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: 10546492
• 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/10546492
• 关键词: Affect; American; Animals; Anterior; Automobile Driving; Basal Ganglia; Behavior; Behavioral; Biological Models; Brain; Brain region; Cell Nucleus; Cerebellum; Classification; 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 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; cost; data-driven model; disability; dynamic system; experimental study; innovation; molecular marker; motor disorder; neural; neuroprosthesis; operation; 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.

项目摘要 运动皮层中的神经动力学对于灵巧行为是必要的，但是产生这种动力学的机制 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 是为了控制运动，因此可以开发治疗方法来识别和修复异常的 与运动障碍相关的活动模式。我的实验室最近发现这些皮层动力学 大脑皮层的内在特性和大脑其他部分的输入之间的合作， 皮层如何接收和处理不同的输入流仍然知之甚少。到 为了描述这些操作，我们必须了解贡献输入的身份及其关系 皮层动力学这个建议的目的是直接测试两个主要输入的作用，从腹侧 前（VA）和腹外侧（VL）丘脑核，初级运动皮质。VA和VL具有可区分的 输入/输出特征：VA接收更多来自基底神经节的输入，VL接收更多来自小脑的输入，VA 和VL投射到不同的皮质靶点，并且它们的内在生理特性不同。中央 这里要检验的假设是，VA到皮层的通路调节，而VL到皮层的通路调节， 大脑皮层动力学和运动控制探讨VA和VL在大脑皮层结构中的作用， 动力学和行为，我们在小鼠中生产并验证了允许选择性监测的遗传工具， 以及对特定丘脑核的操纵。通过这些工具，我们将评估 皮层依赖性的注意力转移任务和VA和VL神经元的活动模式。然后我们将决定 VL和VA活动如何驱动或调节皮质活动。努力模拟皮质的产生 命令几乎完全集中在皮层的放电模式上，而不考虑外部因素的影响。 输入，导致以皮质为中心的模式生成视图。通过我们收集的数据，我们将产生更多 一个现实的计算模型的模式生成，考虑到的作用，既内在的皮质动力学 外部输入。因此，这些目标的完成将促进对皮质动力学如何 潜在的神经元是通过与基底神经节和小脑的相互作用而构建的。的 拟议中的研究是创新的，因为它将使用一种新的遗传工具箱来探索丘脑， 在一项新的复杂任务中，对丘脑皮质动力学的深入评估，将促进 使用因果扰动来测试大脑区域之间的相互作用，并将产生一个更全面的 用于灵巧行为的模式生成的模型。这项工作意义重大，因为了解 皮质、小脑和基底节之间的关系可以阐明它们的损伤或疾病 导致运动障碍，并支持旨在取代丢失或损坏的治疗方法的发展 信号.