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 从一个地方移动到另一个地方并获得不同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、亨廷顿氏病和图雷特综合征， 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是 无论是在基础科学方面，还是在理解他们在疾病模型中的功能障碍方面， 导致运动缺陷。束旁丘脑（PF）在基底神经节内具有广泛的连通性 运动系统，并参与反向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经在细胞水平上被报道， 运动行为中不同的PF亚群仍然未知。这一提议的核心假设是， PF丘脑包含不同的投射特定的亚群，介导不同的运动过程。 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！背侧纹状体）通路主要参与运动，而 丘脑底丘脑（PF！丘脑底核）通路主要参与运动学习。通过比较 从运动皮层、苍白球和黑质输入到这些PF亚群， 光遗传学电路操作，我将确定PF亚群特异性输入，这是关键的， 行为贡献。在R 00阶段，使用离体电生理学，我将确定这两个 在帕金森病小鼠模型中，PF回路发生了改变，这将为识别 基于电路的操作，可以拯救运动和运动学习在这个小鼠模型。到 为了进一步进行这些拯救实验，我将对两个PF亚群进行单细胞RNA测序， 野生型小鼠，以确定潜在的分子靶点，能够挽救帕金森氏症的两种运动表型 病鼠总的来说，拟议的项目不仅将加强我们对 不同的PF回路在运动功能，但也可能表明，目标PF回路可能足以 在神经退行性疾病模型中拯救多种运动表型。建议的研究和职业 开发计划将在麻省理工学院和哈佛布罗德研究所冯国平博士的实验室进行， 这将为Dheeraj Roy博士作为独立调查员指导创新研究项目做好准备 研究调节正常和疾病状态的神经回路机制。