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

确定不同的束旁丘脑回路在帕金森病相关运动行为中的作用

• 批准号: 10348316
• 负责人: Dheeraj Roy
• 金额: $ 10.83万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348316
• 关键词: Acceleration; Basal Ganglia; Basic Science; Behavior; Behavioral; Biological Assay; Brain region; Calcium; Complement; Complex; Corpus striatum structure; Data; Deep Brain Stimulation; Defect; Development Plans; Disease; Disease model; Dorsal; Electrophysiology (science); Exhibits; Functional disorder; Future; Gilles de la Tourette syndrome; Globus Pallidus; Heterogeneity; Human; Huntington Disease; Image; Institutes; Life; Locomotion; Mediating; Mentors; Molecular Target; Motor; Motor Cortex; Motor Skills; Movement; Movement Disorders; Mus; Muscarinic Acetylcholine Receptor; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathway interactions; Pattern; Phase; Phenotype; Play; Process; Rattus; Receptor Activation; Reporting; Research; Research Personnel; Reversal Learning; Role; Structure of subthalamic nucleus; Substantia nigra structure; System; Testing; Thalamic Nuclei; Thalamic structure; Therapeutic; Wild Type Mouse; base; career development; disabling symptom; experimental study; in vivo; in vivo calcium imaging; innovation; learned behavior; motor behavior; motor deficit; motor disorder; motor impairment; motor learning; motor symptom; mouse model; neural circuit; optogenetics; programs; putamen; relating to nervous system; research and development; response; single-cell RNA sequencing; tool

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.

项目摘要 从一个地方转移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。许多 包括帕金森氏病，亨廷顿氏病和图雷特综合症在内的人类疾病，原因 运动行为异常。因此，确定介导运动和运动学习的神经回路是 在基础科学和了解其疾病模型中的功能障碍方面的关键 有助于运动缺陷。副毛皮（PF）丘脑在基底神经节内具有广泛的连通性 运动系统，并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报道 运动行为中不同的PF亚群仍然未知。该提议的核心假设是 PF丘脑包含介导不同运动过程的独特投影特异性亚群。 在K99阶段，使用化学发生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）途径主要参与运动 丘脑丘脑（PF！丘脑下核）途径主要参与运动学习。通过比较 来自运动皮层，帕利德斯球员和黑质的输入到这些PF亚群，然后是 光遗传电路操作，我将确定PF亚群特异性输入对其至关重要 行为贡献。在R00阶段，使用离体电生理学，我将确定这两个 PF电路在帕金森氏病小鼠模型中发生了变化，这将为识别 基于电路的操作可能会在此鼠标模型中挽救运动和运动学习。到 此外，这些救援实验，我将执行两个PF亚群的单细胞RNA测序 野生型小鼠，以识别能够在帕金森氏症中拯救两种运动表型的潜在分子靶标 疾病小鼠。共同的项目不仅将增强我们对 电机功能中不同的PF电路，但也有可能表明靶向PF电路可能足以足以 在神经退行性疾病模型中营救多个运动表型。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广泛研究所的Guoping Feng博士实验室进行。 这将使Dheeraj Roy博士准备作为独立研究者的创新研究计划 研究介导正常状态和疾病状态的神经回路机制。