A HYPOTHALAMUS-CORTEX-PRETHALAMIC CIRCUIT DRIVING COURAGE IN AVERSIVE ENVIRONMENTS

Flexible choice of defensive behaviors in response to environmental threats is fundamental for survival and critically depends on context, internal state, and prior experience. Such flexibility reflects the recruitment of neural circuits that rapidly and precisely gate innate fear responses with limited sensory evidence. We identified the ventral lateral geniculate nucleus (vLGN), an inhibitory prethalamic nucleus whose activity is modulated by prior experience and expectation of threat, as a critical node for choosing between behavioral strategies in aversive contexts. Using optogenetics and fiber-photometry in freely behaving mice, we show that vLGN activity can dictate decisions to leave safety, biasing animals towards risk-taking under threat. Importantly, manipulating vLGN activity affects behavior only in aversive conte/xts. Moreover, opto- and chemogenetic vLGN stimulation robustly rescue heightened defensive behavior in an acute corticosterone model of anxiety, indicating that the regulation of defensive behaviors by vLGN is a function of anxiety-like state and may represent a clinically-relevant treatment target. Finally, we find that inputs from both cognitive cortical systems and affective subcortical systems converge in vLGN, modulating this behaviour in opposing directions: corticofugal layer V afferents from retrosplenial cortex (RSC) promote decisions to leave safety, while inputs from the ventromedial hypothalamus (VMH) mediate risk-avoidance. These inputs target largely distinct vLGN populations which likely interact locally to integrate opposing drives within vLGN. Together, these results identify the vLGN as a subcortical gate that integrates various inputs such as prior experience and biological needs to regulate courage and inform decisions to confront or avoid potential threats.