The ultimate goal of the proposed research is to identify neural and molecular determinants of skilled motor behavior. Animals, including humans, are able to perform exquisitely skilled motor behaviors that are essential for their survival and quality of life. Indeed, motor skill goes awry in disorders such as amyotrophic lateral sclerosis and Parkison?s disease. It is thus necessary to understand the neural circuitry underlying motor skill with sufficient detail to enable design of therapeutic interventions that specifically treat symptoms without causing side effects. However, our current understanding of motor circuitry is insufficiently detailed to develop effective treatments. This insufficiency is in part due to the fact that the model systems used to study motor circuitry have little natural variation in motor skill and are therefore are of little use for finding novel details of the neural determinants of motor behavior. Thus, these systems have provided only a broad strokes view of the circuitry that controls skilled motor behavior. To overcome this limitation, this research will use a comparative approach to identify novel, fine-grained motor circuitry controlling skilled behavior. Specifically, it will compare four subspecies of deer mice (Peromyscus maniculatus)?two that evolved in a forest and two in a prairie?with innate differences in skilled climbing behavior: forest mice are skilled climbers. This work will use optogenetic silencing of motor cortex to test the hypothesis that cortex specifically controls skilled rather than unskilled climbing (Aim 1). Next, the proposed research will use viral tracing and single-nucleus RNA-sequencing to make a comparative neuroanatomical (Aim 2) and molecular (Aim 3) atlas of deer mouse motor circuitry. This atlas will (1) test specific hypotheses about how differences in anatomy or cell type affect climbing behavior and (2) identify new, unexpected anatomical and molecular differences between climbers and non-climbers. Specifically, this research will compare two convergently- evolved pairs of subspecies, each pair containing a forest subspecies and a closely-related prairie subspecies. If the same differences are observed in both pairs, it will suggest that those differences robustly correlate with climbing behavior. Successful completion of this project will identify both the functional role of cortex in climbing skill in deer mice and what variation motor circuits between skilled and unskilled mice may underlie this difference in skill. Importantly, it will identify neural determinants of skilled behavior that would not be found using more traditional model systems. This research plan is part of a comprehensive training plan that combines training in comparative biology and systems neuroscience with training in communication and mentoring. This plan will be sponsored by Dr. Hopi Hoekstra at Harvard University and experiments will be performed in collaboration with Dr. Adam Hantman at Janelia Research Campus. Together, it will provide excellent training for an independent research career in a unique, interdisciplinary niche at the interface of molecular neuroscience, behavior, and evolutionary biology.
A deficit in skilled motor behavior is a symptom of several diseases, including amyotrophic lateral sclerosis and Parkinson?s disease, but we currently have a poor understanding of the neural basis of skilled motor behavior resulting in insufficient treatment options for these disorders. Deer mice (Peromyscus maniculatus) offer a unique solution to this problem as an experimentally tractable system with innate natural variation in motor skill. This proposal thus aims to use deer mice to identify novel neural determinants of skilled motor behavior, deepening our understanding of the mechanisms underlying movement disorders and opening new avenues for therapeutic interventions.
