Thalamocortical control of skilled motor behaviour

运动控制是人类和动物行为的一个基本但基本的重要方面，我们与世界互动的唯一方式是通过运动。因此，神经科学中最具挑战性的问题之一是了解大脑如何产生和控制运动行为。在过去的一个世纪里，在理解皮层和脑干运动区的下行信息如何调节脊髓活动以执行从简单的节奏行为到复杂、灵活的任务(如伸手和物体操纵)的广泛运动任务方面取得了重大进展。对于准备和执行大量习得的、灵巧的动作来说，一个关键的途径是基底节-丘脑皮质途径。这条通路被认为是将动机和/或背景信息从基底节通过丘脑传递到初级运动皮质，以便选择、准备和执行不同的运动行为。沿着这一通路的信息传输中断会导致严重的运动障碍和运动控制的丧失。尽管我们对基底节-丘脑皮质活动如何与哺乳动物运动行为的特定方面有了深入的了解，但这些数据中的绝大多数是使用细胞外记录方法产生的，这些方法排除了对躯体树突整合、输入-输出转换、连接特定的动力学和跨神经元整体活动模式的时空映射的测量。这就引出了我们的疑问，在运动准备/执行/抑制过程中，初级运动皮质(M1)丘脑皮质输入的时空活动模式是什么？在行为过程中，这些输入如何在M1的第5层投射神经元中形成躯体树突整合？基底节-丘脑皮质通路的活动、M1的输出和行为之间的因果联系是什么？为了解决这些问题，我们将研究受训执行我们实验室开发的听觉提示Go/NoGo前肢推送任务的小鼠M1中运动的神经表示。这种行为模式特别令人感兴趣，因为它提供了一个实验上易于处理的复杂运动控制的模型，并促进了在头枕小鼠中使用体内双光子钙成像、全细胞膜片钳电生理学和细胞选择性光/化学发生操作技术。通过结合体内最先进的细胞和电路方法，我们将研究基底节-丘脑皮质输入通路在塑造M1层5投射神经元在行为过程中的躯体树突计算中的重要性。鉴于来自运动丘脑基底节接受区的轴突主要针对M1中第5层投射神经元的顶端树突，并且与行为相关的MThBG活动先于运动启动，我们将检验这样一种假设，即来自MThBG的运动丘脑皮质轴突(MTCBG)在运动准备期间驱动对树突活动和第5层输出的任务上下文特定的调制。我们还将使用细胞和路径特定的光/化学发生操纵策略来确定mTCBG活性、第5层躯体树突计算和运动计划/执行之间的因果关系。该项目的总体目标是为学习的、灵活的运动任务的执行过程中M1细胞和电路计算的重要性提供新的见解，作为发展对皮质运动控制的更一般机械理解的典范。

Motor control is a basic but fundamentally important aspect of human and animal behaviour and the only we way interact with the world is though movement. Thus, one of the most challenging problems in neuroscience is to understand how the brain generates and controls motor behaviour. Over the past century significant advances have been made in understanding how descending information from cortical and brainstem motor areas regulate spinal cord activity in order to execute a wide range of motor tasks from simple rhythmic behaviours to complex, dexterous tasks such as reaching and object manipulation. One pathway that is pivotal to the preparation and execution of a large repertoire of learned, dextrous movements is the basal ganglia-thalamcortical pathway. This pathway is thought to convey motivational and/or contextual information from the basal ganglia via thalamus to the primary motor cortex in order to select, prepare and execute different motor behaviours. Disruption to information transmission along this pathway leads to severe motor deficits and loss of motor control. Although we have an in-depth understanding of how basal ganglia-thalamocortical activity correlates with specific aspects of mammalian motor behaviour, the vast majority of these data have been generated using extracellular recording methods that preclude measurement of somatodendritic integration, input-output transformations, connection specific dynamics and spatiotemporal mapping of activity patterns across neuronal ensembles. This leads us to question, what are the spatiotemporal activity patterns of thalamocortical inputs in primary motor cortex (M1) during movement preparation/execution/suppression? How do these inputs shape somatodendritic integration in layer 5 projection neurons in M1 during behaviour? What is the causal link between activity along the basal ganglia-thalamocortical pathway, M1 output and behaviour?To address these questions, we will investigate the neural representations of movement in M1 in mice trained to execute an auditory cued Go/NoGo forelimb push task developed in our lab. This behavioural paradigm is of particular interest as it provides an experimentally tractable model of complex motor control and facilitates the use of in vivo 2-photon calcium imaging, whole-cell patch-clamp electrophysiology and cell-selective opto-/chemogenetic manipulation techniques in head-restrained mice. By combining state-of-the-art cellular and circuit approaches in vivo, we will investigate the importance of the basal ganglia-thalamocortical input pathway in shaping M1 layer 5 projection neuron somatodendritic computations during behaviour. Given that axons from the basal ganglia-recipient area of motor thalamus (MThBG) primarily target the apical dendrites of layer 5 projection neurons in M1 and that behaviour-related MThBG activity precedes movement initiation, we will test the hypothesis that motor thalamocortical axons from MThBG (mTCBG) drive task context-specific modulation of dendritic activity and layer 5 output during movement preparation. We will also use cell- and pathway-specific opto-/chemogenetic manipulation strategies to determine the causal relationship between mTCBG activity, layer 5 somatodendritic computations and movement planning/execution. The overarching aim of the project is to provide new insights into the importance of M1 cellular and circuit computations during the execution of a learned, dextrous motor task, serving as an exemplar for the development of a more general mechanistic understanding of cortical motor control.