Determining the role of distinct parafascicular thalamic circuits in motor behaviors relevant to Parkinson’s disease

项目摘要 从一个地方移动到另一个地方并获得不同的运动技能的能力对我们的生存至关重要。许多 人类疾病包括帕金森氏病、亨廷顿病和图雷特综合征，导致 异常的运动行为。因此，识别调节运动和运动学习的神经回路 在基础科学和理解它们在疾病模型中的功能障碍方面都是至关重要的 会导致马达缺陷。束旁丘脑在基底节内有广泛的连接 运动系统，参与反转学习和动作序列的启动。虽然 已经在细胞水平上报道了黑质丘脑神经元内的异质性，其功能相关性 运动行为中不同的PF亚群仍不清楚。这项提议的中心假设是 Pf丘脑包含不同的投射特定亚群，它们调节不同的运动过程。 在K99期，使用化学生成神经元抑制和活体钙成像，我将测试 丘脑纹状体(PF！背侧纹状体)通路主要参与运动的假说，而 丘脑下丘脑通路主要参与运动学习。通过比较 运动皮质、苍白球和黑质对这些PF亚群的传入 光遗传电路操作，我将确定Pf亚群特定的输入对其 行为贡献。在R00阶段，使用体外电生理学，我将确定这两个 在帕金森氏病小鼠模型中，改变了Pf回路，这将为识别 在这个小鼠模型中，基于电路的操作可以同时挽救运动和运动学习。至 在进一步的这些救援实验中，我将对Pf的两个亚群进行单细胞RNA测序 野生型小鼠寻找能够挽救帕金森病两种运动表型的潜在分子靶点 生病的小鼠。综上所述，拟议的项目不仅将加深我们对 运动功能中不同的PF电路，但也潜在地表明，靶向PF电路可能足以 挽救神经退行性疾病模型中的多种运动表型。拟议的研究和职业 发展计划将在麻省理工学院和哈佛大学的冯国平博士的实验室进行， 这将使Dheeraj Roy博士做好准备，作为一名独立研究员领导一个创新的研究项目 研究调节正常和疾病状态的神经回路机制。

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.