http://physrev.physiology.org/cgi/content/full/81/2/871). Physiological Reviews 18 (2): 871927.
PMID 11274346 (http://www.ncbi.nlm.nih.gov/pubmed/11274346). Retrieved 2007-07-13 More than one of
|surname1= and |last1= specified (help); More than one of |given1= and |first1= specified (help);
More than one of |surname2= and |last2= specified (help); More than one of |given2= and
|first2= specified (help)
Ragheb, Fadi (1999). The M3 Muscarinic Acetylcholine Receptor Mediates p42mapk Activation and c-fos mRNA
Expression in Oligodendrocyte Progenitors (http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/
PQDD_0025/MQ50862.pdf). Ottawa: National Library of Canada. Retrieved 2006-03-07
Raine, C.S. (1991). Oligodendrocytes and central nervous system myelin. In Textbook of Neuropathology, second
edition, R.L. Davis and D.M. Robertson, eds. (Baltimore, Maryland: Williams and Wilkins), pp.115141.
40
Oligodendrocyte
Tkachev D, Mimmack ML, Ryan MM, et al. (September 2003). "Oligodendrocyte dysfunction in schizophrenia
and bipolar disorder". Lancet 362 (9386): 798805. doi: 10.1016/S0140-6736(03)14289-4 (http://dx.doi.org/
10.1016/S0140-6736(03)14289-4). PMID 13678875 (http://www.ncbi.nlm.nih.gov/pubmed/13678875).
Kradttir, R.; D. Attwell (14). "Neurotransmiter receptors in the life and death of oligodendrocytes" (http://
www.ncbi.nlm.nih.gov/pmc/articles/PMC2173944). Neuroscience 145 (4): 14261438. doi:
10.1038/bjc.1990.391 (http://dx.doi.org/10.1038/bjc.1990.391). PMC 2173944 (http://www.ncbi.nlm.
nih.gov/pmc/articles/PMC2173944). PMID 2173944 (http://www.ncbi.nlm.nih.gov/pubmed/2173944).
Carlson, Neil (2010). Physiology of Behavior. Boston, MA: Allyn & Bacon. pp.3839. ISBN0-205-66627-2.
Sokol, Stacey. "The Physiology and Pathophysiology of Multiple Sclerosis" (http://mylifehealthandprosperity.
com/index.php?option=com_content&view=article&id=65&Itemid=160). Multiple Sclerosis: Physiological
Tutorial. Retrieved 2012-04-29.
Fields, Douglas (18). "White Matter Matters" (http://www.scientificamerican.com/article.
cfm?id=white-matter-matters). Scientific American 298 (March 2008): 5461. Bibcode: 2008SciAm.298c..54D
(http://adsabs.harvard.edu/abs/2008SciAm.298c..54D). doi: 10.1038/scientificamerican0308-54 (http://dx.
doi.org/10.1038/scientificamerican0308-54). Retrieved 2012-04-29.
Menn, Benedicte; Jose Manuel Garcia-Verdugo, Cynthia Yaschine, Oscar Gonzalez-Perez, David Rowitch,
Arturo Alvarez-Buylla (26). "Origin of Oligodendrocytes in the Subventricular Zone of the Adult Brain" (http://
www.jneurosci.org/content/26/30/7907.full). The Journal of Neuroscience 26 (30): 79077918. doi:
10.1523/JNEUROSCI.1299-06.2006 (http://dx.doi.org/10.1523/JNEUROSCI.1299-06.2006). PMID
16870736 (http://www.ncbi.nlm.nih.gov/pubmed/16870736). Retrieved 2012-04-29.
Vallstedt, A; Klos JM, Ericson F (6). "Multiple dorsoventral origins of oligodendrocyte generation in the spinal
cord and hindbrain". Neuron. 1 45 (1): 5567. doi: 10.1016/j.neuron.2004.12.026 (http://dx.doi.org/10.1016/j.
neuron.2004.12.026). PMID 15629702 (http://www.ncbi.nlm.nih.gov/pubmed/15629702).
Thomas, JL; Spassky N, Perez Villegas EM, Olivier C, Cobos I, Goujet-Zalc C, Martnez S, Zalc B. (15).
"Spatiotemporal development of oligodendrocytes in the embryonic brain" (http://www.ncbi.nlm.nih.gov/
pubmed/10679785). Journal of Neuroscience Research 59 (4): 471476. doi:
10.1002/(SICI)1097-4547(20000215)59:4<471::AID-JNR1>3.0.CO;2-3 (http://dx.doi.org/10.1002/
(SICI)1097-4547(20000215)59:4<471::AID-JNR1>3.0.CO;2-3). PMID 10679785 (http://www.ncbi.nlm.nih.
gov/pubmed/10679785). Retrieved 2012-04-29.
Richardson, W; D., Kessaris, Pringle, N (2006). "Oligodendrocyte wars". Nature Neuroscience Reviews. 1 7:
11-18.
External links
NIF Search - Oligodendrocyte (https://www.neuinfo.org/mynif/search.php?q="Oligodendrocyte"&t=data&
s=cover&b=0&r=20) via the Neuroscience Information Framework
41
Myelin
42
Myelin
Structure of a typical neuron
Myelin sheath
Myelin is a dielectric (electrically insulating) material that forms a layer, the myelin sheath, usually around only the
axon of a neuron. It is essential for the proper functioning of the nervous system. It is an outgrowth of a type of glial
cell. The production of the myelin sheath is called myelination. In humans, the production of myelin begins in the
14th week of fetal development, although little myelin exists in the brain at the time of birth. During infancy,
myelination occurs quickly and continues through the adolescent stages of life.
Schwann cells supply the myelin for peripheral neurons, whereas oligodendrocytes, specifically of the interfascicular
type, myelinate the axons of the central nervous system. Myelin is considered a defining characteristic of the
(gnathostome) vertebrates, but myelin-like sheaths have also arisen by parallel evolution in some invertebrates,
although they are quite different from vertebrate myelin at the molecular level.[] Myelin was discovered in 1854 by
Rudolf Virchow.[1]
Composition of myelin
Myelin is made up by different cell types, and varies in chemical composition and configuration, but performs the
same insulating function. Myelinated axons are white in appearance, hence the "white matter" of the brain. The fat
helps to insulate the axons from electrically charged atoms and molecules. These charged particles (ions) are found
in the fluid surrounding the entire nervous system. Under a microscope, myelin looks like strings of sausages.
Myelin is also a part of the maturation process leading to a child's fast development, including crawling and walking
in the first year.
Myelin is about 40% water; the dry mass is about 70 - 85% lipids and about 15 - 30% proteins. Some of the proteins
are myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein. The primary lipid of myelin
is a glycolipid called galactocerebroside. The intertwining hydrocarbon chains of sphingomyelin serve to strengthen
the myelin sheath.
Myelin
43
Function of myelin layer

The main purpose of a myelin layer (or sheath) is to increase the speed
at which impulses propagate along the myelinated fiber. Along
unmyelinated fibers, impulses move continuously as waves, but in
myelinated fibers, they hop or "propagate by saltation." Myelin
decreases capacitance across the cell membrane, and increases
electrical resistance. Thus, myelination helps prevent the electrical
current from leaving the axon. It has been suggested that myelin
enables larger body size by maintaining agile communication between
distant body parts. [2]
When a peripheral fiber is severed, the myelin sheath provides a track
along which regrowth can occur. Unfortunately, the myelin layer does
not ensure a perfect regeneration of the nerve fiber. Some regenerated
nerve fibers do not find the correct muscle fibers and some damaged
motor neurons of the peripheral nervous system die without regrowth.
Damage to the myelin sheath and nerve fiber is often associated with
increased functional insufficiency.
Transmission electron micrograph of a

myelinated axon, generated at the Electron
Microscopy Facility at Trinity College, Hartford,
CT
Unmyelinated fibers and myelinated axons of the mammalian central nervous system do not regenerate.
Some studies have revealed optic nerve fibers can be regenerated in postnatal rats. This regeneration depends upon
two conditions: axonal die-back has to be prevented with appropriate neurotrophic factors, and neurite growth
inhibitory components have to be inactivated. These studies may lead to further understanding of nerve fiber
regeneration in the central nervous system.[citation needed]
Disorders of the myelin sheath

Demyelination
Demyelination is the loss of the myelin sheath insulating the nerves, and is the hallmark of some neurodegenerative
autoimmune diseases, including multiple sclerosis, acute disseminated encephalomyelitis, Neuromyelitis Optica,
transverse myelitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barr syndrome, central pontine
myelinosis, inherited demyelinating diseases such as leukodystrophy, and Charcot-Marie-Tooth disease. Sufferers of
pernicious anaemia can also suffer nerve damage if the condition is not diagnosed quickly. Subacute combined
degeneration of spinal cord secondary to pernicious anaemia can lead to slight peripheral nerve damage to severe
damage to the central nervous system, affecting speech, balance and cognitive awareness. When myelin degrades,
conduction of signals along the nerve can be impaired or lost and the nerve eventually withers. A more serious case
of when myelin is deteriorated is also called Canavan Disease.
The immune system may play a role in demyelination associated with such diseases, including inflammation causing
demyelination by overproduction of cytokines via upregulation of tumor necrosis factor[] or interferon.
Myelin
44
Symptoms
Demyelination results in diverse symptoms determined by the functions of the affected neurons. It disrupts signals
between the brain and other parts of the body; symptoms differ from patient to patient, and have different
presentations upon clinical observation and in laboratory studies.
Typical symptoms include:
blurriness in the central visual field that affects only one eye, may be accompanied by pain upon eye movement
double vision
loss of vision/hearing
odd sensation in legs, arms, chest, or face, such as tingling or numbness (neuropathy)
weakness of arms or legs
cognitive disruption, including speech impairment and memory loss
heat sensitivity (symptoms worsen or reappear upon exposure to heat, such as a hot shower)
loss of dexterity
difficulty coordinating movement or balance disorder
difficulty controlling bowel movements or urination
fatigue
Myelin repair
Research to repair damaged myelin sheaths is ongoing. Techniques include surgically implanting oligodendrocyte
precursor cells in the central nervous system and inducing myelin repair with certain antibodies. While results in
mice have been encouraging (via stem cell transplantation), whether this technique can be effective in replacing
myelin loss in humans is still unknown.[] Cholinergic treatments, such as acetylcholinesterase inhibitors (AChEIs),
may have beneficial effects on myelination, myelin repair, and myelin integrity. Increasing cholinergic stimulation
also may act through subtle trophic effects on brain developmental processes and particularly on oligodendrocytes
and the lifelong myelination process they support. By increasing oligodendrocyte cholinergic stimulation, AChEIs,
and other cholinergic treatments, such as nicotine, possibly could promote myelination during development and
myelin repair in older age.[] Glycogen synthase kinase 3 inhibitors such as lithium chloride have been found to
promote myelination in mice with damaged facial nerves.[]
Dysmyelination
Dysmyelination is characterized by a defective structure and function of myelin sheaths; unlike demyelination, it
does not produce lesions. Such defective sheaths often arise from genetic mutations affecting the biosynthesis and
formation of myelin. The shiverer mouse represents one animal model of dysmyelination. Human diseases where
dysmyelination has been implicated include leukodystrophies (PelizaeusMerzbacher disease, Canavan disease,
phenylketonuria) and schizophrenia.[3][4][5]
Invertebrate Myelin
Functionally equivalent myelin-like sheaths are found in several invertebrate taxa including Oligochaete, Penaeid,
Palaemonid, and Calanoids. These myelin-like sheaths share several structural features with the sheaths found in
vertebrates including multiplicity of membranes, condensation of membrane, and nodes. [2] However, the nodes in
vertebrates are annular: i.e., they encircle the axon. In contrast, nodes found in the sheaths of invertebrates are either
annular or fenestrated: i.e., they are restricted to "spots." It is notable that the fastest recorded conduction speed
(across both vertebrates and invertebrates) is found in the ensheathed axons of the Kuruma shrimp, an invertebrate.[2]
Myelin
45
References
[2] Daniel K. Hartline (2008). What is myelin?. Neuron Glia Biology, 4, pp 153163 doi:10.1017/S1740925X09990263
External links
The Myelin Project (http://www.myelin.org/)
Athabasca University Biological Psychology Website (http://psych.athabascau.ca/html/Psych402/
Biotutorials/2/myelin.shtml)
The MS Information Sourcebook, Myelin (http://www.nationalmssociety.org/about-multiple-sclerosis/
what-we-know-about-ms/what-is-ms/myelin/index.aspx)
The Myelin Repair Foundation (http://www.myelinrepair.org/)
H & E Histology (http://www-medlib.med.utah.edu/WebPath/HISTHTML/HISTOTCH/HISTOTCH.html)
Luxol Fast Blue: Modified Kluver's Method to stain for Myelin Sheath (http://www-medlib.med.utah.edu/
WebPath/HISTHTML/MANUALS/LFB.PDF)
Radiology and Pathology of Myelin (http://rad.usuhs.edu/medpix/medpix.html?mode=image_finder&
srchstr=myelination myelin&srch_type=any&action=search#top) the MedPix Medical Image Database
(http://archneur.ama-assn.org/cgi/content/abstract/34/10/585) Archives of Neurology
American Society for Neurochemistry (http://www.asneurochem.org)

Myelin_MBP
Identifiers
Symbol
Myelin_MBP
Pfam
PF01669
InterPro
IPR000548
PROSITE
PDOC00492
SCOP
1bx2
SUPERFAMILY
1bx2
[1]
[2]
[3]
[4]
[5]
OPM superfamily 464 [6]

OPM protein
2lug
[7]
Available protein structures:

[8]
Pfam
structures
PDB
RCSB PDB
[9]
; PDBe
[10]
PDBsum structure summary [11]
46
Rendering of MBP from PDB 1BX2
[12]
Available structures
PDB Ortholog search: PDBe [13], RCSB [14]
List of PDB id codes
1BX2
[12]
, 1FV1
[15]
, 1HQR
[16]
, 1YMM
[17]
, 1ZGL
[18]
Identifiers
[19]
Symbols
MBP
External IDs
OMIM: 159430
; MGC99675
[20]
MGI: 96925
[21]
HomoloGene: 1788
Gene Ontology
Molecular function protease binding [24]
[25]
structural constituent of myelin sheath
Cellular component plasma membrane [26]
[27]
internode region of axon
[28]
neuronal cell body
[29]
compact myelin
Biological process
[30]
immune response
[31]
synaptic transmission
[32]
central nervous system development
[33]
axon ensheathment
[34]
response to toxic substance
[35]
myelination
[36]
negative regulation of axonogenesis
[37]
membrane organization
Sources: Amigo
[38]
/ QuickGO
[39]
RNA expression pattern
[22]
GeneCards: MBP Gene
[23]
47
More reference expression data
[40]
Orthologs
Species
Human
Mouse
Entrez
4155
Ensembl
ENSG00000197971
UniProt
P02686
RefSeq (mRNA)
NM_001025081
RefSeq (protein)
NP_001020252
[41]
17196
[43]
[45]
[42]
ENSMUSG00000041607
P04370
[47]
[49]
[46]
NM_001025245
NP_001020416
[48]
[50]
Location (UCSC) Chr 18:

[51]
74.69 74.85 Mb
Chr 18:
[52]
82.48 82.59 Mb
PubMed search
[54]
[53]
[44]
Myelin basic protein (MBP) is a protein believed to be important in the process of myelination of nerves in the
nervous system. The myelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an
insulator to greatly increase the velocity of axonal impulse conduction.[] MBP maintain the correct structure of
myelin, interacting with the lipids in the myelin membrane.[][]
MBP was initially sequenced in 1971 after isolation from myelin membranes.[] Since that time, knockout mice
deficient in MBP that showed decreased amounts of CNS myelination and a progressive disorder characterized by
tremors, seizures, and early death have been developed. The human gene for MBP is on chromosome 18;[] the
protein localizes to the CNS and to various cells of the hematopoietic system.
The pool of MBP in the central nervous system is very diverse, with several splice variants being expressed and a
large number of post-translational modifications on the protein, which include phosphorylation, methylation,
deamidation, and citrullination. These forms differ by the presence or the absence of short (10 to 20 residues)
peptides in various internal locations in the sequence. The major form of MBP is generally a protein of about 18.5
Kd (170 residues).
In melanocytic cell types, MBP gene expression may be regulated by MITF.[]
Function
The protein encoded by the classic MBP gene is a major constituent of the myelin sheath of oligodendrocytes and
Schwann cells in the nervous system. However, MBP-related transcripts are also present in the bone marrow and the
immune system. These mRNAs arise from the long MBP gene (otherwise called "Golli-MBP") that contains 3
additional exons located upstream of the classic MBP exons. Alternative splicing from the Golli and the MBP
transcription start sites gives rise to 2 sets of MBP-related transcripts and gene products. The Golli mRNAs contain 3
exons unique to Golli-MBP, spliced in-frame to 1 or more MBP exons. They encode hybrid proteins that have
N-terminal Golli aa sequence linked to MBP aa sequence. The second family of transcripts contain only MBP exons
and produce the well characterized myelin basic proteins. This complex gene structure is conserved among species
suggesting that the MBP transcription unit is an integral part of the Golli transcription unit and that this arrangement

is important for the function and/or regulation of these genes.[]
Role in disease
Interest in MBP has centered on its role in demyelinating diseases, in particular, multiple sclerosis (MS). Several
studies have shown a role for antibodies against MBP in the pathogenesis of MS.[] Some studies have linked a
genetic predisposition to MS to the MBP gene, though a majority have not.
Some recent works have shown that inoculating an animal with MBP to generate an immune response against it
increases bloodbrain barrier permeability.[citation needed]
A targeted immune response to MBP has been researched in lethal rabies infection. The inoculation of MBP
generates increases the permeability of the bloodbrain barrier (BBB), allowing immune cells to enter the brain, the
primary site of rabies virus replication. In a study of mice infected with Silver-haired bat rabies virus (SHBRV), the
mortality rate of mice treated with MBP improved 20%-30% over the untreated control group. It is significant to
note that healthy uninfected mice treated with MBP showed an increase in mortality rate between 0% and 40%.[]
A "molecular mimicry" hypothesis of multiple sclerosis has been suggested in which T cells are essentially
confusing MBP with human herpesvirus-6. Researchers in the United States created a synthetic peptide with a
sequence identical to that of an HHV-6 peptide. They were able to show that T cells were activated by this peptide.
These activated T cells also recognized and initiated an immune response against a synthetically created peptide
sequence that is identical to part of human MBP. During their research, they found that the levels of these
cross-reactive T cells are significantly elevated in multiple sclerosis patients.[55]
Interactions
Myelin basic protein has been shown to interact with Proteolipid protein 1.[][]
References
[1] http:/ / pfam. sanger. ac. uk/ family?acc=PF01669
[2] http:/ / www. ebi. ac. uk/ interpro/ entry/ IPR000548
[3] http:/ / www. expasy. org/ cgi-bin/ prosite-search-ac?PDOC00492
[4] http:/ / scop. mrc-lmb. cam. ac. uk/ scop/ search. cgi?tlev=fa;& amp;pdb=1bx2
[5] http:/ / supfam. org/ SUPERFAMILY/ cgi-bin/ search. cgi?search_field=1bx2
[6] http:/ / opm. phar. umich. edu/ families. php?superfamily=464
[7] http:/ / opm. phar. umich. edu/ protein. php?search=2lug
[8] http:/ / pfam. sanger. ac. uk/ family/ PF01669?tab=pdbBlock
[9] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=PfamIdQuery& pfamID=PF01669
[10] http:/ / www. ebi. ac. uk/ pdbe-srv/ PDBeXplore/ pfam/ ?pfam=PF01669
[11] http:/ / www. ebi. ac. uk/ thornton-srv/ databases/ cgi-bin/ pdbsum/ GetPfamStr. pl?pfam_id=PF01669
[12] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1BX2
[13] http:/ / www. ebi. ac. uk/ pdbe/ searchResults. html?display=both& term=P02686%20or%20P04370%20or%20P15720%20or%20E7EYA2
[14] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=UpAccessionIdQuery&
accessionIdList=P02686,P04370,P15720,E7EYA2
[15] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1FV1
[16] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1HQR
[17] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1YMM
[18] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1ZGL
[19] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=6925
[20] http:/ / omim. org/ entry/ 159430
[21] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:96925
[22] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=1788
[23] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=4155
[24] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0002020
[25] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0019911
48

[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005886
http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P02686
http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P02686
http:/ / biogps. org/ gene/ 4155/
http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=4155& rn=1
http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=17196& rn=1
http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000197971;db=core
http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000041607;db=core
http:/ / www. uniprot. org/ uniprot/ P02686
http:/ / www. uniprot. org/ uniprot/ P04370
http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_001025081
[48]
[49]
[50]
[51]
[52]
[53]
[54]
http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_001025245

http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_001020252
http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_001020416
http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Human& db=hg19& position=chr18:74690783-74845639
http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Mouse& db=mm9& position=chr18:82475146-82585637
http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=4155
http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=17196
Further reading
Boylan KB, Ayres TM, Popko B, et al. (1990). "Repetitive DNA (TGGA)n 5' to the human myelin basic protein
gene: a new form of oligonucleotide repetitive sequence showing length polymorphism.". Genomics 6 (1): 1622.
doi: 10.1016/0888-7543(90)90443-X (http://dx.doi.org/10.1016/0888-7543(90)90443-X). PMID 1689270
(http://www.ncbi.nlm.nih.gov/pubmed/1689270).
Kishimoto A, Nishiyama K, Nakanishi H, et al. (1985). "Studies on the phosphorylation of myelin basic protein
by protein kinase C and adenosine 3':5'-monophosphate-dependent protein kinase.". J. Biol. Chem. 260 (23):
124929. PMID 2413024 (http://www.ncbi.nlm.nih.gov/pubmed/2413024).
Saxe DF, Takahashi N, Hood L, Simon MI (1985). "Localization of the human myelin basic protein gene (MBP)
to region 18q22----qter by in situ hybridization.". Cytogenet. Cell Genet. 39 (4): 2469. doi: 10.1159/000132152
(http://dx.doi.org/10.1159/000132152). PMID 2414074 (http://www.ncbi.nlm.nih.gov/pubmed/
2414074).
Kamholz J, de Ferra F, Puckett C, Lazzarini R (1986). "Identification of three forms of human myelin basic
protein by cDNA cloning." (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC323864). Proc. Natl. Acad. Sci.
U.S.A. 83 (13): 49626. doi: 10.1073/pnas.83.13.4962 (http://dx.doi.org/10.1073/pnas.83.13.4962). PMC
323864 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC323864). PMID 2425357 (http://www.ncbi.nlm.
nih.gov/pubmed/2425357).
Scoble HA, Whitaker JN, Biemann K (1986). "Analysis of the primary sequence of human myelin basic protein
peptides 1-44 and 90-170 by fast atom bombardment mass spectrometry.". J. Neurochem. 47 (2): 6146. doi:
10.1111/j.1471-4159.1986.tb04544.x (http://dx.doi.org/10.1111/j.1471-4159.1986.tb04544.x). PMID
2426402 (http://www.ncbi.nlm.nih.gov/pubmed/2426402).
Roth HJ, Kronquist K, Pretorius PJ, et al. (1986). "Isolation and characterization of a cDNA coding for a novel
human 17.3K myelin basic protein (MBP) variant.". J. Neurosci. Res. 16 (1): 22738. doi: 10.1002/jnr.490160120
49
(http://dx.doi.org/10.1002/jnr.490160120). PMID 2427738 (http://www.ncbi.nlm.nih.gov/pubmed/

2427738).
Popko B, Puckett C, Lai E, et al. (1987). "Myelin deficient mice: expression of myelin basic protein and
generation of mice with varying levels of myelin.". Cell 48 (4): 71321. doi: 10.1016/0092-8674(87)90249-2
(http://dx.doi.org/10.1016/0092-8674(87)90249-2). PMID 2434243 (http://www.ncbi.nlm.nih.gov/
pubmed/2434243).
Kamholz J, Spielman R, Gogolin K, et al. (1987). "The human myelin-basic-protein gene: chromosomal
localization and RFLP analysis." (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1684086). Am. J. Hum.
Genet. 40 (4): 36573. PMC 1684086 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1684086). PMID
2437795 (http://www.ncbi.nlm.nih.gov/pubmed/2437795).
Roth HJ, Kronquist KE, Kerlero de Rosbo N, et al. (1987). "Evidence for the expression of four myelin basic
protein variants in the developing human spinal cord through cDNA cloning.". J. Neurosci. Res. 17 (4): 3218.
doi: 10.1002/jnr.490170402 (http://dx.doi.org/10.1002/jnr.490170402). PMID 2442403 (http://www.ncbi.
Shoji S, Ohnishi J, Funakoshi T, et al. (1988). "Phosphorylation sites of bovine brain myelin basic protein
phosphorylated with Ca2+-calmodulin-dependent protein kinase from rat brain.". J. Biochem. 102 (5): 111320.
Wood DD, Moscarello MA (1989). "The isolation, characterization, and lipid-aggregating properties of a
citrulline containing myelin basic protein.". J. Biol. Chem. 264 (9): 51217. PMID 2466844 (http://www.ncbi.
Edwards AM, Ross NW, Ulmer JB, Braun PE (1989). "Interaction of myelin basic protein and proteolipid
protein.". J. Neurosci. Res. 22 (1): 97102. doi: 10.1002/jnr.490220113 (http://dx.doi.org/10.1002/jnr.
490220113). PMID 2467009 (http://www.ncbi.nlm.nih.gov/pubmed/2467009).
Streicher R, Stoffel W (1989). "The organization of the human myelin basic protein gene. Comparison with the
mouse gene.". Biol. Chem. Hoppe-Seyler 370 (5): 50310. PMID 2472816 (http://www.ncbi.nlm.nih.gov/
pubmed/2472816).
Lennon VA, Wilks AV, Carnegie PR (1971). "Immunologic properties of the main encephalitogenic peptide from
the basic protein of human myelin.". J. Immunol. 105 (5): 122330. PMID 4099924 (http://www.ncbi.nlm.
nih.gov/pubmed/4099924).
Carnegie PR (1972). "Amino acid sequence of the encephalitogenic basic protein from human myelin." (http://
www.ncbi.nlm.nih.gov/pmc/articles/PMC1176899). Biochem. J. 123 (1): 5767. PMC 1176899 (http://
www.ncbi.nlm.nih.gov/pmc/articles/PMC1176899). PMID 4108501 (http://www.ncbi.nlm.nih.gov/
pubmed/4108501).
Baldwin GS, Carnegie PR (1971). "Specific enzymic methylation of an arginine in the experimental allergic
encephalomyelitis protein from human myelin.". Science 171 (3971): 57981. doi: 10.1126/science.171.3971.579
(http://dx.doi.org/10.1126/science.171.3971.579). PMID 4924231 (http://www.ncbi.nlm.nih.gov/
pubmed/4924231).
Baldwin GS, Carnegie PR (1972). "Isolation and partial characterization of methylated arginines from the
encephalitogenic basic protein of myelin." (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1176900).
Biochem. J. 123 (1): 6974. PMC 1176900 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1176900).
Wood DD, Vella GJ, Moscarello MA (1985). "Interaction between human myelin basic protein and lipophilin.".
Neurochem. Res. 9 (10): 152331. doi: 10.1007/BF00964678 (http://dx.doi.org/10.1007/BF00964678).
Gibson BW, Gilliom RD, Whitaker JN, Biemann K (1984). "Amino acid sequence of human myelin basic protein
peptide 45-89 as determined by mass spectrometry.". J. Biol. Chem. 259 (8): 502831. PMID 6201481 (http://
www.ncbi.nlm.nih.gov/pubmed/6201481).
50

Pribyl TM, Campagnoni CW, Kampf K, et al. (1993). "The human myelin basic protein gene is included within a
179-kilobase transcription unit: expression in the immune and central nervous systems." (http://www.ncbi.nlm.
nih.gov/pmc/articles/PMC47844). Proc. Natl. Acad. Sci. U.S.A. 90 (22): 106959. doi:
10.1073/pnas.90.22.10695 (http://dx.doi.org/10.1073/pnas.90.22.10695). PMC 47844 (http://www.ncbi.
nlm.nih.gov/pmc/articles/PMC47844). PMID 7504278 (http://www.ncbi.nlm.nih.gov/pubmed/7504278).
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
51
52
Classification and external resources
Photomicrograph of a demyelinating MS-Lesion. Immunohistochemical staining for CD68 highlights numerous macrophages (brown). Original
magnification 10.
[1]
ICD-10
G35
ICD-9
340
MeSH
D003711
-G37
[4]
-341
[2]
[5]
, G61.0
, 357.0
[3]
[6]
[7]
A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged.[8]
This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability
causes deficiency in sensation, movement, cognition, or other functions depending on which nerves are involved.
Some demyelinating diseases are caused by genetics, some by infectious agents, some by autoimmune reactions, and
some by unknown factors. Organophosphates, a class of chemicals which are the active ingredients in commercial
insecticides such as sheep dip, weed-killers, and flea treatment preparations for pets, etc., will also demyelinate
nerves. Neuroleptics can also cause demyelination.[9]
The precise mechanism of demyelination is not clearly understood but there is good evidence that the body's own
immune system is at least partially responsible. Acquired immune system cells called T-cells are known to be
present at the site of lesions. Other immune system cells called Macrophages (and possibly Mast cells as well) also
contribute to the damage.[10]
Causes
Some demyelinating diseases are caused by genetics, some by infectious agents, some by autoimmune reactions,
some by exposure to chemical agents, and some by unknown factors.
Signs and symptoms

Symptoms that present in demyelinating diseases are different for each condition. Below is a list of symptoms that
can present in a person with a demyelinating disease.:[11]
53
Blurred double vision
Ataxia
Clonus
Dysarthria
Fatigue
Clumsiness
Hand paralysis
Hemiparesis
Genital anaesthesia
Incoordination
Paresthesias
Ocular paralysis
Impaired muscle coordination
Weakness (muscle)
Loss of sensation
Impaired vision
Neurological symptoms
Unsteady gait
Spastic paraparesis
Incontinence
Hearing problems
Speech problems
Diagnosis
Below are various methods/techniques used to diagnose Demyelinating Diseases.
Exclusion of other conditions that have overlapping symptoms[]
Magnetic Resonance Imaging (MRI) is a medical imaging technique used in radiology to visualize internal
structures of the body in detail. MRI makes use of the property of nuclear magnetic resonance (NMR) to image
nuclei of atoms inside the body. This method is unreliable because MRIs assess changes in proton density. Spots
can occur as a result of changes in brain water content.[]
Evoked potential is an electrical potential recorded from the nervous system following the presentation of a
stimulus as detected by electroencephalography (EEG), electromyography (EMG), or other electrophysiological
recording method.[]
Cerebrospinal fluid analysis (CSF) can be extremely beneficial in the diagnosis of central nervous system
infections. A CSF Culture examination may yield the Microorganism that caused the infection.[]
Quantitative proton magnetic resonance spectroscopy (MRS) is a non-invasive analytical technique that has been
used to study metabolic changes in brain tumors, strokes, seizure disorders, Alzheimer's disease, depression and
other diseases affecting the brain. It has also been used to study the metabolism of other organs such as muscles.[]
Diagnostic Criteria refers to a specific combination of signs, symptoms, and test results that the clinician uses in
an attempt to determine the correct diagnosis.[]
Treatment
Treatment typically involves improving the patient's quality of life. This is accomplished through the management of
symptoms or slowing the rate of demyelination. Treatment can include medication, lifestyle changes (i.e. quit
smoking, adjusting daily schedules to include rest periods and dietary changes), counselling, relaxation, physical
exercise, patient education and, in some cases, deep brain thalamic stimulation (in the case of Tremors).[] The
progressive phase of MS appears to driven by the innate immune system, which may directly contribute to the
neurodegenerative changes that occur in progressive MS. Until now, there are no therapies that specically target
innate immune cells in MS. As the role of innate immunity in MS becomes better dened, it may be possible to
better treat MS by targeting the innate immune system.[12]
Treatments are patient-specific and depend on the symptoms that present with the disorder, as well as the
progression of the condition.
Prognosis
Prognosis depends on the condition itself. Some conditions such as multiple sclerosis depend on the subtype of the
disease and various attributes of the patient such as age, sex, initial symptoms and the degree of disability the patient
experiences.[13] Life expectancy in Multiple sclerosis patients is 5 to 10 years lower than unaffected people.[14] MS
is an inflammatory demyelinating disease of the central nervous system (CNS) that develops in genetically
susceptible individuals after exposure to unknown environmental trigger(s).The bases for MS are unknown but are
strongly suspected to involve immune reactions against autoantigens, particularly myelin proteins. The most
accepted hypothesis is that dialogue between T-cell receptors and myelin antigens leads to an immune attack on the
myelin-oligodendrocyte complex. These interactions between active T cells and myelin antigens provoke a massive
destructive inflammatory response and promotes continuing proliferation of T and B cells and macrophage
activation, which sustains secretion of inflammatory mediators.[15] Other conditions such as Central pontine
myelinolysis have about a third of patients recover and the other two thirds experience varying degrees of disability.[]
There are cases, such as Transverse myelitis where the patient can begin recovery as early as 2 to 12 weeks after the
onset of the condition.
Epidemiology
Incidence of demyelinating diseases vary from disorder to disorder. Some conditions, such as Tabes dorsalis appear
predominantly in males and begins in mid-life. Optic neuritis on the other hand, occurs preferentially in females
typically between the ages of 30 and 35.[16] Other conditions such as multiple sclerosis vary in prevalence depending
on the country and population.[17] This condition can appear in children as well as adults.[18]
Types
Demyelinating diseases of the central nervous system include:
Multiple sclerosis (together with the similar diseases called idiopathic inflammatory demyelinating diseases)
Vitamin B12 deficiency
Central pontine myelinolysis
Tabes dorsalis
Transverse myelitis
Devic's disease
Progressive multifocal leukoencephalopathy
Optic neuritis
Leukodystrophies
Demyelinating diseases of the peripheral nervous system include:
54
Guillain-Barr syndrome and its chronic counterpart, chronic inflammatory demyelinating polyneuropathy
Anti-MAG peripheral neuropathy
Charcot-Marie-Tooth Disease
Copper deficiency
Progressive inflammatory neuropathy
Research
Research is being conducted in a variety of very specific areas. The focus of this research is aimed at gaining more
insight into how demyelinating disorders affect the central nervous system and peripheral nervous system,[][][19][][20]
how they develop and how these disorders are affected by various external inputs[][21][][22][23] . Much of the research
is targeted towards learning about the mechanisms by which these disorders function in an attempt to develop
therapies and treatments for individuals affected by these conditions.
Insights
Currently it is believed that N-cadherin plays a role in the myelination process. Experimentation has shown that
N-cadherin plays an important role in producing a remyelination-facilitating environment.[] It has been shown in
animal models that there is a direct correlation between the amount of myelin debris present and the degree of
Inflammation observed.[]
Effects of environmental inputs

Experimentation has shown that manipulating the levels of Thyroid hormone can be considered as a strategy to
promote remyelination and prevent irreversible damage in Multiple sclerosis patients.[] N-cadherin agonists have
been identified and observed to stimulate Neurite growth and cell migration, key aspects of promoting axon growth
and remyelination after injury or disease.[] It has been shown that intranasal administration of aTf (apotransferrin)
can protect myelin and induce remyelination.[]
Much of the research referenced in this section has been conducted in 2012 and represents very new information
about demyelinating diseases and potential therapies for them.
In Other Animals
Demyelinating diseases/disorders have been found worldwide in various animals. Some of these animals include
mice, pigs, cattle, hamsters, rats, sheep, Siamese kittens, and a number of dog breeds (including Chow Chow,
Springer Spaniel, Dalmatian, Samoyed, Golden Retriever, Lurcher, Bernese Mountain Dog, Vizsla, Weimaraner,
Australian Silky Terrier, and mixed breeds).[24][25]
References
[1] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ G35
[2] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ G37
[3] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ G61. 0
[4] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=340
[5] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=341
[6] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=357. 0
[7] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D003711
[11] "Symptoms of Demyelinating Disorders - Right Diagnosis." Right Diagnosis. Right Diagnosis, 01 Feb 2012. Web. 24 Sep 2012
55
56
Neurons
Axon
Axon
An axon (from Greek, axis) also known as a nerve fibre; is a long, slender projection of a nerve cell, or neuron, that
typically conducts electrical impulses away from the neuron's cell body. The function of the axon is to transmit
information to different neurons, muscles and glands. In certain sensory neurons (pseudounipolar neurons), such as
those for touch and warmth, the electrical impulse travels along an axon from the periphery to the cell body, and
from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction causes many
inherited and acquired neurological disorders which can affect both the peripheral and central neurons.
An axon is one of two types of protoplasmic protrusions that extrude from the cell body of a neuron, the other type
being dendrites. Axons are distinguished from dendrites by several features, including shape (dendrites often taper
while axons usually maintain a constant radius), length (dendrites are restricted to a small region around the cell
body while axons can be much longer), and function (dendrites usually receive signals while axons usually transmit
them). All of these rules have exceptions, however.
Some types of neurons have no axon and transmit signals from their dendrites. No neuron ever has more than one
axon; however in invertebrates such as insects or leeches the axon sometimes consists of several regions that
function more or less independently of each other.[1] Most axons branch, in some cases very profusely.
Axons make contact with other cellsusually other neurons but sometimes muscle or gland cellsat junctions
called synapses. At a synapse, the membrane of the axon closely adjoins the membrane of the target cell, and special
molecular structures serve to transmit electrical or electrochemical signals across the gap. Some synaptic junctions
appear partway along an axon as it extendsthese are called en passant ("in passing") synapses. Other synapses
appear as terminals at the ends of axonal branches. A single axon, with all its branches taken together, can innervate
multiple parts of the brain and generate thousands of synaptic terminals.
Axon
57
Anatomy
Axons are the primary transmission lines of the nervous system, and as bundles they form nerves. Some axons can
extend up to one meter or more while others extend as little as one millimeter. The longest axons in the human body
are those of the sciatic nerve, which run from the base of the spinal cord to the big toe of each foot. The diameter of
axons is also variable. Most individual axons are microscopic in diameter (typically about 1 micron across). The
largest mammalian axons can reach a diameter of up to 20 microns. The squid giant axon, which is specialized to
conduct signals very rapidly, is close to 1 millimetre in diameter, the size of a small pencil lead. Axonal arborization
(the branching structure at the end of a nerve fiber) also differs from one nerve fiber to the next. Axons in the central
nervous system typically show complex trees with many branch points. In comparison, the cerebellar granule cell
axon is characterized by a single T-shaped branch node from which two parallel fibers extend. Elaborate arborization
allows for the simultaneous transmission of messages to a large number of target neurons within a single region of
the brain.
There are two types of axons occurring in the peripheral system and the central nervous system: unmyelinated and
myelinated axons.[2] Myelin is a layer of a fatty insulating substance, which is formed by two types of glial cells:
Schwann cells ensheathing peripheral neurons and oligodendrocytes insulating those of the central nervous system.
Along myelinated nerve fibers, gaps in the myelin sheath known as nodes of Ranvier occur at evenly spaced
intervals. The myelination enables an especially rapid mode of electrical impulse propagation called saltatory
conduction. Demyelination of axons causes the multitude of neurological symptoms found in the disease Multiple
sclerosis.
If the brain of a vertebrate is extracted and sliced into thin sections,
some parts of each section appear dark and other parts lighter in color.
The dark parts are known as grey matter and the lighter parts as white
matter. White matter gets its light color from the myelin sheaths of
axons: the white matter parts of the brain are characterized by a high
density of myelinated axons passing through them, and a low density
of cell bodies of neurons. The cerebral cortex has a thick layer of grey
matter on the surface and a large volume of white matter underneath:
what this means is that most of the surface is filled with neuron cell
bodies, whereas much of the area underneath is filled with myelinated
axons that connect these neurons to each other.[citation needed]
A dissected human brain, showing grey matter

and white matter
Initial segment
The axon initial segment the thick, unmyelinated part of an axon that connects directly to the cell body
consists of a specialised complex of proteins. It is approximately 25m in length and functions as the site of action
potential initiation.[3] The density of voltage-gated sodium channels is much higher in the initial segment than in the
remainder of the axon or in the adjacent cell body, excepting the axon hillock.[4] The voltage-gated ion channels are
known to be found within certain areas of the axonal membrane and initiate action potential, conduction, and
synaptic transmission.[2]
Nodes of Ranvier
Nodes of Ranvier (also known as myelin sheath gaps) are short unmyelinated segments of a myelinated axon, which
are found periodically interspersed between segments of the myelin sheath. Therefore, at the point of the node of
Ranvier, the axon is reduced in diameter.[5] These nodes are areas where action potentials can be generated. In
saltatory conduction, electrical currents produced at each node of Ranvier are conducted with little attenuation to the
next node in line, where they remain strong enough to generate another action potential. Thus in a myelinated axon,
action potentials effectively "jump" from node to node, bypassing the myelinated stretches in between, resulting in a
Axon
58
propagation speed much faster than even the fastest unmyelinated axon can sustain.
Action potentials
Structure of a typical chemical synapse
Most axons carry signals in the form of action potentials, which are discrete electrochemical impulses that travel
rapidly along an axon, starting at the cell body and terminating at points where the axon makes synaptic contact with
target cells. The defining characteristic of an action potentials is that it is "all-or-nothing" every action potential
that an axon generates has essentially the same size and shape. This all-or-nothing characteristic allows action
potentials to be transmitted from one end of a long axon to the other without any reduction in size. There are,
however, some types of neurons with short axons that carry graded electrochemical signals, of variable amplitude.
When an action potential reaches a presynaptic terminal, it activates the synaptic transmission process. The first step
is rapid opening of calcium ion channels in the membrane of the axon, allowing calcium ions to flow inward across
the membrane. The resulting increase in intracellular calcium concentration causes vesicles (tiny containers enclosed
by a lipid membrane) filled with a neurotransmitter chemical to fuse with the axon's membrane and empty their
contents into the extracellular space. The neurotransmitter is released from the presynaptic nerve through exocytosis.
The neurotransmitter chemical then diffuses across to receptors located on the membrane of the target cell. The
neurotransmitter binds to these receptors and activates them. Depending on the type of receptors that are activated,
the effect on the target cell can be to excite the target cell, inhibit it, or alter its metabolism in some way. This entire
sequence of events often takes place in less than a thousandth of a second. Afterward, inside the presynaptic
terminal, a new set of vesicles are moved into position next to the membrane, ready to be released when the next
action potential arrives. The action potential is the final electrical step in the integration of synaptic messages at the
scale of the neuron.[2]
Axon
59
Growth and development

Growing axons move through their environment via the growth cone, which is at
the tip of the axon. The growth cone has a broad sheet like extension called
lamellipodia which contain protrusions called filopodia. The filopodia are the
mechanism by which the entire process adheres to surfaces and explores the
surrounding environment. Actin plays a major role in the mobility of this system.
Environments with high levels of cell adhesion molecules or CAM's create an ideal
environment for axonal growth. This seems to provide a "sticky" surface for axons
to grow along. Examples of CAM's specific to neural systems include N-CAM,
neuroglial CAM or NgCAM, TAG-1, and MAG all of which are part of the
immunoglobulin superfamily. Another set of molecules called extracellular matrix
adhesion molecules also provide a sticky substrate for axons to grow along.
Examples of these molecules include laminin, fibronectin, tenascin, and perlecan.
Some of these are surface bound to cells and thus act as short range attractants or
repellents. Others are difusible ligands and thus can have long range effects.
Axon of 9 day old mouse with

growth cone visible
Cells called guidepost cells assist in the guidance of neuronal axon growth. These cells are typically other,
sometimes immature, neurons.
It has also been discovered through research that if the axons of a neuron were damaged, as long as the soma (the
cell body of a neuron) is not damaged, the axons would regenerate and remake the synaptic connections with
neurons with the help of guidepost cells. This is also referred to as neuroregeneration.[6]
Nogo-A is a type of neurite growth inhibitory component that is present in the central nervous system myelin
membranes (found in an axon). It has a crucial role in restricting axonal regeneration in adult mammalian central
nervous system. In recent studies, if Nogo- A is blocked and neutralized, it is possible to induce long-distance axonal
regeneration which leads to enhancement of functional recovery in rats and mouse spinal cord. This has yet to be
done on humans.[7] A recent study has also found that macrophages activated through a specific inflammatory
pathway activated by the Dectin-1 receptor are capable of promoting axon recovery, also however causing
neurotoxicity in the neuron.[8]
History
Some of the first intracellular recordings in a nervous system were made in the late 1930s by K. Cole and H. Curtis.
German anatomist Otto Friedrich Karl Deiters is generally credited with the discovery of the axon by distinguishing
it from the dendrites.[2] Swiss Rdolf Albert von Klliker and German Robert Remak were the first to identify and
characterize the axon initial segment. Alan Hodgkin and Andrew Huxley also employed the squid giant axon (1939)
and by 1952 they had obtained a full quantitative description of the ionic basis of the action potential, leading the
formulation of the Hodgkin-Huxley Model. Hodgkin and Huxley were awarded jointly the Nobel Prize for this work
in 1963. The formulas detailing axonal conductance were extended to vertebrates in the Frankenhaeuser-Huxley
equations. Louis-Antoine Ranvier was the first to describe the gaps or nodes found on axons and for this contribution
these axonal features are now commonly referred to as the Nodes of Ranvier. Santiago Ramn y Cajal, a Spanish
anatomist, proposed that axons were the output components of neurons, describing their functionality.[2] Erlanger
and Gasser earlier developed the classification system for peripheral[9] nerve fibers, based on axonal conduction
velocity, myelination, fiber size etc. Even recently our understanding of the biochemical basis for action potential
propagation has advanced, and now includes many details about individual ion channels.
Axon
60
Injury
In order of degree of severity, injury to a nerve can be described as neuropraxia, axonotmesis, or neurotmesis.
Concussion is considered a mild form of diffuse axonal injury.[10] The dysfunction of axons in the nervous system is
one of the major causes of many inherited neurological disorders that affect both peripheral and central neurons.[11]
Classification
The axons that make up nerves in the human peripheral nervous system can be classified based on their physical
features and signal conduction properties.
Motor
Lower motor neurons have two kind of fibers:
Motor fiber types

Type Erlanger-Gasser Diameter Myelin Conduction velocity Associated muscle fibers
Classification
13-20 m Yes
80120m/s
Extrafusal muscle fibers
5-8 m
[12][13]
424m/s
Intrafusal muscle fibers
Yes
Sensory
Different sensory receptors are innervated by different types of nerve fibers. Proprioceptors are innervated by type
Ia, Ib and II sensory fibers, mechanoreceptors by type II and III sensory fibers and nociceptors and thermoreceptors
by type III and IV sensory fibers.
Sensory fiber types

Type Erlanger-Gasser Diameter Myelin Conduction velocity
Classification
Associated sensory receptors
Ia
13-20 m
Yes
80120m/s
Primary receptors of muscle spindle
Ib
13-20 m
Yes
80120m/s
Golgi tendon organ
II
6-12 m
Yes
3375m/s
Secondary receptors of muscle spindle

All cutaneous mechanoreceptors
III
1-5 m
Thin
330m/s
Free nerve endings of touch and

pressure
Nociceptors of neospinothalamic tract
Cold thermoreceptors
IV
0.2-1.5 m No
0.5-2.0m/s
Nociceptors of paleospinothalamic tract

Warmth receptors
Axon
61
Autonomic
The autonomic nervous system has two kinds of peripheral fibers:
Fiber types
Type
Erlanger-Gasser Diameter Myelin[14] Conduction velocity

Classification
preganglionic fibers B
1-5 m
Yes
postganglionic fibers C
0.2-1.5 m No
315m/s
0.5-2.0m/s
References
[1] Yau, K.-W. (1976) Receptive fields, geometry and conduction block of sensory neurons in the CNS of the leech. J. Physiol. (Lond)
263:513-538.
[2] Retrieved 20 November 2011.
[7] Current Opinion in Neurobiology (February 2004), 14 (1), pg. 118-124
[8] Gensel et al. "Macrophages promote axon regeneration with concurrent neurotoxicity" (http:/ / www. ncbi. nlm. nih. gov/ pmc/ articles/
PMC2693768/ ) The Journal of Neuroscience.
[9] Sansom B, "Reflex Isolation" http:/ / www. sansomnia. com
[10] eMedicine - Traumatic Brain Injury: Definition, Epidemiology, Pathophysiology : Article by Segun T Dawodu, MD, FAAPMR, FAANEM,
CIME, DipMI(RCSed) (http:/ / www. emedicine. com/ pmr/ topic212. htm)
[11] Debanne, D., Campanac, E., Bialowas, A., Carlier, E., & Alcaraz, G. (2009). Axon physiology. Physiological Reviews, 91(2), 555-602. doi:
10.1152/physrev.00048.2009
[12] Andrew BL, Part NJ (1972) Properties of fast and slow motor units in hind limb and tail muscles of the rat. Q J Exp Physiol Cogn Med Sci
57:213-225.
[14] pp.187-9 ISBN 0-19-858527-6
External links
Histology at OU 3_09 (http://w3.ouhsc.edu/histology/Glass slides/3_09.jpg) - "Slide 3 Spinal cord"
- Bialowas, Andrzej, Carlier, Edmond, Campanac, Emilie, Debanne, Dominique, Alcaraz. Axon Physiology,
GislePHYSIOLOGICAL REVIEWS, V. 91 (2), 04/2011, p.555-602. (http://physrev.physiology.org.
myaccess.library.utoronto.ca/content/91/2/555)
Neuron
62
Neuron
Neuron: nerve cell
Drawing by Santiago Ramn y Cajal of neurons in the pigeon cerebellum. (A) Denotes Purkinje cells, an example of a multipolar neuron. (B)
Denotes granule cells, which are also multipolar.
NeuroLex ID
sao1417703748
[1]
A neuron (/njrn/ NYEWR-on or /nrn/ NEWR-on; also known as a neurone or nerve cell) is an
electrically excitable cell that processes and transmits information through electrical and chemical signals. A
chemical signal occurs via a synapse, a specialized connection with other cells. Neurons connect to each other to
form neural networks. Neurons are the core components of the nervous system, which includes the brain, spinal cord,
and peripheral ganglia. A number of specialized types of neurons exist: sensory neurons respond to touch, sound,
light and numerous other stimuli affecting cells of the sensory organs that then send signals to the spinal cord and
brain. Motor neurons receive signals from the brain and spinal cord, cause muscle contractions, and affect glands.
Interneurons connect neurons to other neurons within the same region of the brain or spinal cord.
A typical neuron possesses a cell body (often called the soma), dendrites, and an axon. Dendrites are thin structures
that arise from the cell body, often extending for hundreds of micrometres and branching multiple times, giving rise
to a complex "dendritic tree". An axon is a special cellular extension that arises from the cell body at a site called the
axon hillock and travels for a distance, as far as 1 meter in humans or even more in other species. The cell body of a
neuron frequently gives rise to multiple dendrites, but never to more than one axon, although the axon may branch
hundreds of times before it terminates. At the majority of synapses, signals are sent from the axon of one neuron to a
dendrite of another. There are, however, many exceptions to these rules: neurons that lack dendrites, neurons that
have no axon, synapses that connect an axon to another axon or a dendrite to another dendrite, etc.
All neurons are electrically excitable, maintaining voltage gradients across their membranes by means of
metabolically driven ion pumps, which combine with ion channels embedded in the membrane to generate
intracellular-versus-extracellular concentration differences of ions such as sodium, potassium, chloride, and calcium.
Changes in the cross-membrane voltage can alter the function of voltage-dependent ion channels. If the voltage
changes by a large enough amount, an all-or-none electrochemical pulse called an action potential is generated,
which travels rapidly along the cell's axon, and activates synaptic connections with other cells when it arrives.
Neurons do not undergo cell division. In most cases, neurons are generated by special types of stem cells.
Astrocytes, a type of glial cell, have also been observed to turn into neurons by virtue of the stem cell characteristic
pluripotency. In humans, neurogenesis largely ceases during adulthoodbut in two brain areas, the hippocampus
and olfactory bulb, there is strong evidence for generation of substantial numbers of new neurons.[2][]
Neuron
63
Overview
Neuron (peripheral nervous system)
A neuron is a specialized type of cell found in the bodies of most animals (all members of the group Eumetazoa).
Only sponges and a few other simpler animals have no neurons. The features that define a neuron are electrical
excitability and the presence of synapses, which are complex membrane junctions that transmit signals to other cells.
The body's neurons, plus the glial cells that give them structural and metabolic support, together constitute the
nervous system. In vertebrates, the majority of neurons belong to the central nervous system, but some reside in
peripheral ganglia, and many sensory neurons are situated in sensory organs such as the retina and cochlea.
Although neurons are very diverse and there are exceptions to nearly every rule, it is convenient to begin with a
schematic description of the structure and function of a "typical" neuron. A typical neuron is divided into three parts:
the soma or cell body, dendrites, and axon. The soma is usually compact; the axon and dendrites are filaments that
extrude from it. Dendrites typically branch profusely, getting thinner with each branching, and extending their
farthest branches a few hundred micrometres from the soma. The axon leaves the soma at a swelling called the axon
hillock, and can extend for great distances, giving rise to hundreds of branches. Unlike dendrites, an axon usually
maintains the same diameter as it extends. The soma may give rise to numerous dendrites, but never to more than
one axon. Synaptic signals from other neurons are received by the soma and dendrites; signals to other neurons are
transmitted by the axon. A typical synapse, then, is a contact between the axon of one neuron and a dendrite or soma
of another. Synaptic signals may be excitatory or inhibitory. If the net excitation received by a neuron over a short
period of time is large enough, the neuron generates a brief pulse called an action potential, which originates at the
soma and propagates rapidly along the axon, activating synapses onto other neurons as it goes.
Many neurons fit the foregoing schema in every respect, but there are also exceptions to most parts of it. There are
no neurons that lack a soma, but there are neurons that lack dendrites, and others that lack an axon. Furthermore, in
addition to the typical axodendritic and axosomatic synapses, there are axoaxonic (axon-to-axon) and
dendrodendritic (dendrite-to-dendrite) synapses.
The key to neural function is the synaptic signaling process, which is partly electrical and partly chemical. The
electrical aspect depends on properties of the neuron's membrane. Like all animal cells, every neuron is surrounded
by a plasma membrane, a bilayer of lipid molecules with many types of protein structures embedded in it. A lipid
bilayer is a powerful electrical insulator, but in neurons, many of the protein structures embedded in the membrane
are electrically active. These include ion channels that permit electrically charged ions to flow across the membrane,
and ion pumps that actively transport ions from one side of the membrane to the other. Most ion channels are
permeable only to specific types of ions. Some ion channels are voltage gated, meaning that they can be switched
Neuron
64
between open and closed states by altering the voltage difference across the membrane. Others are chemically gated,
meaning that they can be switched between open and closed states by interactions with chemicals that diffuse
through the extracellular fluid. The interactions between ion channels and ion pumps produce a voltage difference
across the membrane, typically a bit less than 1/10 of a volt at baseline. This voltage has two functions: first, it
provides a power source for an assortment of voltage-dependent protein machinery that is embedded in the
membrane; second, it provides a basis for electrical signal transmission between different parts of the membrane.
Neurons communicate by chemical and electrical synapses in a process known as synaptic transmission. The
fundamental process that triggers synaptic transmission is the action potential, a propagating electrical signal that is
generated by exploiting the electrically excitable membrane of the neuron. This is also known as a wave of
depolarization.
Anatomy and histology

Neurons are highly specialized for the
processing and transmission of cellular
signals. Given the diversity of
functions performed by neurons in
different parts of the nervous system,
there is, as expected, a wide variety in
the shape, size, and electrochemical
properties of neurons. For instance, the
soma of a neuron can vary from 4 to
100 micrometers in diameter.[3]
The soma is the central part of the
neuron. It contains the nucleus of
the cell, and therefore is where most
protein synthesis occurs. The
nucleus ranges from 3 to 18
micrometers in diameter.[4]
Diagram of a typical myelinated vertebrate motoneuron
The dendrites of a neuron are cellular extensions with many branches, and metaphorically this overall shape and
structure is referred to as a dendritic tree. This is where the majority of input to the neuron occurs via the dendritic
spine.
The axon is a finer, cable-like projection that can extend tens, hundreds, or even tens of thousands of times the
diameter of the soma in length. The axon carries nerve signals away from the soma (and also carries some types
of information back to it). Many neurons have only one axon, but this axon mayand usually willundergo
extensive branching, enabling communication with many target cells. The part of the axon where it emerges from
the soma is called the axon hillock. Besides being an anatomical structure, the axon hillock is also the part of the
neuron that has the greatest density of voltage-dependent sodium channels. This makes it the most easily excited
part of the neuron and the spike initiation zone for the axon: in electrophysiological terms it has the most negative
action potential threshold. While the axon and axon hillock are generally involved in information outflow, this
region can also receive input from other neurons.
The axon terminal contains synapses, specialized structures where neurotransmitter chemicals are released to
communicate with target neurons.
Although the canonical view of the neuron attributes dedicated functions to its various anatomical components,
dendrites and axons often act in ways contrary to their so-called main function.
Neuron
Axons and dendrites in the central nervous system are typically only about one micrometer thick, while some in the
peripheral nervous system are much thicker. The soma is usually about 1025 micrometers in diameter and often is
not much larger than the cell nucleus it contains. The longest axon of a human motoneuron can be over a meter long,
reaching from the base of the spine to the toes. Sensory neurons have axons that run from the toes to the dorsal
columns, over 1.5 meters in adults. Giraffes have single axons several meters in length running along the entire
length of their necks. Much of what is known about axonal function comes from studying the squid giant axon, an
ideal experimental preparation because of its relatively immense size (0.51 millimeters thick, several centimeters
long).
Fully differentiated neurons are permanently postmitotic;[5] however, recent research shows that additional neurons
throughout the brain can originate from neural stem cells found throughout the brain but in particularly high
concentrations in the subventricular zone and subgranular zone through the process of neurogenesis.[6]
Histology and internal structure

Nerve cell bodies stained with basophilic dyes show
numerous microscopic clumps of Nissl substance
(named after German psychiatrist and neuropathologist
Franz Nissl, 18601919), which consists of rough
endoplasmic reticulum and associated ribosomal RNA.
The prominence of the Nissl substance can be
explained by the fact that nerve cells are metabolically
very active, and hence are involved in large amounts of
protein synthesis.
The cell body of a neuron is supported by a complex
meshwork of structural proteins called neurofilaments,
which are assembled into larger neurofibrils. Some
Golgi-stained neurons in human hippocampal tissue
neurons also contain pigment granules, such as
neuromelanin (a brownish-black pigment, byproduct of
synthesis of catecholamines) and lipofuscin (yellowish-brown pigment that accumulates with age).
There are different internal structural characteristics between axons and dendrites. Typical axons almost never
contain ribosomes, except some in the initial segment. Dendrites contain granular endoplasmic reticulum or
ribosomes, with diminishing amounts with distance from the cell body.
65
Neuron
66
Classes
Neurons exist in a number of different shapes and sizes
and can be classified by their morphology and function.
The anatomist Camillo Golgi grouped neurons into two
types; type I with long axons used to move signals over
long distances and type II with short axons, which can
often be confused with dendrites. Type I cells can be
further divided by where the cell body or soma is
located. The basic morphology of type I neurons,
represented by spinal motor neurons, consists of a cell
body called the soma and a long thin axon covered by
the myelin sheath. Around the cell body is a branching
dendritic tree that receives signals from other neurons.
The end of the axon has branching terminals (axon
terminal) that release neurotransmitters into a gap
called the synaptic cleft between the terminals and the
dendrites of the next neuron.
Image of pyramidal neurons in mouse cerebral cortex expressing

green fluorescent protein. The red staining indicates GABAergic
[7]
interneurons.
Structural classification
SMI32-stained pyramidal neurons in cerebral cortex
Neuron
67
Polarity
Most neurons can be anatomically characterized as:
Unipolar or pseudounipolar: dendrite and axon emerging from same
process.
Bipolar: axon and single dendrite on opposite ends of the soma.
Multipolar: more than two dendrites:
Golgi I: neurons with long-projecting axonal processes;
examples are pyramidal cells, Purkinje cells, and anterior horn
cells.
Golgi II: neurons whose axonal process projects locally; the best
example is the granule cell.
Other
Furthermore, some unique neuronal types can be identified according
to their location in the nervous system and distinct shape. Some
examples are:
Different kinds of neurons:

1 Unipolar neuron
2 Bipolar neuron
3 Multipolar neuron
4 Pseudounipolar neuron
Basket cells, interneurons that form a dense plexus of terminals

around the soma of target cells, found in the cortex and cerebellum.
Betz cells, large motor neurons.
Medium spiny neurons, most neurons in the corpus striatum.
Purkinje cells, huge neurons in the cerebellum, a type of Golgi I multipolar neuron.
Pyramidal cells, neurons with triangular soma, a type of Golgi I.
Renshaw cells, neurons with both ends linked to alpha motor neurons.
Granule cells, a type of Golgi II neuron.
Anterior horn cells, motoneurons located in the spinal cord.
Spindle cells, interneurons that connect widely separated areas of the brain
Functional classification
Direction
Afferent neurons convey information from tissues and organs into the central nervous system and are sometimes
also called sensory neurons.
Efferent neurons transmit signals from the central nervous system to the effector cells and are sometimes called
motor neurons.
Interneurons connect neurons within specific regions of the central nervous system.
Afferent and efferent also refer generally to neurons that, respectively, bring information to or send information from
the brain region.
Action on other neurons
A neuron affects other neurons by releasing a neurotransmitter that binds to chemical receptors. The effect upon the
postsynaptic neuron is determined not by the presynaptic neuron or by the neurotransmitter, but by the type of
receptor that is activated. A neurotransmitter can be thought of as a key, and a receptor as a lock: the same type of
key can here be used to open many different types of locks. Receptors can be classified broadly as excitatory
(causing an increase in firing rate), inhibitory (causing a decrease in firing rate), or modulatory (causing long-lasting
effects not directly related to firing rate).
Neuron
The two most common neurotransmitters in the brain, glutamate and GABA, have actions that are largely consistent.
Glutamate acts on several different types of receptors, and have effects that are excitatory at ionotropic receptors and
a modulatory effect at metabotropic receptors. Similarly GABA acts on several different types of receptors, but all of
them have effects (in adult animals, at least) that are inhibitory. Because of this consistency, it is common for
neuroscientists to simplify the terminology by referring to cells that release glutamate as "excitatory neurons," and
cells that release GABA as "inhibitory neurons." Since over 90% of the neurons in the brain release either glutamate
or GABA, these labels encompass the great majority of neurons. There are also other types of neurons that have
consistent effects on their targets, for example "excitatory" motor neurons in the spinal cord that release
acetylcholine, and "inhibitory" spinal neurons that release glycine.
The distinction between excitatory and inhibitory neurotransmitters is not absolute, however. Rather, it depends on
the class of chemical receptors present on the postsynaptic neuron. In principle, a single neuron, releasing a single
neurotransmitter, can have excitatory effects on some targets, inhibitory effects on others, and modulatory effects on
others still. For example, photoreceptor cells in the retina constantly release the neurotransmitter glutamate in the
absence of light. So-called OFF bipolar cells are, like most neurons, excited by the released glutamate. However,
neighboring target neurons called ON bipolar cells are instead inhibited by glutamate, because they lack the typical
ionotropic glutamate receptors and instead express a class of inhibitory metabotropic glutamate receptors.[8] When
light is present, the photoreceptors cease releasing glutamate, which relieves the ON bipolar cells from inhibition,
activating them; this simultaneously removes the excitation from the OFF bipolar cells, silencing them.
It is possible to identify the type of inhibitory effect a presynaptic neuron will have on a postsynaptic neuron, based
on the proteins the presynaptic neuron expresses. Parvalbumin-expressing neurons typically dampen the output
signal of the postsynaptic neuron in the visual cortex, whereas somatostatin-expressing neurons typically block
dendritic inputs to the postsynaptic neuron.[9]
Discharge patterns
Neurons can be classified according to their electrophysiological characteristics:
Tonic or regular spiking. Some neurons are typically constantly (or tonically) active. Example: interneurons in
neurostriatum.
Phasic or bursting. Neurons that fire in bursts are called phasic.
Fast spiking. Some neurons are notable for their high firing rates, for example some types of cortical inhibitory
interneurons, cells in globus pallidus, retinal ganglion cells.[10][11]
Classification by neurotransmitter production
Neurons differ in the type of neurotransmitter they manufacture. Some examples are:
Cholinergic neuronsacetylcholine. Acetylcholine is released from presynaptic neurons into the synaptic cleft. It
acts as a ligand for both ligand-gated ion channels and metabotropic (GPCRs) muscarinic receptors. Nicotinic
receptors, are pentameric ligand-gated ion channels composed of alpha and beta subunits that bind nicotine.
Ligand binding opens the channel causing influx of Na+ depolarization and increases the probability of
presynaptic neurotransmitter release.
GABAergic neuronsgamma aminobutyric acid. GABA is one of two neuroinhibitors in the CNS, the other
being Glycine. GABA has a homologous function to ACh, gating anion channels that allow Cl- ions to enter the
post synaptic neuron. Cl- causes hyperpolarization within the neuron, decreasing the probability of an action
potential firing as the voltage becomes more negative (recall that for an action potential to fire, a positive voltage
threshold must be reached).
Glutamatergic neuronsglutamate. Glutamate is one of two primary excitatory amino acids, the other being
Aspartate. Glutamate receptors are one of four categories, three of which are ligand-gated ion channels and one of
which is a G-protein coupled receptor (often referred to as GPCR).
68
Neuron
69
1. AMPA and Kainate receptors both function as cation channels permeable to Na+ cation channels mediating
fast excitatory synaptic transmission
2. NMDA receptors are another cation channel that is more permeable to Ca2+. The function of NMDA receptors
is dependant on Glycine receptor binding as a co-agonist within the channel pore. NMDA receptors do not
function without both ligands present.
3. Metabotropic receptors, GPCRs modulate synaptic transmission and postsynaptic excitability.
Glutamate can cause excitotoxicity when blood flow to the brain is interrupted, resulting in brain
damage. When blood flow is suppressed, glutamate is released from presynaptic neurons causing
NMDA and AMPA receptor activation moreso than would normally be the case outside of stress
conditions, leading to elevated Ca2+ and Na+ entering the post synaptic neuron and cell damage.
Dopaminergic neuronsdopamine. Dopamine is a neurotransmitter that acts on D1 type (D1 and D5) Gs coupled
receptors, which increase cAMP and PKA, and D2 type (D2, D3, and D4) receptors, which activate Gi-coupled
receptors that decrease cAMP and PKA. Dopamine is connected to mood and behavior, and modulates both pre
and post synaptic neurotransmission. Loss of dopamine neurons in the substantia nigra has been linked to
Parkinson's disease.
Serotonergic neuronsserotonin. Serotonin,(5-Hydroxytryptamine, 5-HT), can act as excitatory or inhibitory. Of
the four 5-HT receptor classes, 3 are GPCR and 1 is ligand gated cation channel. Serotonin is synthesized from
tryptophan by tryptophan hydroxylase, and then further by aromatic acid decarboxylase. A lack of 5-HT at
postsynaptic neurons has been linked to depression. Drugs that block the presynaptic serotonin transporter are
used for treatment, such as Prozac and Zoloft.
Connectivity
Neurons communicate with one another via synapses, where the axon terminal or en passant boutons (terminals
located along the length of the axon) of one cell impinges upon another neuron's dendrite, soma or, less commonly,
axon. Neurons such as Purkinje cells in the cerebellum can have over 1000 dendritic branches, making connections
with tens of thousands of other cells; other neurons, such as the magnocellular neurons of the supraoptic nucleus,
have only one or two dendrites, each of which receives thousands of synapses. Synapses can be excitatory or
inhibitory and either increase or decrease activity in the target neuron. Some neurons also communicate via electrical
synapses, which are direct, electrically conductive junctions between cells.
In a chemical synapse, the process of synaptic transmission is as follows: when an action potential reaches the axon
terminal, it opens voltage-gated calcium channels, allowing calcium ions to enter the terminal. Calcium causes
synaptic vesicles filled with neurotransmitter molecules to fuse with the membrane, releasing their contents into the
synaptic cleft. The neurotransmitters diffuse across the synaptic cleft and activate receptors on the postsynaptic
neuron.
The human brain has a huge number of synapses. Each of the 1011 (one hundred billion) neurons has on average
7,000 synaptic connections to other neurons. It has been estimated that the brain of a three-year-old child has about
1015 synapses (1 quadrillion). This number declines with age, stabilizing by adulthood. Estimates vary for an adult,
ranging from 1014 to 5 x 1014 synapses (100 to 500 trillion).[12]
Neuron
70
Mechanisms for propagating action potentials

In 1937, John Zachary Young suggested that
the squid giant axon could be used to study
neuronal electrical properties.[13] Being larger
than but similar in nature to human neurons,
squid cells were easier to study. By inserting
electrodes into the giant squid axons, accurate
measurements were made of the membrane
potential.
The cell membrane of the axon and soma
contain voltage-gated ion channels that allow
the neuron to generate and propagate an
electrical signal (an action potential). These
signals are generated and propagated by
charge-carrying ions including sodium (Na+),
potassium (K+), chloride (Cl-), and calcium
(Ca2+).
There are several stimuli that can activate a
neuron leading to electrical activity,
including
pressure,
stretch,
chemical
transmitters, and changes of the electric
potential across the cell membrane.[14]
Stimuli cause specific ion-channels within the
cell membrane to open, leading to a flow of
ions through the cell membrane, changing the
membrane potential.
A signal propagating down an axon to the cell body and dendrites of the next cell
Thin neurons and axons require less metabolic expense to produce and carry action potentials, but thicker axons
convey impulses more rapidly. To minimize metabolic expense while maintaining rapid conduction, many neurons
have insulating sheaths of myelin around their axons. The sheaths are formed by glial cells: oligodendrocytes in the
central nervous system and Schwann cells in the peripheral nervous system. The sheath enables action potentials to
travel faster than in unmyelinated axons of the same diameter, whilst using less energy. The myelin sheath in
peripheral nerves normally runs along the axon in sections about 1mm long, punctuated by unsheathed nodes of
Ranvier, which contain a high density of voltage-gated ion channels. Multiple sclerosis is a neurological disorder
that results from demyelination of axons in the central nervous system.
Some neurons do not generate action potentials, but instead generate a graded electrical signal, which in turn causes
graded neurotransmitter release. Such nonspiking neurons tend to be sensory neurons or interneurons, because they
cannot carry signals long distances.
Neuron
Neural coding
Neural coding is concerned with how sensory and other information is represented in the brain by neurons. The main
goal of studying neural coding is to characterize the relationship between the stimulus and the individual or ensemble
neuronal responses, and the relationships amongst the electrical activities of the neurons within the ensemble.[] It is
thought that neurons can encode both digital and analog information.[15]
All-or-none principle
The conduction of nerve impulses is an example of an all-or-none response. In other words, if a neuron responds at
all, then it must respond completely. Greater intensity of stimulation does not produce a stronger signal but can
produce a higher frequency of firing. There are different types of receptor response to stimulus, slowly adapting or
tonic receptors respond to steady stimulus and produce a steady rate of firing. These tonic receptors most often
respond to increased intensity of stimulus by increasing their firing frequency, usually as a power function of
stimulus plotted against impulses per second. This can be likened to an intrinsic property of light where to get greater
intensity of a specific frequency (color) there have to be more photons, as the photons can't become "stronger" for a
specific frequency.
There are a number of other receptor types that are called quickly adapting or phasic receptors, where firing
decreases or stops with steady stimulus; examples include: skin when touched by an object causes the neurons to
fire, but if the object maintains even pressure against the skin, the neurons stop firing. The neurons of the skin and
muscles that are responsive to pressure and vibration have filtering accessory structures that aid their function.
The pacinian corpuscle is one such structure. It has concentric layers like an onion, which form around the axon
terminal. When pressure is applied and the corpuscle is deformed, mechanical stimulus is transferred to the axon,
which fires. If the pressure is steady, there is no more stimulus; thus, typically these neurons respond with a transient
depolarization during the initial deformation and again when the pressure is removed, which causes the corpuscle to
change shape again. Other types of adaptation are important in extending the function of a number of other
neurons.[16]
History
The term neuron was coined by the German anatomist Heinrich
Wilhelm Waldeyer. The neuron's place as the primary functional unit
of the nervous system was first recognized in the early 20th century
through the work of the Spanish anatomist Santiago Ramn y Cajal.[]
Ramn y Cajal proposed that neurons were discrete cells that
communicated with each other via specialized junctions, or spaces,
between cells.[] This became known as the neuron doctrine, one of the
central tenets of modern neuroscience.[] To observe the structure of
individual neurons, Ramn y Cajal improved a silver staining process
Drawing by Camillo Golgi of a hippocampus
stained with the silver nitrate method
known as Golgi's method, which had been developed by his rival,
Camillo Golgi.[] Cajal's improvement, which involved a technique he
called "double impregnation", is still in use. The silver impregnation stains are an extremely useful method for
neuroanatomical investigations because, for reasons unknown, it stains a very small percentage of cells in a tissue, so
one is able to see the complete micro structure of individual neurons without much overlap from other cells in the
densely packed brain.[]
71
Neuron
72
The neuron doctrine

The neuron doctrine is the now fundamental idea that neurons are the
basic structural and functional units of the nervous system. The theory
was put forward by Santiago Ramn y Cajal in the late 19th century. It
held that neurons are discrete cells (not connected in a meshwork),
acting as metabolically distinct units.
Later discoveries yielded a few refinements to the simplest form of the
doctrine. For example, glial cells, which are not considered neurons,
play an essential role in information processing.[17] Also, electrical
synapses are more common than previously thought,[18] meaning that
there are direct, cytoplasmic connections between neurons. In fact,
there are examples of neurons forming even tighter coupling: the squid
giant axon arises from the fusion of multiple axons.[19]
Ramn y Cajal also postulated the Law of Dynamic Polarization,
which states that a neuron receives signals at its dendrites and cell
body and transmits them, as action potentials, along the axon in one
direction: away from the cell body.[20] The Law of Dynamic
Polarization has important exceptions; dendrites can serve as synaptic
output sites of neurons[21] and axons can receive synaptic inputs.[22]
Drawing of a Purkinje cell in the cerebellar cortex

done by Santiago Ramn y Cajal, demonstrating
the ability of Golgi's staining method to reveal
fine detail
Neurons in the brain

The number of neurons in the brain varies dramatically from species to species.[] One estimate puts the human brain
at about 100 billion (1011) neurons and 100 trillion (1014) synapses.[] A lower 2012 estimate is 86 billion neurons, of
which 16.3 billion are in the cerebral cortex, and 69 billion in the cerebellum.[] By contrast, the nematode worm
Caenorhabditis elegans has just 302 neurons, making it an ideal experimental subject as scientists have been able to
map all of the organism's neurons. The fruit fly Drosophila melanogaster, a common subject in biological
experiments, has around 100,000 neurons and exhibits many complex behaviors. Many properties of neurons, from
the type of neurotransmitters used to ion channel composition, are maintained across species, allowing scientists to
study processes occurring in more complex organisms in much simpler experimental systems.
Neurological disorders
CharcotMarieTooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN),
hereditary sensorimotor neuropathy and peroneal muscular atrophy, is a heterogeneous inherited disorder of nerves
(neuropathy) that is characterized by loss of muscle tissue and touch sensation, predominantly in the feet and legs but
also in the hands and arms in the advanced stages of disease. Presently incurable, this disease is one of the most
common inherited neurological disorders, with 37 in 100,000 affected.
Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease characterized by
progressive cognitive deterioration together with declining activities of daily living and neuropsychiatric symptoms
or behavioral changes. The most striking early symptom is loss of short-term memory (amnesia), which usually
manifests as minor forgetfulness that becomes steadily more pronounced with illness progression, with relative
preservation of older memories. As the disorder progresses, cognitive (intellectual) impairment extends to the
domains of language (aphasia), skilled movements (apraxia), and recognition (agnosia), and functions such as
decision-making and planning become impaired.
Neuron
Parkinson's disease (PD), also known as Parkinson disease, is a degenerative disorder of the central nervous system
that often impairs the sufferer's motor skills and speech. Parkinson's disease belongs to a group of conditions called
movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia),
and in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased
stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of
dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level
cognitive dysfunction and subtle language problems. PD is both chronic and progressive.
Myasthenia gravis is a neuromuscular disease leading to fluctuating muscle weakness and fatigability during simple
activities. Weakness is typically caused by circulating antibodies that block acetylcholine receptors at the
post-synaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine.
Myasthenia is treated with immunosuppressants, cholinesterase inhibitors and, in selected cases, thymectomy.
Demyelination
Demyelination is the act of demyelinating, or the loss of the myelin sheath insulating the nerves. When myelin
degrades, conduction of signals along the nerve can be impaired or lost, and the nerve eventually withers. This leads
to certain neurodegenerative disorders like multiple sclerosis and chronic inflammatory demyelinating
polyneuropathy.
Axonal degeneration
Although most injury responses include a calcium influx signaling to promote resealing of severed parts, axonal
injuries initially lead to acute axonal degeneration (AAD), which is rapid separation of the proximal and distal ends
within 30 minutes of injury. Degeneration follows with swelling of the axolemma, and eventually leads to bead like
formation. Granular disintegration of the axonal cytoskeleton and inner organelles occurs after axolemma
degradation. Early changes include accumulation of mitochondria in the paranodal regions at the site of injury.
Endoplasmic reticulum degrades and mitochondria swell up and eventually disintegrate. The disintegration is
dependent on Ubiquitin and Calpain proteases (caused by influx of calcium ion), suggesting that axonal degeneration
is an active process. Thus the axon undergoes complete fragmentation. The process takes about roughly 24 hrs in the
PNS, and longer in the CNS. The signaling pathways leading to axolemma degeneration are currently unknown.
Nerve regeneration
It has been demonstrated that neurogenesis can sometimes occur in the adult vertebrate brain, a finding that led to
controversy in 1999.[23] However, more recent studies of the age of human neurons suggest that this process occurs
only for a minority of cells, and the overwhelming majority of neurons comprising the neocortex were formed before
birth and persist without replacement.[]
It is often possible for peripheral axons to regrow if they are severed. A report in Nature suggested that researchers
had found a way to transform human skin cells into working nerve cells using a process called transdifferentiation in
which "cells are forced to adopt new identities."[]
73
Neuron
References
[1] http:/ / www. neurolex. org/ wiki/ sao1417703748
[15] Thorpe, SJ (1990) Spike arrival times: A highly efficient coding scheme for neural networks (http:/ / web. archive. org/ web/
20120215151304/ http:/ / pop. cerco. ups-tlse. fr/ fr_vers/ documents/ thorpe_sj_90_91. pdf). In R. Eckmiller, G. Hartmann, & G. Hauske
(Eds.) Parallel processing in neural systems, Elsevier, pp. 9194 ISBN 0444883908
[20] Sabbatini R.M.E. AprilJuly 2003. Neurons and Synapses: The History of Its Discovery (http:/ / www. cerebromente. org. br/ n17/ history/
neurons3_i. htm). Brain & Mind Magazine, 17. Retrieved on March 19, 2007.
Further reading
Kandel E.R., Schwartz, J.H., Jessell, T.M. 2000. Principles of Neural Science, 4th ed., McGraw-Hill, New York.
Bullock, T.H., Bennett, M.V.L., Johnston, D., Josephson, R., Marder, E., Fields R.D. 2005. The Neuron Doctrine,
Redux, Science, V.310, p.791793.
Ramn y Cajal, S. 1933 Histology, 10th ed., Wood, Baltimore.
Richard S. Snell: Clinical neuroanatomy (Lippincott Williams & Wilkins, Ed.6th 2006) Philadelphia, Baltimore,
New York, London. ISBN 978-963-226-293-2
Roberts A., Bush B.M.H. 1981. Neurones Without Impulses. Cambridge University Press, Cambridge.
Peters, A., Palay, S.L., Webster, H, D., 1991 The Fine Structure of the Nervous System, 3rd ed., Oxford, New
York
External links
IBRO (International Brain Research Organization) (http://www.ibro.info). Fostering neuroscience research
especially in less well-funded countries.
NeuronBank (http://NeuronBank.org) an online neuromics tool for cataloging neuronal types and synaptic
connectivity.
High Resolution Neuroanatomical Images of Primate and Non-Primate Brains (http://brainmaps.org).
The Department of Neuroscience at Wikiversity, which presently offers two courses: Fundamentals of
Neuroscience and Comparative Neuroscience.
NIF Search Neuron (https://www.neuinfo.org/mynif/search.php?q=Neuron&t=data&s=cover&b=0&
r=20) via the Neuroscience Information Framework
Cell Centered Database Neuron (http://ccdb.ucsd.edu/sand/main?event=showMPByType&typeid=0&
start=1&pl=y)
Complete list of neuron types (http://neurolex.org/wiki/Category:Neuron) according to the Petilla convention,
at NeuroLex.
NeuroMorpho.Org (http://NeuroMorpho.org) an online database of digital reconstructions of neuronal
morphology.
Immunohistochemistry Image Gallery: Neuron (http://www.immunoportal.com/modules.
php?name=gallery2&g2_view=keyalbum.KeywordAlbum&g2_keyword=Neuron)
74
Action potential
75
Action potential
In physiology, an action potential is a
short-lasting event in which the electrical
membrane potential of a cell rapidly rises
and falls, following a consistent trajectory.
Action potentials occur in several types of
animal cells, called excitable cells, which
include neurons, muscle cells, and endocrine
cells, as well as in some plant cells. In
neurons, they play a central role in
cell-to-cell communication. In other types of
cells, their main function is to activate
intracellular processes. In muscle cells, for
example, an action potential is the first step
in the chain of events leading to contraction.
In beta cells of the pancreas, they provoke
release of insulin.[] Action potentials in
neurons are also known as "nerve impulses"
or "spikes", and the temporal sequence of
action potentials generated by a neuron is
called its "spike train". A neuron that emits
an action potential is often said to "fire".
As an action potential travels down the axon, there is a change in polarity across
the membrane. The Na+ and K+ gated ion channels open and close as the membrane
reaches the threshold potential, in response to a signal from another neuron. At the
beginning of the action potential, the Na+ channels open and Na+ moves into the
axon, causing depolarization. Repolarization occurs when the K+ channels open
and K+ moves out of the axon. This creates a change in polarity between the
outside of the cell and the inside. The impulse travels down the axon in one
direction only, to the axon terminal where it signals other neurons.
Action potentials are generated by special types of voltage-gated ion channels embedded in a cell's plasma
membrane.[] These channels are shut when the membrane potential is near the resting potential of the cell, but they
rapidly begin to open if the membrane potential increases to a precisely defined threshold value. When the channels
open (by detecting the depolarization in transmembrane voltage[]), they allow an inward flow of sodium ions, which
changes the electrochemical gradient, which in turn produces a further rise in the membrane potential. This then
causes more channels to open, producing a greater electric current, and so on. The process proceeds explosively until
all of the available ion channels are open, resulting in a large upswing in the membrane potential. The rapid influx of
sodium ions causes the polarity of the plasma membrane to reverse, and the ion channels then rapidly inactivate. As
the sodium channels close, sodium ions can no longer enter the neuron, and they are actively transported out of the
plasma membrane. Potassium channels are then activated, and there is an outward current of potassium ions,
returning the electrochemical gradient to the resting state. After an action potential has occurred, there is a transient
negative shift, called the afterhyperpolarization or refractory period, due to additional potassium currents. This is the
mechanism that prevents an action potential from traveling back the way it just came.
In animal cells, there are two primary types of action potentials, one type generated by voltage-gated sodium
channels, the other by voltage-gated calcium channels. Sodium-based action potentials usually last for under one
millisecond, whereas calcium-based action potentials may last for 100 milliseconds or longer. In some types of
neurons, slow calcium spikes provide the driving force for a long burst of rapidly emitted sodium spikes. In cardiac
muscle cells, on the other hand, an initial fast sodium spike provides a "primer" to provoke the rapid onset of a
calcium spike, which then produces muscle contraction.
Action potential
Overview
Function
Nearly all cells from animals, plants and fungi function as batteries, in the sense that they maintain a voltage
difference between the interior and the exterior of the cell, with the interior being the negative pole of the battery.
The voltage of a cell is usually measured in millivolts (mV), or thousandths of a volt. A typical voltage for an animal
cell is 65 mVapproximately one-fifteenth of a volt. Because cells are so small, voltages of this magnitude give
rise to very strong electric forces within the cell membrane.
In the majority of cells, the voltage stays fairly constant over time. There are some types of cells, however, that are
electrically active in the sense that their voltages fluctuate. In some of these, the voltages sometimes show very rapid
up-and-down fluctuations that have a stereotyped form: these up-and-down cycles are known as action potentials.
The durations of action potentials vary across a wide range, and consequently they are analog signals. In brain cells
of animals, the entire up-and-down cycle may take place in less than a thousandth of a second. In other types of cells,
the cycle may last for several seconds.
The electrical properties of an animal cell are determined by the structure of the membrane that surrounds it. A cell
membrane consists of a layer of lipid molecules with larger protein molecules embedded in it. The lipid layer is
highly resistant to movement of electrically charged ions, so it functions mainly as an insulator. The large
membrane-embedded molecules, in contrast, provide channels through which ions can pass across the membrane,
and some of the large molecules are capable of actively moving specific types of ions from one side of the
membrane to the other.
76
Action potential
Process in a typical neuron

All cells in animal body tissues are electrically
polarized in other words, they maintain a voltage
difference across the cell's plasma membrane, known
as the membrane potential. This electrical
polarization results from a complex interplay between
protein structures embedded in the membrane called
ion pumps and ion channels. In neurons, the types of
ion channels in the membrane usually vary across
different parts of the cell, giving the dendrites, axon,
and cell body different electrical properties. As a
result, some parts of the membrane of a neuron may
be excitable (capable of generating action potentials),
whereas others are not. The most excitable part of a
neuron is usually the axon hillock (the point where
the axon leaves the cell body), but the axon and cell
body are also excitable in most cases.
Each excitable patch of membrane has two important
levels of membrane potential: the resting potential,
which is the value the membrane potential maintains
as long as nothing perturbs the cell, and a higher
value called the threshold potential. At the axon
hillock of a typical neuron, the resting potential is
Figure 1. A. view of an idealized action potential shows its various
around 70 millivolts (mV) and the threshold
phases as the action potential passes a point on a cell membrane. B.
potential is around 55 mV. Synaptic inputs to a
Recordings of action potentials are often distorted compared to the
neuron cause the membrane to depolarize or
schematic view because of variations in electrophysiological techniques
hyperpolarize; that is, they cause the membrane
used to make the recording.
potential to rise or fall. Action potentials are triggered
when enough depolarization accumulates to bring the membrane potential up to threshold. When an action potential
is triggered, the membrane potential abruptly shoots upward, often reaching as high as +100 mV, then equally
abruptly shoots back downward, often ending below the resting level, where it remains for some period of time. The
shape of the action potential is stereotyped; that is, the rise and fall usually have approximately the same amplitude
and time course for all action potentials in a given cell. (Exceptions are discussed later in the article.) In most
neurons, the entire process takes place in less than a thousandth of a second. Many types of neurons emit action
potentials constantly at rates of up to 10100 per second; some types, however, are much quieter, and may go for
minutes or longer without emitting any action potentials.
77
Action potential
Biophysical basis
Action potentials result from the presence in a cell's membrane of special types of voltage-gated ion channels. A
voltage-gated ion channel is a cluster of proteins embedded in the membrane that has three key properties:
1. It is capable of assuming more than one conformation.
2. At least one of the conformations creates a channel through the membrane that is permeable to specific types of
ions.
3. The transition between conformations is influenced by the membrane potential.
Thus, a voltage-gated ion channel tends to be open for some values of the membrane potential, and closed for others.
In most cases, however, the relationship between membrane potential and channel state is probabilistic and involves
a time delay. Ion channels switch between conformations at unpredictable times: The membrane potential determines
the rate of transitions and the probability per unit time of each type of transition.
Voltage-gated ion channels are capable of producing action potentials because they can give rise to positive feedback
loops: The membrane potential controls the state of the ion channels, but the state of the ion channels controls the
membrane potential. Thus, in some situations, a rise in the membrane potential can cause ion channels to open,
thereby causing a further rise in the membrane potential. An action potential occurs when this positive feedback
cycle proceeds explosively. The time and amplitude trajectory of the action potential are determined by the
biophysical properties of the voltage-gated ion channels that produce it. Several types of channels that are capable of
producing the positive feedback necessary to generate an action potential exist. Voltage-gated sodium channels are
responsible for the fast action potentials involved in nerve conduction. Slower action potentials in muscle cells and
some types of neurons are generated by voltage-gated calcium channels. Each of these types comes in multiple
variants, with different voltage sensitivity and different temporal dynamics.
The most intensively studied type of voltage-dependent ion channels comprises the sodium channels involved in fast
nerve conduction. These are sometimes known as Hodgkin-Huxley sodium channels because they were first
characterized by Alan Hodgkin and Andrew Huxley in their Nobel Prize-winning studies of the biophysics of the
action potential, but can more conveniently be referred to as NaV channels. (The "V" stands for "voltage".) An NaV
channel has three possible states, known as deactivated, activated, and inactivated. The channel is permeable only to
sodium ions when it is in the activated state. When the membrane potential is low, the channel spends most of its
time in the deactivated (closed) state. If the membrane potential is raised above a certain level, the channel shows
increased probability of transitioning to the activated (open) state. The higher the membrane potential the greater the
probability of activation. Once a channel has activated, it will eventually transition to the inactivated (closed) state. It
tends then to stay inactivated for some time, but, if the membrane potential becomes low again, the channel will
eventually transition back to the deactivated state. During an action potential, most channels of this type go through
a cycle deactivatedactivatedinactivateddeactivated. This is only the population average behavior, however
an individual channel can in principle make any transition at any time. However, the likelihood of a channel's
transitioning from the inactivated state directly to the activated state is very low: A channel in the inactivated state is
refractory until it has transitioned back to the deactivated state.
The outcome of all this is that the kinetics of the NaV channels are governed by a transition matrix whose rates are
voltage-dependent in a complicated way. Since these channels themselves play a major role in determining the
voltage, the global dynamics of the system can be quite difficult to work out. Hodgkin and Huxley approached the
problem by developing a set of differential equations for the parameters that govern the ion channel states, known as
the Hodgkin-Huxley equations. These equations have been extensively modified by later research, but form the
starting point for most theoretical studies of action potential biophysics.
As the membrane potential is increased, sodium ion channels open, allowing the entry of sodium ions into the cell.
This is followed by the opening of potassium ion channels that permit the exit of potassium ions from the cell. The
inward flow of sodium ions increases the concentration of positively charged cations in the cell and causes
depolarization, where the potential of the cell is higher than the cell's resting potential. The sodium channels close at
78
Action potential
the peak of the action potential, while potassium continues to leave the cell. The efflux of potassium ions decreases
the membrane potential or hyperpolarizes the cell. For small voltage increases from rest, the potassium current
exceeds the sodium current and the voltage returns to its normal resting value, typically 70mV.[1] However, if the
voltage increases past a critical threshold, typically 15mV higher than the resting value, the sodium current
dominates. This results in a runaway condition whereby the positive feedback from the sodium current activates even
more sodium channels. Thus, the cell "fires," producing an action potential.[2][3]
Currents produced by the opening of voltage-gated channels in the course of an action potential are typically
significantly larger than the initial stimulating current. Thus, the amplitude, duration, and shape of the action
potential are determined largely by the properties of the excitable membrane and not the amplitude or duration of the
stimulus. This all-or-nothing property of the action potential sets it apart from graded potentials such as receptor
potentials, electrotonic potentials, and synaptic potentials, which scale with the magnitude of the stimulus. A variety
of action potential types exist in many cell types and cell compartments as determined by the types of voltage-gated
channels, leak channels, channel distributions, ionic concentrations, membrane capacitance, temperature, and other
factors.
The principal ions involved in an action potential are sodium and potassium cations; sodium ions enter the cell, and
potassium ions leave, restoring equilibrium. Relatively few ions need to cross the membrane for the membrane
voltage to change drastically. The ions exchanged during an action potential, therefore, make a negligible change in
the interior and exterior ionic concentrations. The few ions that do cross are pumped out again by the continuous
action of the sodiumpotassium pump, which, with other ion transporters, maintains the normal ratio of ion
concentrations across the membrane. Calcium cations and chloride anions are involved in a few types of action
potentials, such as the cardiac action potential and the action potential in the single-cell alga Acetabularia,
respectively.
Although action potentials are generated locally on patches of excitable membrane, the resulting currents can trigger
action potentials on neighboring stretches of membrane, precipitating a domino-like propagation. In contrast to
passive spread of electric potentials (electrotonic potential), action potentials are generated anew along excitable
stretches of membrane and propagate without decay.[4] Myelinated sections of axons are not excitable and do not
produce action potentials and the signal is propagated passively as electrotonic potential. Regularly spaced
unmyelinated patches, called the nodes of Ranvier, generate action potentials to boost the signal. Known as saltatory
conduction, this type of signal propagation provides a favorable tradeoff of signal velocity and axon diameter.
Depolarization of axon terminals, in general, triggers the release of neurotransmitter into the synaptic cleft. In
addition, backpropagating action potentials have been recorded in the dendrites of pyramidal neurons, which are
ubiquitous in the neocortex.[] These are thought to have a role in spike-timing-dependent plasticity.
Neurotransmission
Anatomy of a neuron
79
Action potential
80

Neuron
Several types of cells support an action potential, such as plant cells, muscle cells, and the specialized cells of the
heart (in which occurs the cardiac action potential). However, the main excitable cell is the neuron, which also has
the simplest mechanism for the action potential.
Neurons are electrically excitable cells composed, in general, of one or more dendrites, a single soma, a single axon
and one or more axon terminals. The dendrite is one of the two types of synapses, the other being the axon terminal
boutons. Dendrites form protrusions in response to the axon terminal boutons. These protrusions, or spines, are
designed to capture the neurotransmitters released by the presynaptic neuron. They have a high concentration of
ligand activated channels. It is, therefore, here where synapses from two neurons communicate with one another.
These spines have a thin neck connecting a bulbous protrusion to the main dendrite. This ensures that changes
occurring inside the spine are less likely to affect the neighbouring spines. The dendritic spine can, therefore, with
rare exception (see LTP), act as an independent unit. The dendrites then connect onto the soma. The soma houses the
nucleus, which acts as the regulator for the neuron. Unlike the spines, the surface of the soma is populated by voltage
activated ion channels. These channels help transmit the signals generated by the dendrites. Emerging out from the
soma is the axon hillock. This region is characterized by having an incredibly high concentration of voltage-activated
sodium channels. In general, it is considered to be the spike initiation zone for action potentials.[5] Multiple signals
generated at the spines, and transmitted by the soma all converge here. Immediately after the axon hillock is the
axon. This is a thin tubular protrusion traveling away from the soma. The axon is insulated by a myelin sheath.
Myelin is composed of either Schwann cells (in the peripheral nervous system) or oligodendrocytes (in the central
nervous system), types of glial cells. Although glial cells are not involved with the transmission of electrical signals,
they communicate and provide important biochemical support to neurons.[6] To be specific, myelin wraps multiple
times around the axonal segment, forming a thick fatty layer that prevents ions from entering or escaping the axon.
This insulation prevents significant signal decay as well as ensuring faster signal speed. This insulation, however,
has the restriction that no channels can be present on the surface of the axon. There are, therefore, regularly spaced
patches of membrane, which have no insulation. These nodes of ranvier can be considered to be 'mini axon hillocks',
as their purpose is to boost the signal in order to prevent significant signal decay. At the furthest end, the axon loses
its insulation and begins to branch into several axon terminals. These axon terminals then end in the form the second
class of synapses, axon terminal buttons. These buttons have voltage-activated calcium channels, which come into
play when signaling other neurons.
Action potential
81
Initiation
Before considering the propagation of action potentials along axons and their termination at the synaptic knobs, it is
helpful to consider the methods by which action potentials can be initiated at the axon hillock. The basic requirement
is that the membrane voltage at the hillock be raised above the threshold for firing.[] There are several ways in which
this depolarization can occur.
Dynamics
Action potentials are most commonly
initiated
by
excitatory
postsynaptic
potentials from a presynaptic neuron.[7]
Typically, neurotransmitter molecules are
released by the presynaptic neuron. These
neurotransmitters then bind to receptors on
the postsynaptic cell. This binding opens
various types of ion channels. This opening
has the further effect of changing the local
permeability of the cell membrane and, thus,
the membrane potential. If the binding
When an action potential arrives at the end of the pre-synaptic axon (yellow), it
increases the voltage (depolarizes the
causes the release of neurotransmitter molecules that open ion channels in the
membrane), the synapse is excitatory. If,
post-synaptic neuron (green). The combined excitatory and inhibitory postsynaptic
potentials of such inputs can begin a new action potential in the post-synaptic
however, the binding decreases the voltage
neuron.
(hyperpolarizes the membrane), it is
inhibitory. Whether the voltage is increased
or decreased, the change propagates passively to nearby regions of the membrane (as described by the cable equation
and its refinements). Typically, the voltage stimulus decays exponentially with the distance from the synapse and
with time from the binding of the neurotransmitter. Some fraction of an excitatory voltage may reach the axon
hillock and may (in rare cases) depolarize the membrane enough to provoke a new action potential. More typically,
the excitatory potentials from several synapses must work together at nearly the same time to provoke a new action
potential. Their joint efforts can be thwarted, however, by the counteracting inhibitory postsynaptic potentials.
Neurotransmission can also occur through electrical synapses.[8] Due to the direct connection between excitable cells
in the form of gap junctions, an action potential can be transmitted directly from one cell to the next in either
direction. The free flow of ions between cells enables rapid non-chemical-mediated transmission. Rectifying
channels ensure that action potentials move only in one direction through an electrical synapse.[citation needed]
Electrical synapses are found in all nervous systems, including the human brain, although they are a distinct
minority.[]
Action potential
82
"All-or-none" principle
The amplitude of an action potential is independent of the amount of current that produced it. In other words, larger
currents do not create larger action potentials. Therefore, action potentials are said to be all-or-none signals, since
either they occur fully or they do not occur at all.[9][10][11] The frequency of action potentials is correlated with the
intensity of a stimulus. This is in contrast to receptor potentials, whose amplitudes are dependent on the intensity of a
stimulus.[]
Sensory neurons
In sensory neurons, an external signal such as pressure, temperature, light, or sound is coupled with the opening and
closing of ion channels, which in turn alter the ionic permeabilities of the membrane and its voltage.[12] These
voltage changes can again be excitatory (depolarizing) or inhibitory (hyperpolarizing) and, in some sensory neurons,
their combined effects can depolarize the axon hillock enough to provoke action potentials. Examples in humans
include the olfactory receptor neuron and Meissner's corpuscle, which are critical for the sense of smell and touch,
respectively. However, not all sensory neurons convert their external signals into action potentials; some do not even
have an axon![13] Instead, they may convert the signal into the release of a neurotransmitter, or into continuous
graded potentials, either of which may stimulate subsequent neuron(s) into firing an action potential. For illustration,
in the human ear, hair cells convert the incoming sound into the opening and closing of mechanically gated ion
channels, which may cause neurotransmitter molecules to be released. In similar manner, in the human retina, the
initial photoreceptor cells and the next layer of cells (comprising bipolar cells and horizontal cells) do not produce
action potentials; only some amacrine cells and the third layer, the ganglion cells, produce action potentials, which
then travel up the optic nerve.
Pacemaker potentials
In sensory neurons, action potentials result from an external stimulus.
However, some excitable cells require no such stimulus to fire: They
spontaneously depolarize their axon hillock and fire action potentials at
a regular rate, like an internal clock.[14] The voltage traces of such cells
are known as pacemaker potentials.[15] The cardiac pacemaker cells of
the sinoatrial node in the heart provide a good example.[] Although
such pacemaker potentials have a natural rhythm, it can be adjusted by
external stimuli; for instance, heart rate can be altered by
pharmaceuticals as well as signals from the sympathetic and
parasympathetic nerves.[16] The external stimuli do not cause the cell's
repetitive firing, but merely alter its timing.[15] In some cases, the
regulation of frequency can be more complex, leading to patterns of
action potentials, such as bursting.
In pacemaker potentials, the cell spontaneously

depolarizes (straight line with upward slope) until
it fires an action potential.
Phases
The course of the action potential can be divided into five parts: the rising phase, the peak phase, the falling phase,
the undershoot phase, and the refractory period. During the rising phase the membrane potential depolarizes
(becomes more positive). The point at which depolarization stops is called the peak phase. At this stage, the
membrane potential reaches a maximum. Subsequent to this, there is a falling phase. During this stage the membrane
potential hyperpolarizes (becomes more negative). The undershoot phase is the point during which the membrane
potential becomes temporarily more negatively charged than when at rest. Finally, the time during which a
subsequent action potential is impossible or difficult to fire is called the refractory period, which may overlap with
Action potential
the other phases.[17]
The course of the action potential is determined by two coupled effects.[18] First, voltage-sensitive ion channels open
and close in response to changes in the membrane voltage Vm. This changes the membrane's permeability to those
ions.[19] Second, according to the Goldman equation, this change in permeability changes in the equilibrium
potential Em, and, thus, the membrane voltage Vm.[] Thus, the membrane potential affects the permeability, which
then further affects the membrane potential. This sets up the possibility for positive feedback, which is a key part of
the rising phase of the action potential.[2] A complicating factor is that a single ion channel may have multiple
internal "gates" that respond to changes in Vm in opposite ways, or at different rates.[20][21] For example, although
raising Vm opens most gates in the voltage-sensitive sodium channel, it also closes the channel's "inactivation gate",
albeit more slowly.[22] Hence, when Vm is raised suddenly, the sodium channels open initially, but then close due to
the slower inactivation.
The voltages and currents of the action potential in all of its phases were modeled accurately by Alan Lloyd Hodgkin
and Andrew Huxley in 1952,[21] for which they were awarded the Nobel Prize in Physiology or Medicine in 1963.[]
However, their model considers only two types of voltage-sensitive ion channels, and makes several assumptions
about them, e.g., that their internal gates open and close independently of one another. In reality, there are many
types of ion channels,[] and they do not always open and close independently.[23]
Stimulation and rising phase

A typical action potential begins at the axon hillock[24] with a sufficiently strong depolarization, e.g., a stimulus that
increases Vm. This depolarization is often caused by the injection of extra sodium cations into the cell; these cations
can come from a wide variety of sources, such as chemical synapses, sensory neurons or pacemaker potentials.
For a neuron at rest, there is a high concentration of sodium and chlorine ions in the extracellular fluid compared to
the intracellular fluid while there is a high concentration of potassium ions in the intracellular fluid compared to the
extracellular fluid. This concentration gradient along with potassium leak channels present on the membrane of the
neuron causes an efflux of potassium ions making the resting potential close to EK 75mV.[25] The depolarization
opens both the sodium and potassium channels in the membrane, allowing the ions to flow into and out of the axon,
respectively. If the depolarization is small (say, increasing Vm from 70mV to 60mV), the outward potassium
current overwhelms the inward sodium current and the membrane repolarizes back to its normal resting potential
around 70mV.[1] However, if the depolarization is large enough, the inward sodium current increases more than
the outward potassium current and a runaway condition (positive feedback) results: the more inward current there is,
the more Vm increases, which in turn further increases the inward current.[2] A sufficiently strong depolarization
(increase in Vm) causes the voltage-sensitive sodium channels to open; the increasing permeability to sodium drives
Vm closer to the sodium equilibrium voltage ENa +55mV. The increasing voltage in turn causes even more sodium
channels to open, which pushes Vm still further towards ENa. This positive feedback continues until the sodium
channels are fully open and Vm is close to ENa.[26] The sharp rise in Vm and sodium permeability correspond to the
rising phase of the action potential.[]
The critical threshold voltage for this runaway condition is usually around 45mV, but it depends on the recent
activity of the axon. A membrane that has just fired an action potential cannot fire another one immediately, since
the ion channels have not returned to their usual state. The period during which no new action potential can be fired
is called the absolute refractory period.[27] At longer times, after some but not all of the ion channels have
recovered, the axon can be stimulated to produce another action potential, but only with a much stronger
depolarization, e.g., 30mV. The period during which action potentials are unusually difficult to evoke is called the
relative refractory period.[27]
83
Action potential
Peak and falling phase

The positive feedback of the rising phase slows and comes to a halt as the sodium ion channels become maximally
open. At the peak of the action potential, the sodium permeability is maximized and the membrane voltage Vm is
nearly equal to the sodium equilibrium voltage ENa. However, the same raised voltage that opened the sodium
channels initially also slowly shuts them off, by closing their pores; the sodium channels become inactivated.[22]
This lowers the membrane's permeability to sodium relative to potassium, driving the membrane voltage back
towards the resting value. At the same time, the raised voltage opens voltage-sensitive potassium channels; the
increase in the membrane's potassium permeability drives Vm towards EK.[22] Combined, these changes in sodium
and potassium permeability cause Vm to drop quickly, repolarizing the membrane and producing the "falling phase"
of the action potential.[28][28]
Afterhyperpolarization
The raised voltage opened many more potassium channels than usual, and some of these do not close right away
when the membrane returns to its normal resting voltage. In addition, further potassium channels open in response to
the influx of calcium ions during the action potential. The potassium permeability of the membrane is transiently
unusually high, driving the membrane voltage Vm even closer to the potassium equilibrium voltage EK. Hence, there
is an undershoot or hyperpolarization, termed an afterhyperpolarization in technical language, that persists until the
membrane potassium permeability returns to its usual value.[29]
Refractory period
Each action potential is followed by a refractory period, which can be divided into an absolute refractory period,
during which it is impossible to evoke another action potential, and then a relative refractory period, during which a
stronger-than-usual stimulus is required.[27] These two refractory periods are caused by changes in the state of
sodium and potassium channel molecules. When closing after an action potential, sodium channels enter an
"inactivated" state, in which they cannot be made to open regardless of the membrane potentialthis gives rise to
the absolute refractory period. Even after a sufficient number of sodium channels have transitioned back to their
resting state, it frequently happens that a fraction of potassium channels remains open, making it difficult for the
membrane potential to depolarize, and thereby giving rise to the relative refractory period. Because the density and
subtypes of potassium channels may differ greatly between different types of neurons, the duration of the relative
refractory period is highly variable.
The absolute refractory period is largely responsible for the unidirectional propagation of action potentials along
axons.[30] At any given moment, the patch of axon behind the actively spiking part is refractory, but the patch in
front, not having been activated recently, is capable of being stimulated by the depolarization from the action
potential.
Propagation
The action potential generated at the axon hillock propagates as a wave along the axon.[31] The currents flowing
inwards at a point on the axon during an action potential spread out along the axon, and depolarize the adjacent
sections of its membrane. If sufficiently strong, this depolarization provokes a similar action potential at the
neighboring membrane patches. This basic mechanism was demonstrated by Alan Lloyd Hodgkin in 1937. After
crushing or cooling nerve segments and thus blocking the action potentials, he showed that an action potential
arriving on one side of the block could provoke another action potential on the other, provided that the blocked
segment was sufficiently short.[32]
Once an action potential has occurred at a patch of membrane, the membrane patch needs time to recover before it
can fire again. At the molecular level, this absolute refractory period corresponds to the time required for the
84
Action potential
85
voltage-activated sodium channels to recover from inactivation, i.e., to return to their closed state.[33] There are many
types of voltage-activated potassium channels in neurons, some of them inactivate fast (A-type currents) and some of
them inactivate slowly or not inactivate at all; this variability guarantees that there will be always an available source
of current for repolarization, even if some of the potassium channels are inactivated because of preceding
depolarization. On the other hand, all neuronal voltage-activated sodium channels inactivate within several
millisecond during strong depolarization, thus making following depolarization impossible until a substantial
fraction of sodium channels have returned to their closed state. Although it limits the frequency of firing,[34] the
absolute refractory period ensures that the action potential moves in only one direction along an axon.[30] The
currents flowing in due to an action potential spread out in both directions along the axon.[35] However, only the
unfired part of the axon can respond with an action potential; the part that has just fired is unresponsive until the
action potential is safely out of range and cannot restimulate that part. In the usual orthodromic conduction, the
action potential propagates from the axon hillock towards the synaptic knobs (the axonal termini); propagation in the
opposite directionknown as antidromic conductionis very rare.[36] However, if a laboratory axon is stimulated in
its middle, both halves of the axon are "fresh", i.e., unfired; then two action potentials will be generated, one
traveling towards the axon hillock and the other traveling towards the synaptic knobs.
Myelin and saltatory conduction
In saltatory conduction, an action potential at one

node of Ranvier causes inwards currents that
depolarize the membrane at the next node,
provoking a new action potential there; the action
potential appears to "hop" from node to node.
In order to enable fast and efficient transduction of electrical signals in

the nervous system, certain neuronal axons are covered with myelin
sheaths. Myelin is a multilamellar membrane that enwraps the axon in
segments separated by intervals known as nodes of Ranvier. It is
produced by specialized cells: Schwann cells exclusively in the
peripheral nervous system, and oligodendrocytes exclusively in the
central nervous system. Myelin sheath reduces membrane capacitance
and increases membrane resistance in the inter-node intervals, thus
allowing a fast, saltatory movement of action potentials from node to
node.[][][37] Myelination is found mainly in vertebrates, but an
analogous system has been discovered in a few invertebrates, such as
some species of shrimp.[38] Not all neurons in vertebrates are
myelinated; for example, axons of the neurons comprising the
autonomous nervous system are not, in general, myelinated.
Myelin prevents ions from entering or leaving the axon along

myelinated segments. As a general rule, myelination increases the conduction velocity of action potentials and makes
them more energy-efficient. Whether saltatory or not, the mean conduction velocity of an action potential ranges
from 1m/s to over 100m/s, and, in general, increases with axonal diameter.[]
Action potentials cannot propagate through the membrane in myelinated segments of the axon. However, the current
is carried by the cytoplasm, which is sufficient to depolarize the first or second subsequent node of Ranvier. Instead,
the ionic current from an action potential at one node of Ranvier provokes another action potential at the next node;
this apparent "hopping" of the action potential from node to node is known as saltatory conduction. Although the
mechanism of saltatory conduction was suggested in 1925 by Ralph Lillie,[39] the first experimental evidence for
saltatory conduction came from Ichiji Tasaki[] and Taiji Takeuchi[40] and from Andrew Huxley and Robert
Stmpfli.[41] By contrast, in unmyelinated axons, the action potential provokes another in the membrane immediately
adjacent, and moves continuously down the axon like a wave.
Action potential
Myelin has two important advantages: fast

conduction speed and energy efficiency. For
axons larger than a minimum diameter
(roughly 1 micrometre), myelination
increases the conduction velocity of an
action
potential,
typically
tenfold.[]
Conversely, for a given conduction velocity,
myelinated fibers are smaller than their
unmyelinated counterparts. For example,
action potentials move at roughly the same
speed (25m/s) in a myelinated frog axon
and an unmyelinated squid giant axon, but
the frog axon has a roughly 30-fold smaller
diameter
and
1000-fold
smaller
cross-sectional area. Also, since the ionic
currents are confined to the nodes of
Ranvier, far fewer ions "leak" across the
membrane, saving metabolic energy. This
saving is a significant selective advantage,
since the human nervous system uses
approximately 20% of the body's metabolic
energy.[]
86
Comparison of the conduction velocities of myelinated and unmyelinated axons in

[42]
the cat.
The conduction velocity v of myelinated neurons varies roughly
[]
linearly with axon diameter d (that is, v d), whereas the speed of unmyelinated
[]
neurons varies roughly as the square root (v d). The red and blue curves are
fits of experimental data, whereas the dotted lines are their theoretical
extrapolations.
The length of axons' myelinated segments is

important to the success of saltatory conduction. They should be as long as possible to maximize the speed of
conduction, but not so long that the arriving signal is too weak to provoke an action potential at the next node of
Ranvier. In nature, myelinated segments are generally long enough for the passively propagated signal to travel for at
least two nodes while retaining enough amplitude to fire an action potential at the second or third node. Thus, the
safety factor of saltatory conduction is high, allowing transmission to bypass nodes in case of injury. However,
action potentials may end prematurely in certain places where the safety factor is low, even in unmyelinated neurons;
a common example is the branch point of an axon, where it divides into two axons.[43]
Some diseases degrade myelin and impair saltatory conduction, reducing the conduction velocity of action
potentials.[44] The most well-known of these is multiple sclerosis, in which the breakdown of myelin impairs
coordinated movement.[45]
Action potential
87
Cable theory
The flow of currents within an axon can be
described quantitatively by cable theory[]
and its elaborations, such as the
compartmental model.[] Cable theory was
developed in 1855 by Lord Kelvin to model
the transatlantic telegraph cable[] and was
shown to be relevant to neurons by Hodgkin
and Rushton in 1946.[] In simple cable
theory, the neuron is treated as an
electrically passive, perfectly cylindrical
transmission cable, which can be described
by a partial differential equation[]
where V(x, t) is the voltage across the

membrane at a time t and a position x along
the length of the neuron, and where and
are the characteristic length and time scales
on which those voltages decay in response
to a stimulus. Referring to the circuit
diagram above, these scales can be
determined from the resistances and
capacitances per unit length[46]
Figure.1: Cable theory's simplified view of a neuronal fiber. The connected RC

circuits correspond to adjacent segments of a passive neurite. The extracellular
resistances re (the counterparts of the intracellular resistances ri) are not shown,
since they are usually negligibly small; the extracellular medium may be assumed
to have the same voltage everywhere.
These time and length-scales can be used to understand the dependence of the conduction velocity on the diameter of
the neuron in unmyelinated fibers. For example, the time-scale increases with both the membrane resistance rm and
capacitance cm. As the capacitance increases, more charge must be transferred to produce a given transmembrane
voltage (by the equation Q=CV); as the resistance increases, less charge is transferred per unit time, making the
equilibration slower. In similar manner, if the internal resistance per unit length ri is lower in one axon than in
another (e.g., because the radius of the former is larger), the spatial decay length becomes longer and the
conduction velocity of an action potential should increase. If the transmembrane resistance rm is increased, that
lowers the average "leakage" current across the membrane, likewise causing to become longer, increasing the
conduction velocity.
Termination
Chemical synapses
In general, action potentials that reach the synaptic knobs cause a neurotransmitter to be released into the synaptic
cleft.[47] Neurotransmitters are small molecules that may open ion channels in the postsynaptic cell; most axons have
the same neurotransmitter at all of their termini. The arrival of the action potential opens voltage-sensitive calcium
channels in the presynaptic membrane; the influx of calcium causes vesicles filled with neurotransmitter to migrate
Action potential
88
to the cell's surface and release their contents into the synaptic cleft.[48] This complex process is inhibited by the
neurotoxins tetanospasmin and botulinum toxin, which are responsible for tetanus and botulism, respectively.[49]
Electrical synapses
Some synapses dispense with the "middleman" of the neurotransmitter,
and connect the presynaptic and postsynaptic cells together.[50] When
an action potential reaches such a synapse, the ionic currents flowing
into the presynaptic cell can cross the barrier of the two cell
membranes and enter the postsynaptic cell through pores known as
connexons.[51] Thus, the ionic currents of the presynaptic action
potential can directly stimulate the postsynaptic cell. Electrical
Electrical synapses between excitable cells allow
synapses allow for faster transmission because they do not require the
ions to pass directly from one cell to another, and
slow diffusion of neurotransmitters across the synaptic cleft. Hence,
are much faster than chemical synapses.
electrical synapses are used whenever fast response and coordination
of timing are crucial, as in escape reflexes, the retina of vertebrates, and the heart.
Neuromuscular junctions
A special case of a chemical synapse is the neuromuscular junction, in which the axon of a motor neuron terminates
on a muscle fiber.[52] In such cases, the released neurotransmitter is acetylcholine, which binds to the acetylcholine
receptor, an integral membrane protein in the membrane (the sarcolemma) of the muscle fiber.[53] However, the
acetylcholine does not remain bound; rather, it dissociates and is hydrolyzed by the enzyme, acetylcholinesterase,
located in the synapse. This enzyme quickly reduces the stimulus to the muscle, which allows the degree and timing
of muscular contraction to be regulated delicately. Some poisons inactivate acetylcholinesterase to prevent this
control, such as the nerve agents sarin and tabun,[] and the insecticides diazinon and malathion.[54]
Other cell types

Cardiac action potentials
The cardiac action potential differs from the neuronal action
potential by having an extended plateau, in which the
membrane is held at a high voltage for a few hundred
milliseconds prior to being repolarized by the potassium
current as usual.[] This plateau is due to the action of slower
calcium channels opening and holding the membrane voltage
near their equilibrium potential even after the sodium
channels have inactivated.
The cardiac action potential plays an important role in
Phases of a cardiac action potential. The sharp rise in voltage
[]
("0") corresponds to the influx of sodium ions, whereas the
coordinating the contraction of the heart. The cardiac cells of
two decays ("1" and "3", respectively) correspond to the
the sinoatrial node provide the pacemaker potential that
sodium-channel inactivation and the repolarizing eflux of
synchronizes the heart. The action potentials of those cells
potassium ions. The characteristic plateau ("2") results from
propagate to and through the atrioventricular node (AV node),
the opening of voltage-sensitive calcium channels.
which is normally the only conduction pathway between the
atria and the ventricles. Action potentials from the AV node travel through the bundle of His and thence to the
Purkinje fibers.[55] Conversely, anomalies in the cardiac action potentialwhether due to a congenital mutation or
injurycan lead to human pathologies, especially arrhythmias.[] Several anti-arrhythmia drugs act on the cardiac
Action potential
89
action potential, such as quinidine, lidocaine, beta blockers, and verapamil.[56]
Muscular action potentials

The action potential in a normal skeletal muscle cell is similar to the action potential in neurons.[] Action potentials
result from the depolarization of the cell membrane (the sarcolemma), which opens voltage-sensitive sodium
channels; these become inactivated and the membrane is repolarized through the outward current of potassium ions.
The resting potential prior to the action potential is typically 90mV, somewhat more negative than typical neurons.
The muscle action potential lasts roughly 24ms, the absolute refractory period is roughly 13ms, and the
conduction velocity along the muscle is roughly 5m/s. The action potential releases calcium ions that free up the
tropomyosin and allow the muscle to contract. Muscle action potentials are provoked by the arrival of a pre-synaptic
neuronal action potential at the neuromuscular junction, which is a common target for neurotoxins.[]
Plant action potentials

Plant and fungal cells [] are also electrically excitable. The fundamental difference to animal action potentials is, that
the depolarization in plant cells is not accomplished by an uptake of positive sodium ions, but by release of negative
chloride ions.[][][] Together with the following release of positive potassium ions, which is common to plant and
animal action potentials, the action potential in plants infers, therefore, an osmotic loss of salt (KCl), whereas the
animal action potential is osmotically neutral, when equal amounts of entering sodium and leaving potassium cancel
each other osmotically. The interaction of electrical and osmotic relations in plant cells [] indicates an osmotic
function of electrical excitability in the common, unicellular ancestors of plants and animals under changing salinity
conditions, whereas the present function of rapid signal transmission is seen as a younger accomplishment of
metazoan cells in a more stable osmotic environment.[] It must be assumed that the familiar signalling function of
action potentials in some vascular plants (e.g. Mimosa pudica), arose independently from that in metazoan excitable
cells.
Taxonomic distribution and evolutionary advantages

Action potentials are found throughout multicellular organisms, including plants, invertebrates such as insects, and
vertebrates such as reptiles and mammals.[] Sponges seem to be the main phylum of multicellular eukaryotes that
does not transmit action potentials, although some studies have suggested that these organisms have a form of
electrical signaling, too.[57] The resting potential, as well as the size and duration of the action potential, have not
varied much with evolution, although the conduction velocity does vary dramatically with axonal diameter and
myelination.
Comparison of action potentials (APs) from a representative cross-section of animals[]

Animal
Cell type
Resting potential (mV) AP increase (mV) AP duration (ms) Conduction speed (m/s)
Squid (Loligo)
Giant axon
60
120
0.75
35
Earthworm (Lumbricus)
Median giant fiber
70
100
1.0
30
Cockroach (Periplaneta)
Giant fiber
70
80104
0.4
10
Frog (Rana)
Sciatic nerve axon
60 to 80
110130
1.0
730
Cat (Felis)
Spinal motor neuron
55 to 80
80110
11.5
30120
Given its conservation throughout evolution, the action potential seems to confer evolutionary advantages. One
function of action potentials is rapid, long-range signaling within the organism; the conduction velocity can exceed
110m/s, which is one-third the speed of sound. For comparison, a hormone molecule carried in the bloodstream
moves at roughly 8m/s in large arteries. Part of this function is the tight coordination of mechanical events, such as
Action potential
90
the contraction of the heart. A second function is the computation associated with its generation. Being an
all-or-none signal that does not decay with transmission distance, the action potential has similar advantages to
digital electronics. The integration of various dendritic signals at the axon hillock and its thresholding to form a
complex train of action potentials is another form of computation, one that has been exploited biologically to form
central pattern generators and mimicked in artificial neural networks.
Experimental methods
The study of action potentials has required the
development of new experimental methods. The initial
work, prior to 1955, focused on three goals: isolating
signals from single neurons or axons, developing fast,
sensitive electronics, and shrinking electrodes enough
that the voltage inside a single cell could be recorded.
The first problem was solved by studying the giant
axons found in the neurons of the squid genus Loligo.[]
These axons are so large in diameter (roughly 1mm, or
100-fold larger than a typical neuron) that they can be
seen with the naked eye, making them easy to extract
and manipulate.[21][] However, the Loligo axons are not
representative of all excitable cells, and numerous other
systems with action potentials have been studied.
The giant axons of the European squid (Loligo vulgaris) were crucial
for scientists to understand the action potential.
The second problem was addressed with the crucial development of the voltage clamp,[] which permitted
experimenters to study the ionic currents underlying an action potential in isolation, and eliminated a key source of
electronic noise, the current IC associated with the capacitance C of the membrane.[58] Since the current equals C
times the rate of change of the transmembrane voltage Vm, the solution was to design a circuit that kept Vm fixed
(zero rate of change) regardless of the currents flowing across the membrane. Thus, the current required to keep Vm
at a fixed value is a direct reflection of the current flowing through the membrane. Other electronic advances
included the use of Faraday cages and electronics with high input impedance, so that the measurement itself did not
affect the voltage being measured.[]
The third problem, that of obtaining electrodes small enough to record voltages within a single axon without
perturbing it, was solved in 1949 with the invention of the glass micropipette electrode,[] which was quickly adopted
by other researchers.[][] Refinements of this method are able to produce electrode tips that are as fine as 100 (10
nm), which also confers high input impedance.[59] Action potentials may also be recorded with small metal
electrodes placed just next to a neuron, with neurochips containing EOSFETs, or optically with dyes that are
sensitive to Ca2+ or to voltage.[60]
As revealed by a patch clamp electrode, an ion

channel has two states: open (high conductance)
and closed (low conductance).
While glass micropipette electrodes measure the sum of the currents

passing through many ion channels, studying the electrical properties
of a single ion channel became possible in the 1970s with the
development of the patch clamp by Erwin Neher and Bert Sakmann.
For this they were awarded the Nobel Prize in Physiology or Medicine
in 1991.[] Patch-clamping verified that ionic channels have discrete
states of conductance, such as open, closed and inactivated.
Action potential
91
Optical imaging technologies have been developed in recent years to measure action potentials, either via
simultaneous multisite recordings or with ultra-spatial resolution. Using voltage-sensitive dyes, action potentials
have been optically recorded from a tiny patch of cardiomyocyte membrane.[]
Neurotoxins
Several neurotoxins, both natural and synthetic, are designed to block
the action potential. Tetrodotoxin from the pufferfish and saxitoxin
from the Gonyaulax (the dinoflagellate genus responsible for "red
tides") block action potentials by inhibiting the voltage-sensitive
sodium channel;[61] similarly, dendrotoxin from the black mamba
snake inhibits the voltage-sensitive potassium channel. Such inhibitors
of ion channels serve an important research purpose, by allowing
scientists to "turn off" specific channels at will, thus isolating the other
channels' contributions; they can also be useful in purifying ion
channels by affinity chromatography or in assaying their concentration.
Tetrodotoxin is a lethal toxin found in pufferfish
However, such inhibitors also make effective neurotoxins, and have
that inhibits the voltage-sensitive sodium channel,
been considered for use as chemical weapons. Neurotoxins aimed at
halting action potentials.
the ion channels of insects have been effective insecticides; one
example is the synthetic permethrin, which prolongs the activation of
the sodium channels involved in action potentials. The ion channels of insects are sufficiently different from their
human counterparts that there are few side effects in humans. Many other neurotoxins interfere with the transmission
of the action potential's effects at the synapses, especially at the neuromuscular junction.
History
The role of electricity in the nervous systems of animals was first
observed in dissected frogs by Luigi Galvani, who studied it from 1791
to 1797.[] Galvani's results stimulated Alessandro Volta to develop the
Voltaic pilethe earliest-known electric batterywith which he
studied animal electricity (such as electric eels) and the physiological
responses to applied direct-current voltages.[]
Image of two Purkinje cells (labeled as A) drawn

by Santiago Ramn y Cajal. Large trees of
dendrites feed into the soma, from which a single
axon emerges and moves generally downwards
with a few branch points. The smaller cells
labeled B are granule cells.
Scientists of the 19th century studied the propagation of electrical

signals in whole nerves (i.e., bundles of neurons) and demonstrated
that nervous tissue was made up of cells, instead of an interconnected
network of tubes (a reticulum).[62] Carlo Matteucci followed up
Galvani's studies and demonstrated that cell membranes had a voltage
across them and could produce direct current. Matteucci's work
inspired the German physiologist, Emil du Bois-Reymond, who
discovered the action potential in 1848. The conduction velocity of
action potentials was first measured in 1850 by du Bois-Reymond's
friend, Hermann von Helmholtz. To establish that nervous tissue is
made up of discrete cells, the Spanish physician Santiago Ramn y
Cajal and his students used a stain developed by Camillo Golgi to
reveal the myriad shapes of neurons, which they rendered
painstakingly. For their discoveries, Golgi and Ramn y Cajal were awarded the 1906 Nobel Prize in Physiology.[]
Their work resolved a long-standing controversy in the neuroanatomy of the 19th century; Golgi himself had argued
Action potential
for the network model of the nervous system.
The 20th century was a golden era for electrophysiology. In 1902 and
again in 1912, Julius Bernstein advanced the hypothesis that the action
potential resulted from a change in the permeability of the axonal
membrane to ions.[63] Bernstein's hypothesis was confirmed by Ken
Cole and Howard Curtis, who showed that membrane conductance
increases during an action potential.[64] In 1907, Louis Lapicque
suggested that the action potential was generated as a threshold was
crossed,[65] what would be later shown as a product of the dynamical
systems of ionic conductances. In 1949, Alan Hodgkin and Bernard
Katz refined Bernstein's hypothesis by considering that the axonal
membrane might have different permeabilities to different ions; in
particular, they demonstrated the crucial role of the sodium
permeability for the action potential.[] They made the first actual
recording of the electrical changes across the neuronal membrane that
mediate the action potential.[66] This line of research culminated in the
Ribbon diagram of the sodiumpotassium pump
five 1952 papers of Hodgkin, Katz and Andrew Huxley, in which they
in its E2-Pi state. The estimated boundaries of the
applied the voltage clamp technique to determine the dependence of
lipid bilayer are shown as blue (intracellular) and
the axonal membrane's permeabilities to sodium and potassium ions on
red (extracellular) planes.
voltage and time, from which they were able to reconstruct the action
potential quantitatively.[21] Hodgkin and Huxley correlated the properties of their mathematical model with discrete
ion channels that could exist in several different states, including "open", "closed", and "inactivated". Their
hypotheses were confirmed in the mid-1970s and 1980s by Erwin Neher and Bert Sakmann, who developed the
technique of patch clamping to examine the conductance states of individual ion channels.[67] In the 21st century,
researchers are beginning to understand the structural basis for these conductance states and for the selectivity of
channels for their species of ion,[] through the atomic-resolution crystal structures,[68] fluorescence distance
measurements[69] and cryo-electron microscopy studies.[70]
Julius Bernstein was also the first to introduce the Nernst equation for resting potential across the membrane; this
was generalized by David E. Goldman to the eponymous Goldman equation in 1943.[] The sodiumpotassium pump
was identified in 1957[71] and its properties gradually elucidated,[][][] culminating in the determination of its
atomic-resolution structure by X-ray crystallography.[] The crystal structures of related ionic pumps have also been
solved, giving a broader view of how these molecular machines work.[72]
92
Action potential
Quantitative models
Mathematical
and
computational
models are essential for understanding
the action potential, and offer
predictions that may be tested against
experimental data, providing a
stringent test of a theory. The most
important and accurate of these models
is the HodgkinHuxley model, which
describes the action potential by a
coupled set of four ordinary
differential equations (ODEs).[21]
Although the HodgkinHuxley model
may be a simplification of a realistic
Equivalent electrical circuit for the HodgkinHuxley model of the action potential. Im and
nervous membrane as it exists in
Vm represent the current through, and the voltage across, a small patch of membrane,
nature, its complexity has inspired
respectively. The Cm represents the capacitance of the membrane patch, whereas the four
several
even-more-simplified
g's represent the conductances of four types of ions. The two conductances on the left, for
models,[73] such as the MorrisLecar
potassium (K) and sodium (Na), are shown with arrows to indicate that they can vary with
the applied voltage, corresponding to the voltage-sensitive ion channels. The two
model[] and the FitzHughNagumo
[74]
conductances on the right help determine the resting membrane potential.
model,
both of which have only two
coupled ODEs. The properties of the
HodgkinHuxley and FitzHughNagumo models and their relatives, such as the Bonhoeffervan der Pol model,[75]
have been well-studied within mathematics,[76] computation[77] and electronics.[] More modern research has focused
on larger and more integrated systems; by joining action-potential models with models of other parts of the nervous
system (such as dendrites and synapses), researches can study neural computation[78] and simple reflexes, such as
escape reflexes and others controlled by central pattern generators.[][]
Notes
[1] Bullock, Orkand, and Grinnell, pp. 150151; Junge, pp. 8990; Schmidt-Nielsen, p. 484.
[2] Purves et al., pp. 4849; Bullock, Orkand, and Grinnell, pp. 141, 150151; Schmidt-Nielsen, p. 483; Junge, p. 89; Stevens, p. 127
[3] In general, while this simple description of action potential initiation is accurate, it does not explain phenomena such as excitation block (the
ability to prevent neurons from eliciting action potentials by stimulating them with large current steps) and the ability to elicit action potentials
by briefly hyperpolarizing the membrane. By analyzing the dynamics of a system of sodium and potassium channels in a membrane patch
using computational models, however, these phenomena are readily explained (http:/ / www. scholarpedia. org/ article/
FitzHugh-Nagumo_model).
[4] Schmidt-Nielsen, p. 484.
[5] Bullock, Orkand, and Grinnell, p. 11.
[7] Bullock, Orkand, and Grinnell, pp. 177240; Schmidt-Nielsen, pp. 490499; Stevens, pp. 4768.
[8] Bullock, Orkand, and Grinnell, pp. 178180; Schmidt-Nielsen, pp. 490491.
[9] Sasaki, T., Matsuki, N., Ikegaya, Y. 2011 Action-potential modulation during axonal conduction Science 331 (6017), pp. 599-601
[10] Aur D., Connolly C.I., Jog M.S., (2005) Computing spike directivity with tetrodes, Journal of Neuroscience Methods, 149 (1), pp. 57-63
[11] Aur D., Jog, MS., 2010 Neuroelectrodynamics: Understanding the brain language, IOS Press, 2010. http:/ / dx. doi. org/ 10. 3233/
978-1-60750-473-3-i
[12] Schmidt-Nielsen, pp. 535580; Bullock, Orkand, and Grinnell, pp. 4956, 7693, 247255; Stevens, 6979
[13] Bullock, Orkand, and Grinnell, pp. 53, 122124.
[14] Junge, pp. 115132
[15] Bullock, Orkand, and Grinnell, pp. 152153.
[17] Purves et al., p. 38.
[18] Stevens, pp. 127128.
93
Action potential
[19] Purves et al., pp. 6165.
[20] Purves et al., pp. 6474; Bullock, Orkand, and Grinnell, pp. 149150; Junge, pp. 8485; Stevens, pp. 152158.
[21]
*
*
*
*
[22] Purves et al., pp. 47, 65; Bullock, Orkand, and Grinnell, pp. 147148; Stevens, p. 128.
[24] Stevens, p. 49.
[25] Purves et al., p. 34; Bullock, Orkand, and Grinnell, p. 134; Schmidt-Nielsen, pp. 478480.
[26] Purves et al., pp. 4950; Bullock, Orkand, and Grinnell, pp. 140141, 150151; Schmidt-Nielsen, pp. 480481, 483484; Junge, pp. 8990.
[27] Purves et al., p. 49; Bullock, Orkand, Grinell, p. 151; Stevens, pp. 1920; Junge, pp. 45.
[28] Purves et al., p. 49; Bullock, Orkand, and Grinnell, pp. 147149, 152; Schmidt-Nielsen, pp. 483484; Stevens, pp. 126127.
[29] Purves et al., p. 37; Bullock, Orkand, and Grinnell, p. 152.
[30] Purves et al., p. 56.
[31] Bullock, Orkland, and Grinnell, pp. 16064.
[32] *
[33] Stevens, pp. 1920.
[34] Stevens, pp. 2123.
[36] Bullock, Orkand, and Grinnell, p. 509.
[39] See also Keynes and Aidley, p. 78.
[40]
*
*
[41]
*
[42] Schmidt-Nielsen, Figure 12.13.
[43] Bullock, Orkland, and Grinnell, p. 163.
[46] Purves et al., pp. 5253.
[55] Note that these Purkinje fibers are muscle fibers and not related to the Purkinje cells, which are neurons found in the cerebellum.
[58] Junge, pp. 6382.
[60] *
[61]
*
*
[62]
*
*
[63]
*
[67]
*
*
[68]
*
*
[69]
*
*
[70] *
[71] ;
[73]
*
*
[74]
*
[75]
*
94
Action potential
*
*
*
[76]
*
*
*
*
[77]
*
[78]
*
References
Bibliography
Aidley DJ, Stanfield PR (1996). Ion Channels: Molecules in Action. Cambridge: Cambridge University Press.
ISBN978-0-521-49882-1.
Bear MF, Connors BW, Paradiso MA (2001). Neuroscience: Exploring the Brain. Baltimore: Lippincott.
ISBN0-7817-3944-6.
Bullock TH, Orkand R, Grinnell A (1977). Introduction to Nervous Systems. New York: W. H. Freeman.
ISBN0-7167-0030-1.
Clay JR (May 2005). "Axonal excitability revisited". Prog Biophys Mol Biol 88 (1): 5990. doi:
10.1016/j.pbiomolbio.2003.12.004 (http://dx.doi.org/10.1016/j.pbiomolbio.2003.12.004). PMID 15561301
(http://www.ncbi.nlm.nih.gov/pubmed/15561301).
Deutsch S, Micheli-Tzanakou E (1987). Neuroelectric Systems. New York: New York University Press.
ISBN0-8147-1782-9.
Hille B (2001). Ion Channels of Excitable Membranes (3rd ed.). Sunderland, MA: Sinauer Associates.
ISBN978-0-87893-321-1.
Hoppensteadt FC (1986). An Introduction to the Mathematics of Neurons. Cambridge: Cambridge University
Press. ISBN0-521-31574-3.
Johnston D, Wu SM-S (1995). Foundations of Cellular Neurophysiology. Cambridge, MA: Bradford Book, The
MIT Press. ISBN0-262-10053-3.
Junge D (1981). Nerve and Muscle Excitation (2nd ed.). Sunderland MA: Sinauer Associates.
ISBN0-87893-410-3.
Kandel ER, Schwartz JH, Jessell TM (2000). Principles of Neural Science (4th ed.). New York: McGraw-Hill.
ISBN0-8385-7701-6.
Keynes RD, Aidley DJ (1991). Nerve and Muscle (2nd ed.). Cambridge: Cambridge University Press.
ISBN0-521-41042-8.
Miller C (1987). "How ion channel proteins work". In LK Kaczmarek, IB Levitan. Neuromodulation: The
Biochemical Control of Neuronal Excitability. New York: Oxford University Press. pp.3963.
ISBN978-0-19-504097-5.
Nelson DL, Cox MM (2008). Lehninger Principles of Biochemistry (5th ed.). New York: W. H. Freeman.
ISBN978-0-7167-7108-1.
Purves D, Augustine GJ, Fitzpatrick D, Hall WC, Lamantia A-S, McNamara JO, Williams SM (2001). "Release
of Transmitters from Synaptic Vesicles" (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.
326). Neuroscience (2nd ed.). Sunderland, MA: Sinauer Associates. ISBN0-87893-725-0.
Purves D, Augustine GJ, Fitzpatrick D, Hall WC, Lamantia A-S, McNamara JO, White LE (2008). Neuroscience
(4th ed.). Sunderland, MA: Sinauer Associates. ISBN978-0-87893-697-7.
95
Action potential
Schmidt-Nielsen K (1997). Animal Physiology: Adaptation and Environment (5th ed.). Cambridge: Cambridge
University Press. ISBN978-0-521-57098-5.
Stevens CF (1966). Neurophysiology: A Primer. New York: John Wiley and Sons. LCCN 6615872 (http://lccn.
loc.gov/6615872).
External links
Animations
Ionic flow in action potentials (http://www.blackwellpublishing.com/matthews/channel.html) at Blackwell
Publishing
Action potential propagation in myelinated and unmyelinated axons (http://www.blackwellpublishing.com/
matthews/actionp.html) at Blackwell Publishing
Generation of AP in cardiac cells (http://thevirtualheart.org/CAPindex.html) and generation of AP in neuron
cells (http://thevirtualheart.org/java/neuron/apneuron.html)
Resting membrane potential (http://bcs.whfreeman.com/thelifewire/content/chp44/4402001.html) from Life:
The Science of Biology, by WK Purves, D Sadava, GH Orians, and HC Heller, 8th edition, New York: WH
Freeman, ISBN 978-0-7167-7671-0.
Ionic motion and the Goldman voltage for arbitrary ionic concentrations (http://www.nernstgoldman.
physiology.arizona.edu/) at The University of Arizona
A cartoon illustrating the action potential (http://www.brainu.org/files/movies/action_potential_cartoon.swf)
Action potential propagation (http://www.1lecture.com/Biochemistry/Action Potential/index.html)
Production of the action potential: voltage and current clamping simulations (http://people.virginia.edu/
~hvg2s/)
Open-source software to simulate neuronal and cardiac action potentials (http://cese.sourceforge.net/) at
SourceForge.net
Introduction to the Action Potential (http://nba.uth.tmc.edu/neuroscience/s1/chapter01.html), Neuroscience
Online (electronic neuroscience textbook by UT Houston Medical School)
96
97
Diseases
Multiple sclerosis
Multiple sclerosis
Classification and external resources
Demyelination by MS. The CD68 colored tissue shows several macrophages in the area of the lesion. Original scale 1:100
[1]
ICD-10
G35
ICD-9
340
OMIM
126200
DiseasesDB
8412
MedlinePlus
000737
eMedicine
neuro/228
MeSH
D009103
GeneReviews
[4]
[1]
[2]
[3]
[4]
oph/179
[5]
emerg/321
[6]
pmr/82
[7]
radio/461
[8]
[9]
Multiple Sclerosis Overview
[10]
Multiple sclerosis (MS), also known as "disseminated sclerosis" or "encephalomyelitis disseminata", is an

inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged,
leading to demyelination and scarring as well as a broad spectrum of signs and symptoms.[] Disease onset usually
occurs in young adults, and it is more common in women.[] It has a prevalence that ranges between 2 and 150 per
100,000.[] MS was first described in 1868 by Jean-Martin Charcot.[11]
MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other effectively. Nerve
cells communicate by sending electrical signals called action potentials down long fibers called axons, which are
contained within an insulating substance called myelin. In MS, the body's own immune system attacks and damages
the myelin. When myelin is lost, the axons can no longer effectively conduct signals.[] The name multiple sclerosis
refers to scars (sclerae-better known as plaques or lesions) particularly in the white matter of the brain and spinal
cord, which is mainly composed of myelin.[11] Although much is known about the mechanisms involved in the
disease process, the cause remains unknown. Theories include genetics or infections. Different environmental risk
factors have also been found.[][]
Multiple sclerosis
Almost any neurological symptom can appear with the disease, and the disease often progresses to physical and
cognitive disability.[] Psychiatric symptoms may also occur.[12] MS takes several forms, with new symptoms
occurring either in discrete attacks (relapsing forms) or accumulating over time (progressive forms).[] Between
attacks, symptoms may go away completely, but permanent neurological deficits often occur, especially as the
disease advances.[]
There is no known cure for multiple sclerosis. Treatments attempt to return function after an attack, prevent new
attacks, and prevent disability.[] MS medications can have adverse effects or be poorly tolerated, and many people
pursue alternative treatments, despite the lack of supporting scientific study. The prognosis is difficult to predict; it
depends on the subtype of the disease, the individual's disease characteristics, the initial symptoms and the degree of
disability the person experiences as time advances.[] Life expectancy of people with MS is 5 to 10 years lower than
that of the unaffected population.[]
Signs and symptoms

A person with MS can suffer almost any neurological symptom or
sign, including changes in sensation such as loss of sensitivity or
tingling, pricking or numbness (hypoesthesia and paresthesia), muscle
weakness, clonus, muscle spasms, or difficulty in moving; difficulties
with coordination and balance (ataxia); problems in speech (dysarthria)
or swallowing (dysphagia), visual problems (nystagmus, optic neuritis
including phosphenes,[13][14] or diplopia), fatigue, acute or chronic
pain, and bladder and bowel difficulties.[] Cognitive impairment of
varying degrees and emotional symptoms of depression or unstable
mood are also common.[] Uhthoff's phenomenon, an exacerbation of
extant symptoms due to an exposure to higher than usual ambient
temperatures, and Lhermitte's sign, an electrical sensation that runs
down the back when bending the neck, are particularly characteristic of
MS although not specific.[] The main clinical measure of disability
progression and symptom severity is the Expanded Disability Status
Scale or EDSS.[15]
Symptoms of MS usually appear in episodic acute periods of
Main symptoms of multiple sclerosis
worsening (called relapses, exacerbations, bouts, attacks, or
"flare-ups"), in a gradually progressive deterioration of neurologic function, or in a combination of both.[] Multiple
sclerosis relapses are often unpredictable, occurring without warning and without obvious inciting factors with a rate
rarely above one and a half per year.[] Some attacks, however, are preceded by common triggers. Relapses occur
more frequently during spring and summer.[] Viral infections such as the common cold, influenza, or gastroenteritis
increase the risk of relapse.[] Stress may also trigger an attack.[] Pregnancy affects the susceptibility to relapse, with a
lower relapse rate at each trimester of gestation. During the first few months after delivery, however, the risk of
relapse is increased.[] Overall, pregnancy does not seem to influence long-term disability. Many potential triggers
have been examined and found not to influence MS relapse rates. There is no evidence that vaccination and breast
feeding,[] physical trauma,[] or Uhthoff's phenomenon[] are relapse triggers.
98
Multiple sclerosis
Causes
Most likely MS occurs as a result of some combination of genetic, environmental and infectious factors,[] and
possibly other factors like vascular problems.[] Epidemiological studies of MS have provided hints on possible
causes for the disease. Theories try to combine the known data into plausible explanations, but none has proved
definitive.
Genetics
MS is not considered a hereditary disease. However, a number of
genetic variations have been shown to increase the risk of developing
the disease.[]
The risk of acquiring MS is higher in relatives of a person with the
disease than in the general population, especially in the case of
siblings, parents, and children.[] The disease has an overall familial
recurrence rate of 20%.[] In the case of monozygotic twins,
concordance occurs only in about 35% of cases, while it goes down to
around 5% in the case of siblings and even lower in half-siblings. This
indicates susceptibility is partly polygenically driven.[][] It seems to be
more common in some ethnic groups than others.[16]
Apart from familial studies, specific genes have been linked with MS.
Differences in the human leukocyte antigen (HLA) systema group of
genes in chromosome 6 that serves as the major histocompatibility
complex (MHC) in humansincrease the probability of suffering
MS.[] That changes in the HLA region are related to the susceptibility
of an individual for MS has been known for over thirty years,[] and
additionally this same region has been implicated in the development
of other autoinmmune diseases such as diabetes type I and systemic
lupus erythematosus.[] The most consistent finding is the association
between multiple sclerosis and alleles of the MHC defined as DR15
HLA region of Chromosome6. Changes in this
area increase the probability of suffering MS.
and DQ6.[] Other loci have shown a protective effect, such as
[]
HLA-C554 and HLA-DRB1*11. Overall, it has been stimated that
HLA changes accounts for between 20 and 60% of the genetic predisposition for MS.[] Modern genetic methods
(Genome-wide association studies, or GWAS) have also permitted to discover at least 12 other genes outside the
HLA locus that modestly increase the probability of suffering MS.[]
Environmental factors
Different environmental factors, both of infectious and non-infectious origin, have been proposed as risk factors for
MS. Although some are partly modifiable, only further researchespecially clinical trialswill reveal whether their
elimination can help prevent MS.[]
MS is more common in people who live farther from the equator, although many exceptions exist.[] Decreased
sunlight exposure has been linked with a higher risk of MS.[] Decreased vitamin D production and intake has been
the main biological mechanism used to explain the higher risk among those less exposed to sun.[][][]
Severe stress may be a risk factor although evidence is weak.[] Smoking has also been shown to be an independent
risk factor for developing MS.[] Association with occupational exposures and toxinsmainly solventshas been
evaluated, but no clear conclusions have been reached.[] Vaccinations were investigated as causal factors for the
disease; however, most studies show no association between MS and vaccines.[] Several other possible risk factors,
99
Multiple sclerosis
100
such as diet[17] and hormone intake, have been investigated; however, evidence on their relation with the disease is
"sparse and unpersuasive".[]
Gout occurs less than would statistically be expected in people with MS, and low levels of uric acid have been found
in people with MS as compared to normal individuals. This led to the theory that uric acid protects against MS,
although its exact importance remains unknown.[]
Infections
Many microbes have been proposed as potential infectious triggers of MS, but none have been substantiated.[]
Moving at an early age from one location in the world to another alters a person's subsequent risk of MS.[] An
explanation for this could be that some kind of infection, produced by a widespread microbe rather than a rare
pathogen, is the origin of the disease.[] There are a number of proposed mechanisms, including the hygiene
hypothesis and the prevalence hypothesis. The hygiene hypothesis proposes that exposure to several infectious
agents early in life is protective against MS, the disease being a response to a later encounter with such agents.[] The
prevalence hypothesis proposes that the disease is due to a pathogen more common in regions of high MS prevalence
where in most individuals it causes an asymptomatic persistent infection. Only in a few cases and after many years
does it cause demyelination.[][] The hygiene hypothesis has received more support than the prevalence hypothesis.[]
Evidence for viruses as a cause includes the presence of oligoclonal bands in the brain and cerebrospinal fluid of
most people with MS, the association of several viruses with human demyelination encephalomyelitis, and induction
of demyelination in animals through viral infection.[] Human herpes viruses are a candidate group of viruses linked
to MS. Individuals who have never been infected by the Epstein-Barr virus have a reduced risk of having the disease,
and those infected as young adults have a greater risk than those who had it at a younger age.[][] Although some
consider that this goes against the hygiene hypothesis, since the noninfected have probably experienced a more
hygienic upbringing,[] others believe that there is no contradiction since it is a first encounter at a later moment with
the causative virus that is the trigger for the disease.[] Other diseases that have also been related with MS are
measles, mumps, and rubella.[]
Pathophysiology
Autoimmunology
MS is believed to be an immune-mediated disorder mediated by a
complex interaction of the individual's genetics and as yet unidentified
environmental insults.[] Damage is believed to be caused by the
person's own immune system attacking the nervous system. Possible
targets of the immune response include myelin basic protein (MBP)
and proteolipid protein (PLP). The commonly prescribed MS drug
Copaxone was designed to mimic MBP and therefore act as a decoy
for autoreactive immune cells. Even so, the role of MBP in MS is
controversial; it is buried within the myelin sheath (rather than on the
surface), where immune cells would not be able to recognize it.
Demyelination in MS. On Klver-Barrera myelin

staining, decoloration in the area of the lesion can
be appreciated (Original scale 1:100).
Recent data suggest a role for myelin lipids in MS.[] Historically, researchers have assumed the myelin target was a
protein, even though the myelin sheath is nearly 80% lipid. Furthermore, lipids are known to be the target of another
prominent nervous system autoimmune condition, Guillain-Barre Syndrome.
Whether the autoantigen is a protein or a lipid, autoimmunity may arise when immune cells recognizing a foreign
antigen cross-react with self antigens. This process is known as molecular mimicry.[][]
Multiple sclerosis
Lesions
The name multiple sclerosis refers to the scars (sclerae better known as plaques or lesions) that form in the nervous
system. MS lesions most commonly involve white matter areas close to the ventricles of the cerebellum, brain stem,
basal ganglia and spinal cord; and the optic nerve. The function of white matter cells is to carry signals between grey
matter areas, where the processing is done, and the rest of the body. The peripheral nervous system is rarely
involved.[]
More specifically, MS destroys oligodendrocytes, the cells responsible for creating and maintaining a fatty
layerknown as the myelin sheathwhich helps the neurons carry electrical signals (action potentials).[] MS results
in a thinning or complete loss of myelin and, as the disease advances, the cutting (transection) of the neuron's axons.
When the myelin is lost, a neuron can no longer effectively conduct electrical signals.[] A repair process, called
remyelination, takes place in early phases of the disease, but the oligodendrocytes cannot completely rebuild the
cell's myelin sheath.[] Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is
built up around the damaged axons.[] Different lesion patterns have been described.[]
Inflammation
Apart from demyelination, the other pathologic hallmark of the disease is inflammation. According to a strictly
immunological explanation of MS, the inflammatory process is caused by T cells, a kind of lymphocyte.
Lymphocytes are cells that play an important role in the body's defenses.[] In MS, T cells gain entry into the brain via
disruptions in the bloodbrain barrier. Evidence from animal models also point to a role of B cells in addition to T
cells in development of the disease.[]
The T cells recognize myelin as foreign and attack it as if it were an invading virus. This triggers inflammatory
processes, stimulating other immune cells and soluble factors like cytokines and antibodies. Further leaks form in the
bloodbrain barrier, which in turn cause a number of other damaging effects such as swelling, activation of
macrophages, and more activation of cytokines and other destructive proteins.[]
Bloodbrain barrier breakdown

The bloodbrain barrier is a part of the capillary system that prevents the entry of T cells into the central nervous
system.[] However, it may become permeable to these types of cells because of an infection or a virus.[] When the
bloodbrain barrier regains its integrity, typically after the infection or virus has cleared, the T cells are trapped
inside the brain.[]
Diagnosis
Multiple sclerosis can be difficult to diagnose since its signs and symptoms may be similar to other medical
problems.[][] Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process
especially in the first stages of the disease.[] Historically, the Schumacher and Poser criteria were both popular.[]
Currently, the McDonald criteria focus on a demonstration with clinical, laboratory and radiologic data of the
dissemination of MS lesions in time and space for non-invasive MS diagnosis, though some have stated that the only
proved diagnosis of MS is autopsy, or occasionally biopsy, where lesions typical of MS can be detected through
histopathological techniques.[][][]
Clinical data alone may be sufficient for a diagnosis of MS if an individual has suffered separate episodes of
neurologic symptoms characteristic of MS.[] Since some people seek medical attention after only one attack, other
testing may hasten and ease the diagnosis. The most commonly used diagnostic tools are neuroimaging, analysis of
cerebrospinal fluid and evoked potentials. Magnetic resonance imaging of the brain and spine shows areas of
demyelination (lesions or plaques). Gadolinium can be administered intravenously as a contrast to highlight active
plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the
101
Multiple sclerosis
moment of the evaluation.[][] Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of
chronic inflammation of the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands of IgG on
electrophoresis, which are inflammation markers found in 7585% of people with MS.[][] The nervous system of a
person with MS responds less actively to stimulation of the optic nerve and sensory nerves due to demyelination of
such pathways. These brain responses can be examined using visual and sensory evoked potentials.[]
Clinical courses
Several subtypes, or patterns of progression,
have been described. Subtypes use the past
course of the disease in an attempt to predict
the future course. They are important not
only for prognosis but also for therapeutic
decisions. In 1996 the United States
National Multiple Sclerosis Society
standardized four clinical courses:[]
1.
2.
3.
4.
relapsing remitting,
secondary progressive,
primary progressive, and
progressive relapsing.
The
relapsing-remitting
subtype
is
characterized by unpredictable relapses
followed by periods of months to years of
relative quiet (remission) with no new signs
of disease activity. Deficits suffered during
attacks may either resolve or leave sequelae,
the latter being more common as a function
of time.[] This describes the initial course of
Progression of MS subtypes
80% of individuals with MS.[] When deficits
always resolve between attacks, this is sometimes referred to as benign MS,[] although people will still accrue some
degree of disability in the long term.[] On the other hand, the term malignant multiple sclerosis is used to describe
MS patients who reach significant level of disability in a short period of time.[18] The relapsing-remitting subtype
usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack suggestive of demyelination,
but does not fulfill the criteria for multiple sclerosis.[][] However only 30 to 70% of persons experiencing CIS later
develop MS.[]
102
Multiple sclerosis
103
Secondary progressive MS describes around 65% of those with an
initial relapsing-remitting MS, who then begin to have progressive
neurologic decline between acute attacks without any definite periods
of remission.[][] Occasional relapses and minor remissions may
appear.[] The median time between disease onset and conversion from
relapsing-remitting to secondary progressive MS is 19years.[] The
primary progressive subtype describes the approximately 1015% of
individuals who never have remission after their initial MS
symptoms.[] It is characterized by progression of disability from onset,
with no, or only occasional and minor, remissions and improvements.[]
The age of onset for the primary progressive subtype is later than for
the relapsing-remitting, but similar to mean age of progression between
the relapsing-remitting and the secondary progressive. In both cases it
is around 40 years of age.[]
Nerve axon with myelin sheath
Progressive relapsing MS describes those individuals who, from onset,

have a steady neurologic decline but also suffer clear superimposed
attacks. This is the least common of all subtypes.[]
Atypical variants of MS with non-standard behavior have been described; these include Devic's disease, Balo
concentric sclerosis, Schilder's diffuse sclerosis and Marburg multiple sclerosis. There is debate on whether they are
MS variants or different diseases.[] Multiple sclerosis also behaves differently in children, taking more time to reach
the progressive stage.[] Nevertheless they still reach it at a lower mean age than adults.[]
Management
Although there is no known cure for multiple sclerosis, several therapies have proven helpful. The primary aims of
therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical
treatment, medications used in the management of MS have several adverse effects. Alternative treatments are
pursued by some people, despite the shortage of supporting, comparable, replicated scientific study.
Acute attacks
During symptomatic attacks, administration of high doses of intravenous corticosteroids, such as
methylprednisolone, is the routine therapy for acute relapses,[] while oral corticosteroids seem to have a similar
efficacy and safety profile.[19] Although generally effective in the short term for relieving symptoms, corticosteroid
treatments do not appear to have a significant impact on long-term recovery.[] Consequences of severe attacks which
do not respond to corticosteroids might be treated by plasmapheresis.[]
Multiple sclerosis
104
Disease-modifying treatments
As of April 2013, eight disease-modifying treatments have been
approved by regulatory agencies of different countries. The approved
drugs are interferon beta-1a, interferon beta-1b, glatiramer acetate,
mitoxantrone, natalizumab, fingolimod, teriflunomide and dimethyl
fumarate.[][][][][]
The interferons and glatiramer acetate are delivered by frequent
injections, varying from once-per-day for glatiramer acetate to
once-per-week (but intra-muscular) for interferon beta-1a. Natalizumab
and mitoxantrone are given by intravenous (IV) infusion at monthly
intervals in the case of natalizumab and every three months in the case
of mitoxantrone.[20][][] In 2010 fingolimod became the first oral drug
approved by the FDA,[] being followed by teriflunomide and dimethyl
fumarate.[][] Fingolimod and teriflunomide are taken through a daily
single dose whereas dimethyl fumarate is administered twice
daily.[][][21] Most drugs are approved only for the relapsing-remitting
course (RRMS). Medications are modestly effective at decreasing the
number of attacks in RRMS.[22]
Disease-modifying treatments are expensive and

most of these require frequent (up-to-daily)
injections. Others require IV infusions (pictured)
at 13 month intervals.
Interferons and glatiramer acetate are roughly equivalent, reducing

relapses by approximately 30%.[] Comparisons to natalizumab show
that the most effective is the latter, both in terms of relapse rate
reduction and halting disability progression.[] Mitoxantrone may be the
most effective of them all; however, it is generally not considered as a
long-term therapy, as its use is limited by severe secondary effects.[][]
While more studies of the long-term effects of the drugs are
needed,[][][] specially for the newest treatments, existing data on the
effects of interferons and glatiramer acetate indicate that early-initiated
long-term therapy is safe and it is related to better outcomes.[][]
The earliest clinical presentation of RRMS is the clinically isolated
Irritation zone after injection of glatiramer
acetate.
syndrome (CIS). Treatment with interferons during an initial attack
[][]
decreases the chance that a person will develop clinical MS.
Treatment of progressive MS is more difficult than relapsing-remitting MS. Mitoxantrone has shown positive effects
in those with secondary progressive and progressive relapsing courses. It is moderately effective in reducing the
progression of the disease and the frequency of relapses in short-term follow-up.[] No treatment has been proven to
modify the course of primary progressive MS.[] Efficacy of most common treatments, interferons and glatiramer
acetate, in early-onset MS (before eighteen years of age) has been estimated to be roughly equivalent to adults.[]
As with many medical treatments, these treatments have several adverse effects. One of the most common is
irritation at the injection site for glatiramer acetate and the interferon treatments. Over time, a visible dent at the
injection site, due to the local destruction of fat tissue, known as lipoatrophy, may develop. Interferons produce
symptoms similar to influenza;[] some people taking glatiramer experience a post-injection reaction manifested by
flushing, chest tightness, heart palpitations, breathlessness, and anxiety, which usually lasts less than thirty minutes.[]
More dangerous but much less common are liver damage from interferons,[] severe cardiotoxicity, infertility, and
acute myeloid leukemia of mitoxantrone,[][] and the putative link between natalizumab and some cases of
progressive multifocal leukoencephalopathy.[]
Multiple sclerosis
105
Fingolimod may give rise to hypertension and bradycardia, macular edema, elevated liver enzymes or reduction in
lymphocite levels.[] Teriflunomide is considered a very safe drug. Nevertheless there have been reports of liver
failure and PML and it is dangerous for fetal development.[] Most common secondary effects of dimethyl fumarate
are flushing and gastrointestinal problems.[] While dimethyl fumarate leads to a reduction in white blood cell count
there were no reported cases of opportunistic infections during clinical trials.[]
Associated symptoms
Disease-modifying treatments reduce the progression rate of the disease, but do not stop it. As multiple sclerosis
progresses, the symptomatology tends to increase. The disease is associated with a variety of symptoms and
functional deficits that result in a range of progressive impairments and disability. Management of these deficits is
therefore very important. Both drug therapy and neurorehabilitation have shown to ease the burden of some
symptoms, though neither influences disease progression.[][] Some symptoms have a good response to medication,
such as unstable bladder and spasticity, while management of many others is much more complicated.[] As for any
person with neurologic deficits, a multidisciplinary approach is key to improving quality of life; however, there are
particular difficulties in specifying a 'core team' because people with MS may need help from almost any health
profession or service at some point.[] Multidisciplinary rehabilitation programs increase activity and participation of
people with MS but do not influence impairment level.[] Due to the paucity of randomized controlled studies, there is
limited evidence of the overall efficacy of individual therapy disciplines,[][][] though there is good evidence that
specific approaches, such as exercise,[][23] psychology therapies, particularly cognitive behavioral approaches[24] and
energy conservation instruction[] are effective.
Alternative treatments
Over 50% of MS patients may use complementary and alternative medicine, although numbers vary greatly
depending on the definition of alternative medicine used.[] The evidence for effectiveness for such treatments in most
cases is weak or absent.[][] Examples of treatments used by patients with unproven efficacy are dietary
supplementation and regimens,[][] relaxation techniques such as yoga,[] herbal medicine (including the use of medical
cannabis),[][25] hyperbaric oxygenation,[] self-infection with hookworm (known generally as helminthic therapy),
reflexology or acupunture.[][26] Regarding the characteristics of users, they are more frequently women, have had
MS for a longer time and tend to be more disabled. Moreover, they also have lower levels of satisfaction with
conventional healthcare.[]
Prognosis
The prognosis (the expected future course of the disease) for a person
with multiple sclerosis depends on the subtype of the disease; the
individual's sex, age, and initial symptoms; and the degree of disability
the person experiences.[] The disease evolves and advances over
decades, 30 being the mean years to death since onset.[]
Female sex, relapsing-remitting subtype, optic neuritis or sensory
symptoms at onset, few attacks in the initial years and especially early
age at onset, are associated with a better course.[][]
Disability-adjusted life year for multiple sclerosis

per 100,000inhabitants in 2004
The life expectancy of people with MS is 5 to 10 years lower than that of unaffected people.[] Almost 40% of people
with MS reach the seventh decade of life.[] Nevertheless, two-thirds of the deaths in people with MS are directly
related to the consequences of the disease.[] Suicide also has a higher prevalence than in the healthy population,
while infections and complications are especially hazardous for the more disabled ones.[]
Multiple sclerosis
Although most people lose the ability to walk before death, 90% are still capable of independent walking at 10 years
from onset, and 75% at 15 years.[][]
Epidemiology
Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new
cases per unit of persontime at risk (usually number of new cases per thousand personyears); while prevalence is
the total number of cases of the disease in the population at a given time. Prevalence is known to depend not only on
incidence, but also on survival rate and migrations of affected people. MS has a prevalence that ranges between 2
and 150 per 100,000 depending on the country or specific population.[] Studies on populational and geographical
patterns of epidemiological measures have been very common in MS,[] and have led to the proposal of different
etiological (causal) theories.[][][][]
MS usually appears in adults in their thirties but it can also appear in children.[] The primary progressive subtype is
more common in people in their fifties.[] As with many autoimmune disorders, the disease is more common in
women, and the trend may be increasing.[][] The CDC data suggest that MS is three times more common in women
than in men in the United States.[27] In children, the sex ratio difference is higher,[] while in people over fifty, MS
affects males and females almost equally.[]
There is a north-to-south gradient in the northern hemisphere and a south-to-north gradient in the southern
hemisphere, with MS being much less common in people living near the equator.[][] Climate, sunlight and intake of
vitamin D have been investigated as possible causes of the disease that could explain this latitude gradient.[]
However, there are important exceptions to the northsouth pattern and changes in prevalence rates over time;[] in
general, this trend might be disappearing.[] This indicates that other factors such as environment or genetics have to
be taken into account to explain the origin of MS.[] MS is also more common in regions with northern European
populations.[] But even in regions where MS is common, some ethnic groups are at low risk of developing the
disease, including the Samis, Turkmen, Amerindians, Canadian Hutterites, Africans, and New Zealand Mori.[28]
Environmental factors during childhood may play an important role in the development of MS later in life. Several
studies of migrants show that if migration occurs before the age of 15, the migrant acquires the new region's
susceptibility to MS. If migration takes place after age 15, the migrant retains the susceptibility of his home
country.[][] However, the agegeographical risk for developing multiple sclerosis may span a larger timescale.[] A
relationship between season of birth and MS has also been found which lends support to an association with sunlight
and vitamin D. For example fewer people with MS are born in November as compared to May.[29]
106
Multiple sclerosis
107
History
Medical discovery
The French neurologist Jean-Martin Charcot (18251893) was the first
person to recognize multiple sclerosis as a distinct disease in 1868.[]
Summarizing previous reports and adding his own clinical and
pathological observations, Charcot called the disease sclerose en
plaques. The three signs of MS now known as Charcot's triad 1 are
nystagmus, intention tremor, and telegraphic speech (scanning speech),
though these are not unique to MS. Charcot also observed cognition
changes, describing his patients as having a "marked enfeeblement of
the memory" and "conceptions that formed slowly".[11]
Before Charcot, Robert Carswell (17931857), a British professor of
pathology, and Jean Cruveilhier (17911873), a French professor of
pathologic anatomy, had described and illustrated many of the disease's
clinical details, but did not identify it as a separate disease.[]
Specifically, Carswell described the injuries he found as "a remarkable
lesion of the spinal cord accompanied with atrophy".[] Under the
microscope, Swiss pathologist Georg Eduard Rindfleisch (18361908)
noted in 1863 that the inflammation-associated lesions were distributed
around blood vessels.[30][31]
Detail of Carswell's drawing of MS lesions in the

brain stem and spinal cord (1838)
After Charcot's description, Eugne Devic (18581930), Jozsef Balo (18951979), Paul Ferdinand Schilder
(18861940), and Otto Marburg (18741948) described special cases of the disease. During all the 20th century
there was an important development on the theories about the cause and pathogenesis of MS while efficacious
treatments began to appear in 1990.[]
Historical cases
There are several historical accounts of people who lived before or shortly after the disease was described by Charcot
and probably had MS.
A young woman called Halldora who lived in Iceland around 1200 suddenly lost her vision and mobility but, after
praying to the saints, recovered them seven days after. Saint Lidwina of Schiedam (13801433), a Dutch nun, may
be one of the first clearly identifiable MS patients. From the age of 16 until her death at 53, she suffered intermittent
pain, weakness of the legs, and vision losssymptoms typical of MS.[] Both cases have led to the proposal of a
'Viking gene' hypothesis for the dissemination of the disease.[]
Augustus Frederick d'Este (17941848), son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta
Murray and the grandson of GeorgeIII of the United Kingdom, almost certainly suffered from MS. D'Este left a
detailed diary describing his 22 years living with the disease. His diary began in 1822 and ended in 1846, although it
remained unknown until 1948. His symptoms began at age 28 with a sudden transient visual loss (amaurosis fugax)
after the funeral of a friend. During the course of his disease, he developed weakness of the legs, clumsiness of the
hands, numbness, dizziness, bladder disturbances, and erectile dysfunction. In 1844, he began to use a wheelchair.
Despite his illness, he kept an optimistic view of life.[32][]
Another early account of MS was kept by the British diarist W. N. P. Barbellion, nom-de-plume of Bruce Frederick
Cummings (18891919), who maintained a detailed log of his diagnosis and struggle with MS.[] His diary was
published in 1919 as The Journal of a Disappointed Man.[33]
Multiple sclerosis
Research
There have been important advances in the research of multiple sclerosis in the last decade that have led to a deeper
comprenhension of the disease mechanisms and also to more effective treatments.[] Nevertheless, MS continues to be
an active field of research.[]
Diagnosis and disease biomarkers

Regarding diagnosis it is not expected that diagnostic criteria may
change in the near future. On the other hand, while the search for
biomarkers of the disease that may aid diagnosis, prediction of disease
evolution,or evaluation of disease evolution, is intense there are not
any expected breakthroughs in the short term.[]
The variable clinical presentation of MS and the lack of diagnostic
laboratory tests lead to delays in diagnosis and the impossibility of
predicting diagnosis. New diagnostic methods that are being
investigated include work with anti-myelin antibodies, and studies with
serum and cerebrospinal fluid but none of them has yielded reliable
positive results.[]
Currently there are no clinically established laboratory investigations
available that can predict prognosis. However, several promising
Magnetic resonance imaging brain scan produced
approaches have been proposed. Investigations on the prediction of
using a Gradient-echo phase sequence. It shows
evolution have centered on monitoring disease activity. Disease
an iron deposition in an existing white matter
activation biomarkers include interleukin-6, nitric oxide and nitric
lesion (inside green box in the middle of the
[]
image;
enhanced and signaled with red arrow at
oxide synthase, osteopontin, and fetuin-A. On the other hand since
top-left hand side corner). This and other imaging
disease progression is the result of neurodegeneration the roles of
[]
techniques are still under development.
proteins indicative of neuronal, axonal, and glial loss such as
neurofilaments, tau and N-acetylaspartate are under investigation.[] A
final investigative field is work with biomarkers that distinguish between medication responders and
nonresponders.[]
The improvement in neuroimaging techniques such as positron emission tomography (PET) or magnetic resonance
imaging (MRI) carry a promise for better diagnosis and prognosis predictions, albeit the effect of such improvements
in daily medical practice may take several decades.[] Regarding MRI, there are on the one hand several techniques
that have already shown some usefulness in research settings and could be introduced into clinical practice, such as
double-inversion recovery sequences, magnetization transfer, diffusion tensor, or functional magnetic resonance
imaging.[] These techniques have a higher pathological specificity than existing ones, but still lack some
development including standarization of acquisition protocols and the creation of normative values.[] On the other
hand, there are also several techniques under development that could be useful.[] These include the use of new
contrast agents capable of measuring levels of peripheral macrophages, inflammation, or neuronal dysfunction.[]
Other techniques may quantify iron deposition and could serve to evaluate the role of this pathological feature in
MS, or cerebral perfusion, which is known to be altered in patients.[] Similary new PET radiotracers might serve as
markers of altered proccessess in MS such as brain inflammation, cortical pathology, apoptosis, or remylienation.[]
108
Multiple sclerosis
109
Clinical measures of evolution

The main measure of evolution of symptoms, specially important as an endpoint in MS trials, is the EDSS. However,
this and other measures used in clinical studies are far from perfect and suffer from insetiveness or inadequate
validation.[] In this sense there is ongoing research to improve the EDSS and other measures such as the Multiple
Sclerosis Functional Composite. This is specially important at the current state of research where the greater efficacy
of existing medications force functional measures in clinical trials to be highly sensitive in order to adequately
measure disease changes.[]
Genetics
Progress in the field of genetics has been outstanding in the last two decades with highly improved methods and
cheaper tests. These advances have in turn led to a greater understanding of the genetic component of MS. This trend
is expected to continue, raising the possibility of discovering key mechanisms implicated in the disease. However, it
is hard to predict how this future discoveries will impact in the clinical practice or in the research for new drugs and
treatments.[]
An example of a soon-to-be finished study is the Wellcome Trust case control consortium, a massive collaboration
study including 120,000 genetic samples, of which 8000 are from individuals with MS.[] This study may
presummibly identify all the common genetic variants involved in MS.[] Further studies will probably involve full
genome sequencing of large samples, or the study of structural genetic variants such as insertions, deletions or
polymorphisms.[]
Drugs
Research directions on MS treatments include investigations of MS
pathogenesis and heterogeneity; research of more effective,
convenient, or tolerable new treatments for RRMS; creation of
therapies for the progressive subtypes; neuroprotection strategies; and
the search for effective symptomatic treatments.[]
Advances during the last decades has led to the recent approval of
several oral drugs. These drugs are expected to gain in popularity and
frequency of use at the expense of previously existing therapies.[]
Further oral drugs are still under investigation, the most notable
example being laquinimod, which was announced in August 2012 to be
the focus of a third phase III trial after mixed results in the previous
ones.[34] Similarly, Other studies are aimed to improve efficacy and
ease of use of already existing therapies through the use of novel
preparations. Such is the case the PEGylated version of
interferon--1a, that has a longer life than normal interferon and
therefore it is being studied if given at less frequent doses has a similar
efficacy than the existing product.[][] Request for approval of
peginterferon beta-1a is expected during 2013.[]
Chemical structure of alemtuzumab
Monoclonal antibodies, which are drugs of the same family as natalizumab, have also raised high levels of interest
and research. Alemtuzumab, daclizumab and CD20 monoclonal antibodies such as rituximab, ocrelizumab and
ofatumumab have all shown some benefit and are under study as potential treatments for MS.[] Nevertheless their use
has also been accompanied by the appearance of potentially dangerous adverse effects, most importantly
opportunistic infections.[] Related to these investigations is the recent development of a test against JC virus
antibodies which might help to predict what patients are at a greater risk of developing progressive multifocal
Multiple sclerosis
leukoencephalopathy when taking natalizumab.[] While monoclonal antibodies are probably going to have some role
in the treatment of the disease in the future, it is believed that it will be small due to the risks associated to them.[]
Another research strategy is to evaluate the combined effectiveness of two or more drugs.[] The main rationale for
polytherapy in MS is that the involved treatments target different mechanisms of the disease and therefore their use
is not necessarily exclusive.[] Moreover synergies, in which a drug potentiates the effect of another are also possible.
Nevertheless there can also appear important drawbacks such as antagonizing mechanisms of action or potentiation
of deleterious secondary effects.[] While there have been several clinical trials of combined therapy none has shown
positive enough effects to merit the consideration as a viable treatment for MS.[]
Finally, regarding neuroprotective and specially regenerative treatments, such as stem cell therapy, while their
research is considered of high importance at the moment they are only a promise of future therapeutic approaches.[]
Likewise, there are not any effective treatments for the progressive variants of the disease. Many of the newest drugs
as well as those under development are probably going to be evaluated as therapies for PPMS or SPMS, and their
improved effectiveness when compared with previously existing drugs may eventually lead to a positive result in
these groups of patients.[]
Chronic cerebrospinal venous insufficiency

In 2008, vascular surgeon Paolo Zamboni suggested that MS involves a vascular process he referred to as chronic
cerebrospinal venous insufficiency (CCSVI), in which veins from the brain are constricted. He found CCSVI in all
patients with MS in his study, performed a surgical procedure, later called in the media "liberation procedure" to
correct it and claimed that 73% of participants improved.[] This theory received important attention in the media and
among MS patients, specially in Canada.[] Concern has been raised with Zamboni's research as it was neither blinded
nor controlled, and additionally its assumptions about the pathophisiology of the disease may not be backed by
known data.[] Also further studies have either not found a relationship or found a much less strong one.[] This has
raised serious objections to the hypothesis of CCSVI originating MS.[] The "liberation procedure" has been criticized
for possibly resulting in serious complications and deaths while its benefits have not been proven.[] Currently it is
recommended not to use the proposed treatment unless its effectiveness is confirmed by controlled studies.[]
Research on CCSVI has been fast tracked but researchers have been unable to confirm whether CCSVI has a role in
causing MS.[]
References
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[2] http:/ / www. diseasesdatabase. com/ ddb8412. htm
[3] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000737. htm
[4] http:/ / www. emedicine. com/ neuro/ topic228. htm
[5] http:/ / www. emedicine. com/ oph/ topic179. htm#
[6] http:/ / www. emedicine. com/ emerg/ topic321. htm#
[7] http:/ / www. emedicine. com/ pmr/ topic82. htm#
[8] http:/ / www. emedicine. com/ radio/ topic461. htm#
[9] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D009103
[10] http:/ / www. ncbi. nlm. nih. gov/ books/ NBK1316/
[11] *
[17] (primary source)
[20] Natalizumab Injection. (http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a605006. html) US National Library of Medicine
(Medline) (2006-10-01). Retrieved on 2007-09-02.
[27] Multiple Sclerosis Fact Sheet (http:/ / voxhealth. org/ project/ diaginfo. php?diag=340--& diag_text=Multiple+ sclerosis& rfv1=& rfv2=&
rfv3=) CDC medical records on VoxHealth. Retrieved on 2013-30-1
110
Multiple sclerosis
Further reading
Langgartner M, Langgartner I, Drlicek M (April 2005). "The patient's journey: multiple sclerosis" (http://bmj.
bmjjournals.com/cgi/content/full/330/7496/885). BMJ 330 (7496): 8858. doi: 10.1136/bmj.330.7496.885
(http://dx.doi.org/10.1136/bmj.330.7496.885). PMC 556161 (http://www.ncbi.nlm.nih.gov/pmc/
articles/PMC556161). PMID 15831874 (http://www.ncbi.nlm.nih.gov/pubmed/15831874).
External links
Multiple sclerosis (http://www.dmoz.org/Health/Conditions_and_Diseases/Neurological_Disorders/
Demyelinating_Diseases/Multiple_Sclerosis//) at the Open Directory Project
Database for analysis and comparison of global data on the epidemiology of MS (http://www.atlasofms.org/)
111
112
Anatomy
Spinal cord
Spinal cord
The spinal cord (in red) connects the brain to the nerves throughout the body the spinal cord links the brains and the nerves
Latin
medulla spinalis
Divisions of Spinal Segments
Segmental Spinal Cord Level and Function

Level
Function
C1-C6
Neck flexors
C1-T1
Neck extensors
C3, C4, C5
Supply diaphragm (mostly C4)
C5, C6
Shoulder movement, raise arm (deltoid); flexion of elbow (biceps); C6 externally rotates the arm (supinates)
C6, C7
Extends elbow and wrist (triceps and wrist extensors); pronates wrist
C7, T1
Flexes wrist
C7, T1
Supply small muscles of the hand
T1 -T6
Intercostals and trunk above the waist
T7-L1
Abdominal muscles
L1, L2, L3, L4 Thigh flexion

L2, L3, L4
Thigh adduction
Spinal cord
113
L4, L5, S1
Thigh abduction
L5, S1, S2
Extension of leg at the hip (gluteus maximus)
L2, L3, L4
Extension of leg at the knee (quadriceps femoris)
L4, L5, S1, S2 Flexion of leg at the knee (hamstrings)

L4, L5, S1
Dorsiflexion of foot (tibialis anterior)
L4, L5, S1
Extension of toes
L5, S1, S2
Plantar flexion of foot
L5, S1, S2
Flexion of toes
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain (the
medulla oblongata specifically). The brain and spinal cord together make up the central nervous system (CNS). The
spinal cord begins at the occipital bone and extends down to the space between the first and second lumbar
vertebrae; it does not extend the entire length of the vertebral column. It is around 45cm (18in) in men and around
43cm (17in) long in women. Also, the spinal cord has a varying width, ranging from 1/2inch thick in the cervical
and lumbar regions to 1/4inch thick in the thoracic area. The enclosing bony vertebral column protects the relatively
shorter spinal cord. The spinal cord functions primarily in the transmission of neural signals between the brain and
the rest of the body but also contains neural circuits that can independently control numerous reflexes and central
pattern generators. The spinal cord has three major functions: as a conduit for motor information, which travels down
the spinal cord, as a conduit for sensory information in the reverse direction, and finally as a center for coordinating
certain reflexes. [1]
Structure
The spinal cord is the only main pathway for information connecting the brain and peripheral nervous system. The
length of the spinal cord is much shorter than the length of the bony spinal column. The human spinal cord extends
from the foramen magnum and continues through to the conus medullaris near the second lumbar vertebra,
terminating in a fibrous extension known as the filum terminale.
It is about 45cm (18in) long in men and around 43cm (17in) in women, ovoid-shaped, and is enlarged in the
cervical and lumbar regions. The cervical enlargement, located from C3 to T2 spinal segments, is where sensory
input comes from and motor output goes to the arms. The lumbar enlargement, located between L1 and S3 spinal
segments, handles sensory input and motor output coming from and going to the legs.
The spinal cord is protected by three layers of tissue, called spinal meninges, that surround the canal. The dura mater
is the outermost layer, and it forms a tough protective coating. Between the dura mater and the surrounding bone of
the vertebrae is a space called the epidural space. The epidural space is filled with adipose tissue, and it contains a
network of blood vessels. The arachnoid mater is the middle protective layer. Its name comes from the fact that the
tissue has a spiderweb-like appearance. The space between the arachnoid and the underlying pia mater is called the
subarachnoid space. The subarachnoid space contains cerebrospinal fluid (CSF). The medical procedure known as a
lumbar puncture (or "spinal tap") involves use of a needle to withdraw cerebrospinal fluid from the subarachnoid
space, usually from the lumbar region of the spine. The pia mater is the innermost protective layer. It is very delicate
and it is tightly associated with the surface of the spinal cord. The cord is stabilized within the dura mater by the
connecting denticulate ligaments, which extend from the enveloping pia mater laterally between the dorsal and
ventral roots. The dural sac ends at the vertebral level of the second sacral vertebra.
In cross-section, the peripheral region of the cord contains neuronal white matter tracts containing sensory and motor
neurons. Internal to this peripheral region is the gray, butterfly-shaped central region made up of nerve cell bodies.
This central region surrounds the central canal, which is an anatomic extension of the spaces in the brain known as
the ventricles and, like the ventricles, contains cerebrospinal fluid.
Spinal cord
The spinal cord has a shape that is compressed dorso-ventrally, giving it an elliptical shape. The cord has grooves in
the dorsal and ventral sides. The posterior median sulcus is the groove in the dorsal side, and the anterior median
fissure is the groove in the ventral side.
Spinal cord segments

The human spinal cord is divided into 31 different segments. At every
segment, right and left pairs of spinal nerves (mixed; sensory and
motor) form. Six to eight motor nerve rootlets branch out of right and
left ventro lateral sulci in a very orderly manner. Nerve rootlets
combine to form nerve roots. Likewise, sensory nerve rootlets form off
right and left dorsal lateral sulci and form sensory nerve roots. The
ventral (motor) and dorsal (sensory) roots combine to form spinal
nerves (mixed; motor and sensory), one on each side of the spinal cord.
Spinal nerves, with the exception of C1 and C2, form inside
intervertebral foramen (IVF). Note that at each spinal segment, the
border between the central and peripheral nervous system can be
observed. Rootlets are a part of the peripheral nervous system.
In the upper part of the vertebral column, spinal nerves exit directly
A model of segments of the human vertebral
column, nerve roots can be seen extending
from the spinal cord, whereas in the lower part of the vertebral column
laterally from the (not visible) spinal cord.
nerves pass further down the column before exiting. The terminal
portion of the spinal cord is called the conus medullaris. The pia mater
continues as an extension called the filum terminale, which anchors the spinal cord to the coccyx. The cauda equina
(horses tail) is the name for the collection of nerves in the vertebral column that continue to travel through the
vertebral column below the conus medullaris. The cauda equina forms as a result of the fact that the spinal cord stops
growing in length at about age four, even though the vertebral column continues to lengthen until adulthood. This
results in the fact that sacral spinal nerves actually originate in the upper lumbar region. The spinal cord can be
anatomically divided into 31 spinal segments based on the origins of the spinal nerves.
Each segment of the spinal cord is associated with a pair of ganglia, called dorsal root ganglia, which are situated
just outside of the spinal cord. These ganglia contain cell bodies of sensory neurons. Axons of these sensory neurons
travel into the spinal cord via the dorsal roots.
Ventral roots consist of axons from motor neurons, which bring information to the periphery from cell bodies within
the CNS. Dorsal roots and ventral roots come together and exit the intervertebral foramina as they become spinal
nerves.
The gray matter, in the center of the cord, is shaped like a butterfly and consists of cell bodies of interneurons and
motor neurons. It also consists of neuroglia cells and unmyelinated axons. Projections of the gray matter (the
wings) are called horns. Together, the gray horns and the gray commissure form the gray H.
The white matter is located outside of the gray matter and consists almost totally of myelinated motor and sensory
axons. Columns of white matter carry information either up or down the spinal cord.
Within the CNS, nerve cell bodies are generally organized into functional clusters, called nuclei. Axons within the
CNS are grouped into tracts.
There are 33 spinal cord nerve segments in a human spinal cord:
8 cervical segments forming 8 pairs of cervical nerves (C1 spinal nerves exit spinal column between occiput and
C1 vertebra; C2 nerves exit between posterior arch of C1 vertebra and lamina of C2 vertebra; C3-C8 spinal nerves
through IVF above corresponding cervica vertebra, with the exception of C8 pair which exit via IVF between C7
and T1 vertebra)
114
Spinal cord
115
12 thoracic segments forming 12 pairs of thoracic nerves (exit spinal column through IVF below corresponding
vertebra T1-T12)
5 lumbar segments forming 5 pairs of lumbar nerves (exit spinal column through IVF, below corresponding
vertebra L1-L5)
5 sacral segments forming 5 pairs of sacral nerves (exit spinal column through IVF, below corresponding vertebra
S1-S5)
3 coccygeal segments joined up becoming a single segment forming 1 pair of coccygeal nerves (exit spinal
column through the sacral hiatus).
In the fetus, vertebral segments correspond with spinal cord segments. However, because the vertebral column grows
longer than the spinal cord, spinal cord segments do not correspond to vertebral segments in the adult, particularly in
the lower spinal cord. For example, lumbar and sacral spinal cord segments are found between vertebral levels T9
and L2, and the spinal cord ends around the L1/L2 vertebral level, forming a structure known as the conus
medullaris.
Although the spinal cord cell bodies end around the L1/L2 vertebral level, the spinal nerves for each segment exit at
the level of the corresponding vertebra. For the nerves of the lower spinal cord, this means that they exit the vertebral
column much lower (more caudally) than their roots. As these nerves travel from their respective roots to their point
of exit from the vertebral column, the nerves of the lower spinal segments form a bundle called the cauda equina.
There are two regions where the spinal cord
enlarges:
Cervical enlargement - corresponds
roughly to the brachial plexus nerves,
which innervate the upper limb. It
includes spinal cord segments from about
C4 to T1. The vertebral levels of the
enlargement are roughly the same (C4 to
T1).
Lumbosacral enlargement - corresponds
to the lumbosacral plexus nerves, which
innervate the lower limb. It comprises the
spinal cord segments from L2 to S3 and
is found about the vertebral levels of T9
to T12.
Spinal cord
Embryology
The spinal cord is made from part of the neural tube during development. As the neural tube begins to develop, the
notochord begins to secrete a factor known as Sonic hedgehog or SHH. As a result, the floor plate then also begins to
secrete SHH, and this will induce the basal plate to develop motor neurons. Meanwhile, the overlying ectoderm
secretes bone morphogenetic protein (BMP). This induces the roof plate to begin to secrete BMP, which will induce
the alar plate to develop sensory neurons. The alar plate and the basal plate are separated by the sulcus limitans.
Spinal cord
116
Additionally, the floor plate also secretes

netrins. The netrins act as chemoattractants
to decussation of pain and temperature
sensory neurons in the alar plate across the
anterior white commissure, where they then
ascend towards the thalamus.
Lastly, it is important to note that the past
studies of Viktor Hamburger and Rita
Levi-Montalcini in the chick embryo have
been further proven by more recent studies
which demonstrated that the elimination of
neuronal cells by programmed cell death
(PCD) is necessary for the correct assembly
of the nervous system.
Medulla spinalis of 8-week-old human embryo
Overall, spontaneous embryonic activity has

been shown to play a role in neuron and muscle development but is probably not involved in the initial formation of
connections between spinal neurons.
Blood supply
The spinal cord is supplied with blood by three arteries that run along its length starting in the brain, and many
arteries that approach it through the sides of the spinal column. The three longitudinal arteries are called the anterior
spinal artery, and the right and left posterior spinal arteries.[] These travel in the subarachnoid space and send
branches into the spinal cord. They form anastamoses (connections) via the anterior and posterior segmental
medullary arteries, which enter the spinal cord at various points along its length.[] The actual blood flow caudally
through these arteries, derived from the posterior cerebral circulation, is inadequate to maintain the spinal cord
beyond the cervical segments.
The major contribution to the arterial blood supply of the spinal cord below the cervical region comes from the
radially arranged posterior and anterior radicular arteries, which run into the spinal cord alongside the dorsal and
ventral nerve roots, but with one exception do not connect directly with any of the three longitudinal arteries.[] These
intercostal and lumbar radicular arteries arise from the aorta, provide major anastomoses and supplement the blood
flow to the spinal cord. In humans the largest of the anterior radicular arteries is known as the artery of
Adamkiewicz, or anterior radicularis magna (ARM) artery, which usually arises between L1 and L2, but can arise
anywhere from T9 to L5. [2] Impaired blood flow through these critical radicular arteries, especially during surgical
procedures that involve abrupt disruption of blood flow through the aorta for example during aortic aneursym repair,
can result in spinal cord infarction and paraplegia.
Spinal cord
Somatosensory organization
Somatosensory organization is divided
into
the
dorsal
column-medial
lemniscus
tract
(the
touch/proprioception/vibration sensory
pathway) and the anterolateral system,
or ALS (the pain/temperature sensory
pathway). Both sensory pathways use
three different neurons to get
information from sensory receptors at
Spinal cord tracts.
the periphery to the cerebral cortex.
These neurons are designated primary,
secondary and tertiary sensory neurons. In both pathways, primary sensory neuron cell bodies are found in the dorsal
root ganglia, and their central axons project into the spinal cord.
In the dorsal column-medial leminiscus tract, a primary neuron's axon enters the spinal cord and then enters the
dorsal column. If the primary axon enters below spinal level T6, the axon travels in the fasciculus gracilis, the medial
part of the column. If the axon enters above level T6, then it travels in the fasciculus cuneatus, which is lateral to the
fasiculus gracilis. Either way, the primary axon ascends to the lower medulla, where it leaves its fasiculus and
synapses with a secondary neuron in one of the dorsal column nuclei: either the nucleus gracilis or the nucleus
cuneatus, depending on the pathway it took. At this point, the secondary axon leaves its nucleus and passes anteriorly
and medially. The collection of secondary axons that do this are known as internal arcuate fibers. The internal
arcuate fibers decussate and continue ascending as the contralateral medial lemniscus. Secondary axons from the
medial lemniscus finally terminate in the ventral posterolateral nucleus (VPL) of the thalamus, where they synapse
with tertiary neurons. From there, tertiary neurons ascend via the posterior limb of the internal capsule and end in the
primary sensory cortex.
The proprioception of the lower limbs differs from the upper limbs and upper trunk. There is a four-neuron pathway
for lower limb proprioception. This pathway initially follows the dorsal spino-cerebellar pathway. It is arranged as
follows: proprioceptive receptors of lower limb -> peripheral process -> dorsal root ganglion -> central process ->
Clarke's column -> 2nd order neuron -> medulla oblogata (Caudate nucleus) -> 3rd order neuron -> VPL of thalamus
-> 4th order neuron -> posterior limb of internal capsule -> corona radiata -> sensory area of cerebrum.
The anterolateral system works somewhat differently. Its primary neurons axons enter the spinal cord and then
ascend one to two levels before synapsing in the substantia gelatinosa. The tract that ascends before synapsing is
known as Lissauer's tract. After synapsing, secondary axons decussate and ascend in the anterior lateral portion of
the spinal cord as the spinothalamic tract. This tract ascends all the way to the VPL, where it synapses on tertiary
neurons. Tertiary neuronal axons then travel to the primary sensory cortex via the posterior limb of the internal
capsule.
It should be noted that some of the "pain fibers" in the ALS deviate from their pathway towards the VPL. In one
such deviation, axons travel towards the reticular formation in the midbrain. The reticular formation then projects to
a number of places including the hippocampus (to create memories about the pain), the centromedian nucleus (to
cause diffuse, non-specific pain) and various parts of the cortex. Additionally, some ALS axons project to the
periaqueductal gray in the pons, and the axons forming the periaqueductal gray then project to the nucleus raphe
magnus, which projects back down to where the pain signal is coming from and inhibits it. This helps control the
sensation of pain to some degree.
117
Spinal cord
Motor organization
The corticospinal tract serves as the motor pathway for upper motor neuronal signals coming from the cerebral
cortex and from primitive brainstem motor nuclei.
Cortical upper motor neurons originate from Brodmann areas 1, 2, 3, 4, and 6 and then descend in the posterior limb
of the internal capsule, through the crus cerebri, down through the pons, and to the medullary pyramids, where about
90% of the axons cross to the contralateral side at the decussation of the pyramids. They then descend as the lateral
corticospinal tract. These axons synapse with lower motor neurons in the ventral horns of all levels of the spinal
cord. The remaining 10% of axons descend on the ipsilateral side as the ventral corticospinal tract. These axons also
synapse with lower motor neurons in the ventral horns. Most of them will cross to the contralateral side of the cord
(via the anterior white commissure) right before synapsing.
The midbrain nuclei give rise to the four subconscious motor tracts that send upper motor neuronal axons down the
spinal cord to lower motor neurons. These are the rubrospinal tract, the vestibulospinal tract, the tectospinal tract and
the reticulospinal tract. The rubrospinal tract descends with the lateral corticospinal tract, and the remaining three
descend with the anterior corticospinal tract.
The function of lower motor neurons can be divided into two different groups: the lateral corticospinal tract and the
anterior cortical spinal tract. The lateral tract contains upper motor neuronal axons which synapse on dorsal lateral
(DL) lower motor neurons. The DL neurons are involved in distal limb control. Therefore, these DL neurons are
found specifically only in the cervical and lumbosacral enlargements within the spinal cord. There is no decussation
in the lateral corticospinal tract after the decussation at the medullary pyramids.
The anterior corticospinal tract descends ipsilaterally in the anterior column, where the axons emerge and either
synapse on lower ventromedial (VM) motor neurons in the ventral horn ipsilaterally or descussate at the anterior
white commissure where they synapse on VM lower motor neurons contralaterally . The tectospinal, vestibulospinal
and reticulospinal descend ipsilaterally in the anterior column but do not synapse across the anterior white
commissure. Rather, they only synapse on VM lower motor neurons ipsilaterally. The VM lower motor neurons
control the large, postural muscles of the axial skeleton. These lower motor neurons, unlike those of the DL, are
located in the ventral horn all the way throughout the spinal cord.
Spinocerebellar tracts
Proprioceptive information in the body travels up the spinal cord via three tracts. Below L2, the proprioceptive
information travels up the spinal cord in the ventral spinocerebellar tract. Also known as the anterior spinocerebellar
tract, sensory receptors take in the information and travel into the spinal cord. The cell bodies of these primary
neurons are located in the dorsal root ganglia. In the spinal cord, the axons synapse and the secondary neuronal
axons decussates and then travel up to the superior cerebellar peduncle where they decussate again. From here, the
information is brought to deep nuclei of the cerebellum including the fastigial and interposed nuclei.
From the levels of L2 to T1, proprioceptive information enters the spinal cord and ascends ipsilaterally, where it
synapses in Clarke's nucleus. The secondary neuronal axons continue to ascend ipsilaterally and then pass into the
cerebellum via the inferior cerebellar peduncle. This tract is known as the dorsal spinocerebellar tract.
From above T1, proprioceptive primary axons enter the spinal cord and ascend ipsilaterally until reaching the
accessory cuneate nucleus, where they synapse. The secondary axons pass into the cerebellum via the inferior
cerebellar peduncle where again, these axons synapse on cerebellar deep nuclei. This tract is known as the
cuneocerebellar tract.
Motor information travels from the brain down the spinal cord via descending spinal cord tracts. Descending tracts
involve two neurons: the upper motor neuron (UMN) and lower motor neuron (LMN).[3] A nerve signal travels down
the upper motor neuron until it synapses with the lower motor neuron in the spinal cord. Then, the lower motor
neuron conducts the nerve signal to the spinal root where efferent nerve fibers carry the motor signal toward the
118
Spinal cord
119
target muscle. The descending tracts are composed of white matter. There are several descending tracts serving
different functions. The corticospinal tracts (lateral and anterior) are responsible for coordinated limb movements.[3]
Injury
Spinal cord injuries can be caused by trauma to the spinal column (stretching, bruising, applying pressure, severing,
laceration, etc.). The vertebral bones or intervertebral disks can shatter, causing the spinal cord to be punctured by a
sharp fragment of bone. Usually, victims of spinal cord injuries will suffer loss of feeling in certain parts of their
body. In milder cases, a victim might only suffer loss of hand or foot function. More severe injuries may result in
paraplegia, tetraplegia (also known as quadriplegia), or full body paralysis below the site of injury to the spinal cord.
Damage to upper motor neuron axons in the spinal cord results in a characteristic pattern of ipsilateral deficits. These
include hyperreflexia, hypertonia and muscle weakness. Lower motor neuronal damage results in its own
characteristic pattern of deficits. Rather than an entire side of deficits, there is a pattern relating to the myotome
affected by the damage. Additionally, lower motor neurons are characterized by muscle weakness, hypotonia,
hyporeflexia and muscle atrophy.
Spinal shock and neurogenic shock can occur from a spinal injury. Spinal shock is usually temporary, lasting only
for 2448 hours, and is a temporary absence of sensory and motor functions. Neurogenic shock lasts for weeks and
can lead to a loss of muscle tone due to disuse of the muscles below the injured site.
The two areas of the spinal cord most commonly injured are the cervical spine (C1-C7) and the lumbar spine
(L1-L5). (The notation C1, C7, L1, L5 refer to the location of a specific vertebra in either the cervical, thoracic, or
lumbar region of the spine.)
Additional images
Diagrams
of the
spinal
cord.
Cross-section through the spinal

cord at the mid-thoracic level.
Cross-sections
of the spinal
cord at
varying
levels.
Cross-section of rabbit spinal

cord.
Sagittal section of pig vertebrae

showing a section of the spinal
cord.
The base of the brain

and the top of the
spinal cord
Spinal cord. Spinal

membranes and nerve
roots.Deep dissection.
Posterior view.
Spinal cord. Spinal

membranes and nerve
roots.Deep dissection.
Posterior view.
Spinal cord
Spinal cord. Spinal membranes

and nerve roots.Deep dissection.
Posterior view.
120

Posterior view.

Posterior view.

Posterior view.

Posterior view.
References
[3] Saladin. Anatomy and Physiology, 5th Ed.
External links
Spinal Cord Histology (http://biology.clc.uc.edu/fankhauser/Labs/Anatomy_&_Physiology/A&P202/
CNS_Histology/Spinal_Cord/Spinal_Cord_Histology.htm) - A multitude of great images from the University of
Cincinnati
Spinal Cord Medical Notes (http://www.rahulgladwin.com/blog/2006/07/spinal-cord-notes.html) - Online
medical notes on the spinal cord
"The Nervous System: Sensory and Motor Tracts of the Spinal Cord" (http://www.napavalley.edu/people/
briddell/Documents/BIO 218/15_lecture_presentation.pdf). Napa Valley College / Southeast Community
College Lincoln, Nebraska. Retrieved 20 May 2013.
eMedicine: Spinal Cord, Topographical and Functional Anatomy (http://www.emedicine.com/neuro/topic657.
htm)
WebMD. May 17, 2005. Spina Bifida - Topic Overview (http://children.webmd.com/tc/
Spina-Bifida-Topic-Overview) Information about spina bifida in fetuses and throughout adulthood. WebMD
children's health. Retrieved March 19, 2007.
Potential for spinal injury repair (http://news.bbc.co.uk/2/hi/uk_news/wales/6274960.stm) Retrieved
February 6, 2008.
4000 sets of digital images, showing spatial expression patterns for various genes in adult and juvenile mouse
spinal cords (http://mousespinal.brain-map.org/) from the Allen Institute for Brain Science
Cerebellum
121
Cerebellum
Brain: Cerebellum
A preserved human brain, with the cerebellum colored in purple
Drawing of the human brain, showing cerebellum and pons

Part of
Metencephalon
Artery
SCA, AICA, PICA
Vein
superior, inferior
NeuroLex ID
birnlex_1489
[1]
The cerebellum (Latin for little brain) is a region of the brain that plays an important role in motor control. It may
also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure
responses,[2] but its movement-related functions are the most solidly established. The cerebellum does not initiate
movement, but it contributes to coordination, precision, and accurate timing. It receives input from sensory systems
of the spinal cord and from other parts of the brain, and integrates these inputs to fine tune motor activity.[] Because
of this fine-tuning function, damage to the cerebellum does not cause paralysis, but instead produces disorders in fine
movement, equilibrium, posture, and motor learning.[]
In its anatomy, the cerebellum has the appearance of a separate structure attached to the bottom of the brain, tucked
underneath the cerebral hemispheres. The surface of the cerebellum is covered with finely spaced parallel grooves, in
striking contrast to the broad irregular convolutions of the cerebral cortex. These parallel grooves conceal the fact
that the cerebellum is actually a continuous thin layer of tissue (the cerebellar cortex), tightly folded in the style of an
accordion. Within this thin layer are several types of neurons with a highly regular arrangement, the most important
being Purkinje cells and granule cells. This complex neural network gives rise to a massive signal-processing
capability, but almost all of its output is directed to a set of small deep cerebellar nuclei lying in the interior of the
cerebellum.
In addition to its direct role in motor control, the cerebellum also is necessary for several types of motor learning, the
most notable one being learning to adjust to changes in sensorimotor relationships. Several theoretical models have
been developed to explain sensorimotor calibration in terms of synaptic plasticity within the cerebellum. Most of
Cerebellum
122
them derive from early models formulated by David Marr and James Albus, which were motivated by the
observation that each cerebellar Purkinje cell receives two dramatically different types of input: On one hand,
thousands of inputs from parallel fibers, each individually very weak; on the other hand, input from one single
climbing fiber, which is, however, so strong that a single climbing fiber action potential will reliably cause a target
Purkinje cell to fire a burst of action potentials. The basic concept of the Marr-Albus theory is that the climbing fiber
serves as a "teaching signal", which induces a long-lasting change in the strength of synchronously activated parallel
fiber inputs. Observations of long-term depression in parallel fiber inputs have provided support for theories of this
type, but their validity remains controversial.
Structure
At the level of large scale anatomy, the cerebellum consists of a tightly folded and crumpled layer of cortex, with
white matter underneath, several deep nuclei embedded in the white matter, and a fluid-filled ventricle at the base. At
the microscopic level, each part of the cortex consists of the same small set of neuronal elements, laid out with a
highly stereotyped geometry. At an intermediate level, the cerebellum and its auxiliary structures can be decomposed
into several hundred or thousand independently functioning modules called "microzones" or "microcompartments".
Anatomy
The cerebellum is located at the bottom of the brain, with the large
mass of the cerebral cortex above it and the portion of the brainstem
called the pons in front of it.[] It is separated from the overlying
cerebrum by a layer of leathery dura mater; all of its connections with
other parts of the brain travel through the pons. Anatomists classify the
cerebellum as part of the metencephalon, which also includes the pons;
the metencephalon is the upper part of the rhombencephalon or
Anterior view of the human cerebellum, with
"hindbrain". Like the cerebral cortex, the cerebellum is divided into
numbers indicating salient landmarks
two hemispheres; it also contains a narrow midline zone called the
vermis. A set of large folds is, by convention, used to divide the overall
structure into 10 smaller "lobules". Because of its large number of tiny granule cells, the cerebellum contains more
neurons than the rest of the brain put together, but it takes up only 10% of total brain volume.[] The number of
neurons in the cerebellum is related to the number of neurons in the neocortex. There are about 3.6 times as many
neurons in the cerebellum as in neocortex, a number that is conserved across many different mammalian species.[3]
Vertical cross-section of the human cerebellum,

showing folding pattern of the cortex, and interior
structures
The unusual surface appearance of the cerebellum conceals the fact

that most of its volume is made up of a very tightly folded layer of gray
matter, the cerebellar cortex. It has been estimated that, if the human
cerebellar cortex were completely unfolded, it would give rise to a
layer of neural tissue about 1 meter long and averaging 5centimeters
wide a total surface area of about 500square cm, packed within a
volume of dimensions 6cm 5cm 10cm.[] Underneath the gray
matter of the cortex lies white matter, made up largely of myelinated
nerve fibers running to and from the cortex. Embedded within the
white matter which is sometimes called the arbor vitae (Tree of
Life) because of its branched, tree-like appearance in cross-section
are four deep cerebellar nuclei, composed of gray matter.[]
Cerebellum
123
Subdivisions
Based on surface appearance, three lobes can be distinguished in the cerebellum, called the flocculonodular lobe,
anterior lobe (above the primary fissure), and posterior lobe (below the primary fissure). These lobes divide the
cerebellum from rostral to caudal (in humans, top to bottom). In terms of function, however, there is a more
important distinction along the medial-to-lateral dimension. Leaving out the flocculonodular part, which has distinct
connections and functions, the cerebellum can be parsed functionally into a medial sector called the spinocerebellum
and a larger lateral sector called the cerebrocerebellum.[] A narrow strip of protruding tissue along the midline is
called the vermis (Latin for "worm").[]
Cerebellum and surrounding regions; sagittal view of one

hemisphere. A: Midbrain. B: Pons. C: Medulla. D: Spinal cord. E:
Fourth ventricle. F: Arbor vitae. G: Tonsil. H: Anterior lobe. I:
Posterior lobe.
Schematic representation of the major anatomical subdivisions of the

cerebellum. Superior view of an "unrolled" cerebellum, placing the vermis in
one plane.
The smallest region, the flocculonodular lobe, is often called the vestibulocerebellum. It is the oldest part in
evolutionary terms (archicerebellum) and participates mainly in balance and spatial orientation; its primary
connections are with the vestibular nuclei, although it also receives visual and other sensory input. Damage to it
causes disturbances of balance and gait.[]
The medial zone of the anterior and posterior lobes constitutes the spinocerebellum, also known as paleocerebellum.
This sector of the cerebellum functions mainly to fine-tune body and limb movements. It receives proprioception
input from the dorsal columns of the spinal cord (including the spinocerebellar tract) and from the trigeminal nerve,
as well as from visual and auditory systems. It sends fibres to deep cerebellar nuclei that, in turn, project to both the
cerebral cortex and the brain stem, thus providing modulation of descending motor systems.[]
The lateral zone, which in humans is by far the largest part, constitutes the cerebrocerebellum, also known as
neocerebellum. It receives input exclusively from the cerebral cortex (especially the parietal lobe) via the pontine
nuclei (forming cortico-ponto-cerebellar pathways), and sends output mainly to the ventrolateral thalamus (in turn
connected to motor areas of the premotor cortex and primary motor area of the cerebral cortex) and to the red
nucleus.[] There is disagreement about the best way to describe the functions of the lateral cerebellum: It is thought
to be involved in planning movement that is about to occur,[4] in evaluating sensory information for action,[] and in a
number of purely cognitive functions as well.[5]
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124
Cellular components
Two types of neuron play dominant roles in the
cerebellar circuit: Purkinje cells and granule cells.
Three types of axons also play dominant roles:
mossy fibers and climbing fibers (which enter the
cerebellum from outside), and parallel fibers
(which are the axons of granule cells). There are
two main pathways through the cerebellar circuit,
originating from mossy fibers and climbing
fibers, both eventually terminating in the deep
cerebellar nuclei.
Microcircuitry of the cerebellum. (+): excitatory; (-): inhibitory; MF: Mossy

fiber; DCN: Deep cerebellar nuclei; IO: Inferior olive; CF: Climbing fiber;
GC: Granule cell; PF: Parallel fiber; PC: Purkinje cell; GgC: Golgi cell; SC:
Stellate cell; BC: Basket cell
Transverse section of a cerebellar folium, showing principal cell

types and connections.
Mossy fibers project directly to the deep nuclei,

but also give rise to the pathway: mossy fiber
granule cells parallel fibers Purkinje cells
deep nuclei. Climbing fibers project to
Purkinje cells and also send collaterals directly to
the deep nuclei.[] The mossy fiber and climbing
fiber inputs each carry fiber-specific information;
the cerebellum also receives dopaminergic,
serotonergic, noradrenergic, and cholinergic
inputs that presumably perform global
modulation.[6]
The cerebellar cortex is divided into three layers.
At the bottom lies the thick granular layer,
densely packed with granule cells, along with
interneurons, mainly Golgi cells but also
including Lugaro cells and unipolar brush cells. In
the middle lies the Purkinje layer, a narrow zone
that contains only the cell bodies of Purkinje
cells. At the top lies the molecular layer, which
contains the flattened dendritic trees of Purkinje
cells, along with the huge array of parallel fibers
penetrating the Purkinje cell dendritic trees at
right angles. This outermost layer of the
cerebellar cortex also contains two types of
inhibitory interneurons, stellate cells, and basket
cells. Both stellate and basket cells form
GABAergic synapses onto Purkinje cell
dendrites.[]
Cerebellum
125
Purkinje cells
Purkinje cells are among the most distinctive neurons in the brain, and also
among the earliest types to be recognized they were first described by the
Czech anatomist Jan Evangelista Purkyn in 1837. They are distinguished by
the shape of the dendritic tree: The dendrites branch very profusely, but are
severely flattened in a plane perpendicular to the cerebellar folds. Thus, the
dendrites of a Purkinje cell form a dense planar net, through which parallel
fibers pass at right angles.[] The dendrites are covered with dendritic spines,
each of which receives synaptic input from a parallel fiber. Purkinje cells
receive more synaptic inputs than any other type of cell in the brain
estimates of the number of spines on a single human Purkinje cell run as high
as 200,000.[] The large, spherical cell bodies of Purkinje cells are packed into
a narrow layer (one cell thick) of the cerebellar cortex, called the Purkinje
layer. After emitting collaterals that innervate nearby parts of the cortex, their
axons travel into the deep cerebellar nuclei, where they make on the order of
1,000 contacts each with several types of nuclear cells, all within a small
domain. Purkinje cells use GABA as their neurotransmitter, and therefore
exert inhibitory effects on their targets.[]
Drawing of a Purkinje cell from cat

cerebellum
Purkinje cells form the heart of the cerebellar circuit, and their large size and distinctive activity patterns have made
it relatively easy to study their response patterns in behaving animals using extracellular recording techniques.
Purkinje cells normally emit action potentials at a high rate even in the absence of synaptic input. In awake, behaving
animals, mean rates averaging around 40Hz are typical. The spike trains show a mixture of what are called simple
and complex spikes. A simple spike is a single action potential followed by a refractory period of about 10ms; a
complex spike is a stereotyped sequence of action potentials with very short inter-spike intervals and declining
amplitudes.[citation needed] Physiological studies have shown that complex spikes (which occur at baseline rates
around 1Hz and never at rates much higher than 10Hz) are reliably associated with climbing fiber activation, while
simple spikes are produced by a combination of baseline activity and parallel fiber input. Complex spikes are often
followed by a pause of several hundred milliseconds during which simple spike activity is suppressed.[]
Granule cells
Cerebellar granule cells, in contrast to Purkinje cells, are among the smallest neurons in the brain. They are also
easily the most numerous neurons in the brain: In humans, estimates of their total number average around 50 billion,
which means that about 3/4 of the brain's neurons are cerebellar granule cells.[] Their cell bodies are packed into a
thick layer at the bottom of the cerebellar cortex. A granule cell emits only four to five dendrites, each of which ends
in an enlargement called a dendritic claw.[] These enlargements are sites of excitatory input from mossy fibers and
inhibitory input from Golgi cells.
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126
The thin, unmyelinated axons of granule cells rise vertically to the
upper (molecular) layer of the cortex, where they split in two, with
each branch traveling horizontally to form a parallel fiber; the splitting
of the vertical branch into two horizontal branches gives rise to a
distinctive "T" shape. A parallel fiber runs for an average of 3mm in
each direction from the split, for a total length of about 6mm (about
1/10 of the total width of the cortical layer).[] As they run along, the
parallel fibers pass through the dendritic trees of Purkinje cells,
contacting one of every 35 that they pass, making a total of 80100
synaptic connections with Purkinje cell dendritic spines.[] Granule cells
use glutamate as their neurotransmitter, and therefore exert excitatory
effects on their targets.
Granule cells receive all of their input from mossy fibers, but
outnumber them 200 to 1 (in humans). Thus, the information in the
granule cell population activity state is the same as the information in
the mossy fibers, but recoded in a much more expansive way. Because
granule cells are so small and so densely packed, it has been very difficult to record their spike activity in behaving
animals, so there is little data to use as a basis of theorizing. The most popular concept of their function was
proposed by David Marr, who suggested that they could encode combinations of mossy fiber inputs. The idea is that
with each granule cell receiving input from only 45 mossy fibers, a granule cell would not respond if only a single
one of its inputs were active, but would respond if more than one were active. This combinatorial coding scheme
would potentially allow the cerebellum to make much finer distinctions between input patterns than the mossy fibers
alone would permit.[]
Granule cells, parallel fibers, and Purkinje cells
with flattened dendritic trees
Mossy fibers
Mossy fibers enter the granular layer from their points of origin, many arising from the pontine nuclei, others from
the spinal cord, vestibular nuclei, etc. In the human cerebellum, the total number of mossy fibers has been estimated
at about 200 million.[] These fibers form excitatory synapses with the granule cells and the cells of the deep
cerebellar nuclei. Within the granular layer, a mossy fiber generates a series of enlargements called rosettes. The
contacts between mossy fibers and granule cell dendrites take place within structures called glomeruli. Each
glomerulus has a mossy fiber rosette at its center, and up to 20 granule cell dendritic claws contacting it. Terminals
from Golgi cells infiltrate the structure and make inhibitory synapses onto the granule cell dendrites. The entire
assemblage is surrounded by a sheath of glial cells.[] Each mossy fiber sends collateral branches to several cerebellar
folia, generating a total of 2030 rosettes; thus a single mossy fiber makes contact with an estimated 400600
granule cells.[]
Climbing fibers
Purkinje cells also receive input from the inferior olivary nucleus (IO) on the contralateral side of the brainstem, via
climbing fibers. Although the IO lies in the medulla oblongata, and receives input from the spinal cord, brainstem,
and cerebral cortex, its output goes entirely to the cerebellum. A climbing fiber gives off collaterals to the deep
cerebellar nuclei before entering the cerebellar cortex, where it splits into about 10 terminal branches, each of which
innervates a single Purkinje cell.[] In striking contrast to the 100,000-plus inputs from parallel fibers, each Purkinje
cell receives input from exactly one climbing fiber; but this single fiber "climbs" the dendrites of the Purkinje cell,
winding around them and making a total of up to 300 synapses as it goes.[] The net input is so strong that a single
action potential from a climbing fiber is capable of producing an extended complex spike in the Purkinje cell: a burst
of several spikes in a row, with diminishing amplitude, followed by a pause during which activity is suppressed. The
Cerebellum
127
climbing fiber synapses cover the cell body and proximal dendrites; this zone is devoid of parallel fiber inputs.[]
Climbing fibers fire at low rates, but a single climbing fiber action potential induces a burst of several action
potentials in a target Purkinje cell (a complex spike). The contrast between parallel fiber and climbing fiber inputs to
Purkinje cells (over 100,000 of one type versus exactly one of the other type) is perhaps the most provocative feature
of cerebellar anatomy, and has motivated much of the theorizing. In fact, the function of climbing fibers is the most
controversial topic concerning the cerebellum. There are two schools of thought, one following Marr and Albus in
holding that climbing fiber input serves primarily as a teaching signal, the other holding that its function is to shape
cerebellar output directly. Both views have been defended in great length in numerous publications. In the words of
one review, "In trying to synthesize the various hypotheses on the function of the climbing fibers, one has the sense
of looking at a drawing by Escher. Each point of view seems to account for a certain collection of findings, but when
one attempts to put the different views together, a coherent picture of what the climbing fibers are doing does not
appear. For the majority of researchers, the climbing fibers signal errors in motor performance, either in the usual
manner of discharge frequency modulation or as a single announcement of an 'unexpected event'. For other
investigators, the message lies in the degree of ensemble synchrony and rhythmicity among a population of climbing
fibers."[]
Deep nuclei
The deep nuclei of the cerebellum are clusters of gray matter lying
within the white matter at the core of the cerebellum. They are, with
the minor exception of the nearby vestibular nuclei, the sole sources of
output from the cerebellum. These nuclei receive collateral projections
from mossy fibers and climbing fibers, as well as inhibitory input from
the Purkinje cells of the cerebellar cortex. The three nuclei (dentate,
interpositus, and fastigial) each communicate with different parts of the
brain and cerebellar cortex. The fastigial and interpositus nuclei belong
to the spinocerebellum. The dentate nucleus, which in mammals is
much larger than the others, is formed as a thin, convoluted layer of
gray matter, and communicates exclusively with the lateral parts of the
cerebellar cortex. The flocculonodular lobe is the only part of the
cerebellar cortex that does not project to the deep nuclei its output
goes to the vestibular nuclei instead.[]
Cross-section of human cerebellum, showing the

dentate nucleus, as well as the pons and inferior
olivary nucleus
The majority of neurons in the deep nuclei have large cell bodies and spherical dendritic trees with a radius of about
400m, and use glutamate as their neurotransmitter. These cells project to a variety of targets outside the
cerebellum. Intermixed with them is a lesser number of small cells, which use GABA as neurotransmitter and project
exclusively to the inferior olivary nucleus, the source of climbing fibers. Thus, the nucleo-olivary projection
provides an inhibitory feedback to match the excitatory projection of climbing fibers to the nuclei. There is evidence
that each small cluster of nuclear cells projects to the same cluster of olivary cells that send climbing fibers to it;
there is strong and matching topography in both directions.[]
When a Purkinje cell axon enters one of the deep nuclei, it branches to make contact with both large and small
nuclear cells, but the total number of cells contacted is only about 35 (in cats). On the converse, a single deep nuclear
cell receives input from approximately 860 Purkinje cells (again in cats).[]
Cerebellum
Compartmentalization
From the viewpoint of gross anatomy, the cerebellar
cortex appears to be a homogeneous sheet of tissue,
and, from the viewpoint of microanatomy, all parts of
this sheet appear to have the same internal structure.
There are, however, a number of respects in which the
structure of the cerebellum is compartmentalized. There
are large compartments that are generally known as
zones; these can be decomposed into smaller
compartments known as microzones.[]
The first indications of compartmental structure came
from studies of the receptive fields of cells in various
Schematic illustration of the structure of zones and microzones in the
parts of the cerebellum cortex.[] Each body part maps to
cerebellar cortex
specific points in the cerebellum, but there are
numerous repetitions of the basic map, forming an
arrangement that has been called "fractured somatotopy".[7] A clearer indication of compartmentalization is obtained
by immunostaining the cerebellum for certain types of protein. The best-known of these markers are called "zebrins",
because staining for them gives rise to a complex pattern reminiscent of the stripes on a zebra. The stripes generated
by zebrins and other compartmentalization markers are oriented perpendicular to the cerebellar folds that is, they
are narrow in the mediolateral direction, but much more extended in the longitudinal direction. Different markers
generate different sets of stripes, and the widths and lengths vary as a function of location, but they all have the same
general shape.[]
Oscarsson in the late 1970s proposed that these cortical zones can be partitioned into smaller units called
microzones.[8] A microzone is defined as a group of Purkinje cells all having the same somatotopic receptive field.
Microzones were found to contain on the order of 1000 Purkinje cells each, arranged in a long, narrow strip, oriented
perpendicular to the cortical folds.[] Thus, as the adjoining diagram illustrates, Purkinje cell dendrites are flattened in
the same direction as the microzones extend, while parallel fibers cross them at right angles.
It is not only receptive fields that define the microzone structure: The climbing fiber input from the inferior olivary
nucleus is equally important. The branches of a climbing fiber (usually numbering about 10) usually innervate
Purkinje cells belonging to the same microzone. Moreover, olivary neurons that send climbing fibers to the same
microzone tend to be coupled by gap junctions, which synchronize their activity, causing Purkinje cells within a
microzone to show correlated complex spike activity on a millisecond time scale.[] Also, the Purkinje cells belonging
to a microzone all send their axons to the same small cluster of output cells within the deep cerebellar nuclei.[]
Finally, the axons of basket cells are much longer in the longitudinal direction than in the mediolateral direction,
causing them to be confined largely to a single microzone.[] The consequence of all this structure is that cellular
interactions within a microzone are much stronger than interactions between different microzones.
In 2005, Richard Apps and Martin Garwicz summarized evidence that microzones themselves form part of a larger
entity they call a multizonal microcomplex. Such a microcomplex includes several spatially separated cortical
microzones, all of which project to the same group of deep cerebellar neurons, plus a group of coupled olivary
neurons that project to all of the included microzones as well as to the deep nuclear area.[]
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Cerebellum
Function
The strongest clues to the function of the cerebellum have come from examining the consequences of damage to it.
Animals and humans with cerebellar dysfunction show, above all, problems with motor control, on the side of the
body ipsilateral to the damaged cerebellum. They continue to be able to generate motor activity, but it loses
precision, producing erratic, uncoordinated, or incorrectly timed movements. A standard test of cerebellar function is
to reach with the tip of the finger for a target at arm's length: A healthy person will move the fingertip in a rapid
straight trajectory, whereas a person with cerebellar damage will reach slowly and erratically, with many mid-course
corrections. Deficits in non-motor functions are more difficult to detect. Thus, the general conclusion reached
decades ago is that the basic function of the cerebellum is not to initiate movements, or to decide which movements
to execute, but rather to calibrate the detailed form of a movement.[]
Prior to the 1990s, the function of the cerebellum was almost universally believed to be purely motor-related, but
newer findings have brought that view strongly into question. Functional imaging studies have shown cerebellar
activation in relation to language, attention, and mental imagery; correlation studies have shown interactions
between the cerebellum and non-motoric areas of the cerebral cortex; and a variety of non-motor symptoms have
been recognized in people with damage that appears to be confined to the cerebellum.[9][] In particular, the
Cerebellar Cognitive Affective Syndrome has been described in adults [10] and children. [11]
Kenji Doya has argued that the function of the cerebellum is best understood not in terms of what behaviors it is
involved in but rather in terms of what neural computations it performs; the cerebellum consists of a large number of
more or less independent modules, all with the same geometrically regular internal structure, and therefore all, it is
presumed, performing the same computation. If the input and output connections of a module are with motor areas
(as many are), then the module will be involved in motor behavior; but, if the connections are with areas involved in
non-motor cognition, the module will show other types of behavioral correlates. The cerebellum, Doya proposes, is
best understood as a device for supervised learning, in contrast to the basal ganglia, which perform reinforcement
learning, and the cerebral cortex, which performs unsupervised learning.[]
Principles
The comparative simplicity and regularity of the cerebellar anatomy led to an early hope that it might imply a similar
simplicity of computational function, as expressed in one of the first books on cerebellar electrophysiology, The
Cerebellum as a Neuronal Machine by John C. Eccles, Masao Ito, and Janos Szentgothai.[12] Although a full
understanding of cerebellar function has remained elusive, at least four principles have been identified as important:
(1) feedforward processing, (2) divergence and convergence, (3) modularity, and (4) plasticity.
1. Feedforward processing: The cerebellum differs from most other parts of the brain (especially the cerebral
cortex) in that the signal processing is almost entirely feedforward - that is, signals move unidirectionally through the
system from input to output, with very little recurrent internal transmission. The small amount of recurrence that
does exist consists of mutual inhibition; there are no mutually excitatory circuits. This feedforward mode of
operation means that the cerebellum, in contrast to the cerebral cortex, cannot generate self-sustaining patterns of
neural activity. Signals enter the circuit, are processed by each stage in sequential order, and then leave. As Eccles,
Ito, and Szentgothai wrote, "This elimination in the design of all possibility of reverberatory chains of neuronal
excitation is undoubtedly a great advantage in the performance of the cerebellum as a computer, because what the
rest of the nervous system requires from the cerebellum is presumably not some output expressing the operation of
complex reverberatory circuits in the cerebellum but rather a quick and clear response to the input of any particular
set of information."[13]
2. Divergence and convergence: In the human cerebellum, information from 200 million mossy fiber inputs is
expanded to 40 billion granule cells, whose parallel fiber outputs then converge onto 15 million Purkinje cells.[]
Because of the way that they are lined up longitudinally, the 1000 or so Purkinje cells belonging to a microzone may
receive input from as many as 100 million parallel fibers, and focus their own output down to a group of less than 50
129
Cerebellum
deep nuclear cells.[] Thus, the cerebellar network receives a modest number of inputs, processes them very
extensively through its rigorously structured internal network, and sends out the results via a very limited number of
output cells.
3. Modularity: The cerebellar system is functionally divided into more or less independent modules, which probably
number in the hundreds to thousands. All modules have a similar internal structure, but different inputs and outputs.
A module (a multizonal microcompartment in the terminology of Apps and Garwicz) consists of a small cluster of
neurons in the inferior olivary nucleus, a set of long narrow strips of Purkinje cells in the cerebellar cortex
(microzones), and a small cluster of neurons in one of the deep cerebellar nuclei. Different modules share input from
mossy fibers and parallel fibers, but in other respects they appear to function independently the output of one
module does not appear to significantly influence the activity of other modules.[]
4. Plasticity: The synapses between parallel fibers and Purkinje cells, and the synapses between mossy fibers and
deep nuclear cells, are both susceptible to modification of their strength. In a single cerebellar module, input from as
many as a billion parallel fibers converges onto a group of less than 50 deep nuclear cells, and the influence of each
parallel fiber on those nuclear cells is adjustable. This arrangement gives tremendous flexibility for fine-tuning the
relationship between cerebellar inputs and outputs.[]
Learning
There is considerable evidence that the cerebellum plays an essential role in some types of motor learning. The tasks
where the cerebellum most clearly comes into play are those in which it is necessary to make fine adjustments to the
way an action is performed. There has, however, been much dispute about whether learning takes place within the
cerebellum itself, or whether it merely serves to provide signals that promote learning in other brain structures.[]
Most theories that assign learning to the circuitry of the cerebellum are derived from early ideas of David Marr and
James Albus, who postulated that climbing fibers provide a teaching signal that induces synaptic modification in
parallel fiberPurkinje cell synapses.[] Marr assumed that climbing fiber input would cause synchronously activated
parallel fiber inputs to be strengthened. Most later cerebellar-learning models, however, have followed Albus in
assuming that climbing fiber activity would be an error signal, and would cause synchronously activated parallel
fiber inputs to be weakened. Some of these later models, such as the Adaptive Filter model of Fujita[14] made
attempts to understand cerebellar function in terms of optimal control theory.
The idea that climbing fiber activity functions as an error signal has been examined in many experimental studies,
with some supporting it but others casting doubt.[] In a pioneering study by Gilbert and Thach from 1977, Purkinje
cells from monkeys learning a reaching task showed increased complex spike activity which is known to reliably
indicate activity of the cell's climbing fiber input during periods when performance was poor.[15] Several studies
of motor learning in cats observed complex spike activity when there was a mismatch between an intended
movement and the movement that was actually executed. Studies of the vestibulo-ocular reflex (which stabilizes the
visual image on the retina when the head turns) found that climbing fiber activity indicated "retinal slip", although
not in a very straightforward way.[]
One of the most extensively studied cerebellar learning tasks is the eyeblink conditioning paradigm, in which a
neutral conditioned stimulus such as a tone or a light is repeatedly paired with an unconditioned stimulus, such as an
air puff, that elicits a blink response. After such repeated presentations of the CS and US, the CS will eventually
elicit a blink before the US, a conditioned response or CR. Experiments showed that lesions localized either to a
specific part of the interpositus nucleus (one of the deep cerebellar nuclei) or to a few specific points in the cerebellar
cortex would abolish learning of a correctly timed blink response. If cerebellar outputs are pharmacologically
inactivated while leaving the inputs and intracellular circuits intact, learning takes place even while the animal fails
to show any response, whereas, if intracerebellar circuits are disrupted, no learning takes place these facts taken
together make a strong case that the learning, indeed, occurs inside the cerebellum.[16]
130
Cerebellum
131
Theories and computational models

The large base of knowledge about the anatomical structure and
behavioral functions of the cerebellum have made it a fertile ground for
theorizing there are perhaps more theories of the function of the
cerebellum than of any other part of the brain. The most basic
distinction among them is between "learning theories" and
"performance theories" that is, theories that make use of synaptic
plasticity within the cerebellum to account for its role in learning,
versus theories that account for aspects of ongoing behavior on the
basis of cerebellar signal processing. Several theories of both types
have been formulated as mathematical models and simulated using
computers.[]
Model of a cerebellar perceptron, as formulated

by James Albus
Perhaps the earliest "performance" theory was the "delay line"

hypothesis of Valentino Braitenberg. The original theory put forth by Braitenberg and Atwood in 1958 proposed that
slow propagation of signals along parallel fibers imposes predictable delays that allow the cerebellum to detect time
relationships within a certain window.[17] Experimental data did not support the original form of the theory, but
Braitenberg continued to argue for modified versions.[18] The hypothesis that the cerebellum functions essentially as
a timing system has also been advocated by Richard Ivry.[19] Another influential "performance" theory is the Tensor
Network Theory of Pellionisz and Llins, which provided an advanced mathematical formulation of the idea that the
fundamental computation performed by the cerebellum is to transform sensory into motor coordinates.[20]
Theories in the "learning" category almost all derive from early publications by David Marr[] and James Albus.[]
Marr's 1969 paper proposed that the cerebellum is a device for learning to associate elemental movements encoded
by climbing fibers with mossy fiber inputs that encode the sensory context. Albus proposed that a cerebellar Purkinje
cell functions as a perceptron, a neurally inspired abstract learning device. The most basic difference between the
Marr and Albus theories is that Marr assumed that climbing fiber activity would cause parallel fiber synapses to be
strengthened, whereas Albus proposed that they would be weakened. Albus also formulated his version as a software
algorithm he called a CMAC (Cerebellar Model Articulation Controller), which has been tested in a number of
applications.[21]
Pathology
The most salient symptoms of cerebellar dysfunction are motor-related
the specific symptoms depend on which part of the cerebellum is
involved and how it is disrupted. Damage to the flocculonodular lobe
(the vestibular part) may show up as a loss of equilibrium and, in
particular, an altered walking gait, with a wide stance that indicates
difficulty in balancing.[] Damage to the lateral zone, or the
cerebrocerebellum, results in problems with skilled voluntary and
planned movements. This can cause errors in the force, direction, speed
and amplitude of movements. Some manifestations include hypotonia
Altered walking gait of a woman with cerebellar
(decreased muscle tone), dysarthria (problems with speech
disease
articulation), dysmetria (problems judging distances or ranges of
movement), dysdiadochokinesia (inability to perform rapid alternating
movements), impaired check reflex or rebound phenomenon, and tremors (involuntary movement caused by
alternating contractions of opposing muscle groups).[22] Damage to the midline portion may disrupt whole-body
movements, whereas damage localized more laterally is more likely to disrupt fine movements of the hands or limbs.
Cerebellum
132
Damage to the upper part of the cerebellum tends to cause gait impairments and other problems with leg
coordination; damage to the lower part is more likely to cause uncoordinated or poorly aimed movements of the
arms and hands, as well as difficulties in speed.[] This complex of motor symptoms is called "ataxia". To identify
cerebellar problems, the neurological examination includes assessment of gait (a broad-based gait being indicative of
ataxia), finger-pointing tests and assessment of posture.[] If cerebellar dysfunction is indicated, a magnetic resonance
imaging scan can be used to obtain a detailed picture of any structural alterations that may exist.[23]
The list of medical problems that can produce cerebellar damage is
long: it includes stroke; hemorrhage; tumors; alcoholism; physical
trauma such as gunshot wounds; and chronic degenerative conditions
such as olivopontocerebellar atrophy.[] Some forms of migraine
headache may also produce temporary dysfunction of the cerebellum,
of variable severity.[24]
Aging
The lower trace shows an attempt by a patient

with cerebellar disease to reproduce the upper
trace.
The human cerebellum changes with age. These changes may differ
from those of other parts of the brain, for example the gene expression
pattern in the human cerebellum shows less age-related alteration than
in the cerebral cortex.[25] Some studies have reported reductions in
numbers of cells or volume of tissue, but the amount of data relating to
this question is not very large.[26][27]
Hemorrhage
Cerebellar hemorrhage is differentiated from other intracranial bleeding in that there is no hemiparesis. Symptoms
can include occipitial headaches, ataxia, nystagmus, gaze palsy, facial weakness and vomiting. The most important
risk factor is hypertension.[28] Early diagnosis is important since emergent decompression may be life-saving.[29]
Tumors
The cerebellum is occasionally afflicted by tumors. In adults, metastatic tumors are very common.
Tumors that commonly arise in the cerebellum include pilocytic astrocytomas, medulloblastomas (especially in
children), ependymomas, and hemangioblastomas (often in the context of von Hippel-Lindau syndrome).
Comparative anatomy and evolution

The circuits in the cerebellum are similar across all classes of
vertebrates, including fish, reptiles, birds, and mammals.[] There is also
an analogous brain structure in cephalopods with well-developed
brains, such as octopuses.[30] This has been taken as evidence that the
cerebellum performs functions important to all animal species with a
brain.
Cross-section of the brain of a porbeagle shark,

with the cerebellum highlighted
There is considerable variation in the size and shape of the cerebellum

in different vertebrate species. In amphibians, lampreys, and hagfish, the cerebellum is little developed; in the latter
two groups, it is barely distinguishable from the brain-stem. Although the spinocerebellum is present in these groups,
the primary structures are small paired nuclei corresponding to the vestibulocerebellum.[] The cerebellum is a bit
larger in reptiles, considerably larger in birds, and larger yet in mammals. The large paired and convoluted lobes
found in humans are typical of mammals, but the cerebellum is, in general, a single median lobe in other groups, and
Cerebellum
is either smooth or only slightly grooved. In mammals, the neocerebellum is the major part of the cerebellum by
mass, but, in other vertebrates, it is typically the spinocerebellum.[]
The cerebellum of cartilaginous and bony fishes is extraordinarily large and complex. In at least one important
respect, it differs in internal structure from the mammalian cerebellum: The fish cerebellum does not contain discrete
deep cerebellar nuclei. Instead, the primary targets of Purkinje cells are a distinct type of cell distributed across the
cerebellar cortex, a type not seen in mammals. In mormyrid fish (a family of weakly electrosensitive freshwater
fish), the cerebellum is considerably larger than the rest of the brain put together. The largest part of it is a special
structure called the valvula, which has an unusually regular architecture and receives much of its input from the
electrosensory system.[31]
The hallmark of the mammalian cerebellum is an expansion of the lateral lobes, whose main interactions are with the
neocortex. As monkeys evolved into great apes, the expansion of the lateral lobes continued, in tandem with the
expansion of the frontal lobes of the neocortex. In ancestral hominids, and in homo sapiens until the middle
Pleistocene period, the cerebellum continued to expand, but the frontal lobes expanded more rapidly. The most
recent period of human evolution, however, may actually have been associated with an increase in the relative size of
the cerebellum, as the neocortex reduced its size somewhat while the cerebellum expanded.[32]
Cerebellum-like structures
Many vertebrate species have brain areas that resemble the cerebellum in terms of cellular architecture and
neurochemistry.[] The only one found in mammals is the dorsal cochlear nucleus (DCN), one of the two primary
sensory nuclei that receive input directly from the auditory nerve. The DCN is a layered structure, with the bottom
layer containing granule cells similar to those of the cerebellum, giving rise to parallel fibers that rise to the
superficial layer and travel across it horizontally. The superficial layer contains a set of GABAergic neurons called
cartwheel cells that resemble Purkinje cells anatomically and chemically they receive parallel fiber input, but do
not have any inputs that resemble climbing fibers. The output neurons of the DCN are called fusiform cells. They are
glutamatergic, but also resemble Purkinje cells in some respects they have spiny, flattened superficial dendritic
trees that receive parallel fiber input, but they also have basal dendrites that receive input from auditory nerve fibers,
which travel across the DCN in a direction at right angles to the parallel fibers. The DCN is most highly developed
in rodents and other small animals, and is considerably reduced in primates. Its function is not well understood; the
most popular speculations relate it to spatial hearing in one way or another.[33]
Most species of fish and amphibians possess a lateral line system that senses pressure waves in water. One of the
brain areas that receives primary input from the lateral line organ, the medial octavolateral nucleus, has a
cerebellum-like structure, with granule cells and parallel fibers. In electrosensitive fish, the input from the
electrosensory system goes to the dorsal octavolateral nucleus, which also has a cerebellum-like structure. In
ray-finned fishes (by far the largest group), the optic tectum has a layer the marginal layer that is
cerebellum-like.[]
All of these cerebellum-like structures appear to be primarily sensory-related rather than motor-related. All of them
have granule cells that give rise to parallel fibers that connect to Purkinje-like neurons with modifiable synapses, but
none have climbing fibers comparable to those of the cerebellum instead they receive direct input from peripheral
sensory organs. None has a demonstrated function, but the most influential speculation is that they serve to transform
sensory inputs in some sophisticated way, perhaps to compensate for changes in body posture.[] In fact, James Bower
and others have argued, partly on the basis of these structures and partly on the basis of cerebellar studies, that the
cerebellum itself is fundamentally a sensory structure, and that it contributes to motor control by moving the body in
a way that controls the resulting sensory signals.[34]
133
Cerebellum
History
The distinctive appearance of the cerebellum caused even the earliest
anatomists to recognize it. Aristotle and Galen, however, did not
consider it truly part of the brain: They called it the parencephalon
("same-as-brain"), as opposed to the encephalon or brain proper. Galen
was the first to give an extensive description, noting that the cerebellar
tissue seemed more solid than the rest of the brain, he speculated that
its function is to strengthen the motor nerves.[35]
Further significant developments did not come until the Renaissance.
Vesalius discussed the cerebellum briefly, and the anatomy was
described more thoroughly by Thomas Willis in 1664. More
anatomical work was done during the 18th century, but it was not until
early in the 19th century that the first insights into the function of the
Base of the human brain, as drawn by Andreas
cerebellum were obtained. Luigi Rolando in 1809 established the key
Vesalius in 1543
insight that damage to the cerebellum results in motor disturbances.
Jean Pierre Flourens in the first half of the 19th century carried out detailed experimental work, which revealed that
animals with cerebellar damage can still move, but with a loss of coordination (strange movements, awkward gait,
and muscular weakness), and that recovery after the lesion can be nearly complete unless the lesion is very
extensive.[] By the dawn of the 20th century, it was widely accepted that the primary function of the cerebellum
relates to motor control; the first half of the 20th century produced several detailed descriptions of the clinical
symptoms associated with cerebellar disease in humans.[]
References
[1] http:/ / www. neurolex. org/ wiki/ birnlex_1489
[10] Schmahmann, J. D., & Sherman, J. C. "The cerebellar cognitive affective syndrome", Brain, 121(Pt 4), 561579, 1998.
[11] Levisohn, L., Cronin-Golomb, A., & Schmahmann, J. D. "Neuropsychological consequences of cerebellar tumour resection in children:
cerebellar cognitive affective syndrome in a paediatric population", Brain, 123(Pt 5), 10411050, 2000.
[13] The Cerebellum as a Neuronal Machine, p. 311
Further reading
Manto M-U, Pandolfo M (2002). The cerebellum and its disorders. Cambridge University Press.
ISBN978-0-521-77156-6.
Manto M (ed.). The Cerebellum (journal) (http://www.springer.com/biomed/neuroscience/journal/12311).
Springer New York. ISSN 1473-4222 (http://www.worldcat.org/issn/1473-4222).
External links
Cerebellum - Cell Centered Database (http://ccdb.ucsd.edu/sand/main?stype=lite&keyword=cerebellum&
Submit=Go&event=display&start=1)
BrainMaps at UCDavis cerebellum (http://brainmaps.org/index.php?q=cerebellum)
134
Brain
Brain
The brain is the center of the nervous system in all vertebrate and most
invertebrate animalsonly a few invertebrates such as sponges,
jellyfish, adult sea squirts and starfish do not have one, even if diffuse
neural tissue is present. It is located in the head, usually close to the
primary sensory organs for such senses as vision, hearing, balance,
taste, and smell. The brain of a vertebrate is the most complex organ of
its body. In a typical human the cerebral cortex (the largest part) is
estimated to contain 1533 billion neurons,[1] each connected by
synapses to several thousand other neurons. These neurons
communicate with one another by means of long protoplasmic fibers
called axons, which carry trains of signal pulses called action potentials
to distant parts of the brain or body targeting specific recipient cells.
Physiologically, the function of the brain is to exert centralized control
over the other organs of the body. The brain acts on the rest of the
A chimpanzee brain
body both by generating patterns of muscle activity and by driving
secretion of chemicals called hormones. This centralized control allows
rapid and coordinated responses to changes in the environment. Some basic types of responsiveness such as reflexes
can be mediated by the spinal cord or peripheral ganglia, but sophisticated purposeful control of behavior based on
complex sensory input requires the information-integrating capabilities of a centralized brain.
From a philosophical point of view, what makes the brain special in comparison to other organs is that it forms the
physical structure that generates the mind. As Hippocrates put it: "Men ought to know that from nothing else but the
brain come joys, delights, laughter and sports, and sorrows, griefs, despondency, and lamentations."[] Through much
of history, the mind was thought to be separate from the brain. Even for present-day neuroscience, the mechanisms
by which brain activity gives rise to consciousness and thought remain very challenging to understand: despite rapid
scientific progress, much about how the brain works remains a mystery. The operations of individual brain cells are
now understood in considerable detail, but the way they cooperate in ensembles of millions has been very difficult to
decipher. The most promising approaches treat the brain as a biological computer, very different in mechanism from
electronic computers, but similar in the sense that it acquires information from the surrounding world, stores it, and
processes it in a variety of ways.
This article compares the properties of brains across the entire range of animal species, with the greatest attention to
vertebrates. It deals with the human brain insofar as it shares the properties of other brains. The ways in which the
human brain differs from other brains are covered in the human brain article. Several topics that might be covered
here are instead covered there because much more can be said about them in a human context. The most important is
brain disease and the effects of brain damage, covered in the human brain article because the most common diseases
of the human brain either do not show up in other species, or else manifest themselves in different ways.
135
Brain
136
Anatomy
The shape and size of the brains of different species vary greatly, and
identifying common features is often difficult.[] Nevertheless, there are
a number of principles of brain architecture that apply across a wide
range of species.[] Some aspects of brain structure are common to
almost the entire range of animals species;[] others distinguish
"advanced" brains from more primitive ones, or distinguish vertebrates
from invertebrates.[]
Cross section of the olfactory bulb of a rat,
The simplest way to gain information about brain anatomy is by visual

stained in two different ways at the same time:
inspection, but many more sophisticated techniques have been
one stain shows neuron cell bodies, the other
shows receptors for the neurotransmitter GABA.
developed. Brain tissue in its natural state is too soft to work with, but
it can be hardened by immersion in alcohol or other fixatives, and then
sliced apart for examination of the interior. Visually, the interior of the brain consists of areas of so-called grey
matter, with a dark color, separated by areas of white matter, with a lighter color. Further information can be gained
by staining slices of brain tissue with a variety of chemicals that bring out areas where specific types of molecules
are present in high concentrations. It is also possible to examine the microstructure of brain tissue using a
microscope, and to trace the pattern of connections from one brain area to another.[]
Cellular structure
The brains of all species are composed primarily of two
broad classes of cells: neurons and glial cells. Glial
cells (also known as glia or neuroglia) come in several
types, and perform a number of critical functions,
including structural support, metabolic support,
insulation, and guidance of development. Neurons,
however, are usually considered the most important
cells in the brain.[2]
The property that makes neurons unique is their ability
to send signals to specific target cells over long
distances.[3] They send these signals by means of an
axon, which is a thin protoplasmic fiber that extends
from the cell body and projects, usually with numerous
branches, to other areas, sometimes nearby, sometimes
in distant parts of the brain or body. The length of an
axon can be extraordinary: for example, if a pyramidal
cell of the cerebral cortex were magnified so that its
cell body became the size of a human body, its axon,
equally magnified, would become a cable a few
Neurons generate electrical signals that travel along their axons.
centimeters in diameter, extending more than a
When a pulse of electricity reaches a junction called a synapse, it
[4]
kilometer. These axons transmit signals in the form
causes a neurotransmitter chemical to be released, which binds to
of electrochemical pulses called action potentials,
receptors on other cells and thereby alters their electrical activity.
which last less than a thousandth of a second and travel
along the axon at speeds of 1100 meters per second. Some neurons emit action potentials constantly, at rates of
10100 per second, usually in irregular patterns; other neurons are quiet most of the time, but occasionally emit a
burst of action potentials.[5]
Brain
137
Axons transmit signals to other neurons by means of specialized junctions called synapses. A single axon may make
as many as several thousand synaptic connections with other cells.[6] When an action potential, traveling along an
axon, arrives at a synapse, it causes a chemical called a neurotransmitter to be released. The neurotransmitter binds
to receptor molecules in the membrane of the target cell.[7]
Neurons often have extensive networks of

dendrites, which receive synaptic connections.
Shown is a pyramidal neuron from the
hippocampus, stained for green fluorescent
protein.
Synapses are the key functional elements of the brain.[] The essential
function of the brain is cell-to-cell communication, and synapses are
the points at which communication occurs. The human brain has been
estimated to contain approximately 100 trillion synapses;[8] even the
brain of a fruit fly contains several million.[9] The functions of these
synapses are very diverse: some are excitatory (excite the target cell);
others are inhibitory; others work by activating second messenger
systems that change the internal chemistry of their target cells in
complex ways.[] A large fraction of synapses are dynamically
modifiable; that is, they are capable of changing strength in a way that
is controlled by the patterns of signals that pass through them. It is
widely believed that activity-dependent modification of synapses is the
brain's primary mechanism for learning and memory.[]
Most of the space in the brain is taken up by axons, which are often
bundled together in what are called nerve fiber tracts. Many axons are
wrapped in thick sheaths of a fatty substance called myelin, which serves to greatly increase the speed of signal
propagation. Myelin is white, so parts of the brain filled exclusively with nerve fibers appear as light-colored white
matter, in contrast to the darker-colored grey matter that marks areas with high densities of neuron cell bodies.[10]
Evolution
The generic bilaterian nervous system
Except for a few primitive types such as
sponges (which have no nervous system[])
and cnidarians (which have a nervous
system consisting of a diffuse nerve net[]),
all living multicellular animals are
bilaterians, meaning animals with a
Nervous system of a generic bilaterian animal, in the form of a nerve cord with
bilaterally symmetric body shape (that is,
segmental enlargements, and a "brain" at the front
left and right sides that are approximate
mirror images of each other).[] All
bilaterians are thought to have descended from a common ancestor that appeared early in the Cambrian period,
550600 million years ago, and it has been hypothesized that this common ancestor had the shape of a simple
tubeworm with a segmented body.[] At a schematic level, that basic worm-shape continues to be reflected in the body
and nervous system architecture of all modern bilaterians, including vertebrates.[11] The fundamental bilateral body
form is a tube with a hollow gut cavity running from the mouth to the anus, and a nerve cord with an enlargement (a
ganglion) for each body segment, with an especially large ganglion at the front, called the brain. The brain is small
and simple in some species, such as nematode worms; in other species, including vertebrates, it is the most complex
organ in the body.[] Some types of worms, such as leeches, also have an enlarged ganglion at the back end of the
nerve cord, known as a "tail brain".[12]
There are a few types of existing bilaterians that lack a recognizable brain, including echinoderms, tunicates, and a
group of primitive flatworms called Acoelomorpha. It has not been definitively established whether the existence of
Brain
138
these brainless species indicates that the earliest bilaterians lacked a brain, or whether their ancestors evolved in a
way that led to the disappearance of a previously existing brain structure.[]
Invertebrates
This category includes arthropods, molluscs, and numerous types of
worms. The diversity of invertebrate body plans is matched by an
equal diversity in brain structures.[13]
Two groups of invertebrates have notably complex brains: arthropods
(insects, crustaceans, arachnids, and others), and cephalopods
(octopuses, squids, and similar molluscs).[] The brains of arthropods
and cephalopods arise from twin parallel nerve cords that extend
through the body of the animal. Arthropods have a central brain with
three divisions and large optical lobes behind each eye for visual
processing.[] Cephalopods such as the octopus and squid have the
largest brains of any invertebrates.[]
Fruit flies (Drosophila) have been extensively

studied to gain insight into the role of genes in
brain development.
There are several invertebrate species whose brains have been studied
intensively because they have properties that make them convenient for experimental work:
Fruit flies (Drosophila), because of the large array of techniques available for studying their genetics, have been a
natural subject for studying the role of genes in brain development.[14] In spite of the large evolutionary distance
between insects and mammals, many aspects of Drosophila neurogenetics have turned out to be relevant to
humans. The first biological clock genes, for example, were identified by examining Drosophila mutants that
showed disrupted daily activity cycles.[15] A search in the genomes of vertebrates turned up a set of analogous
genes, which were found to play similar roles in the mouse biological clockand therefore almost certainly in the
human biological clock as well.[16]
The nematode worm Caenorhabditis elegans, like Drosophila, has been studied largely because of its importance
in genetics.[17] In the early 1970s, Sydney Brenner chose it as a model system for studying the way that genes
control development. One of the advantages of working with this worm is that the body plan is very stereotyped:
the nervous system of the hermaphrodite morph contains exactly 302 neurons, always in the same places, making
identical synaptic connections in every worm.[18] Brenner's team sliced worms into thousands of ultrathin sections
and photographed every section under an electron microscope, then visually matched fibers from section to
section, to map out every neuron and synapse in the entire body.[19] Nothing approaching this level of detail is
available for any other organism, and the information has been used to enable a multitude of studies that would
not have been possible without it.[20]
The sea slug Aplysia was chosen by Nobel Prize-winning neurophysiologist Eric Kandel as a model for studying
the cellular basis of learning and memory, because of the simplicity and accessibility of its nervous system, and it
has been examined in hundreds of experiments.[21]
Brain
139
Vertebrates
The first vertebrates appeared over 500million years ago (Mya), during the
Cambrian period, and may have resembled the modern hagfish in form.[22]
Sharks appeared about 450Mya, amphibians about 400Mya, reptiles about
350Mya, and mammals about 200Mya. No modern species should be described
as more "primitive" than others, strictly speaking, since each has an equally long
evolutionary historybut the brains of modern hagfishes, lampreys, sharks,
amphibians, reptiles, and mammals show a gradient of size and complexity that
roughly follows the evolutionary sequence. All of these brains contain the same
set of basic anatomical components, but many are rudimentary in the hagfish,
whereas in mammals the foremost part (the telencephalon) is greatly elaborated
and expanded.[23]
The brain of a shark
Brains are most simply compared in terms of their size. The relationship between brain size, body size and other
variables has been studied across a wide range of vertebrate species. As a rule, brain size increases with body size,
but not in a simple linear proportion. In general, smaller animals tend to have larger brains, measured as a fraction of
body size: the animal with the largest brain-size-to-body-size ratio is the hummingbird. For mammals, the
relationship between brain volume and body mass essentially follows a power law with an exponent of about
0.75.[24] This formula describes the central tendency, but every family of mammals departs from it to some degree,
in a way that reflects in part the complexity of their behavior. For example, primates have brains 5 to 10 times larger
than the formula predicts. Predators tend to have larger brains than their prey, relative to body size.[25]
All vertebrate brains share a common underlying form,
which appears most clearly during early stages of
embryonic development. In its earliest form, the brain
appears as three swellings at the front end of the neural
tube; these swellings eventually become the forebrain,
midbrain, and hindbrain (the prosencephalon,
mesencephalon, and rhombencephalon, respectively).
At the earliest stages of brain development, the three
areas are roughly equal in size. In many classes of
vertebrates, such as fish and amphibians, the three parts
remain similar in size in the adult, but in mammals the
forebrain becomes much larger than the other parts, and
the midbrain becomes very small.[26]
The main subdivisions of the embryonic vertebrate brain, which later
differentiate into the forebrain, midbrain and hindbrain
The brains of vertebrates are made of very soft

tissue.[27] Living brain tissue is pinkish on the outside
and mostly white on the inside, with subtle variations in
color. Vertebrate brains are surrounded by a system of connective tissue membranes called meninges that separate
the skull from the brain. Blood vessels enter the central nervous system through holes in the meningeal layers. The
cells in the blood vessel walls are joined tightly to one another, forming the so-called bloodbrain barrier, which
protects the brain from toxins that might enter through the bloodstream.[]
Neuroanatomists usually divide the vertebrate brain into six main regions: the telencephalon (cerebral hemispheres),
diencephalon (thalamus and hypothalamus), mesencephalon (midbrain), cerebellum, pons, and medulla oblongata.
Each of these areas has a complex internal structure. Some parts, such as the cerebral cortex and cerebellum, consist
of layers that are folded or convoluted to fit within the available space. Other parts, such as the thalamus and
hypothalamus, consist of clusters of many small nuclei. Thousands of distinguishable areas can be identified within
Brain
140
the vertebrate brain based on fine distinctions of neural structure, chemistry, and connectivity.[27]
Although the same basic components are present in all vertebrate brains, some branches of vertebrate evolution have
led to substantial distortions of brain geometry, especially in the forebrain area. The brain of a shark shows the basic
components in a straightforward way, but in teleost fishes (the great majority of existing fish species), the forebrain
has become "everted", like a sock turned inside out. In birds, there are also major changes in forebrain structure.[28]
These distortions can make it difficult to match brain components from one species with those of another species.[29]
Here is a list of some of the most important vertebrate brain
components, along with a brief description of their functions as
currently understood:
The medulla, along with the spinal cord, contains many small
nuclei involved in a wide variety of sensory and motor functions.[30]
The pons lies in the brainstem directly above the medulla. Among
other things, it contains nuclei that control sleep, respiration,
swallowing, bladder function, equilibrium, eye movement, facial
expressions, and posture.[31]
The hypothalamus is a small region at the base of the forebrain,
whose complexity and importance belies its size. It is composed of
numerous small nuclei, each with distinct connections and
neurochemistry. The hypothalamus regulates sleep and wake cycles,
eating and drinking, hormone release, and many other critical
biological functions.[32]
The thalamus is another collection of nuclei with diverse functions.
Some are involved in relaying information to and from the cerebral
hemispheres. Others are involved in motivation. The subthalamic
area (zona incerta) seems to contain action-generating systems for
several types of "consummatory" behaviors, including eating,
drinking, defecation, and copulation.[33]
The main anatomical regions of the vertebrate

brain, shown for shark and human. The same
parts are present, but they differ greatly in size
and shape.
The cerebellum modulates the outputs of other brain systems to make them precise. Removal of the cerebellum
does not prevent an animal from doing anything in particular, but it makes actions hesitant and clumsy. This
precision is not built-in, but learned by trial and error. Learning how to ride a bicycle is an example of a type of
neural plasticity that may take place largely within the cerebellum.[34]
The optic tectum allows actions to be directed toward points in space, most commonly in response to visual
input. In mammals it is usually referred to as the superior colliculus, and its best-studied function is to direct eye
movements. It also directs reaching movements and other object-directed actions. It receives strong visual inputs,
but also inputs from other senses that are useful in directing actions, such as auditory input in owls and input from
the thermosensitive pit organs in snakes. In some fishes, such as lampreys, this region is the largest part of the
brain.[35] The superior colliculus is part of the midbrain.
The pallium is a layer of gray matter that lies on the surface of the forebrain. In reptiles and mammals, it is called
the cerebral cortex. Multiple functions involve the pallium, including olfaction and spatial memory. In mammals,
where it becomes so large as to dominate the brain, it takes over functions from many other brain areas. In many
mammals, the cerebral cortex consists of folded bulges called gyri that create deep furrows or fissures called
sulci. The folds increase the surface area of the cortex and therefore increase the amount of gray matter and the
amount of information that can be processed.[36]
The hippocampus, strictly speaking, is found only in mammals. However, the area it derives from, the medial
pallium, has counterparts in all vertebrates. There is evidence that this part of the brain is involved in spatial
memory and navigation in fishes, birds, reptiles, and mammals.[37]
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141
The basal ganglia are a group of interconnected structures in the forebrain. The primary function of the basal
ganglia appears to be action selection: they send inhibitory signals to all parts of the brain that can generate motor
behaviors, and in the right circumstances can release the inhibition, so that the action-generating systems are able
to execute their actions. Reward and punishment exert their most important neural effects by altering connections
within the basal ganglia.[]
The olfactory bulb is a special structure that processes olfactory sensory signals and sends its output to the
olfactory part of the pallium. It is a major brain component in many vertebrates, but is greatly reduced in
primates.[38]
Mammals
The most obvious difference between the brains of mammals and other vertebrates is in terms of size. On average, a
mammal has a brain roughly twice as large as that of a bird of the same body size, and ten times as large as that of a
reptile of the same body size.[]
Size, however, is not the only difference: there are also substantial differences in shape. The hindbrain and midbrain
of mammals are generally similar to those of other vertebrates, but dramatic differences appear in the forebrain,
which is greatly enlarged and also altered in structure.[] The cerebral cortex is the part of the brain that most strongly
distinguishes mammals. In non-mammalian vertebrates, the surface of the cerebrum is lined with a comparatively
simple three-layered structure called the pallium. In mammals, the pallium evolves into a complex six-layered
structure called neocortex or isocortex.[] Several areas at the edge of the neocortex, including the hippocampus and
amygdala, are also much more extensively developed in mammals than in other vertebrates.[]
The elaboration of the cerebral cortex carries with it changes to other brain areas. The superior colliculus, which
plays a major role in visual control of behavior in most vertebrates, shrinks to a small size in mammals, and many of
its functions are taken over by visual areas of the cerebral cortex.[] The cerebellum of mammals contains a large
portion (the neocerebellum) dedicated to supporting the cerebral cortex, which has no counterpart in other
vertebrates.[39]
Primates
Encephalization Quotient
[]
Species
EQ
Human
7.47.8
Chimpanzee
2.22.5
Rhesus monkey
2.1
Bottlenose dolphin 4.14[]

[40]
Elephant
1.132.36
Dog
1.2
Horse
0.9
Rat
0.4
The brains of humans and other primates contain the same structures as the brains of other mammals, but are
generally larger in proportion to body size.[] The most widely accepted way of comparing brain sizes across species
is the so-called encephalization quotient (EQ), which takes into account the nonlinearity of the brain-to-body
relationship.[] Humans have an average EQ in the 7-to-8 range, while most other primates have an EQ in the 2-to-3
range. Dolphins have values higher than those of primates other than humans,[] but nearly all other mammals have
Brain
EQ values that are substantially lower.
Most of the enlargement of the primate brain comes from a massive expansion of the cerebral cortex, especially the
prefrontal cortex and the parts of the cortex involved in vision.[41] The visual processing network of primates
includes at least 30 distinguishable brain areas, with a complex web of interconnections. It has been estimated that
visual processing areas occupy more than half of the total surface of the primate neocortex.[] The prefrontal cortex
carries out functions that include planning, working memory, motivation, attention, and executive control. It takes up
a much larger proportion of the brain for primates than for other species, and an especially large fraction of the
human brain.[42]
Physiology
The functions of the brain depend on the ability of neurons to transmit electrochemical signals to other cells, and
their ability to respond appropriately to electrochemical signals received from other cells. The electrical properties of
neurons are controlled by a wide variety of biochemical and metabolic processes, most notably the interactions
between neurotransmitters and receptors that take place at synapses.[7]
Neurotransmitters and receptors

Neurotransmitters are chemicals that are released at synapses when an action potential activates
themneurotransmitters attach themselves to receptor molecules on the membrane of the synapse's target cell, and
thereby alter the electrical or chemical properties of the receptor molecules. With few exceptions, each neuron in the
brain releases the same chemical neurotransmitter, or combination of neurotransmitters, at all the synaptic
connections it makes with other neurons; this rule is known as Dale's principle.[43] Thus, a neuron can be
characterized by the neurotransmitters that it releases. The great majority of psychoactive drugs exert their effects by
altering specific neurotransmitter systems. This applies to drugs such as marijuana, nicotine, heroin, cocaine,
alcohol, fluoxetine, chlorpromazine, and many others.[44]
The two neurotransmitters that are used most widely in the vertebrate brain are glutamate, which almost always
exerts excitatory effects on target neurons, and gamma-aminobutyric acid (GABA), which is almost always
inhibitory. Neurons using these transmitters can be found in nearly every part of the brain.[45] Because of their
ubiquity, drugs that act on glutamate or GABA tend to have broad and powerful effects. Some general anesthetics
act by reducing the effects of glutamate; most tranquilizers exert their sedative effects by enhancing the effects of
GABA.[46]
There are dozens of other chemical neurotransmitters that are used in more limited areas of the brain, often areas
dedicated to a particular function. Serotonin, for examplethe primary target of antidepressant drugs and many
dietary aidscomes exclusively from a small brainstem area called the Raphe nuclei.[47] Norepinephrine, which is
involved in arousal, comes exclusively from a nearby small area called the locus coeruleus.[] Other neurotransmitters
such as acetylcholine and dopamine have multiple sources in the brain, but are not as ubiquitously distributed as
glutamate and GABA.[48]
142
Brain
Electrical activity
As a side effect of the electrochemical processes used by neurons for
signaling, brain tissue generates electric fields when it is active. When
large numbers of neurons show synchronized activity, the electric
fields that they generate can be large enough to detect outside the skull,
using electroencephalography (EEG) [] or magnetoencephalography
(MEG). EEG recordings, along with recordings made from electrodes
implanted inside the brains of animals such as rats, show that the brain
of a living animal is constantly active, even during sleep.[] Each part of
the brain shows a mixture of rhythmic and nonrhythmic activity, which
may vary according to behavioral state. In mammals, the cerebral
cortex tends to show large slow delta waves during sleep, faster alpha
waves when the animal is awake but inattentive, and chaotic-looking
Brain electrical activity recorded from a human
irregular activity when the animal is actively engaged in a task. During
patient during an epileptic seizure
an epileptic seizure, the brain's inhibitory control mechanisms fail to
function and electrical activity rises to pathological levels, producing
EEG traces that show large wave and spike patterns not seen in a healthy brain. Relating these population-level
patterns to the computational functions of individual neurons is a major focus of current research in
neurophysiology.[]
Metabolism
All vertebrates have a bloodbrain barrier that allows metabolism inside the brain to operate differently from
metabolism in other parts of the body. Glial cells play a major role in brain metabolism, by controlling the chemical
composition of the fluid that surrounds neurons, including levels of ions and nutrients.[]
Brain tissue consumes a large amount of energy in proportion to its volume, so large brains place severe metabolic
demands on animals. The need to limit body weight in order, for example, to fly, has apparently led to selection for a
reduction of brain size in some species, such as bats.[49] Most of the brain's energy consumption goes into sustaining
the electric charge (membrane potential) of neurons.[] Most vertebrate species devote between 2% and 8% of basal
metabolism to the brain. In primates, however, the fraction is much higherin humans it rises to 2025%.[50] The
energy consumption of the brain does not vary greatly over time, but active regions of the cerebral cortex consume
somewhat more energy than inactive regions; this forms the basis for the functional brain imaging methods PET,
fMRI,[51] and NIRS.[52] The brain typically gets most of its energy from oxygen-dependent metabolism of glucose
(i.e., blood sugar),[] but ketones provide a major alternative source, together with contributions from medium chain
fatty acids (octanoic [53] and hexanoic [54] acids), lactate [55], acetate [56], and possibly amino acids.[57]
Functions
From an evolutionary-biological perspective, the function of the brain is to provide coherent control over the actions
of an animal. A centralized brain allows groups of muscles to be co-activated in complex patterns; it also allows
stimuli impinging on one part of the body to evoke responses in other parts, and it can prevent different parts of the
body from acting at cross-purposes to each other.[]
To generate purposeful and unified action, the brain first brings information from sense organs together at a central
location. It then processes this raw data to extract information about the structure of the environment. Next it
combines the processed sensory information with information about the current needs of an animal and with memory
of past circumstances. Finally, on the basis of the results, it generates motor response patterns that are suited to
maximize the welfare of the animal. These signal-processing tasks require intricate interplay between a variety of
143
Brain
functional subsystems.[]
Information processing
The invention of electronic computers in the 1940s, along with the development of mathematical information theory,
led to a realization that brains can potentially be understood as information processing systems. This concept formed
the basis of the field of cybernetics, and eventually gave rise to the field now known as computational neuroscience.[]
The earliest attempts at cybernetics were somewhat crude in that they treated the brain as essentially a digital
computer in disguise, as for example in John von Neumann's 1958 book, The Computer and the Brain.[58] Over the
years, though, accumulating information about the electrical responses of brain cells recorded from behaving animals
has steadily moved theoretical concepts in the direction of increasing realism.[]
The essence of the information processing approach is to try to
understand brain function in terms of information flow and
implementation of algorithms.[] One of the most influential early
contributions was a 1959 paper titled What the frog's eye tells the frog's
brain: the paper examined the visual responses of neurons in the retina
and optic tectum of frogs, and came to the conclusion that some
neurons in the tectum of the frog are wired to combine elementary
responses in a way that makes them function as "bug perceivers".[59] A
few years later David Hubel and Torsten Wiesel discovered cells in the
primary visual cortex of monkeys that become active when sharp edges
Model of a neural circuit in the cerebellum, as
move across specific points in the field of viewa discovery that
proposed by James S. Albus
[60]
eventually brought them a Nobel Prize.
Follow-up studies in
higher-order visual areas found cells that detect binocular disparity, color, movement, and aspects of shape, with
areas located at increasing distances from the primary visual cortex showing increasingly complex responses.[61]
Other investigations of brain areas unrelated to vision have revealed cells with a wide variety of response correlates,
some related to memory, some to abstract types of cognition such as space.[62]
Theorists have worked to understand these response patterns by constructing mathematical models of neurons and
neural networks, which can be simulated using computers.[] Some useful models are abstract, focusing on the
conceptual structure of neural algorithms rather than the details of how they are implemented in the brain; other
models attempt to incorporate data about the biophysical properties of real neurons.[63] No model on any level is yet
considered to be a fully valid description of brain function, though. The essential difficulty is that sophisticated
computation by neural networks requires distributed processing in which hundreds or thousands of neurons work
cooperativelycurrent methods of brain activity recording are only capable of isolating action potentials from a few
dozen neurons at a time.[64]
144
Brain
145
Perception
One of the primary functions of a brain is to extract biologically
relevant information from sensory inputs. The human brain is provided
with information about light, sound, the chemical composition of the
atmosphere, temperature, head orientation, limb position, the chemical
composition of the bloodstream, and more. In other animals additional
senses may be present, such as the infrared heat-sense of snakes, the
magnetic field sense of some birds, or the electric field sense of some
types of fish. Moreover, other animals may develop existing sensory
systems in new ways, such as the adaptation by bats of the auditory
sense into a form of sonar. One way or another, all of these sensory
modalities are initially detected by specialized sensors that project
signals into the brain.[65]
Diagram of signal processing in the auditory

system
Each sensory system begins with specialized receptor cells, such as light-receptive neurons in the retina of the eye,
vibration-sensitive neurons in the cochlea of the ear, or pressure-sensitive neurons in the skin. The axons of sensory
receptor cells travel into the spinal cord or brain, where they transmit their signals to a first-order sensory nucleus
dedicated to one specific sensory modality. This primary sensory nucleus sends information to higher-order sensory
areas that are dedicated to the same modality. Eventually, via a way-station in the thalamus, the signals are sent to
the cerebral cortex, where they are processed to extract biologically relevant features, and integrated with signals
coming from other sensory systems.[65]
Motor control
Motor systems are areas of the brain that are directly or indirectly involved in producing body movements, that is, in
activating muscles. Except for the muscles that control the eye, which are driven by nuclei in the midbrain, all the
voluntary muscles in the body are directly innervated by motor neurons in the spinal cord and hindbrain.[66] Spinal
motor neurons are controlled both by neural circuits intrinsic to the spinal cord, and by inputs that descend from the
brain. The intrinsic spinal circuits implement many reflex responses, and contain pattern generators for rhythmic
movements such as walking or swimming. The descending connections from the brain allow for more sophisticated
control.[67]
The brain contains several motor areas that project directly to the spinal cord. At the lowest level are motor areas in
the medulla and pons, which control stereotyped movements such as walking, breathing, or swallowing. At a higher
level are areas in the midbrain, such as the red nucleus, which is responsible for coordinating movements of the arms
and legs. At a higher level yet is the primary motor cortex, a strip of tissue located at the posterior edge of the frontal
lobe. The primary motor cortex sends projections to the subcortical motor areas, but also sends a massive projection
directly to the spinal cord, through the pyramidal tract. This direct corticospinal projection allows for precise
voluntary control of the fine details of movements. Other motor-related brain areas exert secondary effects by
projecting to the primary motor areas. Among the most important secondary areas are the premotor cortex, basal
ganglia, and cerebellum.[68]
Brain
146
Major areas involved in controlling movement

Area
Location
Function
[69]
Ventral horn
Spinal cord
Contains motor neurons that directly activate muscles
Oculomotor nuclei
Midbrain
Contains motor neurons that directly activate the eye muscles
Cerebellum
Hindbrain
[34]
Calibrates precision and timing of movements
Basal ganglia
Forebrain
Action selection on the basis of motivation
Motor cortex
Frontal lobe Direct cortical activation of spinal motor circuits
Premotor cortex
Frontal lobe Groups elementary movements into coordinated patterns[72]
[70]
[71]
Supplementary motor area Frontal lobe Sequences movements into temporal patterns[73]
Prefrontal cortex
Frontal lobe Planning and other executive functions[74]
In addition to all of the above, the brain and spinal cord contain extensive circuitry to control the autonomic nervous
system, which works by secreting hormones and by modulating the "smooth" muscles of the gut.[75] The autonomic
nervous system affects heart rate, digestion, respiration rate, salivation, perspiration, urination, and sexual arousal,
and several other processes. Most of its functions are not under direct voluntary control.
Arousal
Perhaps the most obvious aspect of the behavior of any animal is the daily cycle between sleeping and waking.
Arousal and alertness are also modulated on a finer time scale, though, by an extensive network of brain areas.[76]
A key component of the arousal system is the suprachiasmatic nucleus (SCN), a tiny part of the hypothalamus
located directly above the point at which the optic nerves from the two eyes cross. The SCN contains the body's
central biological clock. Neurons there show activity levels that rise and fall with a period of about 24 hours,
circadian rhythms: these activity fluctuations are driven by rhythmic changes in expression of a set of "clock genes".
The SCN continues to keep time even if it is excised from the brain and placed in a dish of warm nutrient solution,
but it ordinarily receives input from the optic nerves, through the retinohypothalamic tract (RHT), that allows daily
light-dark cycles to calibrate the clock.[77]
The SCN projects to a set of areas in the hypothalamus, brainstem, and midbrain that are involved in implementing
sleep-wake cycles. An important component of the system is the reticular formation, a group of neuron-clusters
scattered diffusely through the core of the lower brain. Reticular neurons send signals to the thalamus, which in turn
sends activity-level-controlling signals to every part of the cortex. Damage to the reticular formation can produce a
permanent state of coma.[76]
Sleep involves great changes in brain activity.[78] Until the 1950s it was generally believed that the brain essentially
shuts off during sleep,[79] but this is now known to be far from true; activity continues, but patterns become very
different. There are two types of sleep: REM sleep (with dreaming) and NREM (non-REM, usually without
dreaming) sleep, which repeat in slightly varying patterns throughout a sleep episode. Three broad types of distinct
brain activity patterns can be measured: REM, light NREM and deep NREM. During deep NREM sleep, also called
slow wave sleep, activity in the cortex takes the form of large synchronized waves, whereas in the waking state it is
noisy and desynchronized. Levels of the neurotransmitters norepinephrine and serotonin drop during slow wave
sleep, and fall almost to zero during REM sleep; levels of acetylcholine show the reverse pattern.[78]
Brain
Homeostasis
For any animal, survival requires maintaining a variety of parameters
of bodily state within a limited range of variation: these include
temperature, water content, salt concentration in the bloodstream,
blood glucose levels, blood oxygen level, and others.[] The ability of an
animal to regulate the internal environment of its bodythe milieu
intrieur, as pioneering physiologist Claude Bernard called itis
known as homeostasis (Greek for "standing still").[80] Maintaining
homeostasis is a crucial function of the brain. The basic principle that
underlies homeostasis is negative feedback: any time a parameter
Cross-section of a human head, showing location
diverges from its set-point, sensors generate an error signal that evokes
of the hypothalamus
a response that causes the parameter to shift back toward its optimum
value.[] (This principle is widely used in engineering, for example in the control of temperature using a thermostat.)
In vertebrates, the part of the brain that plays the greatest role is the hypothalamus, a small region at the base of the
forebrain whose size does not reflect its complexity or the importance of its function.[] The hypothalamus is a
collection of small nuclei, most of which are involved in basic biological functions. Some of these functions relate to
arousal or to social interactions such as sexuality, aggression, or maternal behaviors; but many of them relate to
homeostasis. Several hypothalamic nuclei receive input from sensors located in the lining of blood vessels,
conveying information about temperature, sodium level, glucose level, blood oxygen level, and other parameters.
These hypothalamic nuclei send output signals to motor areas that can generate actions to rectify deficiencies. Some
of the outputs also go to the pituitary gland, a tiny gland attached to the brain directly underneath the hypothalamus.
The pituitary gland secretes hormones into the bloodstream, where they circulate throughout the body and induce
changes in cellular activity.[81]
Motivation
According to evolutionary theory, all
species are genetically programmed to
act as though they have a goal of
surviving and propagating offspring.
At the level of an individual animal,
this overarching goal of genetic fitness
translates into a set of specific
survival-promoting behaviors, such as
seeking food, water, shelter, and a
mate.[82] The motivational system in
Components of the basal ganglia, shown in two cross-sections of the human brain. Blue:
caudate nucleus and putamen. Green: globus pallidus. Red: subthalamic nucleus. Black:
the brain monitors the current state of
substantia nigra.
satisfaction of these goals, and
activates behaviors to meet any needs
that arise. The motivational system works largely by a rewardpunishment mechanism. When a particular behavior
is followed by favorable consequences, the reward mechanism in the brain is activated, which induces structural
changes inside the brain that cause the same behavior to be repeated later, whenever a similar situation arises.
Conversely, when a behavior is followed by unfavorable consequences, the brain's punishment mechanism is
activated, inducing structural changes that cause the behavior to be suppressed when similar situations arise in the
future.[83]
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Brain
Every type of animal brain that has been studied uses a rewardpunishment mechanism: even worms and insects can
alter their behavior to seek food sources or to avoid dangers.[84] In vertebrates, the reward-punishment system is
implemented by a specific set of brain structures, at the heart of which lie the basal ganglia, a set of interconnected
areas at the base of the forebrain.[] There is substantial evidence that the basal ganglia are the central site at which
decisions are made: the basal ganglia exert a sustained inhibitory control over most of the motor systems in the brain;
when this inhibition is released, a motor system is permitted to execute the action it is programmed to carry out.
Rewards and punishments function by altering the relationship between the inputs that the basal ganglia receive and
the decision-signals that are emitted. The reward mechanism is better understood than the punishment mechanism,
because its role in drug abuse has caused it to be studied very intensively. Research has shown that the
neurotransmitter dopamine plays a central role: addictive drugs such as cocaine, amphetamine, and nicotine either
cause dopamine levels to rise or cause the effects of dopamine inside the brain to be enhanced.[85]
Learning and memory

Almost all animals are capable of modifying their behavior as a result of experienceeven the most primitive types
of worms. Because behavior is driven by brain activity, changes in behavior must somehow correspond to changes
inside the brain. Theorists dating back to Santiago Ramn y Cajal argued that the most plausible explanation is that
learning and memory are expressed as changes in the synaptic connections between neurons.[86] Until 1970,
however, experimental evidence to support the synaptic plasticity hypothesis was lacking. In 1971 Tim Bliss and
Terje Lmo published a paper on a phenomenon now called long-term potentiation: the paper showed clear evidence
of activity-induced synaptic changes that lasted for at least several days.[87] Since then technical advances have made
these sorts of experiments much easier to carry out, and thousands of studies have been made that have clarified the
mechanism of synaptic change, and uncovered other types of activity-driven synaptic change in a variety of brain
areas, including the cerebral cortex, hippocampus, basal ganglia, and cerebellum.[88]
Neuroscientists currently distinguish several types of learning and memory that are implemented by the brain in
distinct ways:
Working memory is the ability of the brain to maintain a temporary representation of information about the task
that an animal is currently engaged in. This sort of dynamic memory is thought to be mediated by the formation
of cell assembliesgroups of activated neurons that maintain their activity by constantly stimulating one
another.[89]
Episodic memory is the ability to remember the details of specific events. This sort of memory can last for a
lifetime. Much evidence implicates the hippocampus in playing a crucial role: people with severe damage to the
hippocampus sometimes show amnesia, that is, inability to form new long-lasting episodic memories.[90]
Semantic memory is the ability to learn facts and relationships. This sort of memory is probably stored largely in
the cerebral cortex, mediated by changes in connections between cells that represent specific types of
information.[91]
Instrumental learning is the ability for rewards and punishments to modify behavior. It is implemented by a
network of brain areas centered on the basal ganglia.[92]
Motor learning is the ability to refine patterns of body movement by practicing, or more generally by repetition.
A number of brain areas are involved, including the premotor cortex, basal ganglia, and especially the cerebellum,
which functions as a large memory bank for microadjustments of the parameters of movement.[93]
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Brain
Development
The brain does not simply grow, but rather
develops in an intricately orchestrated
sequence of stages.[94] It changes in shape
from a simple swelling at the front of the
nerve cord in the earliest embryonic stages,
to a complex array of areas and connections.
Neurons are created in special zones that
contain stem cells, and then migrate through
the tissue to reach their ultimate locations.
Once neurons have positioned themselves,
their axons sprout and navigate through the
brain, branching and extending as they go,
until the tips reach their targets and form
synaptic connections. In a number of parts
Brain of a human embryo in the sixth week of development
of the nervous system, neurons and synapses
are produced in excessive numbers during
the early stages, and then the unneeded ones are pruned away.[95]
For vertebrates, the early stages of neural development are similar across all species.[94] As the embryo transforms
from a round blob of cells into a wormlike structure, a narrow strip of ectoderm running along the midline of the
back is induced to become the neural plate, the precursor of the nervous system. The neural plate folds inward to
form the neural groove, and then the lips that line the groove merge to enclose the neural tube, a hollow cord of cells
with a fluid-filled ventricle at the center. At the front end, the ventricles and cord swell to form three vesicles that are
the precursors of the forebrain, midbrain, and hindbrain. At the next stage, the forebrain splits into two vesicles
called the telencephalon (which will contain the cerebral cortex, basal ganglia, and related structures) and the
diencephalon (which will contain the thalamus and hypothalamus). At about the same time, the hindbrain splits into
the metencephalon (which will contain the cerebellum and pons) and the myelencephalon (which will contain the
medulla oblongata). Each of these areas contains proliferative zones where neurons and glial cells are generated; the
resulting cells then migrate, sometimes for long distances, to their final positions.[94]
Once a neuron is in place, it extends dendrites and an axon into the area around it. Axons, because they commonly
extend a great distance from the cell body and need to reach specific targets, grow in a particularly complex way.
The tip of a growing axon consists of a blob of protoplasm called a growth cone, studded with chemical receptors.
These receptors sense the local environment, causing the growth cone to be attracted or repelled by various cellular
elements, and thus to be pulled in a particular direction at each point along its path. The result of this pathfinding
process is that the growth cone navigates through the brain until it reaches its destination area, where other chemical
cues cause it to begin generating synapses. Considering the entire brain, thousands of genes create products that
influence axonal pathfinding.[96]
The synaptic network that finally emerges is only partly determined by genes, though. In many parts of the brain,
axons initially "overgrow", and then are "pruned" by mechanisms that depend on neural activity.[97] In the projection
from the eye to the midbrain, for example, the structure in the adult contains a very precise mapping, connecting
each point on the surface of the retina to a corresponding point in a midbrain layer. In the first stages of
development, each axon from the retina is guided to the right general vicinity in the midbrain by chemical cues, but
then branches very profusely and makes initial contact with a wide swath of midbrain neurons. The retina, before
birth, contains special mechanisms that cause it to generate waves of activity that originate spontaneously at a
random point and then propagate slowly across the retinal layer. These waves are useful because they cause
neighboring neurons to be active at the same time; that is, they produce a neural activity pattern that contains
149
Brain
information about the spatial arrangement of the neurons. This information is exploited in the midbrain by a
mechanism that causes synapses to weaken, and eventually vanish, if activity in an axon is not followed by activity
of the target cell. The result of this sophisticated process is a gradual tuning and tightening of the map, leaving it
finally in its precise adult form.[]
Similar things happen in other brain areas: an initial synaptic matrix is generated as a result of genetically
determined chemical guidance, but then gradually refined by activity-dependent mechanisms, partly driven by
internal dynamics, partly by external sensory inputs. In some cases, as with the retina-midbrain system, activity
patterns depend on mechanisms that operate only in the developing brain, and apparently exist solely to guide
development.[]
In humans and many other mammals, new neurons are created mainly before birth, and the infant brain contains
substantially more neurons than the adult brain.[98] There are, however, a few areas where new neurons continue to
be generated throughout life. The two areas for which adult neurogenesis is well established are the olfactory bulb,
which is involved in the sense of smell, and the dentate gyrus of the hippocampus, where there is evidence that the
new neurons play a role in storing newly acquired memories. With these exceptions, however, the set of neurons that
is present in early childhood is the set that is present for life. Glial cells are different: as with most types of cells in
the body, they are generated throughout the lifespan.[99]
There has long been debate about whether the qualities of mind, personality, and intelligence can be attributed to
heredity or to upbringingthis is the nature versus nurture controversy.[100] Although many details remain to be
settled, neuroscience research has clearly shown that both factors are important. Genes determine the general form of
the brain, and genes determine how the brain reacts to experience. Experience, however, is required to refine the
matrix of synaptic connections, which in its developed form contains far more information than the genome does. In
some respects, all that matters is the presence or absence of experience during critical periods of development.[101] In
other respects, the quantity and quality of experience are important; for example, there is substantial evidence that
animals raised in enriched environments have thicker cerebral cortices, indicating a higher density of synaptic
connections, than animals whose levels of stimulation are restricted.[102]
Research
The field of neuroscience encompasses all approaches that seek to understand the
brain and the rest of the nervous system.[103] Psychology seeks to understand
mind and behavior, and neurology is the medical discipline that diagnoses and
treats diseases of the nervous system. The brain is also the most important organ
studied in psychiatry, the branch of medicine that works to study, prevent, and
treat mental disorders.[104] Cognitive science seeks to unify neuroscience and
psychology with other fields that concern themselves with the brain, such as
computer science (artificial intelligence and similar fields) and philosophy.[105]
The oldest method of studying the brain is anatomical, and until the middle of the
20th century, much of the progress in neuroscience came from the development
of better cell stains and better microscopes. Neuroanatomists study the
Human subject with EEG recording
large-scale structure of the brain as well as the microscopic structure of neurons
electrodes arranged around his head
and their components, especially synapses. Among other tools, they employ a
plethora of stains that reveal neural structure, chemistry, and connectivity. In
recent years, the development of immunostaining techniques has allowed investigation of neurons that express
specific sets of genes. Also, functional neuroanatomy uses medical imaging techniques to correlate variations in
human brain structure with differences in cognition or behavior.[106]
150
Brain
Neurophysiologists study the chemical, pharmacological, and electrical properties of the brain: their primary tools
are drugs and recording devices. Thousands of experimentally developed drugs affect the nervous system, some in
highly specific ways. Recordings of brain activity can be made using electrodes, either glued to the scalp as in EEG
studies, or implanted inside the brains of animals for extracellular recordings, which can detect action potentials
generated by individual neurons.[107] Because the brain does not contain pain receptors, it is possible using these
techniques to record brain activity from animals that are awake and behaving without causing distress. The same
techniques have occasionally been used to study brain activity in human patients suffering from intractable epilepsy,
in cases where there was a medical necessity to implant electrodes to localize the brain area responsible for epileptic
seizures.[108] Functional imaging techniques such as functional magnetic resonance imaging are also used to study
brain activity; these techniques have mainly been used with human subjects, because they require a conscious subject
to remain motionless for long periods of time, but they have the great advantage of being noninvasive.[109]
Another approach to brain function is to
examine the consequences of damage to
specific brain areas. Even though it is
protected by the skull and meninges,
surrounded by cerebrospinal fluid, and
isolated from the bloodstream by the
bloodbrain barrier, the delicate nature of
the brain makes it vulnerable to numerous
diseases and several types of damage. In
humans, the effects of strokes and other
types of brain damage have been a key
source of information about brain function.
Design of an experiment in which brain activity from a monkey was used to
Because there is no ability to experimentally
[110]
control a robotic arm
control the nature of the damage, however,
this information is often difficult to
interpret. In animal studies, most commonly involving rats, it is possible to use electrodes or locally injected
chemicals to produce precise patterns of damage and then examine the consequences for behavior.[111]
Computational neuroscience encompasses two approaches: first, the use of computers to study the brain; second, the
study of how brains perform computation. On one hand, it is possible to write a computer program to simulate the
operation of a group of neurons by making use of systems of equations that describe their electrochemical activity;
such simulations are known as biologically realistic neural networks. On the other hand, it is possible to study
algorithms for neural computation by simulating, or mathematically analyzing, the operations of simplified "units"
that have some of the properties of neurons but abstract out much of their biological complexity. The computational
functions of the brain are studied both by computer scientists and neuroscientists.[]
Recent years have seen increasing applications of genetic and genomic techniques to the study of the brain.[] The
most common subjects are mice, because of the availability of technical tools. It is now possible with relative ease to
"knock out" or mutate a wide variety of genes, and then examine the effects on brain function. More sophisticated
approaches are also being used: for example, using Cre-Lox recombination it is possible to activate or deactivate
genes in specific parts of the brain, at specific times.[]
151
Brain
152
History
Early philosophers were divided as to whether the seat of the soul lies
in the brain or heart. Aristotle favored the heart, and thought that the
function of the brain was merely to cool the blood. Democritus, the
inventor of the atomic theory of matter, argued for a three-part soul,
with intellect in the head, emotion in the heart, and lust near the liver.[]
Hippocrates, the "father of medicine", came down unequivocally in
favor of the brain. In his treatise on epilepsy he wrote:
Men ought to know that from nothing else but the brain come
joys, delights, laughter and sports, and sorrows, griefs,
despondency, and lamentations. ... And by the same organ we
become mad and delirious, and fears and terrors assail us, some
by night, and some by day, and dreams and untimely
wanderings, and cares that are not suitable, and ignorance of
present circumstances, desuetude, and unskillfulness. All these
things we endure from the brain, when it is not healthy...
Illustration by Ren Descartes of how the brain

implements a reflex response
Hippocrates, On the Sacred Disease[]
Andreas Vesalius' Fabrica,

published in 1543, showing the base
of the human brain, including optic
chiasma, cerebellum, olfactory bulbs,
etc.
The Roman physician Galen also argued for the importance of the brain, and
theorized in some depth about how it might work. Galen traced out the
anatomical relationships among brain, nerves, and muscles, demonstrating that
all muscles in the body are connected to the brain through a branching network
of nerves. He postulated that nerves activate muscles mechanically by carrying a
mysterious substance he called pneumata psychikon, usually translated as
"animal spirits".[] Galen's ideas were widely known during the Middle Ages, but
not much further progress came until the Renaissance, when detailed anatomical
study resumed, combined with the theoretical speculations of Ren Descartes and
those who followed him. Descartes, like Galen, thought of the nervous system in
hydraulic terms. He believed that the highest cognitive functions are carried out
by a non-physical res cogitans, but that the majority of behaviors of humans, and
all behaviors of animals, could be explained mechanistically.[112]
The first real progress toward a modern understanding of nervous function,

though, came from the investigations of Luigi Galvani, who discovered that a shock of static electricity applied to an
exposed nerve of a dead frog could cause its leg to contract. Since that time, each major advance in understanding
has followed more or less directly from the development of a new technique of investigation. Until the early years of
the 20th century, the most important advances were derived from new methods for staining cells.[113] Particularly
critical was the invention of the Golgi stain, which (when correctly used) stains only a small fraction of neurons, but
stains them in their entirety, including cell body, dendrites, and axon. Without such a stain, brain tissue under a
microscope appears as an impenetrable tangle of protoplasmic fibers, in which it is impossible to determine any
structure. In the hands of Camillo Golgi, and especially of the Spanish neuroanatomist Santiago Ramn y Cajal, the
new stain revealed hundreds of distinct types of neurons, each with its own unique dendritic structure and pattern of
connectivity.[114]
Brain
153
In the first half of the 20th century, advances in electronics enabled

investigation of the electrical properties of nerve cells, culminating in
work by Alan Hodgkin, Andrew Huxley, and others on the biophysics
of the action potential, and the work of Bernard Katz and others on the
electrochemistry of the synapse.[115] These studies complemented the
anatomical picture with a conception of the brain as a dynamic entity.
Reflecting the new understanding, in 1942 Charles Sherrington
visualized the workings of the brain waking from sleep:
The great topmost sheet of the mass, that where hardly a light
had twinkled or moved, becomes now a sparkling field of
rhythmic flashing points with trains of traveling sparks hurrying
hither and thither. The brain is waking and with it the mind is
returning. It is as if the Milky Way entered upon some cosmic
dance. Swiftly the head mass becomes an enchanted loom where
millions of flashing shuttles weave a dissolving pattern, always a
meaningful pattern though never an abiding one; a shifting
harmony of subpatterns.
Drawing by Santiago Ramn y Cajal of two types

of Golgi-stained neurons from the cerebellum of
a pigeon
Sherrington, 1942, Man on his Nature[116]

In the second half of the 20th century, developments in chemistry, electron microscopy, genetics, computer science,
functional brain imaging, and other fields progressively opened new windows into brain structure and function. In
the United States, the 1990s were officially designated as the "Decade of the Brain" to commemorate advances made
in brain research, and to promote funding for such research.[117]
In the 21st century, these trends have continued, and several new approaches have come into prominence, including
multielectrode recording, which allows the activity of many brain cells to be recorded all at the same time;[118]
genetic engineering, which allows molecular components of the brain to be altered experimentally;[] and genomics,
which allows variations in brain structure to be correlated with variations in DNA properties.[119]
References
[2] Principles of Neural Science p. 20
[3] Principles of Neural Science, p. 21
[6] Principles of Neural Science, Ch.10, p. 175
[7] Principles of Neural Science, Ch. 10
[26] Principles of Neural Science, p. 1019
[30] Principles of Neural Science, Chs. 44, 45
[53] http:/ / www. jneurosci. org/ content/ 23/ 13/ 5928. full
[54] http:/ / www. nature. com/ jcbfm/ journal/ v33/ n2/ abs/ jcbfm2012151a. html
[55] http:/ / www. jneurosci. org/ content/ 30/ 42/ 13983. full
[56] http:/ / onlinelibrary. wiley. com/ doi/ 10. 1111/ j. 1471-4159. 2009. 05895. x/ full
[67] Principles of Neural Science, Chs. 36, 37
Brain
[94] Principles of Neural Development, Ch. 1
[96] Principles of Neural Development, Chs. 5, 7
Further reading
Kandel, ER; Schwartz, JH; Jessel, TM (2000). Principles of Neural Science. McGraw-Hill Professional.
ISBN978-0-8385-7701-1.
Purves, D; Lichtman, J (1985). Principles of Neural Development (http://books.google.com/
?id=t9JqAAAAMAAJ). Sinauer Associates. ISBN978-0-87893-744-8.
External links
Brain Museum (http://brainmuseum.org/), comparative mammalian brain collection
BrainInfo (http://braininfo.rprc.washington.edu), neuroanatomy database
Neuroscience for Kids (http://faculty.washington.edu/chudler/neurok.html)
BrainMaps.org (http://www.brainmaps.org/), interactive high-resolution digital brain atlas of primate and
non-primate brains
The Brain from Top to Bottom (http://thebrain.mcgill.ca), at McGill University
The HOPES Brain Tutorial (http://www.stanford.edu/group/hopes/cgi-bin/wordpress/?p=3787), at Stanford
University
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5) Neurosience

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5) Neurosience

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Neuroscience

Central nervous system

Myelin basic protein

Image Sources, Licenses and Contributors

American Society for Neurochemistry

Activated Astrocytes in Cortex of TgAPP mouse

Cultured Astrocyte. Green

American Society for Neurochemistry

American Society for Neurochemistry

ASN NEURO, the ASN journal home page (http://www.asnneuro.org/)

Other Neurochemistry Societies

Central nervous system

Brain regions of a 4 week old human embryo

Central Brain Prosencephalon Telencephalon

Rhinencephalon, Amygdala, Hippocampus, Neocortex, Basal ganglia, Lateral ventricles

Central nervous system

Diseases of the central nervous system

Sylvius: 400+ structure neuroanatomical visual glossary (http://www.sylvius.com)

Excitatory and inhibitory

Lateral tegmental field

motor system, reward, cognition, endocrine, nausea

caudal dorsal raphe nucleus

medial septal nucleus

Small: Amino acids

Small: Amino acids

Metabotropic glutamate receptors;

Glutamate (glutamic acid)

Metabotropic glutamate receptor

NMDA receptor, Kainate

Small: Amino acids

GABAA, GABAA- receptor

Small: Amino acids

Muscarinic acetylcholine receptor

Serotonin receptor, all but 5-HT3

Small: Diamine (His)

PP: Neurohypophyseals Vasopressin

PP: Neurohypophyseals Oxytocin

PP: Neurohypophyseals Neurophysin I

PP: Neurohypophyseals Neurophysin II

Corticotropin (adrenocorticotropic ACTH

Vasoactive intestinal peptide

Vasoactive intestinal peptide

Growth hormone-releasing factor

Gastrin releasing peptide

Soluble guanylyl cyclase

Heme bound to potassium

Degradation and elimination

128C, 401K, 262F

linked to a catechol structure called dihydroxyphenethylamine, the decarboxylated form of dihydroxyphenylalanine

Major dopamine pathways. As part of the reward

The substantia nigra, a small midbrain area that forms a component

Increase intracellular levels of cAMP

Decrease intracellular levels of

The substantia nigra dopamine system and motor control

The ventral tegmental area, reward, and cognition

Reinforcement and reward-seeking behavior

Other brain functions

Evolution and cross-species comparisons

Effects of drugs that reduce dopamine activity

L-Tyrosine L-DOPA Dopamine

is converted into L-tyrosine by the enzyme phenylalanine

Storage, release, and reuptake

Dopamine DOPAL, mediated by MAO