ACTING OR REACTING? DISENTANGLING MOTOR THALAMUS CIRCUITS IN SELF-PACED VERSUS CUED MOVEMENT INITIATION

Parkinson's disease (PD) impairs movement initiation, particularly self-paced actions, while externally cued movements appear less perturbed. However, neural mechanisms underlying this cueing benefit remain unclear. The motor thalamus (mThal) integrates inputs from the basal ganglia, cerebellum, and midbrain to orchestrate movement initiation. We hypothesise that self-paced movements rely on basal ganglia pathways, disrupted in PD, while external cues engage cerebellar and midbrain circuitry, more resilient to dopaminergic dysfunction.
Our aim is to characterise the activity of input-defined mThal neuronal populations and determine their differential roles in self-paced versus cued movement initiation, providing mechanistic insight into why external cues facilitate movement in PD.
We developed a head-fixed behavioural task where mice initiate identical forward locomotion either spontaneously or following an auditory cue. Mice learned both paradigms, displaying similar kinematic profiles for rewarded locomotion across conditions. Yet, initiation probability showed a distinctive peak immediately following cue presentation that was absent in spontaneous blocks, confirming effective use of the auditory cue. Pharmacological validation with dopaminergic antagonists confirmed self-paced initiations were preferentially impaired, establishing translational relevance. Ongoing experiments are investigating input-defined mThal population activity dynamics during both types of initiation using electrophysiology combined with optogenetics to identify neurons receiving basal ganglia, cerebellar, or midbrain inputs.
This approach establishes a framework to dissect how specific mThal circuits contribute to different types of movement initiation. Understanding which pathways external cues recruit to bypass basal ganglia dysfunction may reveal circuit-level mechanisms explaining cueing benefits in PD and providing insights into its underlying motor impairments.