Neuromodulation of Vertebrate

Neuromodulation of Vertebrate Locomotor Control
Networks
Gareth B. Miles and Keith T. Sillar
Physiology 26:393-411, 2011. ;
doi: 10.1152/physiol.00013.2011
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PHYSIOLOGY 26: 393 411, 2011; doi:10.1152/physiol.00013.2011
Neuromodulation of Vertebrate
Locomotor Control Networks
Gareth B. Miles and Keith T. Sillar

School of Biology, University of St. Andrews,
St. Andrews, Scotland, United Kingdom
kts1@st-andrews.ac.uk
Vertebrate locomotion must be adaptable in light of changing environmental,

organismal, and developmental demands. Much of the underlying flexibility in
the output of central pattern generating (CPG) networks of the spinal cord
and brain stem is endowed by neuromodulation. This review provides a
synthesis of current knowledge on the way that various neuromodulators
modify the properties of and connections between CPG neurons to sculpt
CPG network output during locomotion.
Need for Flexibility in Spinal

Motor Network Output
The precision, grace, and elegance with which animals navigate smoothly and efficiently through
their environment ultimately results from a complex set of interactions between the individual
neural components, the CPG networks that drive
rhythmic firing in motoneuron, the biomechanical
properties of peripheral propulsive structures, and
the integration of sensory information with central
motor control networks. The ability of a neural
1548-9213/11 2011 Int. Union Physiol. Sci./Am. Physiol. Soc.
system to adapt in the face of external demands is

often essential for survival, and this ability in turn
requires that it generates a motor output that is
inherently flexible. Neuromodulators represent an
important source of this flexibility at the level of
the underlying neuronal networks of the central
nervous system and the motor output they produce. Here, we review current evidence on the
sources and effects of the various neuromodulators
that influence vertebrate locomotor control networks and provide an account of how they achieve
their modulatory influences.
The neural networks that control locomotion in

vertebrates, so called central pattern generators
(CPGs), are located primarily in the spinal cord.
CPGs produce a basic rhythmic motor output in
the absence of sensory feedback, largely from the
interplay between the electrical properties of the
constituent neurons and the nature of the synaptic
interconnections between them. However, these
components of CPGs are subject to neuromodulation deriving from a wide range of sources both
intrinsic to the spinal cord and also projecting to
the spinal cord from other, extrinsic sources. The
neuromodulators involved are chemically diverse,
ranging from simple amino acids to biogenic
amines, peptides, and even a gas, nitric oxide. For
the most part, these neuromodulators act on Gprotein-coupled receptors to alter the concentration of
intracellular second messengers. The response properties of individual CPG neurons can be dramatically
modified in the presence of any one of this range of
neuromodulators. Growing evidence points to the
existence of complex interactions between different modulatory inputs to the motor system. In
effect, the prevailing cocktail of neuromodulators endows locomotor CPGs with an almost infinite range of output configurations. This is
necessary to enable the short term flexibility and
long term adaptability required of locomotion during the life time of the individual.
Role of Neuromodulation in
Modifying Centrally Generated
Activity
The rhythmic firing patterns of motoneuron that underpin locomotory movements such as walking,
swimming, or flying, result from the activity and
inter-connections of premotor interneurons that
form complex networks residing in the spinal cord
and brain stem (reviewed in Ref. 65). Neuromodulators change locomotor activity via one or both of two
routes: modulation of the integrative electrical properties of motoneuron and CPG interneurons, and
modulation of the synaptic connections between interneurons and motoneuron. As a broad rule of
thumb, it is possible to infer the locus of a neuromodulators influence on the locomotor output by
determining whether it affects the frequency and/or
the amplitude of the output. The hypothetical locomotor rhythm shown in FIGURE 1 illustrates motor
nerve recordings from functionally antagonistic motorneuron pools in which the pattern of bursting
activity strictly alternates during rhythm generation.
If the frequency of the rhythm stays the same in
the presence of a neuromodulator but the amplitude
or duration of each motor burst changes, then the
effects are most likely occurring predominantly at the
level of the motoneuron (or last order interneurons;
Bi in FIGURE 1). Alternatively, if the burst properties
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Opposing Effects of Neuromodulators

on Sensory vs. Motor Systems
For monoamines, 5-hydroxytryptamine (5-HT)
in particular, there is a strong inverse correlation
between their effects on motor output and sensory
input: if motor output is facilitated, then sensory

inputs are diminished and vice versa. This seems
logical because at times when an increase in locomotor activity is necessary, a down-tuning of sensory
transmission will help to ensure that innocuous
extrinsic sensory inputs do not interfere with ongoing locomotor activity. How are these opposing
effects accomplished? The most likely explanation
for this functional dichotomy is that the receptors
to which 5-HT is coupled are expressed differentially in sensory and motor circuits such that receptors in one pathway are positively coupled to a
second messenger and are negatively linked to the
same second messenger in the other pathway and
vice versa. In addition, monoamines differentially
modulate ascending sensory information relating
to locomotor movements (68). However, this review focuses on neuromodulation of motor systems, and effects on sensory systems will not be
discussed further.
Role of Neuromodulation Developmental

Network Adaptation
Some of the neuromodulators that exert acute
modulation of locomotor activity also play important
FIGURE 1. Schematic showing rhythmic, alternating motor output generated by antagonistic motor pools
Schematic showing how rhythmic, alternating motor output generated by antagonistic motor pools (A) can be altered in amplitude (i), frequency (ii), or both (iii), depending on whether a given modulator acts at the level of the
motoneurons (Bi), the CPG (Bii), or a combination of the two (Biii).
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PHYSIOLOGY Volume 26 December 2011 www.physiologyonline.org
are unaffected but the frequency is altered, then the

neuromodulator is most likely affecting rhythmgenerating circuitry without major influences on
downstream neurons (Bii in FIGURE 1). In many
cases, both amplitude and frequency change,
which suggests that the neuromodulator affects
motoneurons and CPG neurons simultaneously
(Biii in FIGURE 1).
Conceptually, there are two possible sources of
neuromodulator that can affect locomotor CPGs
(89): extrinsic sources such as modulatory inputs
that descend from the brain and that affect CPGs
remotely, and intrinsic modulators that are released from cells that are embedded within the
CPGs (89). In both cases, neuromodulators usually
exert their effects by acting as agonists at metabotropic receptors, some of which increase excitability, whereas others decrease excitability.
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Sources and Types of

Neuromodulator
The neuromodulators that have been shown to
affect vertebrate locomotion fall into three main
categories: the biogenic amines (5-HT, noradrenaline, dopamine, and trace amines), amino acids
normally acting on metabotropic receptors (GABAB,
mGluRs), and peptides (e.g., substance P). In addition, many other molecules that do not fit neatly
into these categories have also been shown to alter
locomotor activity including the purines (ATP and
adenosine), d-serine, endocannabinoids, and nitric oxide. In the following sections, we summarize
evidence on the sources and effects of these neuromodulators across a range of vertebrate locomotor networks.
Biogenic Amines
The sources of the amines depend partly on the
species of vertebrate in question. Homologous
groups of aminergic neurons are located in the
brain stem of most if not all species, including the
raphe nuclei (5-HT), the locus coeruleus (noradrenaline), and the substantia nigra (dopamine).
Additional groups include in mammals the serotonergic parapyramidal region (PPR) of the brain
stem and the A11 dopaminergic nucleus of the
dorsoposterior hypothalamus. In lower vertebrates, notably the lamprey, there are additional
sources of amines located in the spinal cord itself
(see below).
Evolution of 5-HT Signaling

5-HT is a phylogenetically ancient signaling molecule, distributed throughout the metazoans, which
plays key roles in the development and modulation
of locomotor function in vertebrates and invertebrates alike. In chordates like the lancelet, immunocytochemical evidence reveals serotonergic neurons in
the dorsal cerebral vesicle and in the spinal cord
arranged in a ladder-like ventral chain close to the
central canal (23). Lampreys belong to a primitive
vertebrate group, the agnathans, which split away
from the main vertebrate line around 500 million
years ago. Lampreys possess an intrinsic modulatory plexus running as a strip spanning the ventral
midline, which serves as an important source of
5-HT (183), dopamine (156), and other modulators
like substance P.
roles in the longer term during motor system development. 5-HT, for example, has been shown in
a variety of vertebrate motor systems to have a
major influence on circuit assembly during early
development, and, in keeping with this role, the
fibers that invade the spinal cord from the brain
stem arrive there at the critical points in circuit
maturation when major changes in the motor output are taking place. In chick embryos, ablation of
serotonergic projections in ovo using neurotoxins
dramatically affects synaptogenesis of inputs to
spinal motoneuron (130a). In Xenopus frog tadpoles, application of a 5-HT neurotoxin or 5-HT
receptor antagonist during embryogenesis prevents the normal postembryonic maturation of
swimming activity, suggesting that descending raphespinal projections are causal to locomotor network development (149). In rodents, as in lower
vertebrates, descending projections of the raphe
system also invade the spinal cord at critical stages
in network assembly, and 5-HT profoundly modulates locomotor activity, inferring a prominent role
for the amine in development (168).
5-HT in Mammalian Systems

Almost all 5-HT in the mammalian spinal cord
originates from brain stem raphe nuclei and the
parapyramidal region (reviewed in Ref. 99). A range
of spinal neurons relevant to locomotor control in
mammals receive serotonergic input, as identified
by their close association with 5-HT-labeled synaptic boutons. These neuronal targets for 5-HT
include spinal motoneurons (3), Renshaw cells
(26), commissural interneurons of laminae VII and
VIII (67), V0C interneurons (182), V2-derived interneurons (2), Hb9 interneurons (178), and neurons, predominantly in laminae VII and VIII,
shown to be activated during locomotion via c-fos
expression (128). There is also widespread expression of 5-HT receptors in the mammalian spinal
cord, with 5-HT2 receptors dominating in the ventral horn (reviewed in Ref. 144).
5-HT can both activate and modulate mammalian locomotor networks. Activation of spinal locomotor networks by 5-HT was first shown in the
rabbit using the 5-HT precursor 5-HTP (167). 5-HT
was later shown to also initiate locomotor activity
in isolated spinal cord preparations obtained from
neonatal rats and mice (27, 36, 92, 112, 127) and
spinalized adult rats and mice (55, 100, 165). In
contrast, 5-HT appears insufficient to initiate locomotion in the spinalized cat (6, 7). However, 5-HT
is not without effect on cat locomotion. In spinalized cats, activation of 5-HT receptors leads to an
increase in the amplitude and duration of bursts of
on-going locomotor-related EMG activity recorded
from hindlimb muscles (6, 7). In addition, in cats
recovering from incomplete spinal transections,
5-HT increases the regularity of stepping (21).
5-HT also modulates on-going locomotor activity
in rodents with the effects varying depending on
the receptor subtypes activated. The effects of
5-HT2 and 5-HT7 receptor activation are generally
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396
modulatory effects on the intrinsic properties of

spinal interneurons, the common consequence of
this modulation is neuronal excitation. This suggests that excitation of either inhibitory or excitatory CPG neurons, depending on the receptor
subtype involved, may underlie the mixed facilitatory and inhibitory actions of 5-HT on locomotor
activity. Alternatively, novel inhibitory actions of
5-HT on spinal interneurons may remain to be
discovered.
Finally, besides affecting locomotion via the
modulation of intrinsic properties of spinal neurons, 5-HT may also exert its effects by modulating
synaptic transmission. Evidence for 5-HT-mediated
modulation of synaptic transmission in the ventral
spinal cord includes the modulation of sensory and
descending inputs to spinal interneurons in the cat
(67, 69, 86) and sensory input to motoneurons in the
rat (11).
Noradrenaline in Mammalian Systems

Noradrenergic input to the mammalian spinal cord
originates from A5, A6 (locus coeruleus), and A7
brain stem nuclei (34, 130, 174). Examples of mammalian spinal neurons innervated by these brain
stem sources of noradrenalin (NA) include motoneurons (61, 79, 138), commissural interneurons
(67), and lamina VII premotor interneurons (116).
There is also widespread expression of adrenergic
receptors in the mammalian spinal cord (60, 129,
142, 143).
Like 5-HT, NA can both initiate locomotor activity and modulate ongoing locomotor patterns. In
spinalized cats, activation of noradrenergic, particularly 2, receptors powerfully stimulates locomotor activity (7, 31, 56, 91). In contrast to the cat, NA
induces only poor locomotor-like activity in isolated
rat spinal cord preparations (57, 93, 154). In both
chronic spinalized cats and isolated rat spinal cord
preparations, application of NA during ongoing
locomotor activity slows the rhythm (31, 93) and
increases the amplitude of EMG or ventral root
activity (31, 93, 154). By using specific agonists, it
can be shown that the modulation of locomotor
activity by NA reflects the net effect of separate
mechanisms activated by different adrenoceptor
subtypes. During locomotion in chronic spinal
cats, 2-adrenoceptor activation increases step cycle duration, primarily by lengthening burst duration in flexor muscles. In contrast, activation of
1-adrenoceptors has little effect on the timing
of locomotion but instead increases the strength of
extensor muscle activity (31). These data suggest
that 2-adrenoceptor activation influences interneurons involved in rhythm generation,
whereas 1-adrenoceptor activation modulates
motoneuron output. Data from rodent studies
demonstrate a similar separation in the effects
facilitatory causing increases in the frequency

and/or amplitude of locomotor activity recorded
from in vitro preparations (14, 46, 62, 108). In addition, the activation of 5-HT2 and 5-HT7 receptors
strengthens left/right and flexor/extensor alternation during fictive locomotion (107, 132). In
contrast, the activation of 5-HT1 receptors has inhibitory effects slowing the frequency of locomotor activity (25, 46). Taken together, these data
indicate that 5-HT can modulate motoneurons or
last-order interneurons to affect the magnitude of
the final output of the locomotor network and interneurons involved in rhythm generation to affect
the timing and coordination of locomotor activity.
Neuromodulators affecting motoneurons often
target persistent inward currents (PICs). PICs can
amplify synaptic inputs and give rise to plateau
potentials that allow for periods of sustained firing
(reviewed in Ref. 74). PICs and their associated
plateau potentials are enhanced by 5-HT receptor
activation in the cat (37, 81), rat (15, 73, 106), and
turtle (82, 134). This enhancement appears to involve the facilitation of Na and Ca2 PICs along
with a reduction in K currents (16, 73, 82, 106,
134). Thus direct or indirect modulation of PICs in
motoneurons is likely to contribute to the effects of
5-HT on the amplitude of locomotor output from
spinal networks. Other modulatory effects of 5-HT
on motoneuronal properties that may contribute
include a reduction in the voltage sensitivity of
NMDA channels and subsequent facilitation of
NMDA receptor-dependent oscillations (110, 111)
and modulation of inwardly rectifying K channels
and Ih currents (94).
In addition to modulating motoneurons, 5-HT
modulates the intrinsic properties of spinal interneurons via several mechanisms that may underlie the effects of 5-HT on the frequency of
locomotor activity. The most common effect of
5-HT on spinal interneurons is to depolarize their
resting membrane potential (24, 40, 184 186). In
addition, 5-HT decreases the action potential
threshold in the majority of commissural interneurons (184, 185), an undefined population of ventral
horn interneurons (52), and interneurons that are
active during locomotion (40). Interestingly, 5-HT
has also been shown to compress the range of
voltage-thresholds for repetitive firing in ventral
horn interneurons by reducing firing thresholds in
high threshold interneurons and increasing firing
thresholds in low threshold interneurons (162).
Other effects of 5-HT on interneurons include a
reduction in the magnitude of the AHP in most
commissural interneurons (45, 184, 185) and
locomotor activity-related interneurons (40), as
well as modulation of Ih currents and enhancement of PICs in locomotor activity-related interneurons (41, 42). Although 5-HT has a range of
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Dopamine in Mammalian Systems

In mammals, dopaminergic inputs, arising predominantly from the hypothalamic A11 region (18,
78, 137, 150), are distributed throughout the ventral horn of the spinal cord (80, 172, 181). In addition, all subtypes of dopamine receptors (D1D5)
are also expressed within the ventral horn (187,
188).
Involvement of dopaminergic input in locomotor control is supported by measurements of increased dopamine levels in the spinal cord during
locomotor activity (59). However, dopamine is not

as effective as 5-HT or NA at initiating locomotion.
In spinal cats, dopaminergic agonists fail to induce
locomotion (7). In contrast, in mice with spinal
cord transections, locomotion can be induced by
D1/D5 receptor agonists (102), suggesting that specific activation of D1/D5 receptor subtypes might
induce locomotor activity in the cat. In isolated
rodent preparations, the ability of dopamine receptor activation to induce locomotion varies by
species. In neonatal rat preparations, dopamine
can induce rhythmic locomotor-like activity, although it is much slower than that induced by
5-HT and in some reports more irregular (10, 92).
In contrast, in neonatal mouse preparations, the
activation of dopamine receptors alone is insufficient to induce locomotor activity, but activation of
dopamine receptors (primarily D1 and D2) by endogenous dopamine is required for 5-HT-induced
locomotor activity (112). Interestingly, at later developmental time points in mice, toward 1 wk old and
beyond, exogenous dopamine is required along with
5-HT and NMDA to elicit locomotor activity in isolated spinal cord preparations (86a, 124).
In both cat and rodents, dopamine can modulate on-going locomotor activity. In the cat, dopamine receptor activation increases the amplitude
of flexor activity during locomotion (7), primarily
suggesting modulation of motoneurons. In comparison, in isolated rodent spinal cord preparations, dopamine receptor activation slows locomotor rhythms
initiated by 5-HT and NMDA while also increasing
the amplitude of locomotor-related output and
making the activity more reliable (10, 62, 175).
Thus, in rodents, dopamine is likely to modulate
the activity of interneurons involved in rhythm
generation and motoneurons.
Analyses of the mechanisms by which dopamine
receptor activation modulates mammalian spinal
neurons are at present limited to motoneurons and
Hb9 interneurons in isolated neonatal mouse spinal cord preparations (70, 71). In mouse motoneurons, dopamine application increases excitability
by modulating potassium currents including Ca2dependent K currents to reduce the mAHP and IA
to reduce the latency to the first spike (70). In
addition, activation of the D1 subtype of dopamine
receptors modulates AMPA receptor-mediated
currents in motoneurons (71). In the case of Hb9
interneurons, dopamine application has been
shown to be necessary but not sufficient to induce oscillatory behavior, which may relate to the
locomotor rhythm (77, 178). In addition to modulating the intrinsic properties of motoneurons and
Hb9 interneurons, dopamine modulates synaptic
input to motoneurons including those from sensory afferents (11, 25, 33) and may modulate
of 1- and 2-adrenoceptor activation. In isolated rat spinal cord preparations, activation of 2adrenoceptors leads to a decrease in the frequency
of pharmacologically induced locomotor activity
with no effect on the amplitude of ventral root
bursts. In contrast, activation of 1-adrenoceptors
results in an increase in locomotor frequency and a
decrease in the amplitude of ventral root bursts
(154). Interestingly, 1-adrenoceptor activation reduces locomotor frequency and increases ventral
root burst amplitude when locomotion is induced
by stimulation of the cauda-equina in isolated
mouse spinal cord preparations (62). This may reflect species differences or indicate that the mode
of activation of locomotion influences the potential modulatory roles of NA.
The dominant effect of NA on spinal neurons
seems to be an increase in excitability, most likely
via activation of 1-adrenoceptors, whereas activation of 2-adrenoceptors can inhibit activity (51,
131, 161, 154, 176). NA shares many cellular mechanisms of neuromodulation with 5-HT. In parallel
with 5-HT, NA activation can facilitate persistent
inward currents and plateau potentials (35, 104,
162), reduce inwardly rectifying K currents (161),
hyperpolarize the action potential threshold (52),
and compress the range of voltage-thresholds for
repetitive firing in ventral horn interneurons (162).
However, unlike 5-HT, NA appears to have little
modulatory effect on the AHP (161).
Adrenoceptor activation, like serotonergic receptor activation, may also alter locomotor activity by
modulating synaptic connectivity with the spinal
cord. One of the most striking examples of this
comes from experiments utilizing the isolated rat
spinal cord in which the application of NA unmasks recurrent excitatory pathways that can modulate locomotor activity, increasing the frequency of
rhythmic activity (109). NA also increases locomotorrelated synaptic drive to motoneurons in the isolated rat spinal cord (161), an effect that may
contribute to the increased motor output seen
upon adrenoceptor activation. Finally, like 5-HT,
NA can modulate sensory and descending inputs
to spinal interneurons in the cat (67, 69, 86) and
sensory input to motoneurons in the rat (11).
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synaptic transmission between motoneurons and
Renshaw cells (113, 146).
Biogenic Amines in Non-Mammalian

Systems
398
In contrast to studies of mammalian systems, research involving aquatic vertebrates has demonstrated that aminergic signaling pathways are
functionally integrated, often providing complementary modulatory effects (118). The modulatory
effects of biogenic amines in these animals will
therefore be discussed together.
In the lamprey, the modulatory effects of 5-HT
have been a topic of intense research and debate.
Bath applied 5-HT has a well defined effect on
locomotor activity; the rhythm slows and the
bursts intensify in a similar manner to other vertebrates. The fact that the 5-HT uptake inhibitor
citalopram has a similar effect to 5-HT indicates
that endogenous release of the amine can regulate
burst formation during locomotion. The mechanisms of action of 5-HT classically involve a reduction of the slow after-hyperpolarization (sAHP)
that follows the action potential in motoneuron
mediated in large part by apamin-sensitive Ca2dependent K (KCa) channels (reviewed in Ref.
65a). The sAHP acts as a brake on motoneuron
discharge by determining the time it takes for the
neuron to recover and fire again. Hence, in reducing the sAHP, 5-HT reduces spike accommodation, and so, for a given excitatory input,
motoneuron fire for longer and at a higher frequency. The serotonergic block of KCa therefore
neatly explains the increase in discharge frequency of motoneurons within each cycle of
swimming. Modulation of the sAHP in CPG interneurons can also affect their firing frequency
and consequently change the frequency of the locomotor rhythm. The same KCa channels also contribute to the plateau phase of the intrinsic NMDA
receptor-mediated membrane potential oscillations
reported in lamprey motoneurons when they are
activated by the calcium entry that follows NMDA
receptor activation (169a). KCa channel activation
drags the membrane potential from the depolarized plateau phase into a sufficiently more hyperpolarized region so that Mg2 ions can block the
open NMDA receptor ion channel and trigger the
falling phase of the oscillation. The serotonergic
block of KCa channels therefore prolongs the depolarized plateau phase, allowing neurons to
fire for longer in each cycle. Thus, through parallel
actions of 5-HT on KCa channels and NMDA
receptors on spinal neurons, 5-HT modulates frequency, duration, and amplitude of locomotor
bursts.
Given that KCa channels play a major role in the
modulation of lamprey locomotion by 5-HT, it
would be anticipated that apamin, which blocks

KCa channels, should have the same effects as 5-HT
on swimming. However, even at high concentrations (10 M) sufficient to block the sAHP and
increase motoneuron firing, apamin had no significant effect on the frequency of NMDA-induced
fictive locomotion (123a). This result can only be
partially reconciled by the fact that the effects depend on the initial concentration of NMDA and the
starting frequencies of swimming that this elicits.
Since 5-HT has also been shown to reduce the
strength of excitatory synaptic transmission via a
presynaptic mechanism (145), a more complete
explanation is that, to mediate its full effects on
locomotion, 5-HT must have additional effects besides blocking KCa channels.
In zebrafish, the effects of 5-HT are developmental stage specific. At early stages, 5-HT modulates
the duration of quiescent periods, and thus the
frequency of swim bouts, without directly affecting
the firing of neurons active during swimming or
the various parameters of a swim cycle (19). This
appears to be mediated by an effect on chloride
homeostasis (20). Once the zebrafish becomes free
swimming, and continuing into adulthood (58),
5-HT has effects that parallel those in the lamprey,
namely the cycle period lengthens. In this case,
however, the mechanism appears to involve a
strengthening of the mid-cycle glycinergic inhibition, akin to the effect of NA in Xenopus tadpoles
(118). In Xenopus tadpoles, 5-HT applied to young
larvae increases the duration of motor bursts but
has little effect on the locomotor frequency, producing a relatively fast, short, and intense version
of the fictive swimming rhythm. In contrast, NA
has the opposite effect of increasing the cycle period but has little or no effect on the duration of
motor bursts. Which receptor subtypes are involved in the serotonergic modulation of locomotion? In both lamprey (76) and Xenopus tadpoles,
there is evidence that 5-HT1a receptors are involved in some of the effects, and for the lamprey
it has been reported that the effects of KCa channels are largely mediated by this receptor and its
negative coupling to adenylate cyclase (AC) (177).
Also in the lamprey, it has been reported that the
serotonergic presynaptic inhibition of excitatory
transmission is mediated by the 5-HT1d receptor
(145), which also negatively couples AC. In mammalian systems, the receptor subtypes differ in that
5HT2 and 5HT7 receptors seem to play a prominent role (see above).
Dopaminergic effects on lower vertebrate locomotor centers are less well described. In zebrafish, dopamine has an inhibitory effect on the frequency of
swim episodes during early development (163). At 3
days postfertilization, zebrafish larvae generate a
small number of relatively long-duration swim
REVIEWS
bouts. Dopamine, or the dopamine uptake inhibitor bupropion, abolishes swimming activity, an effect mediated in the brain stem. Dopamine has no
effect on the integrative electrical properties of spinal neurons. Pharmacological blockade of D2
receptors or activation of adenylate cyclase (a
downstream target that is inhibited by D2 receptors) blocks the inhibitory effect of dopamine. The
suppression of swim initiation appears to be transient since, by 5 days postfertilization, dopamine
uptake no longer affects the frequency of swim
episodes.
Conventional Fast Excitatory

Transmitters
Glutamate (mGluRs)
Glutamate is best known for its role as the major
fast, excitatory neurotransmitter in the CNS, a role
it fulfils via the activation of ionotropic glutamate
receptors. However, glutamate can also act as a
neuromodulator by binding to three groups (IIII)
of G-protein-coupled metabotropic glutamate receptors (5, 136). Given that the functioning of the
locomotor CPG is dependent on glutamatergic signaling between spinal interneurons (13, 160, 175),
there are considerable intraspinal sources of glutamate. In addition, the locomotor CPG receives
glutamatergic input from both descending (66, 88)
and sensory systems (117). In addition to the abundance of glutamatergic transmission affecting spinal motor circuitry, there is widespread expression
of mGluRs in the ventral horn (4, 103) that could
be activated in parallel with ionotropic glutamate
receptors (44).
Conventional transmitters involved in the fast synaptic interactions that occur during locomotor network operation mediate their effects by activating
ionotropic postsynaptic receptors (glutamate:
NMDA, AMPA; GABA: GABAa; acetylcholine: nAChR;
glycine: glyR). However, the same transmitters (with
the possible exception of glycine) also activate
metabotropic receptors located both pre- and postsynaptically to modulate ongoing activity. In many
cases (e.g., group 2,3 mGluRs, mAChR, GABAB), the
presynaptic receptors mediate homosynaptic depression of transmitter release and thus function as
negative feedback autoreceptors. In certain cases,
pharmacologically similar receptors are located on
the terminals of adjacent neurons where they can
mediate heterosynaptic depression or facilitation of
transmitter release. However, other metabotropic receptors for classically fast transmitters are located
postsynaptically, such as mGluR1 receptors, where a
range of complex modulatory effects have been
described.
The effects of metabotropic glutamate receptors

(mGluRs) within vertebrate motor systems have
been most extensively studied in the lamprey (49,
95) (FIGURE 2), with comparative data arising from
the tadpole (28, 29) model system. In aquatic vertebrates, as in other species, group 2 and 3 mGluRs
appear to be located primarily presynaptically
where they mediate presynaptic inhibition of glutamate release and therefore function as negative
feedback controllers of excitatory transmission.
Activation of these receptors generally slows fictive
locomotion. In contrast, group 1 mGluRs play a
variety of different, mainly excitatory, roles, and in
both lamprey and tadpole their activation leads to an
increase in the locomotor frequency. In both species,
there is evidence that this effect is due partly to
postsynaptic modulation of neuronal excitability and
partly to presynaptic inhibition of glycinergic inhibitory transmission. Group 1 mGluRs can be further
subdivided into mGluR1 and mGluR5 subtypes. In
the lamprey spinal cord, mGluR1 (but not mGluR5)
receptors cause membrane potential depolarization and excitation of spinal cord neurons by
blocking a leak (mixed Na-K) current.
The effect requires activation of phospholipase C
(PLC) and the release of calcium ions from intracellular stores. mGluR1s also enhance excitability
of lamprey spinal neurons by facilitating current
flow through NMDA receptors that play a key role
in the rhythmic excitation that occurs in each cycle
of locomotion. In parallel, mGluR5 receptors regulate lamprey locomotion but via different mechanisms that trigger oscillations in intracellular
calcium and have a net inhibitory effect on the
frequency of locomotion (90). In contrast, in frog
tadpoles, both subtypes of group I mGluRs increase locomotor frequency (29). Experiments using mGluR1- and mGluR5-specific antagonists
demonstrate that endogenous activation of both
types of receptors contribute to intrinsic spinal
modulation of locomotor output in lamprey and
frog tadpoles (29, 90, 95). These data on both
young frog tadpoles and adult lampreys also infer a
conserved mGluR-mediated modulatory mechanism that is established early in vertebrate development (tadpole) and evolution (lamprey), namely
the presynaptic inhibition of glycine release by
group 1 mGluRs. Although this conserved modulatory mechanism suggests a strategic positioning of
group 1 mGluRs on the synaptic terminals of inhibitory interneurons of the spinal CPG, there is
extensive evidence from the lamprey system that
activation of group 1 mGluRs couples to an intracellular signaling cascade that triggers the release
of the endocannabinoid 2-AG from postsynaptic
membranes that activates presynaptic endocannaboind receptors to reduce inhibitory transmission.
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This pathway is reviewed in detail in a recent issue of
this journal (50).
Activation of mGluRs also modulates, but does
not initiate, locomotor activity in isolated rodent
spinal cord preparations (85, 157159). Analyses
have concentrated on the role of group I mGluRs,
although group II and III mGluRs also modulate rat
locomotor activity (159). In the rat spinal cord, the
application of group I mGluR agonists either disrupts locomotor activity completely or slows it
(158). Seemingly paradoxically, group I-specific
mGluR antagonists also decrease the frequency of
locomotor activity (158). The authors of these studies suggest that this apparent discrepancy reflects
diffuse excitatory effects of exogenous agonist

overshadowing more specific depressant effects of
endogenous group I mGluR activation. In contrast
to these data in the rat but consistent with findings in lamprey (95) and Xenopus tadpoles (29),
recent data obtained from isolated mouse spinal
cord preparations have demonstrated an increase in locomotor activity on activation of
group I mGluRs (85). In addition to affecting the
frequency of locomotion, group I mGluR activation also modulates the amplitude of locomotorrelated motoneuron output in mice, indicating
modulatory effects at the level of CPG interneurons and motoneurons.
FIGURE 2. Activation of mGluR1 receptors increases locomotor frequency in the lamprey by divergent
neuromodulatory effects
Glutamate released from excitatory interneurons in the spinal cord activates locomotor network neurons via ionotropic AMPA and NMDA receptors
and simultaneously activates postsynaptic mGluR1 receptors. mGluR1s block a leak K channel, enhance NMDA receptor-mediated currents, and
trigger release of the endocannabinoids, which bind to EC receptors on glycinergic interneurons to reduce mid-cycle inhibition. Figure was adapted
from Ref. 50 and used with permission.
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Acetylcholine
All cholinergic inputs to mammalian spinal neurons are thought to originate from within the spinal cord (119, 147, 166). Motoneurons represent
the major acetylcholine-producing cells of the spinal cord. The acetylcholine they produce is mostly
destined for the periphery where it mediates transmission at the neuromuscular junction, although
motoneuron axon collaterals also activate recurrent inhibitory pathways mediated by Renshaw
cells (38, 98). Other intraspinal sources of acetylcholine include small cholinergic neurons scattered in the dorsal horn, central canal cluster cells
surrounding the central canal, and partition cells
that lie between the dorsal and ventral horns in a
region extending from lamina X to the lateral edge
of the gray matter (8, 83, 124, 135, 182). Along with
neuronal sources of acetylcholine, there is considerable expression of muscarinic metabotropic acetylcholine receptors in the ventral horn of the
mammalian spinal cord (75, 125, 171, 173, 179).
Taken together with the fact that cholinergic interneurons are activated during locomotion (83), these data
highlight the potential importance of acetylcholine
as a modulator of locomotor behavior.
In the early embryonic mouse spinal cord, cholinergic transmission, arising from the axon collaterals of motoneurons and involving nicotinic
receptors, drives early locomotor-related rhythm
and appears to contribute to the appropriate assembly of spinal locomotor circuitry (72, 126).
Later, at neonatal stages in the rat, locomotorlike activity can be initiated by activation of
metabotropic receptors following the application
of acetylcholine or cholinesterase inhibitors (36,

151, 152). It should, however, be noted that this
acetylcholine-driven activity often lacks appropriate alternation between ipsilateral extensors
and flexors (36).
Although there have been no reports of acetylcholine modulating the frequency of ongoing locomotor
activity in mammals, cholinergic transmission at Cbouton synapses, which densely cover motoneuronal
somata and arise from spinal interneurons (V0c
interneurons), has recently been shown to modulate the strength of locomotor-related motoneuron
output in a task-dependent manner (124, 182)
(FIGURE 3). Spinal V0c interneurons, which are the
source of C-bouton inputs to motoneurons, appear
to be tonically active throughout locomotion with the
frequency of their activity tightly phase locked to
motoneuron output. Genetic inactivation of the
output of V0c interneurons results in an impaired
ability to increase the activation of hindlimb muscles during motor tasks that require greater force.
From these data, it is predicted that task-specific
modulation of the intensity of motoneuron output
is in part controlled by V0c interneurons and their
C-bouton contacts with motoneurons.
At the cellular level, acetylcholine-mediated
modulation generally has a net excitatory effect on
spinal neurons. Studies in mice have shown that
acetylcholine depolarizes the resting membrane
potential and decreases input resistance in both
commissural interneurons and interneurons that
are activated during locomotion (which may include some commissural interneurons) (24, 40).
Additional effects of acetylcholine observed in locomotor activity-related interneurons include a
hyperpolarization of the action potential threshold, an increase in the magnitude of the AHP, and
a decrease in Ih (40, 41). The net excitatory effect of
acetylcholine on mouse interneurons is evidenced
by a leftward shift in frequency current relationships (24), although in locomotor activity-related
interneurons this is accompanied by a decrease in
slope such that excitability is only increased at
lower stimulus intensities (40).
In mouse motoneurons, activation of metabotropic muscarinic receptors also has a net excitatory effect on firing output (124). Although
muscarinic receptor activation can either hyperpolarize or depolarize the resting membrane potential
of motoneurons, it always leads to a reduction
in AHP amplitude via the activation of m2-type
muscarinic receptors (124), which are found at Cbouton synapses (75, 125, 179) (FIGURE 3). This
reduction in the AHP leads to increased motoneuron excitability as evidenced by an increase in the
slope of frequency current plots (124) and is
thought to underlie the task-dependent regulation
Data concerning the cellular effects of mGluRs

on mammalian spinal neurons are limited to the
effects of group I mGluR activation on motoneurons (85, 114, 115). Application of group I mGluR
agonists leads to depolarization of motoneuronal
resting membrane potentials in both rats and
mice. In rat motoneurons, this is associated with
reports of no change (115) or an increase in resistance (114), whereas in mouse motoneurons
mGluR-dependent depolarization is associated
with a decrease in resistance (85). In mouse motoneurons, group I mGluR activation also reduces
the amplitude of transient Na currents, an effect that seems to lead to reduced motoneuron
firing and decreased locomotor-related motoneuron output (85). In both rats and mice,
group I mGluRs also modulate synaptic transmission within the spinal cord. In rats, group I
mGluRs appear to depress inhibitory transmission
involved in sensorimotor pathways (115) and recurrent inhibitory transmission to motoneurons
(114). In mice, activation of group I mGluRs depresses excitatory locomotor-related input (85).
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of the strength of motoneuron output during locomotion discussed above (182).
For lower vertebrates, much less is currently
known about the role of metabotropic muscarinic
receptors for acetylcholine in the modulation of
locomotor activity. However, there is ample evidence that motoneurons express muscarinic receptors. In the salamander, for example, M2-type
receptor activation alters the integrative electrical
properties of motoneurons by modulating three
ionic currents: a hyperpolarization-activated cationic
current (Ih), a calcium-dependent potassium current (KCa), and an inwardly rectifying potassium
current (IKir) (32).
Conventional Fast Inhibitory

Transmitters
GABA/Glycine
There is an abundance of inhibitory interneurons
within the mammalian spinal cord, which, in addition to controlling key aspects of the locomotor
pattern such as the alternation of activity between
FIGURE 3. Intrinsic cholinergic modulation of mouse locomotion

A: a small cluster of cholinergic interneurons (V0C interneurons) located near the central canal of the spinal cord represents the sole source of Cbouton synaptic inputs to motoneurons (MN). Both motoneurons and V0C interneurons receive rhythmic input from the locomotor CPG. B: acetylcholine (Ach), released at C-bouton synapses, activates postsynaptic m2-type muscarinic receptors on motoneurons, which in turn leads to a
reduction in currents mediated by SK-type Ca2-dependent K channels. C-bouton activation therefore leads to a decrease in the action potential
afterhyperpolarisation (AHP) and an increase in motoneuron firing frequency. C: recordings of EMG activity from gastrocnemius (Gs) and tibialis
anterior (TA) hindlimb muscles during walking and swimming in control mice and mice in which C-bouton signaling has been silenced demonstrate
a task-dependent and muscle-specific role for the C-bouton system in the modulation of motoneuron output. Note reduced modulation of EMG
amplitude from walking to swimming in the Gs muscle in mutant animals. D: these findings suggest that V0C interneurons and their C-bouton contacts with motoneurons form a feed-forward facilitatory system for the control of motoneuron output during locomotion. Inputs from the locomotor CPG,
sensory afferents, and descending systems appear to control the level of activity of V0C interneurons and hence motoneuron output and muscle activation in a task-dependent manner. The question mark indicates the uncertain nature of the descending and/or sensory inputs that mediate task-dependent
regulation of the activity of V0C interneurons. Images and data are modified from Refs. 124 and 182 and used with permission.
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Purinergic Transmitters
In Xenopus embryos, ATP and adenosine control
the duration of swimming episodes (43). The
sources of ATP are not identified, but it is presumed to be co-released by neurons that are part
of the spinal CPG. At the onset of a swimming bout,
extracellular ATP levels rise as a result of the activity. Initially, near the onset of the bout when swim
frequency is at its highest, ATP blocks K channels
to help maintain a high level of excitability within
the network so the swimming frequency is at its
highest. However, as the episode progresses, the
ATP is gradually broken down in the extracellular
space by a 5-ectonucleotidase to adenosine. Adenosine is able to block Ca2 channels, which impairs
synaptic transmission and reduces excitability. Evidence suggests that adenosine mediates its effects
via A1 receptors and that both an N-type calcium
current and a further unidentified HVA calcium
current are inhibited by adenosine (18b). The effect of adenosines inhibition of calcium channels
is to lower the swim frequency, reducing the activity-dependent production of ATP by the swim
CPG. With time, the inhibitory effects of adenosine
overcome the excitatory effects of ATP, and the
swim frequency eventually reaches a critical low
level that can no longer be sustained, and thus the
swimming bout ceases. This is a very elegant example of a role for an intrinsic neuromodulator
that may be important in ensuring that swimming
does not continue ad infinitum. There are more
traditional mechanisms for terminating swimming
such as inhibitory reticulospinal neurons that produce rapid GABAergic inhibition whenever the rostral cement gland is contacted by objects in the
environment (18a). In behavioral terms, this descending inhibition from the brain stem is likely to
be involved before the purinergic biochemical
clock mechanism is engaged.
Recent work utilizing isolated neonatal mouse
spinal cord preparations has also revealed a role
for purines in the intrinsic modulation of the mammalian locomotor CPG (180). In the mouse, spinal
cord adenosine, derived from the breakdown of
ATP following its release from glia, appears to play
an endogenous role in setting the excitability and
frequency of the locomotor CPG. This is revealed
by an increase in locomotor frequency upon blockade of adenosine receptors that is absent in
the presence of glial toxins or ectonucleotidase
inhibitors.
the left and right sides of the spinal cord and between flexor and extensor motoneurons, may also
modulate on-going locomotor activity. Commonly
studied examples of inhibitory ventral interneurons include Ia inhibitory interneurons (53, 84),
Renshaw cells (141), and inhibitory commissural
interneurons (e.g., Refs. 22, 101). Along with the
presence of many sources of inhibitory transmission within the spinal cord, there is also widespread
expression of metabotropic GABAB receptors (30, 164),
supporting a potential role for neuromodulation of locomotion via inhibitory transmission.
In the mammalian spinal cord, a number of
studies in cats (e.g., Refs. 39, 48, 87, 105, 155) and
rodents (17, 170) have shown that the main modulatory actions of GABAB receptors involve the
presynaptic inhibition of transmitter release with
little or no effect on postsynaptic properties of
neurons. In isolated neonatal rat spinal cord
preparations, the consequences of GABAB receptor activation on locomotor output include a reduction in the amplitude of ventral root bursts,
probably due to reduced locomotor-related synaptic drive to motoneurons, and a reduction in
locomotor frequency due to undefined actions
on CPG interneurons (17).
With respect to GABAB receptors in lower vertebrates, it has been shown that their activation in
Xenopus embryos also causes presynaptic inhibition of transmitter release, specifically from the
terminals of glycinergic interneurons that mediate
reciprocal inhibition during swimming (169). The
effect involves a direct presynaptic action on
omega-conotoxin-sensitive (N-type) calcium
channels, leading to a reduction in the probability
of quantal release. In addition, a GABAB receptor
agonist reduces the firing threshold of motoneurons, indicating parallel pre- and postsynaptic effects that unite to reduce the duration and
frequency of fictive swimming. Similar effects of
GABAB receptor activation have been reported in
the lamprey where tonic activation of these receptors during fictive swimming contributes to the
setting of the locomotor burst frequency. In addition, GABAB receptors play an important role in
controlling the intersegmental propagation of activity along the spinal cord during fictive locomotion (115a, 161a). Activation of GABAB receptors by
endogenously released GABA during locomotor
network activity reduces the locomotor frequency
and modifies the intersegmental phase lag as the
activity propagates rostrocaudally along the spinal
cord (161a). These effects are mediated in large
part by the GABAB-mediated depression of voltage-activated calcium currents and Ca2-dependent K channels, which affects post-inhibitory
rebound and the post-spike after hyperpolarization (115a).
Peptide Neuromodulators
The best understood peptide with respect to roles
in motor control is the tackykinin, substance P. In
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404
comotor burst amplitudes. Presumably, the peptides acting solely on amplitude can directly
influence motoneuron firing, whereas the others
also act at the level of premotor interneuronal
circuitry.
Gaseous Neuromodulation
The free radical nitric oxide (NO) is an unusual but
potent modulator of locomotor activity in lower
vertebrates such as the Xenopus tadpole (120, 122)
and the lamprey (96, 97). NO is manufactured by
cells that possess the enzyme NO synthase, which
breaks down L-arginine to L-citrulline, liberating a
molecule of NO in the process. In Xenopus tadpoles, the neuronal sources of NO, as revealed by
NADPH-diaphorase histochemistry, are located in
the brain stem in distinct and bilaterally symmetrical neuronal clusters (120, 123). NOS expression
in these neurons appears in a well defined temporal sequence such that all three clusters are labeled
around the time of hatching from the egg membrane when the young larva is only 3 days old.
These three clusters remain throughout development (139). NO has a net inhibitory effect
and acts as a break on swimming: NO donors
reduce episode durations and slow swimming;
NOS inhibitors or NO scavengers have the opposite
effect, indicating that NOS is constitutively active
and produces an intrinsic NO tone that regulates
swimming output (120). The primary mechanisms
through which these effects on locomotion occur
include NOs presynaptic facilitation of 1) glycinergic transmission (which slows the swimming
rhythm) and 2) GABAergic transmission (which
leads to premature termination of activity by activating a descending stopping pathway mediated
by reticulospinal inhibitory interneurons) (121,
122) (FIGURE 4). At these early stages of development, before the onset of free swimming, NO is
inhibitory. However, later in larval development,
around the time when the limbs are developing,
NOS-positive neurons appear in the spinal cord
(139), and NO donors have the opposite effect of
facilitating rhythmic activity (148).
Although there is extensive anatomical evidence that NO synthesis is widespread in the
nervous system of most vertebrates studied, its
potential role in the modulation of locomotion in
other model systems has received considerably
less attention than other more conventional signaling molecules. Recent studies have shown
that NO plays a significant role in modulating
locomotion in both the lamprey (96, 97) and
mouse (1, 47).
In the lamprey system, NOS is located in a
variety of spinal neuron types including proprioceptive edge cells and gray matter neurons. NO
lower vertebrates, it has been extensively studied

in the isolated spinal cord of the lamprey where a
brief (10 min) application of substance P leads to
both short-term (2 h) and long-term (24 h)
increases in the frequency of NMDA-induced fictive locomotion (131a, 131b). The short-term effects are protein kinase C-dependent and appear
to involve a potentiation of cellular responses to
NMDA and the associated induction of membrane
potential oscillations. The long-term effects, in
which a 10-min exposure to substance P triggers an
increase in the baseline swimming frequency that
lasts for up to 24 h, require changes in protein
synthesis. The tachykinin receptor antagonist
spantide II leads to a lowering of the baseline
NMDA-induced locomotor frequency, strongly
suggesting that the release of substance P or a
related peptide during swimming modulates the
locomotor CPG. Substance P also has a presynaptic
facilitatory effect on the release of glutamate onto
spinal neurons via a calcium-independent mechanism (Parker & Grillner, 1998). There is an intrinsic
source of tackykinins in the spinal cord: substance
P immunoreactivity is found in cells of the ventral
plexus. However, there is also evidence for two
tackykinins (substance P and neurokinin B) in numerous cell groups in the brain, including regions
that project to the spinal cord and may play a role
in the initiation and/or modulation of swimming.
It is not known under what circumstances the lamprey might engage this positive feedback system to
maintain high-frequency swimming, but since
these animals undergo long migrations to their
breeding grounds it has been hypothesized that
the tackykinin system may be well suited to contributing to such a behavioral role.
In mammals, a large number of peptides and
their associated receptors are present in the ventral aspect of the spinal cord and are therefore in
a position to modulate motor activity (12, 133).
In one study (9), 11 such peptides were applied
to the isolated rat spinal cord, either on their
own or in the presence of NMA or NMA plus
5-HT, a cocktail of drugs that activates the locomotor CPG, while recordings were made from
lumbar ventral roots. Only four of the peptides
(oxytocin, vasopressin, bombesin, and TRH)
were able to trigger tonic or loosely coordinated
rhythmic activity when bath applied alone. However, all of the peptides were able to modulate
ongoing locomotor cocktail-induced CPG activity, although the effects were different for each
peptide. For example, proctolin and neurotensin
increased the frequency of locomotion, whereas
met-enkephalin and oxytocin decreased it. Some
peptides (bombesin, somatostatin) acted purely
on the frequency of locomotion, whereas most
affected both the rhythm frequency and the lo-
REVIEWS
biogenic amines, 5-HT and NA, on the spontaneously generated fictive locomotor patterns recorded from ventral roots at this later stage (140). It
is first shown that these isolated preparations display one of two forms of circuit coordination: either the limb and tail circuits generate rhythms
with independent frequencies or they generate a
conjoint rhythm with 1:1 coordination. Following
the addition of 5-HT to preparations displaying the
frequency-independent rhythms, the slower limb
rhythm accelerates while the faster axial rhythm
slows until the two are united at a single common
frequency. Conversely, in preparations already dis-
has an excitatory effect, increasing the frequency

of NMDA-induced locomotor activity. NOS inhibition or NO scavenging has the opposite effect,
showing that there is an intrinsic release of NO
during locomotor rhythm generation. The synaptic effects of NO in the lamprey are complex.
NO simultaneously reduces mid-cycle (glycinergic) inhibition and potentiates on-cycle (glutamatergic) excitation. Analysis of miniature synaptic
currents reveals a purely presynaptic effect on glycine release but a parallel pre- and postsynaptic effect on glutamatergic transmission.
Spinal interneurons expressing NOS are also found
throughout the mouse spinal cord. Although NOSpositive interneurons are most abundant in the dorsal horn, they are also present at lower levels in areas
surrounding the central canal and parts of the ventral
horn, particularly lamina VII (47, 124, 153). The addition of NO donors to isolated mouse spinal cord
preparations modulates both the amplitude and
frequency of on-going locomotor activity (47).
Interestingly, the amplitude of locomotor activity
can either be increased or decreased, depending
on the dose of the NO donor, whereas frequency
is consistently reduced. NO scavengers also affect the amplitude and frequency of locomotor
output, indicating an endogenous role for NO in
modulating the activity of both CPG interneurons and
motoneurons.
Metamodulation and Interactions

Between Modulators
In some notable cases, the effects of 5-HT and NA
are opposing and can switch during development
(118, 140). 5-HT, in general, facilitates the locomotor drive, increasing the duration and intensity of ventral root bursts. In Xenopus tadpoles,
NA exerts effectively the opposite effects by
lengthening the cycle period without any obvious effect on the duration of motor bursts. How
are these differential effects produced? The two
amines have a common target in modulating the
strength of glycinergic inhibition (118). Both
amines act presynaptically to regulate glycine
release from commissural interneurons, but
whereas 5-HT depresses release, NA enhances it.
In the case of 5-HT, the effect is to reduce the
amplitude of the inhibition at mid-cycle, allowing
neurons to escape from inhibition sooner and fire
for longer. In the case of NA, the effect is to increase the amplitude of mid-cycle inhibition and
delay the onset of the next cycle.
Later in development, during the metamorphic
period when the limbs and associated central circuits are being assembled, the roles of 5-HT and
NA, although still acting in opposition, switch.
Rauscent and colleagues studied the effects of two
FIGURE 4. Modulation and metamodulation of the Xenopus tadpole locomotor network

Summary diagram illustrating the metamodulation of spinal inhibition by NO in Xenopus tadpoles. At larval stage 42 (top), the major subdivisions of the CNS (middle) are
recognizable, including the forebrain (fb), midbrain (mb), hindbrain (hb), and spinal
cord (sc). Brain regions are separated by dotted lines. The noradrenergic locus coeruleus (in orange) is located just caudal to the midbrain-forebrain boundary. The midhindbrain reticulospinal (Mhr) region (purple) is located dorsally in the caudal
hindbrain, with axons that cross the midline (dashed line) and descend to the spinal
cord, providing a major source of spinal GABAergic inhibition. Commissural interneurons (blue) cross the midline and provide the major source of spinal glycinergic inhibition. NO modulates swimming frequency by altering endogenous NA release (orange),
which in turn modulates glycine release (blue) to motoneurons (MN). NO modulates
episode durations by directly modulating GABA release (purple) to motoneurons.
However, the nitrergic modulation of GABA could also affect swimming frequency.
Basal levels of NO are indicated in middle circle, reduced NO levels in left circle (pale
colors), raised NO levels in right circle (dark colors). Figure adapted from Ref. 121,
and used with permission from Journal of Neuroscience.
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406
turn mediates the direct presynaptic facilitation of

glycine release.
Conclusions and Future Prospects

Vertebrate locomotor control networks are richly
endowed with neuromodulatory inputs that provide the locomotor output with the degree of flexibility that is necessary to maneuver efficiently
through the environment. These inputs derive
from multiple locations both within the spinal cord
and also from extrinsic modulatory centers in the
brain. At the cellular level, we know most about
modulators deriving from neuronal sources, but it
is clear that, even though we appreciate them less,
glia are able to synthesize and release neuromodulators with very potent effects on central circuitry,
including ATP, D-serine, and neurosteroids.
In aquatic vertebrates, such as the lamprey and frog
tadpole, the links between cellular mechanisms of action and their consequences for locomotor network output are well described for a number of
neuromodulators. In comparison, the relationships between cellular mechanisms and network
output are less clear for the neuromodulation of
complex mammalian systems. This largely reflects
our lack of knowledge regarding the components
of the mammalian CPG and their interconnectivity. However, with an increasing number of mammalian interneurons being defined and described
using molecular genetic techniques (63), we are
now much better placed to go on to define specific
sources of neuromodulation, their cellular targets,
and their roles in the regulation of mammalian
locomotor output (e.g., Ref. 182).
Although knowledge of locomotor circuitry is critical toward understanding the actions of neuromodulators, conversely, studies of neuromodulation
may aid in deciphering locomotor networks. This has
indeed proved to be the case for brain stem networks
controlling mammalian respiration where knowledge of substance P and opioid-mediated modulation of the respiratory rhythm led to the discovery
that NK-1 and mu-opioid receptors serve as markers
of critical respiratory rhythm-generating neurons
within the pre-Botzinger complex (64). More recently, the specific neuromodulatory effects of opioids on pre-Botzinger complex neurons have also
revealed the existence of a second respiratory oscillator in the brain stem, the parafacial respiratory
group (reviewed by Ref. 54).
From the perspective of the individual components comprising locomotor control networks (i.e.,
neurons and synapses), it is abundantly clear that
they are constantly exposed to an ever changing
neuromodulatory environment. At any moment in
time, the extent to which the plethora of modulatory receptors embedded in the neuronal mem-
playing the frequency-coupled rhythm, bath applications of NA exerts the opposite effect of
decelerating the limb and accelerating the axial
rhythm until the two display independent frequencies. These effects are similar to those exerted by
the amines at stages both before and after metamorphosis; 5-HT decelerates the axial rhythm of
earlier stages before limb development, whereas
NA slows (while 5-HT accelerates) the limb rhythm
generated by froglets after the tail has disappeared.
At the intermediate stages when both circuits are
present, it is presumably important for the organism to be able to functionally couple and decouple
the two locomotor systems, and Rauscent and colleagues suggest that two aminergic systems with
opposing behavioral effects may be involved in this
tactical switching between two locomotory
networks.
Metamodulation defines a second-order form of
modulation in which the effects of one modulatory
system are influenced by the effects of another
modulatory system (89). Metamodulation can occur
in series or in parallel. A clear example of serial metamodulation in vertebrate locomotor control involving NO signaling is to be found in the swimming
system of Xenopus tadpoles (121) (FIGURE 4). The
differential effects of the amines 5-HT and NA on
inhibitory transmission have already been described
(see above). In the case of NA, there is a presynaptic
facilitation of glycine release from commissural inhibitory interneurons and a parallel presynaptic
facilitation of GABA release from descending midhindbrain reticulospinal interneurons. The effects
of NO bear a remarkable similarity, raising the
question of whether these two modulators have
convergent targets at the terminals of GABAergic
and glycinergic interneurons or whether there
might be serial interactions between the two modulatory systems. Considering first the modulation
of GABA synapses, there is an apparent convergence along two parallel routes: one a nitrergic
effect and the other noradrenergic. The evidence is
that the effects of a given neuromodulator on
GABA transmission is unaffected by blockage of
the other modulator and vice versa. For example,
the shortening of swim episode durations (due to
enhanced GABA release) by NA persists when NO
is scavenged or NOS is inhibited, and the effects of
NO donors on episode durations remain when alpha-adrenoreceptors are blocked.
In the case of glycinergic transmission, however,
the situation is very different because the effects of
NO are occluded when alpha-adrenoreceptors are
blocked by phentolamine, but the effects of noradrenaline are unaffected by NO scavenging or
NOS inhibition. This leads to the conclusion that
NOs effects on glycinergic transmission involve a
facilitation of the noradrenergic system, which in
REVIEWS
brane are activated will determine the levels of the
intracellular second messenger molecules that ultimately determine the computational ability of the
neuron to integrate fast synaptic inputs and generate output. In this sense, the neurons can be
thought of as biochemical integrators, a role that
ought to be given equal credence with their role of
transmitting electrical information to their own
synaptic targets. This idea is by no means a new
one (89), and yet in the last decade there has been
very little progress in advancing the hypothesis.
This is surely an area in which future research
effort should advance our understanding of how
neuromodulation sculpts an infinite variety of outputs from a single anatomically defined network.
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Neuromodulation of Vertebrate

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Neuromodulation of Vertebrate Locomotor Control

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Additional material and information about Physiology can be found at:

PHYSIOLOGY 26: 393 411, 2011; doi:10.1152/physiol.00013.2011

Gareth B. Miles and Keith T. Sillar

Vertebrate locomotion must be adaptable in light of changing environmental,

Need for Flexibility in Spinal

system to adapt in the face of external demands is

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The neural networks that control locomotion in

Opposing Effects of Neuromodulators

input: if motor output is facilitated, then sensory

Role of Neuromodulation Developmental

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are unaffected but the frequency is altered, then the

Sources and Types of

Evolution of 5-HT Signaling

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5-HT in Mammalian Systems

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modulatory effects on the intrinsic properties of

Noradrenaline in Mammalian Systems

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facilitatory causing increases in the frequency

Dopamine in Mammalian Systems

locomotor activity (59). However, dopamine is not

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Biogenic Amines in Non-Mammalian

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would be anticipated that apamin, which blocks

Conventional Fast Excitatory

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The effects of metabotropic glutamate receptors

diffuse excitatory effects of exogenous agonist

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of acetylcholine or cholinesterase inhibitors (36,

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Data concerning the cellular effects of mGluRs

Conventional Fast Inhibitory

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FIGURE 3. Intrinsic cholinergic modulation of mouse locomotion

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lower vertebrates, it has been extensively studied

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has an excitatory effect, increasing the frequency

Metamodulation and Interactions

FIGURE 4. Modulation and metamodulation of the Xenopus tadpole locomotor network

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turn mediates the direct presynaptic facilitation of

Conclusions and Future Prospects

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