Deanery of Biomedical Sciences
Executing appropriately timed, reproducible actions is essential for interacting with our environment and ultimately survival. From object manipulation and tool use to complex locomotion and prey capture, the brain continuously processes sensory information to learn, initiate and coordinate well timed, accurate movements. Pathological states that affect movement-relevant computations reduce survival fitness and lifespan. Thus, obtaining a mechanistic understanding of how different brain areas combine to generate spatiotemporally coordinated actions is fundamental for developing and refining theories of motor control and for identifying entry points for therapeutic intervention.
Movement execution requires initiation of the correct movement with appropriate trajectory and continuous modulation of limb speed to ensure endpoint accuracy, which we classify as action specification. The circuit mechanisms underlying these processes have not been resolved. One key brain area thought to be involved is the motor thalamus, which acts as a central hub linking subcortical and cortical motor areas. This project will focus on determining the neural mechanisms of action specification in thalamocortical circuits during directional reaching.
We will use a multidisciplinary approach combining large-scale 2 photon population calcium imaging of neural activity, in vivo electrophysiology, viral based manipulation strategies, 3D kinematic analysis of movement, Bayesian decoders of population data and computational modelling. We will address 3 main aims:
Aim 1: Implement and optimise a novel centre-out multidirectional reaching task for mice. To investigate how thalamocortical circuits control the execution of directional movement we will implement and optimise a cued multi-directional forelimb reaching task for mice.
Aim 2. Determine the role of thalamocortical input in controlling directional reaching. We will use 2-photon population calcium imaging and high-density electrophysiological recordings of neuronal activity in motor cortex during execution of multi-directional forelimb reaches. Viral-based opto-/chemogenetic manipulation strategies will be used to investigate how thalamocortical circuits drive patterns of motor commands necessary for executing accurate trajectories during movement.
Aim 3. Modelling motor cortical dynamics using a biologically realistic model of motor cortex. In collaboration with Dr. Salvador Dura-Bernal (NYU, USA) we will continue to develop a biologically realistic model of mouse motor cortex. The model will be adapted based on initial experimental findings to refine testable hypotheses regarding the neural basis of action specification. Parallel development of a multiscale model of mouse motor cortex will rapidly advance our understanding of how and when thalamocortical circuits are engaged to drive behaviourally relevant patterns of cortical activity.
Training outcomes
This project will develop skills in experimental design, 2-photon imaging, in vivo electrophysiology, statistics and advanced computational methods for data analysis and modelling.
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