Subthalamic nucleus controls cautious action timing under threat

Abstract Adaptive goal-directed actions performed under the threat of punishment introduce a demand for caution, often expressed as delayed response timing that balances urgency against error risk by allowing more time for cognitive evaluation. Although this form of temporal regulation is essential for survival, its underlying neural mechanisms remain poorly understood. We show that glutamatergic neurons in the subthalamic nucleus (STN) regulate the timing of cued actions to 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 to the extent that animals can no longer respond cautiously, defer actions, or stop initiated actions. These results show that the STN shapes goal-directed behavior by gating action-initiation timing, establishing its midbrain projections as a key circuit 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 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. Competing Interest Statement The authors have declared no competing interest.