Scientific Understanding of Consciousness
Movement Control via Propriospinal Internal Copy Circuit
Nature 508, 357–363 (17 April 2014)
Skilled reaching relies on a V2a propriospinal internal copy circuit
Eiman Azim, Juan Jiang, Bror Alstermark & Thomas M. Jessell
Howard Hughes Medical Institute, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA
Department of Integrative Medical Biology, Section of Physiology, Umeĺ University, Umeĺ, Sweden
The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear. One class of spinal interneurons implicated in the control of mammalian forelimb movement, cervical propriospinal neurons (PNs), has the potential to convey an internal copy of premotor signals through dual innervation of forelimb-innervating motor neurons and precerebellar neurons of the lateral reticular nucleus. Here we examine whether the PN internal copy pathway functions in the control of goal-directed reaching. In mice, PNs include a genetically accessible subpopulation of cervical V2a interneurons, and their targeted ablation perturbs reaching while leaving intact other elements of forelimb movement. Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics. Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour.
Skilled forelimb movements constitute some of the more impressive accomplishments of the mammalian motor system. Goal-directed reaching involves the activation of descending pathways that provide commands for task-appropriate motor programs. Less clear is the issue of how such descending commands engage spinal circuits to achieve the modularity and precision evident in reach, grasp and object manipulation. One view holds that skilled motor performance requires on-line refinement throughout the course of movement, through internally directed copies of motor commands that engage cerebellar circuits and permit rapid updating of motor output. But putative internal copy pathways, by their nature, are closely interwoven with motor output circuits, a feature that has made it hard to isolate the neural substrate of such internal copies or to assess whether they do, in fact, influence motor performance.
One interneuron class, cervical PNs, has long been implicated in the control of forelimb behaviour. In cat and primate, PNs comprise excitatory and inhibitory neuronal subtypes that serve as intermediary relays for descending motor commands. PNs are characterized by an ipsilateral bifurcated output: one axonal branch projects caudally to the cervical motor neurons that control forelimb muscles, and the other projects rostrally to the lateral reticular nucleus (LRN), a precerebellar relay. In principle, the intriguing duality of PN axonal projections offers a simple anatomical substrate for the internal copying of premotor signals. In cat, severing the premotor axonal branch of PNs by lesioning the ventrolateral funiculus perturbs reaching but not grasping, whereas silencing PN output in monkey perturbs both reaching and grasping. Neither of these manipulations, however, has addressed the relevance of an internal copy branch for on-line refinement of motor output.
In this study, we sought to define the contribution of excitatory PNs to skilled reach behaviour in mice. We reasoned that their molecular delineation could provide a genetic means of eliminating PNs as well as manipulating their internal copy projections. We show that one major population of excitatory PNs belongs to the Chx10 (also known as Vsx2)-expressing V2a interneuron class—one of the cardinal subtypes of ventral interneurons implicated in motor control. Genetic elimination of cervical V2a interneurons elicits a reach-specific defect in forelimb movement, revealed by quantitative kinematics. Selective activation of the PN internal copy branch triggers a rapid cerebellar feedback loop that excites motor neurons and degrades forelimb movement. Our findings show that excitatory PNs establish an internal feedback circuit assigned to the control of mammalian skilled reaching.
The refinement of goal-directed reaching movements is thought to rely on the generation of internally directed copies of motor commands. Here we provide evidence that V2a PNs lie at the core of an internal copy feedback circuit crucial for skilled reaching. Ablation of cervical V2a interneurons elicits selective reaching defects, photostimulation of PN terminals within the LRN erodes the fidelity of forelimb movement, and activation of the PN internal copy branch recruits a fast cerebellar–motor feedback loop.
Our functional analysis has provided insights into two general issues in limb motor control: the degree to which distinct microcircuits control elemental aspects of movement, and the evolutionary conservation of circuits and strategies for skilled reaching. Targeted elimination of PNs, albeit through ablation of the entire set of cervical V2a interneurons, disrupts forelimb reaching in a selective manner. Thus PNs in particular, and cervical V2a interneurons as a whole, appear to have little impact on aspects of mouse forelimb movement that engage distal musculature during grasping. These findings add to an emerging view that limb motor modularity has its basis in the recruitment of distinct spinal interneuron subtypes and circuits. Genetic inactivation of dI3 excitatory premotor interneurons preferentially impairs forepaw grasp behaviours, and elimination of dI4 presynaptic inhibitory interneurons uncovers forelimb oscillation during reaching, phenotypes distinct from that seen after V2a interneuron ablation. Classical studies in cat and primate also speak to the issue of conservation in PN function and behavioural modularity. As with V2a neuronal ablation, severing the premotor output of cat PNs undermines reaching but not grasping. The consistency of behavioural defects across mammalian species and interventional approaches suggests that PNs represent a major subpopulation of V2a interneurons involved in the control of reaching. In monkey, however, blocking the output of PNs disrupts both reach and grasp, which may reflect an evolutionary elaboration in the wiring of circuits for distal forelimb dexterity
Our findings also provide insight into the nature of feedback provided by internal copy pathways. The PN-mediated recruitment of LRN neurons activates motor neurons through a fast cerebellar feedback loop. The most likely substrate for such rapid feedback is the collateral projection of LRN axons to deep cerebellar nuclei, which then recruit reticulospinal neurons that activate motor neurons as well as PNs themselves. Yet our findings pose the problem of the logical underpinnings of a circuit in which enhanced PN activity triggers a reinforcing feedback loop that further excites PNs and motor neurons, potentially destabilizing motor output. One potential resolution lies in the fact that we manipulated solely an excitatory subpopulation of PNs—the physiological operation of the PN system may depend critically on parallel recruitment of inhibitory PNs. Our focus on the most rapid PN response pathway does not preclude the engagement of cerebellar granule and Purkinje circuits that display plasticity during motor adaptation and learning, permitting an additional level of dynamic response to PN activity.
Finally, we consider the merits of an internal copy conveyed from the spinal cord. By virtue of their privileged status as last-order interneurons, and their role as mediators of convergent descending and segmental sensory input, PNs may be afforded access to a degree of integrated premotor information not available upstream. We note that the PN internal copy strategy differs in design from more conventional spinal efference copy systems that lack a premotor output arm, and as a consequence are required to receive and transmit a facsimile of the diverse inputs that impinge on motor neurons. Admittedly, PNs provide only one of many convergent inputs to motor neurons. Yet their bifurcating output reduces the burden inherent in conveying an accurate copy of premotor information, simplifying the task of matching premotor signal and internal report.
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