A neural circuit for female-specific defensive homeostasis in risk assessment

Risk assessment in defensive behavior is an adaptive mechanism shaped by natural selection, enabling individuals to evaluate potential threats and thereby maintain defensive homeostasis. Although risk assessment is essential for survival, it remains unknown whether specific neural circuits maintain their behavioral homeostasis in a sex-specific manner. Here, we show that visual survival threats activated cannabinoid 1 receptor (CB ₁ R)-expressing neurons in the superior colliculus (SC), initiating consistent risk assessment in both sexes. Deletion of CB ₁ R in SC GABAergic neurons female-specifically impairs risk assessment by disinhibiting GABA release in SC-lateral habenula (LHb) projections, resulting in abnormally shortened risk assessment. Furthermore, loss of CB ₁ R in SC GABAergic neurons increases the occurrence of abnormal spontaneous behavior following chronic stress exclusively in females. Our findings revealed a female-specific CB ₁ R-modulated SC-LHb GABAergic circuit crucial for maintaining defensive homeostasis in risk assessment, highlighting how disruptions in this circuit underlie deficits in risk assessment and adaptive stress coping.