Elsevier

Current Opinion in Neurobiology

Volume 29, December 2014, Pages 73-81
Current Opinion in Neurobiology

Neuromodulation in developing motor microcircuits

https://doi.org/10.1016/j.conb.2014.05.009Get rights and content

Highlights

  • Neuromodulation confers flexibility upon locomotor network output.

  • Neuromodulators exert both acute and longer term effects on motor networks.

  • Neuromodulation configures neural networks during development.

  • Neuromodulatory mechanisms can be re-engaged in response to spinal injury.

Neuromodulation confers operational flexibility on motor network output and resulting behaviour. Furthermore, neuromodulators play crucial long-term roles in the assembly and maturational shaping of the same networks as they develop. Although previous studies have identified such modulator-dependent contributions to microcircuit ontogeny, some of the underlying mechanisms are only now being elucidated. Deciphering the role of neuromodulatory systems in motor network development has potentially important implications for post-lesional regenerative strategies in adults.

Introduction

All neuronal networks underlying motor behaviour must adapt their output to prevailing organismal, developmental and environmental needs. Traditionally, however, such motor networks are portrayed as 2D electrochemical automata; anatomically hard-wired and physiologically stereotyped in their output. However, the dexterity of a dressage horse, the flexibility of an Olympic gymnast, and the ability to learn new motor skills, suggest this description is over simplistic. Which intrinsic neural processes impart such behavioural plasticity? Short-term adaptations of underlying network output can be conferred by differing discharge patterns of sensory or descending brain inputs. However, the longer-lasting, often 2nd messenger-mediated neuromodulation of neuronal electrical properties and synaptic strengths within motor networks is the essential source of adaptive motor circuit function [1•, 2].

In addition to the acute regulation of ongoing network operation, neuromodulation is intimately involved in the actual assembly and fine-tuning of motor networks during ontogeny. Neuromodulators regulate the number, types and properties of neurons in developing motor networks, which in turn determines the detailed features of adult network output. Concomitantly, the neuromodulatory systems themselves may be changing as their own transmitters and actions evolve. Here we review how certain neuromodulators perform such instructive roles in the maturation of network architecture and function. Furthermore, recent evidence indicates that the same modulators, receptors and signalling pathways can be re-activated following spinal injury in adults suggesting that pathophysiology recapitulates ontogeny.

Section snippets

Neuromodulation of motor network assembly

Many neuromodulators, but biogenic amines in particular, regulate the developmental configuration of the same networks they will modulate later in life. For example, during Xenopus tadpole development, serotonin deriving from raphespinal projections is causal to the maturation of a flexible larval locomotor pattern [3]. Similarly, descending serotonergic pathways contribute to the differentiation of motorneuron firing properties and the maturation of spinal motor networks in the perinatal rat [4

Modulation and activity-dependence in network development

Spontaneous activity is a ubiquitous feature that plays a fundamental role in network development and maturation [12, 13•]. Thus, by regulating network activity, precociously acting modulators can indirectly govern activity-dependent processes of motor network development ranging from neurotransmitter specification in embryonic spinal neurons [14], synaptic maturation [15], motorneuron neurite outgrowth [16] and axon pathfinding [17]. Interestingly, activity-dependent processes can also

Repressive neuromodulatory control of circuit development

Further to a permissive role in motor circuit development, neuromodulators can also restrain target network maturation. For example, serotonin from descending raphé projections to the embryonic mouse spinal cord slows the integration of inhibitory synaptic transmission [24] by delaying GABAergic interneuron maturation [25]. This repressive effect might ensure the coordinated maturation of spinal motor circuit and sensory input pathways, or the delay in GABAergic pathway function could relate to

Changes in modulatory actions during network development

In parallel with their target network development, neuromodulatory input systems themselves may change in terms of their transmitter substances, receptors and actions. Consequently, individual neuromodulators may exert very different or even opposing influences on the same motor circuit depending on the maturational stage of the animal. In lamprey spinal motor circuitry, for example, peptidergic modulation of synaptic transmission differs substantially in larvae and young adults [34]. Substance

Switching aminergic modulation in developing Xenopus spinal networks

The monoaminergic modulation of spinal locomotor circuitry in hatchling Xenopus tadpoles during metamorphosis from larval tail-based to adult limb-based locomotion represents a striking example of switching modulatory actions during motor network development (Figure 2). Throughout the entire maturational process, 5-HT and NA exert overall opposing modulatory influences on the motor rhythms that drive undulatory and eventually appendicular swimming. In early postembryonic larvae, exogenous 5-HT

Higher order metamodulation, NO and network development

The ethereal nature of NO has hindered elucidation of its roles in neural circuit function such as in the hippocampus, cerebellum, brainstem and spinal cord. For the latter, NO exerts a net suppressive regulation of spinal locomotor CPG activity in Xenopus tadpoles via its facilitation of inhibitory synapses [50, 51]. Subsequent experiments revealed NO's role as a higher order ‘metamodulator’ (that is, a modulator of other modulatory systems) of spinal CPG function [52]. Thus, from discrete

Conclusions

The development of functional motor circuitry occurs through a combination of genetically-programmed changes in a network's intrinsic properties and extrinsic short-term and long-term influences from its equally changing neuromodulatory environment. Intriguingly, recent evidence suggests that certain roles played by neuromodulatory signalling during network development may also extend into the mature nervous system and promote regenerative plasticity in adult motor circuits after lesion. In a

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We are grateful to the ‘Projet International de Coopération Scientifique’ (PICS) of the CNRS and LabEx BRAIN for recent support of collaborative interactions between the authors’ laboratories.

References (63)

  • V.S. Fénelon et al.

    Sequential developmental acquisition of neuromodulatory inputs to a central pattern-generating network

    J Comp Neurol

    (1999)
  • A. Rauscent et al.

    Opposing aminergic modulation of distinct spinal locomotor circuits and their functional coupling during amphibian metamorphosis

    J Neurosci

    (2009)
  • J.R. McDearmid et al.

    Aminergic modulation of glycine release in a spinal network controlling swimming in Xenopus laevis

    J Physiol

    (1997)
  • A. Kyriakatos et al.

    Nitric oxide potentiation of locomotor activity in the spinal cord of the lamprey

    J Neurosci

    (2009)
  • G.B. Miles et al.

    Neuromodulation of vertebrate locomotor control networks

    Physiology

    (2011)
  • K.T. Sillar et al.

    Involvement of brainstem serotonergic interneurons in the development of a vertebrate spinal locomotor circuit

    Proc Biol Sci

    (1995)
  • L. Vinay et al.

    Development of posture and locomotion: an interplay of endogenously generated activities and neurotrophic actions by descending pathways

    Brain Res Brain Res Rev

    (2002)
  • G. Hilaire et al.

    The role of serotonin in respiratory function and dysfunction

    Respir Physiol Neurobiol

    (2010)
  • A.M. Lambert et al.

    The conserved dopaminergic diencephalospinal tract mediates vertebrate locomotor development in zebrafish

    J Neurosci

    (2012)
  • A.R. Decker et al.

    Abnormal differentiation of dopaminergic neurons in zebrafish trpm7 mutant larvae impairs development of the motor pattern

    Dev Biol

    (2014)
  • B.R. Souza et al.

    Dopamine D2 receptor activity modulates Akt signaling and alters GABAergic neuron development and motor behavior in zebrafish larvae

    J Neurosci

    (2011)
  • A.G. Blankenship et al.

    Mechanisms underlying spontaneous patterned activity in developing neural circuits

    Nat Rev Neurosci

    (2010)
  • L.N. Borodinsky et al.

    Activity-dependent homeostatic specification of transmitter expression in embryonic neurons

    Nature

    (2004)
  • C. Gonzalez-Islas et al.

    Spontaneous network activity in the embryonic spinal cord regulates AMPAergic and GABAergic synaptic strength

    Neuron

    (2006)
  • Inglis FM1 et al.

    The AMPA receptor subunit GluR1 regulates dendritic architecture of motor neurons

    J Neurosci

    (2002)
  • M. Demarque et al.

    Activity-dependent expression of Lmx1b regulates specification of serotonergic neurons modulating swimming behavior

    Neuron

    (2010)
  • J.A. Gally et al.

    The NO hypothesis: possible effects of a short-lived, rapidly diffusible signal in the development and function of the nervous system

    Proc Natl Acad Sci USA

    (1990)
  • C.P. Myers et al.

    Cholinergic input is required during embryonic development to mediate proper assembly of spinal locomotor circuits

    Neuron

    (2005)
  • P. Branchereau et al.

    Descending 5-hydroxytryptamine raphe inputs repress the expression of serotonergic neurons and slow the maturation of inhibitory systems in mouse embryonic spinal cord

    J Neurosci

    (2002)
  • A.E. Allain et al.

    Ontogenic changes of the spinal GABAergic cell population are controlled by the serotonin (5-HT) system: implication of 5-HT1 receptor family

    J Neurosci

    (2005)
  • E. Brustein et al.

    Serotonin patterns locomotor network activity in the developing zebrafish by modulating quiescent periods

    J Neurobiol

    (2003)
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