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

项目概要 从一个地方移动到另一个地方并获得不同运动技能的能力对于我们的生存至关重要。很多 人类疾病，包括帕金森病、亨廷顿病和抽动秽语综合征， 异常的运动行为。因此，识别介导运动和运动学习的神经回路是 无论是在基础科学方面还是理解它们在疾病模型中的功能障碍方面都至关重要 导致运动缺陷。束旁 (PF) 丘脑在基底神经节内具有广泛的连接 运动系统，参与逆转学习以及运动序列的启动。虽然 PF 丘脑神经元内的异质性已在细胞水平上得到报道， 运动行为中不同的 PF 亚群仍然未知。该提案的中心假设是 PF 丘脑包含不同的投射特异性亚群，介导不同的运动过程。 在 K99 阶段，使用化学遗传学神经元抑制和体内钙成像，我将测试 假设丘脑纹状体（PF！背纹状体）通路主要参与运动，而 丘脑底丘脑（PF！底丘脑核）通路主要参与运动学习。通过比较 从运动皮层、苍白球和黑质到这些 PF 亚群的输入，然后是 光遗传学电路操作，我将确定 PF 亚群特定的输入，这些输入对其至关重要 行为贡献。在 R00 阶段，使用离体电生理学，我将确定这两个 帕金森病小鼠模型中的 PF 回路发生改变，这将为识别帕金森病奠定基础 基于电路的操作可以挽救该小鼠模型的运动和运动学习。至 为了进一步进行这些救援实验，我将对两个 PF 亚群进行单细胞 RNA 测序 野生型小鼠识别能够挽救帕金森氏症两种运动表型的潜在分子靶标 病鼠。总之，拟议的项目不仅将增强我们对以下角色的理解： 运动功能中不同的 PF 电路，但也可能表明目标 PF 电路可能足以 拯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 开发计划将在麻省理工学院和哈佛大学博德研究所冯国平博士的实验室进行， 这将使 Dheeraj Roy 博士做好准备，以独立研究者的身份指导一项创新研究项目 研究介导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.