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

Innate defensive behaviors, such as freezing, fleeing, and fighting, are essential for survival, enabling animals to effectively respond to predatory threats. These behaviors involve a complex interplay of sensory processing, decision-making, and motor output. As a core component of the medial hypothalamic defense system, the anterior hypothalamic nucleus (AHN) is a key brain region implicated in orchestrating innate defensive responses. Although the AHN is predominantly GABAergic, it also contains a smaller population of excitatory neurons, reflecting a sophisticated balance between inhibitory and excitatory signaling within this region. However, despite its importance, the specific behavioral functions of these diverse neuronal populations have not been systemically examined. In this study, 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, likely facilitating risk assessment during the pre-encounter stage. Conversely, AHN glutamatergic neurons drive escape initiation and freezing responses associated with the post-encounter stage. The AHN CaMKIIa+ neurons, which exhibit significant heterogeneity, suggest a more nuanced role, potentially balancing escape and freezing responses. By elucidating the functional specialization of different AHN neuron subtypes, this study provides a foundation for future investigations into the neural circuits underlying innate defensive behaviors and its dysregulation in neuropsychiatric conditions characterized by dysregulated responses to threats, such as PTSD and panic disorder.