Determining the Role of Distinct Parafascicular Thalamic Circuits in Motor Behaviors Relevant to Parkinson’s Disease

项目总结

Project Summary The ability to move from one place to another and acquire different motor skills is critical for our survival. Many human disorders including Parkinson's disease, Huntington's disease, and Tourette syndrome, cause abnormal motor behaviors. Identifying neural circuits that mediate locomotion and motor learning are therefore crucial both in terms of basic science and understanding how their dysfunction in disease models may contribute to motor defects. Parafascicular (PF) thalamus has extensive connectivity within the basal ganglia motor system, and is involved in reversal learning as well as the initiation of movement sequences. Although heterogeneity within PF thalamic neurons has been reported at the cellular level, the functional relevance of distinct PF subpopulations in motor behaviors remains unknown. The central hypothesis of this proposal is that PF thalamus contains distinct projection-specific subpopulations that mediate different motor processes. During the K99 phase, using chemogenetic neuronal inhibition and in vivo calcium imaging, I will test the hypothesis that the thalamostriatal (PF!dorsal striatum) pathway is mainly involved in locomotion whereas the thalamosubthalamic (PF!subthalamic nucleus) pathway is mainly involved in motor learning. By comparing inputs from motor cortex, globus pallidus, and substantia nigra to these PF subpopulations followed by optogenetic circuit manipulations, I will identify PF subpopulation-specific inputs that are critical for their behavioral contributions. During the R00 phase, using ex vivo electrophysiology, I will determine how these two PF circuits are altered in a mouse model of Parkinson's disease, which will set the stage for the identification of circuit-based manipulations that may rescue both locomotion and motor learning in this mouse model. To further these rescue experiments, I will perform single cell RNA sequencing of the two PF subpopulations in wild type mice to identify potential molecular targets capable of rescuing both motor phenotypes in Parkinson's disease mice. Together, the proposed project will not only enhance our understanding regarding the role of distinct PF circuits in motor functions, but also potentially indicate that targeting PF circuits may be sufficient to rescue multiple motor phenotypes in neurodegenerative disease models. The proposed research and career development plan will be conducted in the lab of Dr. Guoping Feng at the Broad Institute of MIT and Harvard, which will prepare Dr. Dheeraj Roy to direct an innovative research program as an independent investigator studying neural circuit mechanisms mediating normal and disease states.