Action-specific dissecting of basal ganglia: from the classical model to diverse action-specific subcircuits

基底神经节的特定动作解剖：从经典模型到不同的特定动作子电路

• 批准号: 10312115
• 负责人: Zirong Gu
• 金额: $ 12.54万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312115
• 关键词: Affect; Area; Attention deficit hyperactivity disorder; Axon; Basal Ganglia; Behavior; Behavioral; Brain; Brain Diseases; Brain Stem; Calcium; Cell Nucleus; Clinical; Communities; Corpus striatum structure; Data; Development Plans; Disease; Functional disorder; Globus Pallidus; Glutamates; Goals; Health; Heterogeneity; Huntington Disease; Image; Investigation; Learning; Life; Light; Locomotion; Mental disorders; Mentors; Methods; Modeling; Motor; Movement; Mus; Neurodegenerative Disorders; Neurologic; Neurons; Neurosciences; Obsessive-Compulsive Disorder; Output; Parafascicular Nucleus; Parkinson Disease; Pathway interactions; Patients; Pattern; Performance; Phase; Play; Population; Process; Reagent; Research; Role; Solid; Supervision; System; Technical Expertise; Testing; Textbooks; Thalamic structure; Training; Universities; Viral; Work; Writing; anatomical tracing; base; career development; cell type; computerized tools; experimental study; in vivo; instrument; new therapeutic target; novel; optogenetics; prevent; rabies viral tracing; response; skills

Our ability to learn and produce action sequences underlies much of what we do: be it communicating through writing, playing instruments, or simply tying shoelaces. Our reliance on these skills leaves us vulnerable to a wide range of brain disorders such as obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, Parkinson’s, and Huntington’s diseases which affect the basal ganglia circuits involved in their acquisition and execution. Our ability to help patients critically depends on a better understanding of basal ganglia function. Yet the principles of basal ganglia function and dysfunction in health and disease conditions remain elusive. The goal of this proposal is to combine objective, unsupervised behavioral clustering, cell-type-specific Cal-light tagging, and closed-loop optogenetic manipulation to test the hypothesis that activities of action-specific striatal ensembles are channeled through unique sets of output neurons that project to different target areas; therefore, modulating specific behaviors (e.g. locomotion, turning, reaching, rearing, etc.). During the K99 phase, I will test the hypothesis that the striatopallidal pathway can function as an action promoting pathway via direct output channels from the external globus pallidus (GPe) to parafascicular nucleus in the thalamus (GPe→Pf) and pedunculopontine nucleus in the brainstem (GPe→PPN). I will test the hypothesis that the GPe→PPN projection is mainly involved in the control of locomotion whereas GPe→Pf projection contributes to the initiation and execution of learned lever press. During the R00 phase, I will use a novel Cal-light system to tag action-specific spiny projection neurons (SPNs) and parse out diverse action-specific SPNs that go beyond the conventional view of direct versus indirect pathways. I will test the hypothesis that different subpopulations of GPe neurons receive input from unique action-specific SPNs, such that GPePPN neurons receive biased input from locomotion- specific SPNs while GPePf neurons are preferentially innervated by lever-pressing-specific SPNs. This work and career development plan will be conducted in the vibrant research community at Columbia University under the supervision of Dr. Rui Costa and Dr. Hyungbae Kwon from Johns Hopkins University. In addition to technical expertise, both Drs. Costa and Kwon have an impressive track record of successful trainees. The candidate has also assembled a team of expert collaborators, including Dr. Darcy Peterka, Dr. Luke Hammond, Dr. Tanya Tabachnik, and Dr. David Ng. The entire mentoring team will guide the candidate in technical and professional training. Together, the proposed experiments will provide a mechanistic, circuit-level understanding of action-specific basal ganglia subcircuits that goes beyond the classical model. This work will have profound implications for a range of psychiatric and neurodegenerative diseases, with the potential to identify novel therapeutic targets. Additionally, all viral reagents, the new Cal-light tagging platform, mouse lines, and the computational tools developed and tested in this proposal will be shared with the broader neuroscience community to accelerate discoveries in other labs.

我们学习和产生动作序列的能力是我们所做的大部分事情的基础：无论是通过写作、演奏乐器还是简单地系鞋带进行交流，我们对这些技能的依赖使我们容易受到各种大脑疾病的影响，例如强迫症。 、注意力缺陷/多动症、帕金森病和亨廷顿病都会影响参与其获取和执行的基底神经节回路，我们帮助患者的能力关键取决于对基底神经节功能的更好理解。该提案的目标是结合客观的、无监督的行为聚类、细胞类型特异性的钙光标记和闭环光遗传学操作来测试基底神经节的活动的假设。特定动作的纹状体集合通过投射到不同目标区域的独特的输出神经元进行引导；因此，在 K99 阶段，我将调节特定的行为（例如运动、转动、伸手、站立等）。检验纹状体苍白球通路可以通过从外部苍白球（GPe）到丘脑束旁核（GPe→Pf）和脑干脚桥核（GPe→PPN）的直接输出通道发挥作用促进通路的假设。将检验以下假设：GPe→PPN 投影主要参与运动控制，而 GPe→Pf 投影有助于学习杠杆的启动和执行在 R00 阶段，我将使用一种新颖的 Cal-light 系统来标记特定于动作的多刺投射神经元 (SPN)，并解析出超出我将测试的直接与间接路径的传统观点的各种特定于动作的 SPN。假设 GPe 神经元的不同亚群从独特的动作特异性 SPN 接收输入，因此 GPePPN 神经元从运动特异性 SPN 接收有偏差的输入，而 GPePf 神经元优先受这项工作和职业发展计划将在约翰·霍普金斯大学的 Rui Costa 博士和 Hyungbae Kwon 博士的监督下，在哥伦比亚大学充满活力的研究社区中进行。 Costa 和 Kwon 拥有令人印象深刻的成功培训记录，该候选人还组建了一支专家团队，包括 Darcy Peterka 博士、Luke Hammond 博士、Tanya Tabachnik 博士和 David Ng 博士。总之，所提出的实验将提供对特定动作基底神经节子回路的机制、回路水平的理解，这超出了经典模型的范围。这项工作将对一系列精神疾病和神经退行性疾病产生深远的影响。此外，所有病毒试剂、新的 Cal-light 标记平台、小鼠品系以及本提案中开发和测试的计算工具将与更广泛的神经科学界共享，以加速其他领域的发现。实验室。