Thalamocortical control of skilled motor behaviour

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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.