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

我们学习和创造动作序列的能力是我们所做事情的基础：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，如强迫症、注意力缺陷/多动障碍、帕金森氏症和亨廷顿氏症，这些疾病影响了与它们的获取和执行有关的基底神经节回路。我们帮助病人的能力关键取决于对基底神经节功能的更好理解。然而，健康和疾病条件下基底神经节功能和功能障碍的原理仍然难以捉摸。本研究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Cal-light标记和闭环光遗传学操作来验证动作特异性纹状体集合的活动是通过投射到不同目标区域的独特输出神经元集来引导的这一假设；因此，调节特定的行为（如移动，转身，伸手，直立等）。在K99期，我将验证纹状体通路作为一个动作促进通路，通过从外白球（GPe）到丘脑束旁核（GPe→Pf）和脑干桥脚核（GPe→PPN）的直接输出通道发挥作用。我将测试GPe→PPN投影主要参与运动控制的假设，而GPe→Pf投影则有助于启动和执行习得的杠杆按压。在R00阶段，我将使用一种新的Cal-light系统来标记动作特异性棘突神经元（spn），并解析出超越直接与间接途径的传统观点的各种动作特异性spn。我将测试GPe神经元的不同亚群从独特的动作特异性spn接收输入的假设，例如GPePPN神经元从运动特异性spn接收偏倚输入，而GPePf神经元优先受杠杆按压特异性spn的支配。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界进行，由约翰霍普金斯大学的Rui Costa博士和Hyungbae Kwon博士指导。除了技术专长，两位博士。Costa和Kwon都有成功的培训记录。候选人还组建了一个专家合作小组，包括Darcy Peterka博士、Luke Hammond博士、Tanya Tabachnik博士和David Ng博士。整个指导团队将指导候选人进行技术和专业培训。总之，提出的实验将提供一个超越经典模型的机制，电路水平的理解行动特异性基底神经节亚回路。这项工作将对一系列精神和神经退行性疾病产生深远的影响，并有可能确定新的治疗靶点。此外，所有病毒试剂，新的Cal-light标记平台，小鼠系，以及在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，以加速其他实验室的发现。

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.