Acute threats modulate hunger circuit dynamics to instruct avoidance behaviour

Abstract During foraging animals must balance food-seeking with predator avoidance, yet how the brain integrates sensory information relating to food and threat remains unclear. Using in vivo calcium imaging in mice, we show that hunger-sensitive AgRP neurons in the hypothalamus are rapidly inhibited by threats across a threat imminence continuum, from a low environmental risk to a high physical restraint threat, independent of fasting state. This suppression is driven by GABAergic inputs from dorsomedial hypothalamus (DMH) neurons, which increase activity during threat exposure. While AgRP population activity shows uniform inhibition, pathway-specific monitoring using axonal GCaMP reveals distinct projection patterns. For example, AgRP terminals in BNST and LH decrease activity to both threat and food, while threats increased AgRP axonal activity in the PVN. Furthermore, location-specific optogenetic inhibition of AgRP neurons conditions spatial avoidance, mimicking a threat-induced defensive behavioural responses. These findings reveal a hypothalamic circuit where DMH GABA neurons suppress AgRP activity in response to external threats, prioritising avoidance over food-seeking to optimise adaptive behavioural responses during foraging. Competing Interest Statement The authors have declared no competing interest. Footnotes Disclosure Statement: The Authors have nothing to disclose