Evaluating the functional organization of forelimb and hindlimb internal copy pathways in the lateral reticular nucleus

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The coordinated execution of movement requires the rapid and continuous refinement of neural activity that drives muscle contraction, a process that is impaired in many forms of injury and disease. In particular, many human movement disorders have been associated with dysfunction of the cerebellum, reinforcing the need for a better understanding of cerebellar circuits. The cerebellum is thought to perform computations necessary for the rapid adjustment of motor output by using internal copies of motor commands to predict movement outcomes. The lateral reticular nucleus (LRN) is a major brainstem nucleus that receives ascending internal copies from the spinal cord and conveys these signals to the cerebellum. Yet little is known about how these motor copy signals are organized and processed in the LRN to facilitate coordinated movement. The LRN is a heterogeneous structure that is classically divided into anatomical subregions. Ascending cervical and lumbar spinal inputs are somatotopically segregated and largely innervate distinct subregions within the LRN, suggesting that LRN neurons are organized into distinct subcircuits that compartmentalize internal copies to regulate the movement of different limbs. Moreover, preliminary findings have revealed at least two molecularly distinct subtypes of LRN neurons that are distributed into different anatomical subregions, potentially forming the cellular basis for these somatotopically organized subcircuits. However, separate studies have shown that a subset of LRN neurons have wide receptive fields spanning multiple limbs, suggesting a convergence of cervical and lumbar inputs onto individual LRN neurons. These findings support a competing model whereby the LRN integrates internal copies from different body parts to coordinate complex multi-limb movements. These two models of divergence versus convergence have contrasting implications for LRN function. The major goal of this proposal is to take advantage of genetic access and molecular tools in mice to resolve these conflicting models. To achieve this goal, Aim 1 will map the connectivity and identity of inputs to each molecularly distinct LRN neuron subtype using viral, genetic, and electrophysiological approaches. These experiments will address the hypothesis that the two discrete LRN neuron subtypes are innervated by distinct sets of inputs that differ in their spatial distributions and molecular identities. Aim 2 will functionally dissect the contributions of these distinct LRN neuron subtypes to forelimb versus hindlimb movements using in vivo electrophysiology and optogenetic perturbations during multi- limb and forelimb-specific movements. These experiments will address the hypothesis that LRN neuron subtypes have different patterns of activity during forelimb versus hindlimb movements, and specific perturbations targeting each LRN neuron subtype will induce distinct movement deficits. This work will provide detailed insights into the functional organization of internal copy cerebellar circuits, and should contribute towards a mechanistic understanding of the etiology of human cerebellar movement disorders.