Thalamic control of motor cortex activity during skilled motor behaviour
Final Report Abstract
The primary motor cortex (M1) plays a pivotal role for the initiation and control of everyday motor movements. The ability to generate movements with appropriate timing in response to sensory stimuli from the environment is a crucial prerequisite for goal-directed behaviours. However, the circuit mechanisms to generate precisely timed motor commands in pyramidal neurons of the main output layer 5B (L5B) of the motor cortex are still largely unresolved. In mammals the cerebellar-thalamocortical system is believed to create movement timing signals, but to what extent M1 activity is directed and timed by the motor thalamus (MTh) remains unknown. Deciphering the underlying cellular and network mechanisms is essential not only to understand the basis of movement control, but also the motor deficits that occur in disorders of the motor system (e.g. stroke, cerebellar ataxia, Parkinson’s disease). In this fellowship project the fundamental question of how motor thalamic input controls membrane potential dynamics and triggers spike output of identified M1 L5B projection neurons was addressed in mice. During skilled forepaw movements we recorded and manipulated activity in the forelimb areas of the primary motor cortex and the motor thalamus. In a multi-level strategy, we combined in vivo deep calcium imaging of population activity in MTh and in vivo whole-cell patchclamp recordings of individual L5B neurons in M1 with targeted pharmacological/optogenetic manipulations in awake, behaving mice, which were trained to perform cued forepaw pushes in a skilled motor task. We found that MTh population responses were dominated by a time-locked increase of calcium activity. As the activity increase occurred immediately prior to movement and was temporally uncoupled from cue presentation, we concluded that this provides a fixed latency feed-forward motor timing signal to M1FL. Perturbing circuit function by selectively silencing output of the MTh (cerebellar-recipient area) suppressed cued movement initiation in the lever push task. Taken together, the fellowship project revealed that motor thalamic input to M1 is essential for the generation of appropriately timed motor commands. This refines our mechanistic understanding of how the cerebellar-thalamocortical circuit contributes to precisely timed goal-directed movements and coordinated movement timing. In a second project, I focussed on the interplay between frontal premotor areas and the primary motor cortex / motor thalamus to investigate the cellular and circuit mechanisms of movement preparation and movement choice to execute or suppress an action. In the premotor cortex (part of the anterior lateral motor cortex) I identified a specific frontal cortical region that monosynaptically innervates the primary forelimb motor cortex. As opposed to the neighbouring rostral forelimb area, this defined premotor region is devoid of projections to the spinal cord. To test functional relevance for motor behaviour, I employed selective in vivo pharmacology and optogenetics in mice trained to perform a cued Go/NoGo lever push task. Targeted silencing of motor preparatory activity impaired correct motor performance and initiation of forelimb movements in a Go/NoGo discrimination task.
Publications
- Cerebellar-recipient motor thalamus drives behavioral context-specific movement initiation
J. Dacre, M. Colligan, J. Ammer, J. Schiemann, T. Clarke, V. Chamosa-Pino, F. Claudi, J.A. Harston, C. Eleftheriou, J.M.P. Pakan, C.C. Huang, A. Hantman, N.L. Rochefort, I. Duguid
(See online at https://doi.org/10.1101/802124)
