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基本但根本重要的方面，而我们唯一与世界互动的方式是运动。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。在过去的一个世纪中，已经取得了重大进展，以了解从皮质和脑干运动区域下降信息如何调节脊髓活动，以便执行从简单的节奏行为到复杂，灵活的任务，例如到达和物体操纵等复杂，灵活的任务。一条途径是基础神经节 - 甲状腺皮质的途径，这是对大量学习，灵巧运动的大量曲目关键的途径。人们认为这一途径可以通过丘脑从基底神经节传达动机和/或上下文信息，以选择，准备和执行不同的运动行为。沿此途径的信息传输的破坏会导致严重的运动缺陷和电动机控制的损失。尽管我们对基础神经节 - 丘脑皮质活性与哺乳动物运动行为的特定方面有何相关性有深入的了解，但这些数据中的绝大多数是使用细胞外记录方法产生的，这些方法排除了体内根系构成的测量，跨性别输入转换，连接特定的动力学和Spatiotemal跨性别的活动模式跨性别模式。这使我们提出质疑，在运动制备/执行/抑制期间，原代运动皮质（M1）中丘脑皮质输入的时空活性模式是什么？这些输入如何在行为过程中M1中的第5层投影神经元中的体层整合？沿基底神经节 - 丘脑皮质途径，M1输出和行为的活动之间的因果关系是什么？为了解决这些问题，我们将研究M1中M1运动的神经表示，经过训练以执行我们实验室中开发的听觉提示的GO/Nogo Forelimb推动任务。这种行为范式特别令人感兴趣，因为它提供了一个可以实验性的复杂运动控制模型，并促进了体内2-光子钙成像，全细胞贴剂钳电生理学和细胞选择性光学/化学遗传学操纵技术的使用。通过在体内结合最先进的细胞和电路接近，我们将研究基底神经节 - 丘脑皮质输入途径的重要性，以塑造行为过程中M1第5层投影神经元的体体计算。 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 准备。我们还将使用细胞和途径特异性的光学/化学遗传操纵策略来确定MTCBG活动，第5层的体育式计算和运动计划/执行之间的因果关系。该项目的总体目的是为执行学习，灵巧的运动任务执行M1细胞和电路计算的重要性提供新的见解，这是开发对皮质运动控制更一般机械理解的典范。

项目成果

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

• DOI: 10.1101/802124
• 发表时间: 2019-01-01
• 期刊: bioRxiv
• 作者: Dacre, J.

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