Anterior hypothalamic nucleus drives distinct defensive responses through cell-type-specific activity

Innate defensive behaviors are essential for survival, allowing animals to appropriately respond to predatory threats. The anterior hypothalamic nucleus (AHN), a key region in the medial hypothalamic defense system, contains both GABAergic and glutamatergic neurons, reflecting a sophisticated balance between inhibitory and excitatory signaling. However, the specific behavioral functions of these neuronal populations have not been systemically examined. Here, we utilized fiber photometry and optogenetic stimulation to investigate the roles of AHN GABAergic, glutamatergic, and CaMKIIa+ neuronal activities in mediating innate defensive behaviors. Our results indicate that AHN GABAergic neurons mediate anxiety-associated investigatory behaviors, while AHN glutamatergic neurons drive escape and freezing responses. The AHN CaMKIIa+ neurons, which exhibit significant heterogeneity, suggest a more nuanced role, potentially balancing escape and freezing responses. Our study provides a foundation for future investigations into the neural circuits underlying innate defensive behaviors and its dysregulation in neuropsychiatric conditions including PTSD and panic disorder.