Reciprocal feedback inhibition and divergent intrinsic firing properties between behaviorally defined classes of neurons in the mouse ventromedial hypothalamus

The capacity to orchestrate appropriate defensive behaviors in response to threatening stimuli is essential for the survival of organisms. Flight, freezing, appeasement, and attack, for example, are common defensive responses evoked depending upon the nature of the threat, the immediate context, and past experiences. Multiple brain regions have been implicated in regulating such responses, with the medial hypothalamus playing a key role in mediating innate responses to social and predator threats. The ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) has been shown to mediate both avoidance and aggression towards conspecific threats in mice, suggesting that it serves as a circuit for context-appropriate defensive responses to social threats. Previous in vivo calcium imaging in VMHvl identified cells whose activity encodes either approach toward or escape from a social threat (Assessment+ and Flight+ cells, respectively), but it remained unclear how the switch in neural encoding from approach to avoidance occurs. Here, we use in vivo single-unit electrophysiology recordings coupled to channelrhodopsin-assisted circuit mapping (optrodes) to explore the functional and structural connectivity basis of the approach-avoidance switch. We confirm the presence of Assessment+ and Flight+ neurons in VMHvl and demonstrate that they are interconnected through feedback excitation and reciprocal feedback inhibition. Moreover, we discover that Assessment+ and Flight+ neurons exhibit a pronounced difference in their intrinsic firing properties. We hypothesize that this asymmetry in intrinsic responsivity coupled to reciprocal feedback inhibition underlies the nonlinear firing changes at the approach-to-avoidance transition and plays a role in triggering escape behavior.