Thalamocortical control of skilled motor behaviour

丘脑皮质对熟练运动行为的控制

• 批准号: BB/R018537/1
• 负责人: Ian Duguid
• 金额: $ 50.18万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR018537%2F1
• 关键词: Thalamocortical; control; skilled; motor; behaviour

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.

运动控制是人类和动物行为的一个基本但重要的方面，我们与世界互动的唯一方式就是运动。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域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的灵巧任务（如伸手和物体操作）的广泛运动任务方面取得了重大进展。基底神经节-丘脑皮质通路是准备和执行大量习得的灵巧动作的关键通路。该通路被认为将动机和/或情境信息从基底神经节经丘脑传递到初级运动皮层，以选择、准备和执行不同的运动行为。这条通路上信息传递的中断会导致严重的运动缺陷和运动控制的丧失。尽管我们对基底神经节-丘脑皮质活动如何与哺乳动物运动行为的特定方面相关有深入的了解，但绝大多数这些数据是使用细胞外记录方法生成的，这些方法排除了对体树突整合、输入-输出转换、连接特定动力学和跨神经元群活动模式的时空映射的测量。这就引出了一个问题：在运动准备/执行/抑制过程中，初级运动皮层（M1）的丘脑皮质输入的时空活动模式是什么？在行为过程中，这些输入如何影响M1第5层投射神经元的体树突整合？基底神经节-丘脑皮质通路的活动、M1输出和行为之间的因果关系是什么？为了解决这些问题，我们将研究在执行听觉提示Go/NoGo前肢推动任务的小鼠中，M1运动的神经表征。这种行为模式是特别有趣的，因为它提供了一个实验上可处理的复杂运动控制模型，并促进了体内2光子钙成像、全细胞膜片钳电生理学和细胞选择性光/化学发生操作技术在头部受限小鼠中的应用。通过结合体内最先进的细胞和电路方法，我们将研究基底神经节-丘脑皮质输入通路在行为过程中形成M1第5层投射神经元体树突计算的重要性。鉴于来自运动丘脑基底神经节-受体区的轴突主要针对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，我们将验证来自MThBG （mTCBG）的运动丘脑皮质轴突在运动准备过程中驱动任务情境特定的树突活动和第5层输出调节的假设。我们还将使用细胞和通路特异性的光/化学发生操作策略来确定mTCBG活性、第5层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M1细胞和电路计算在执行学习灵巧运动任务期间的重要性提供新的见解，作为对皮层运动控制的更一般机制理解的发展的范例。

项目成果

A cranial implant for stabilizing whole-cell patch-clamp recordings in behaving rodents.

• DOI: 10.1016/j.jneumeth.2023.109827
• 发表时间: 2023-04-15
• 期刊: JOURNAL OF NEUROSCIENCE METHODS
• 影响因子: 3
• 作者: Dacre, Joshua;Rivera, Michelle Sanchez;Schiemann, Julia J.;Currie, Stephen;Ammer, Julian J.;Duguid, Ian
• 通讯作者: Duguid, Ian

Movement-specific signaling is differentially distributed across motor cortex layer 5 projection neuron classes.

• DOI: 10.1016/j.celrep.2022.110801
• 发表时间: 2022-05-10
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Currie, Stephen P.;Ammer, Julian J.;Premchand, Brian;Dacre, Joshua;Wu, Yufei;Eleftheriou, Constantinos;Colligan, Matt;Clarke, Thomas;Mitchell, Leah;Faisal, A. Aldo;Hennig, Matthias H.;Duguid, Ian
• 通讯作者: Duguid, Ian

A cerebellar-thalamocortical pathway drives behavioral context-dependent movement initiation.

小脑-丘脑皮质通路驱动行为环境相关的运动启动。

• DOI: 10.1016/j.neuron.2021.05.016
• 发表时间: 2021-07-21
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Dacre J;Colligan M;Clarke T;Ammer JJ;Schiemann J;Chamosa-Pino V;Claudi F;Harston JA;Eleftheriou C;Pakan JMP;Huang CC;Hantman AW;Rochefort NL;Duguid I
• 通讯作者: Duguid I

Cerebellar-recipient motor thalamus drives behavioural context-specific movement initiation

小脑接收运动丘脑驱动行为特定的运动启动

• 发表时间: 2019
• 作者: Dacre J