Neuromodulation in developing motor microcircuits
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.
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