A Forebrain Hub for Cautious Actions via the Midbrain

Abstract

Adaptive goal-directed behavior requires dynamic coordination of movement, motivation, and environmental cues. Among these, cautious actions, where animals adjust their behavior in anticipation of predictable threats, are essential for survival. Yet, their underlying neural mechanisms remain less well understood than those of appetitive behaviors, where caution plays little role. Using calcium imaging in freely moving mice we show that glutamatergic neurons in the subthalamic nucleus (STN) are robustly engaged by contraversive movement during cue-evoked avoidance and exploratory behavior. Model-based analyses controlling for movement and other covariates revealed that STN neurons additionally encode salient sensory cues, punished errors, and especially cautious responding, where their activity anticipates avoidance actions. Targeted lesions and optogenetic manipulations reveal that STN projections to the midbrain are necessary for executing cued avoidance. These findings identify a critical role for the STN in orchestrating adaptive goal-directed behavior by integrating sensory, motor, and punitive signals to guide timely, cautious actions via its midbrain projections. Significance statementThis study provides new insights into the neural pathways that mediate adaptive goal-directed behaviors in response to environmental cues, identifying a critical role for glutamatergic projections from the subthalamic nucleus (STN) to the midbrain. We show that STN activation encodes caution and is essential for cued goal-directed actions. These findings deepen our understanding of the circuits involved in cued goal-directed adaptive behaviors used to cope with contextual challenges, which are often altered by brain disorders.