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.

我们学习和制作动作序列的能力是我们所做的很多事情：它是通过写作，演奏乐器或简单地绑鞋来交流。我们帮助这些技能的能力使我们容易受到广泛的脑部疾病，例如强迫症，注意力缺陷/多动障碍，帕金森氏症和亨廷顿疾病，这些疾病影响了涉及其获取和执行的基础神经节电路。我们帮助患者的能力取决于对基本神经节功能的更好理解。然而，健康和疾病状况中基本神经节功能和功能障碍的原理仍然难以捉摸。该提案的目的是结合客观，无监督的行为聚类，细胞类型特异性的Cal-light标记和闭环光遗传学操纵，以测试以下假说：动作特异性纹状体结合体的活动是通过投影到不同目标区域的独特输出神经元集进行的；因此，调节特定行为（例如运动，转弯，伸展，饲养等）。在K99阶段，我将检验以下假设：纹状体式途径可以通过直接输出通道（GPE）（GPE）到丘脑（GPE→PF）中的副核核的直接输出通道来促进途径。我将检验以下假设：GPE→PPN投影主要参与机能的控制，而GPE→PF投影有助于学习和执行Learding Lever Press的主动性和执行。在R00阶段，我将使用一种新颖的Cal-Light系统来标记特定的棘突投影神经元（SPN），并解析潜水员动作特定的SPN，这些SPN超出了直接与间接途径的常规视图。我将检验以下假设：GPE神经元的不同亚群从独特的动作特异性SPN中接收输入，使得GPEPPN神经元从运动特异性SPN中获得偏见的输入，而GPEPF神经元更可能通过杠杆压榨特定的SPN神经支配。这项工作和职业发展计划将在哥伦比亚大学充满活力的研究社区中，在约翰·霍普金斯大学的Rui Costa博士和Hyungbae Kwon博士的监督下。除技术专长外，两位博士。 Costa和Kwon拥有成功的学员的令人印象深刻的记录。候选人还召集了一个专家合作伙伴团队，包括达西·彼得卡（Darcy Peterka）博士，卢克·哈蒙德（Luke Hammond）博士，塔尼亚·塔巴赫尼克（Tanya Tabachnik）博士和戴维·NG博士。整个心理团队将指导候选人进行技术和专业培训。共同提出的实验将提供对特定于动作的基本神经节亚电路的机械性电路级别的理解，这超出了经典模型。这项工作将对一系列精神病和神经退行性疾病产生深远的影响，并有可能识别新颖的治疗靶标。此外，将与更广泛的神经科学社区共享所有病毒试剂，新的Cal-Light标记平台，鼠标线条以及在本提案中开发和测试的计算工具，以加速其他实验室的发现。