Transcribed by Tina Park

Thursday, January 30, 2014

Neuroscience Lecture 14 Central Nervous System & Review by Dr. Jean-Pierre Saint-Jeannet [In continuation of CNS Part VI] [54] C- Regeneration in the CNS Dr. Jean-Pierre Saint-Jeannet If you have damage to CNS it is usually a permanent damage. The reason for so we dont have a full understanding of why this is happening but we have some clue that this is not happening in the CNS. This is the environment that the axon is growing is the limiting factor for that process to take place. The environment in the CNS is described as non-permissive for regeneration. One of the cell types that is the most critical in that aspect are the astrocytes that you found in the CNS. As an axon is being damaged in the CNS, the astrocytes that are in the vincinity of the axon will go through process known as astroglial scarring. Where there is a proliferation that is going to take place probably as a result of some of the factors that are being released by those cells that have been damaged in the process of nerve injury. There is astroglial reaction that takes place. Astroglial scarring. Those astrocytes have to proliferate and essentially create a physical barrier at the end of the damage axon and prevent the physical growth of this axon. Not only that but there is also a number of molecule that are secreted by the astrocyte inhibiting the growth of those neurons. In addition to that, another factor that is also involved in this inhibitory activity on the regenerative capacity of the damaged axon in the CNS is the myelin that is coming from those oligodendroctyes that have been damaged that stick around for a longer time. They are not removed by macrophage like you see in the PNS and those are inhibitory activity on the growth of those axons. [55] Central axons fail to regenerate Dr. Jean-Pierre Saint-Jeannet So I found this drawing from uh its not in your powerpoint. I uploaded earlier this morning, a powerpoint with this diagram. I found out just last week in a review that was published in Developmental Cell, last week. That is focusing on the comparison. If youre interested in the reference I can email you that. Comparison of regeneration capacity of axon in PNS and CNS. Its just a way to illustrate here those two inhibitory factors that are preventing those axons to grow. This is the axon and here is where it has been damaged. Whahts been represented here is the astrocyte reaction that takes place. It starts to proliferate and secrete most specifically chondroitin sulfate proteoglyacns CSPGs which is a molecule you found in the extracellular matrix ECM that have an inhibitory growth on the axon. In addition to that, the myelin debris that are at the end of the damaged portion of the axon remain on site and have an inhibitory activity on the growth of the axon. Student: [I cant hear] Dr. SJ the reason for that happening. We dont know. We know that if take a neuron from the PNS and challenge it with those CSPGs that will prevent the growth of the axon. So we know it has inhibotry activity. How it mediated, we dont understand how. So this is some of the difference between CNS and PNS. If you are interested in looking at this, its a very very well-done review, that analyzes all those aspects and point out some of

the lack of knowledge we have in that respect. Whats interesting is that in Schwann cell also secrete those chondroitin proteoglycans but they dont have the inhibitory activity in the PNS. And so people believe that it could be amount or level of expression in those proteoglycans present in the CNS vs. PNS. Especially in this context of this scarring reaction that the astrocytes are going through. So you have ..preparation of astrocytes and they make a lot of that compound. [56] D- Adult Neural Stem Cells (NSCs) Dr. Jean-Pierre Saint-Jeannet Okay a few words about stem cells associated with the nervous system, the CNS. There is as you may know a number of tissues that have a natural ability to regenerate. That is the case of the liver, which is believed to have a very small population of stem cells associated with the liver and injury can regenerate quite well. Not only this population of stem cells that ire presented but also believed that there are some of those cells that are found in different compartments of the liver can differentiate and compensate for the loss of damaged tissue. So in case of the liver, there is a now growing number of evidence that most organs of the body have small population of stem cells associated with them. You heard about the lecture about the skin, which is a very nice example. The skin and the hair follicle are these small group of cells of stem cells which is associated with each hair follicle that are known as small group of cell that are associated with this hair follicle that has the ability upon injury not only to regenerate the layer of the epidermis but also the ability to regenerate sebaceous gland and also regenerate hair and hair follicle by itself. So pretty much every organ, the more we look at them, we have been able to identify small pool of cell that are associated with this involving regeneration. There is recent evidence that in dorsal root ganglia, there is a small group of fraction of population found in the DRG that have stem cell like- that are quiescent, that have ability under certain experimental conditions to produce neurons and satellite cells in the DRG. So there is this small pool that are present in the different tissues. The evidence for stem cell in the CNS has been more difficult to evaluate. And only very recently that there is evidence that CNS contains, as least the brain contains a small number of stem cells. So what are stem cells by definition? They are defined by two different properties. The first one is that a stem cell is a cell that has the ability to divide indefintitely. So when it divides, the stem cell has ability to give rise to another stem cell so you dont loose the pool of stem cell. And they have the ability to give rise to a common progenitor to multiple different cell types. So in the case of the CNS this NSC that divides give rise to NSC and give rise to common progenitor that can give rise to a neuronal progenitor that will give rise to neuron. And glial progenitor that will give rise to astrocytes and oligodendrocytes. So thats the basic definition of a NSC. Capacity to self renew and capacity to give rise to different derivatives. [57] Subventricular zone (SVZ) of the lateral ventricle as a source of NSCs Dr. Jean-Pierre Saint-Jeannet So recent evidence suggest that there is a small group of cell that are associated with the lateral ventricle in the brain. Its known as the SVZ of the lateral ventricle, which is the source of stem cells. For a while it was believed that those cells were coming from this ependyma cells that are lining the ventricles, we talked about already its one of the four glial cell of the CNS. Those cells are not really the pool of stem cells. The actual pool of stem cells derive from this population here, which is a population

of GFAP-expressing cells that are found in this region that have ability to give rise not only to neuron but also to astrocytes and oligodendrocytes. If you remember GFAP is this intermediate filament that is found specifically in the astrocyte. And this GFAP population, the GFAP-expressing cell appear to have the ability to differentiate in some sort and give rise to those three different cell types: neurons, astrocytes, and oligodendrocytes. That was shown in in-vivo as well as in-vitro. So thats what I wanted to tell you in a nutshell about regeneration in the nervous system and some of those differences in the PNS and CNS. And now I will like to take the rest of the time, we have next thirty minutes to maybe go through a review of the material that we covered during those 4 lectures. And in preparation for the quiz you will have Wednesday. [Part VII- Review] [1] Neurohistology and Nervous System Structure: REVIEW Dr. Jean-Pierre Saint-Jeannet So this set of lecture was dedicated at the each of the Nervous System to look at the organization and composition of the NS in general. [2] I- Organization and composition of the Nervous system [3] Functional divisions of the nervous system. Dr. Jean-Pierre Saint-Jeannet So we talked about the different components of the NS anatomically and the view of the function of the NS and the different components of the CNS and PNS and what makes anatomically different the central from the PNS. [4] Development of the Nervous System Dr. Jean-Pierre Saint-Jeannet We also talked about the development of the NS. And one thing important to remember is that the NS is derived from the ectorderm and during the process of neuralation, the ectoderm become divided into three different domains. One that becomes the non-neural ectoderm that gives rise to epidermis. One that gives rise to neural plate will form into the neural tube that gives rise to the CNS, brain and spinal cord. And then the third domain that is the forming during that process is the neural crest which is this population of cells that are derived from the dorsal aspect of the neural tube and will migrate to quite a distant to give rise a quite a number of derivatives. But one most critical for this course is that they will contribute to the PNS. So we talked about the enteric nervous system ENS. If you remember those neurons that we found in the two plexuses associated with the digestive tract. All those neurons are derived from the neural crest. [5] Neuron structure Dr. Jean-Pierre Saint-Jeannet We also talked about the structure of neuron and different compartments of the neuron. The cell body characterized by presence of nissl bodies which are very important landmarks to identify those neurons. The only cells in body to have those structures, the nissl bodies, which are sacs of rER. This region here which his devoid of nissl bodies which is known as the axon hillock which is the region for which the nerve impulse is initiated before it propagated along the axon. Coming off the cell body we find the dendrites that make connections with other neurons that carry those dendritic spines

that wil be involved in the synaptic transmission. The axon itself that conduct the impulse towards the synaptic terminasl which will be involved in the transmission. So this is the step in where the electric impulse here is converted into the chemical signal for the transmission of information. [6] Synapse Dr. Jean-Pierre Saint-Jeannet We talked about synapse. And you will hear more about that in lectures by Dr. Schiff. Just to summarize briefly, here the different steps that are involved in synaptic transmission. So we are looking here at the terminal bouton of the presynaptic neuron. And here is the membrane of the postsynaptic cell. The nerve impulse is propagated along the axon and when it arrives at the terminal bouton, one of the first response is the opening of the voltage-gated calcium channels. Which leads to an influx of calcium at the terminal bouton. This calcium influx leads to detachment of the seminal vesicles that contain the neurotransmitters; detachment from the microtubules which are essential for carrying those neurotransmitters all the way to the terminal bouton. And also at the same time, fusion of those vesicles with the presynaptic PM. The neurotransmitters are released into the synaptic cleft and interact with the ligand-gated channels. So the neurotransmitter will bdin to the ligand-gated channel and lead to influx of Na+ or Cldepending on the type of synapse, and that will lead to the propagation of nerve impulse. The neurotransmitter doesnt stick around in the synaptic cleft. It will either be degraded or recycled by uptake. The presynaptic bouton will take back most of the neurotransmitters. 80% of it is recycled [7] Neurotransmitters Dr. Jean-Pierre Saint-Jeannet we talk about some neurotransmitters. And you will hear more about that. Achetylcholine, catecholamines, GABA, serotonine, and small peptides. [8] Classifications of neurons Dr. Jean-Pierre Saint-Jeannet We talk bout classification of neurons which can be classified on structure, based on size, and based on function. So based on structure you need to know the three types of neurons you will find and you should know some examples of those neurons in the body. First type is the bipolar neuron that has one axon and one dendrite. Whats an example of bipolar neuron? Yea. Sensory neurons are neurons associated with sense: such as the olfactory - epithelium of the nose, and the retina - are bipolar neurons. Multipolar neurons - one axon, multiple dendrites or more than two dendrites coming off of the cell body. Example of multipolar neurons? Perkinje cells. Pyramidal cells. Motor neurons are all multipolar neurons. The third one is pseudounipolar neurons which has one small segment coming off the cell body and split into two, the central and peripheral axon that will make connection to the periphery and one to the CNS to the spinal cord. Example of the pseudounipolar neuron? Sensory neuron of the DRG. So technically they dont have dendrites. You may see some textbooks so the axon splits from the cell body into two. The two there are a central axon that goes to spinal cord and peripheral that goes to the target tissue that will sense stimuli in the environment. So sometimes those terminal arborizations are referred to as dendritic arborizations. But they are not true dendrites. Dendrites are coming off of the cell body right?

As a type based on size, Golgi type I and golgie type II based on the length of the processes. Example of golgi type I? cells very good. [pyramidal cells] Golgi type II? Satellite cells or interneurons of any kind. Based on function: sensory, motor, and interneurons. [9] Supporting cells of the PNS Dr. Jean-Pierre Saint-Jeannet We also talked about the supporting cells of the PNS. Two cells. Schwann cells and satellite cells both derived from the neural crest. Schwann cells are providing myelin sheath to the axon in the PNS. One segment of myelin is coming form one single Schwann cell the gap between two shwann cells -myelin is known as node of Ranvier. And the distance between two nodes of ranvier is known as the internode. Satellite cells also provide insulation to the cells. Those satellite cells are associated with the cell body and found wrapped all around every individual neuron that you find in the DRG. [10] Supporting cells of the CNS Dr. Jean-Pierre Saint-Jeannet Supporting cell of the CNS. Four types: astrocytes, oligodendroctyes, microlia, and ependymal cells. The ependymal cells are making the lining of the ventricles and also the central canal of the spinal cord. Microglia are involved in the immune response. They have phagocytic properties. Oligodendrocytes are equivalent to Schwann cells that are in the PNS. They provide myelin sheaths around the axon. One difference here is that one oligodendrocyte can have multiple projection and making multiple myelin sheaths on multiple neurons at the same time and make multiple segments on the same axon. And the astrocyte come in two types. Protoplasmic and fibrous astrocytes. [11] Blood-brain barrier Dr. Jean-Pierre Saint-Jeannet and astrocytes have an important role to remember in the establishment of blood-brain barrier. The end feet of astrocytes make connection with endothelial cells. And they stimulate the endothelial cells to produce protein that are involved in formation of tight junction that will establish a seal between the blood stream and the rest of the nervous system. [12] II- Peripheral nervous system [13] Myelinated and unmyelinated fibers Dr. Jean-Pierre Saint-Jeannet we talked about the PNS. And we found two types of neurons in the PNS. Myelinated or unmyelinated. Those are two examples. Okay we already gone over this. This is myelin axon here with multiple wrappings of schwann cell around the axon. This is an unmyelineated fiber in the PNS where grooves in the Schwann cell accommodate multiple axons, but there is no multiple wrappings around those axons so there is no insulation. You still have nodes but those are not true nodes of ranvier. They dont propagate influx by salutatory conduction. One thing I want to point out the difference between PNS and CNS is you have myelin sheath also in the CNS. The so called unmyelinated neurons of the CNS do not have any covering on them. They are bare axons; that is one difference.

[14] Nerves Dr. Jean-Pierre Saint-Jeannet Talk about nerves and the different components of the nerves. With the endoneurium, perineurium, epidneurium. The endoneurium is the CT that is surrounding single axon. The perineurium is CT that surrounds bundles of fascicles of axon. And the epineuroun is CT surrounding multiple bundles of axons. [15] Nerve endings Dr. Jean-Pierre Saint-Jeannet We talked about nerve endings. They can be free nerve endings or encapsulated nerve endings so you need to know examples of those nerve endings and know where they are located and what are their functions. [16] Ganglia Dr. Jean-Pierre Saint-Jeannet we talk about ganglia, spinal and autonomic ganglion. [17] Sensory ganglia: spinal ganglia (DRG) Dr. Jean-Pierre Saint-Jeannet This is an example of spinal ganglia. Just a reminder those are neurons that are pseudounipolar that are sending axons in both directions. The central part of the axon are going to the CNS. And one peripheral that goes to the periphery. And all those cell bodies in the DRG are surrounded by satellite cells. [18] Autonomic ganglia Dr. Jean-Pierre Saint-Jeannet Talked about autonomic ganglia and some of the differences in terms of structure and location for sympathetic vs. parasympathetic nervous systems. Just to go over that one more time. So the ANS uses two neuron system. The first order neuron, the cell body of the first order neuron in the sympathetic nervous system is located in the CNS and will have relatively short preganglionic fiber, which make connection with cell body found in ganglion that is located in chain on each side of the spinal cord. So it is in close proximity on the spinal cord. And those are true ganglions. The second order neuron has a long postganglionic fiber that will make connection with the target tissue. In the case of the parasympathetic Nervous system, the first order neuron cell body is located also in the CNS but in different locations. It has a very long preganglionic fibers that makes a connection with the second order neuron that is typically located in the close vicinity of the target organ or embedded in the target organ. As a reason the postganglionic fibers are short. [19] Sympathetic ANS vs Parasympathetic ANS Dr. Jean-Pierre Saint-Jeannet So that is what is shown here. The cell bodies of the.. first order neuron in the sympathetic NS are located in the thoracic and lumbar spinal cord where as in the case of the parasympathetic NS are located in the brainstem and sacral spinal cord. The ganglia I want to point out the difference here is that the ganglia in the sympathetic NS are true ganglia. They form those two chains on each side of the spinal cord. They have capsule around cell bodies and have actual satellite cells around each one of those cell bodies. Most of the ganglia in the Parasympathetic are exception tot hat. They are not true ganglia and in fact embedded in the target organ tissue and form the loose network in that tissue.

And dont have capsule and target organ providing support to the cell body and typically find very few satellite ells. [20] Diagram of ANS Dr. Jean-Pierre Saint-Jeannet and this is a diagram to illustrate this same point. The origin of the cell body in the sympathetic NS derive from thoracic and lumbar region that make connection to ganglionic chain that is adjacent to the spinal cord. In the case of the parasympathetic, start from this region here, the sacral region and have long preganglionic fibers that make connection with second order cell bodies that are in the vicinity of the target tissue. [21] Plexuses of the ENS Dr. Jean-Pierre Saint-Jeannet talk about also part of the PNS. The Enteric NS sometimes viewed as component of the PNS. Those are not true ganglion either that you find in the ENS you find two plexuses that are asspcoated with the digestive tract. One is known as the submucosal plexus or meissner and one is known as myenteric plexus or Auerbachs plexus. So the myenteric plexus is located between two layers of muscles that yo find in the wall of the digestive tract. Those two layers of muscles are in opposite orientiation and this innervation will be essential to stimulate this muscle layer to allow for the peristaltic movement of the gut. The submucosal plexus which is located in the submucosa of the digestive tract as you can see here. And the role of this plexus will be to send impulse to the musclaris mucosa. Which will be important in allowing for the secretion to be released from the mucosa itself, the secretion from the intestinal tract. So those two plexuses have different functions in that respect. [22] III- Central nervous system Dr. Jean-Pierre Saint-Jeannet central nervous system. [23] Spinal cord: white matter vs. gray matter Dr. Jean-Pierre Saint-Jeannet so I tried to contrast here some ofthe differences between gray and white matter. [24] Spinal cord (H&E Staining) Dr. Jean-Pierre Saint-Jeannet And put back this picture rom the lecture that show ou here the junction between the gray matter and this is the white matter here. You can clearly see that gray matter contains the very large cell bodies with the nissl bodies found all around the nucleus. And the white matter is quite different in appearance which contains most of the axons coming from the neurons here. And this is an example of what we see by histology this corresponds to the axon itself that was surrounded by oligodendroctyes that provided myelin here. Myelin is not preserved in this type of preparation so it looks like empty space. But those were all axons surrounded by oligodendrocytes. [25] Central cortex Dr. Jean-Pierre Saint-Jeannet we talked about the cerebral cortex. The different layers of the cerebral cortex, you need to know the number and the name. And the similar

compositions of those different layers and the diagnostic cell types for the cerebral cortex is the pyramidal neuron that are found throughout this structure. [26] Cerebellum Dr. Jean-Pierre Saint-Jeannet we talked about the cerebellum and here the diagnostic cell types are the purkinje cells which are squeezed between the granule cell layer and molecular layer. And that has this very intricate dendritic arborization that makes its way through the molecular layer. [27] Meninges Dr. Jean-Pierre Saint-Jeannet we talked about meninges that was somewhat duplicated with what you heard with neuroanatomy but again we talk about the different layers of the meninges. The dura mater, the arachnoid and the pia mater. And the different space that are defined by those different layers. Subarachnoid space which will contain the Cerebralspinal fluid CSF and the subdural space found between dura mater and arachnoid. [28] Choroid plexus Dr. Jean-Pierre Saint-Jeannet Choroid plexus, which is this portion of pia mater that is changing shape at the level of the ventricle and that will be essential in the production of CSF. [29] IV- Regeneration Dr. Jean-Pierre Saint-Jeannet and finally what we talked about today [30] PNS vs. CNS regeneration Dr. Jean-Pierre Saint-Jeannet some of the difference between the regenerative capacity of the nerve in the PNS vs the CNS. Know about the Wallerian degeneration which is a prerequisite for the growth of those axon after injury and then the process of chromatolysis is prerequisite for that process. [31] NSCs Dr. Jean-Pierre Saint-Jeannet And know a few things about stem cells. Need to know that those stem cells actually exist in the CNS and we dont know how they are involved in repopulation certain regions of the brain yet but know that they exist and where they are located based on what has been shown recently. Alright so that is it. So Ill stop here.