The subthalamic nucleus controls action timing under threat

Adaptive goal-directed actions performed under threat require caution, often expressed as delayed response timing that balances urgency against error risk by allowing more time for evaluation. Although this temporal regulation is essential for survival, its neural mechanisms remain poorly understood. In mice of either sex, we show that glutamatergic neurons in the subthalamic nucleus (STN) regulate the timing of cued actions that avoid harm. Optogenetic activation of the STN, or its projections to the midbrain but not the globus pallidus, modulates action timing in a frequency-dependent manner, accelerating initiation such that animals lose the ability to respond cautiously, defer actions, or stop ongoing responses. STN excitation can also substitute for a natural cue and prevents the development of cautious responding, indicating a direct role in controlling avoidance action initiation timing. These effects were not driven by aversiveness, as mice did not avoid STN excitation, indicating that stimulation promotes movement rather than negative valence. Together, these findings identify the STN as a key regulator of action-initiation timing and establish its midbrain projections as a circuit mechanism for balancing urgency and caution under threat. Significance statement This work shows that activity in the subthalamic nucleus (STN) helps set the timing of actions triggered by warning cues. By activating STN neurons and their projections to the midbrain, we found that stimulation made animals respond faster, and high-frequency activation eliminated their ability to delay actions when caution was required or to withhold or stop actions that would otherwise be punished. These findings highlight a key brain pathway that governs when actions are initiated, a function that is often disrupted in neurological and psychiatric disorders.