Deconstructing the roles of basal ganglia and cerebellum-related thalamic inputs to motor cortex during control of dexterous behavior

解构基底神经节和小脑相关丘脑输入在控制灵巧行为过程中对运动皮层的作用

• 批准号: 10366236
• 负责人: Adam Hantman
• 金额: $ 41.62万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366236
• 关键词: Affect; American; Animals; Anterior; Automobile Driving; Basal Ganglia; Behavior; Behavioral; Behavioral Mechanisms; Biological Models; Brain; Brain region; Cell Nucleus; Cerebellum; Collaborations; Complex; Computer Models; Cues; Data; Dimensions; Disease; Electrophysiology (science); Experimental Models; Foundations; Future; Generations; Genetic; Goals; Hand; Health; Human; Laboratories; Lateral; Lighting; Methods; Mission; Modeling; Monitor; Motor; Motor Cortex; Movement; Mus; Nature; Neurons; Neurosciences; Opsin; Output; Pathway interactions; Pattern; Physiological; Population; Process; Production; Property; Research; Research Personnel; Rest; Rewards; Role; Shapes; Signal Transduction; Stream; System; Testing; Thalamic Nuclei; Thalamic structure; Transgenic Organisms; United States National Institutes of Health; Ventral Lateral Thalamic Nucleus; Work; arm; base; cost; data-driven model; disability; dynamic system; experimental study; innovation; molecular marker; motor disorder; neuroprosthesis; operation; relating to nervous system; repaired; selective expression; therapy design/development; tool; transmission process

PROJECT SUMMARY Neural dynamics in motor cortex are necessary for dexterous behavior, but the mechanisms that generate these activity patterns are unclear. The long-term goal of our research is to understand how cortical dynamics are constructed to control movement, so that therapies could be developed to identify and repair aberrant activity patterns associated with motor disorders. My laboratory recently showed that these cortical dynamics arise from a collaboration between the intrinsic properties of cortex and inputs from the rest of the brain, but how distinct input streams are received and processed by the cortex remains poorly understood. To characterize these operations, we must understand the identity of the contributing inputs and their relationship to cortical dynamics. The objective of this proposal is to directly test the role of two major inputs, from ventral anterior (VA) and ventral lateral (VL) thalamic nuclei, to primary motor cortex. VA and VL have distinguishable input/output features: VA receives more input from basal ganglia, VL receives more input from cerebellum, VA and VL project to distinct cortical targets, and their intrinsic physiological properties differ. The central hypothesis to be tested here is that the VA-to-cortex pathway modulates, while the VL-to-cortex pathway drives, cortical dynamics and control of movement. To test the roles of VA and VL in the construction of cortical dynamics and behavior, we produced and validated genetic tools in the mouse that allow selective monitoring and manipulation of specific thalamic nuclei. With these tools, we will assess the relationship between a cortically dependent prehension task and the activity patterns of VA and VL neurons. We will then determine how activity in VL and VA drive or modulate cortical activity. Efforts to model the production of cortical commands have focused almost exclusively on firing patterns of cortex, leaving aside the influence of external inputs, leading to a cortico-centric view of pattern generation. With the data we collect, we will generate a more realistic computational model for pattern generation that considers the role of both intrinsic cortical dynamics and external inputs. Thus completion of these aims will advance understanding of how the cortical dynamics underlying prehension are constructed through interactions with the basal ganglia and cerebellum. The proposed research is innovative because it will use a new genetic toolbox for exploring thalamus, will produce an in-depth assessment of thalamocortical dynamics during a new complex prehension task, will advance the use of causal perturbations for testing interactions between brain regions, and will generate a more holistic model for pattern generation for dexterous behavior. The proposed work is significant because understanding the relationships among cortex, cerebellum, and basal ganglia can elucidate how their damage or disease leads to motor disorders and support the development of therapies designed to replace lost or corrupted signals.

项目总结 运动皮质中的神经动力学对于灵巧的行为是必要的，但产生 这些活动模式尚不清楚。我们研究的长期目标是了解大脑皮层动力学 是用来控制运动的，所以可以开发治疗方法来识别和修复畸形 与运动障碍相关的活动模式。我的实验室最近发现，这些大脑皮层动力学 源于大脑皮层的内在属性和来自大脑其他部分的输入之间的协作，但 大脑皮层如何接收和处理不同的输入流仍然知之甚少。至 要描述这些操作，我们必须了解贡献输入的身份及其关系 到大脑皮层动力学。这个建议的目标是直接测试来自腹侧的两个主要输入的作用 丘脑前核(VA)和腹侧核(VL)位于初级运动皮质。VA和VL具有可区分的 输入/输出特征：VA接受更多来自基底节的输入，VL接受更多来自小脑的输入 和VL投射到不同的皮质靶点，其内在的生理特性也不同。中环 这里要检验的假设是VA到皮质的通路调节，而VL到皮质的通路调节 驱动力、大脑皮层动力学和运动控制。检测VA和VL在大脑皮层结构中的作用 动力学和行为，我们在小鼠身上制造并验证了允许选择性监测的遗传工具 以及对特定丘脑核团的操纵。使用这些工具，我们将评估 依赖皮层的抓握任务和VA和VL神经元的活动模式。然后我们将确定 VL和VA中的活动如何驱动或调节皮质活动。建立皮质醇生产模型的努力 指令几乎完全集中在大脑皮层的放电模式上，而不考虑外部因素的影响 输入，导致了模式生成的以皮质为中心的观点。有了我们收集的数据，我们将产生更多 用于模式生成的现实计算模型，该模型考虑了两种内在皮质动力学的作用 和外部输入。因此，这些目标的完成将促进对大脑皮质动力学如何 潜在的抓取是通过与基底节和小脑的相互作用来构建的。这个 拟议的研究具有创新性，因为它将使用一种新的基因工具箱来探索丘脑，将产生 在一项新的复杂的抓取任务中，对丘脑皮质动力学的深入评估将推动 使用因果扰动来测试大脑区域之间的相互作用，并将生成更全面的 灵巧行为的模式生成模型。拟议的工作意义重大，因为理解 皮质、小脑和基底节之间的关系可以阐明它们的损害或疾病 导致运动障碍，并支持旨在取代丢失或腐败的治疗方法的开发 信号。