A hippocampal-hypothalamic circuit essential for anxiety-related behavioral avoidance

Anxiety over perceived threats triggers avoidance behavior, but the underlying neural circuit mechanism remains poorly understood. Taking hints from the deep connection between anxiety and predator defense, we examined the role of the anterior hypothalamic nucleus (AHN), a critical node in the predator defense network, in anxiety-related behaviors. By recording Ca2+ transients in behaving mice, we found that activity of AHN GABAergic (AHNVgat+) neurons showed individually stable increases when animals approached unfamiliar objects in an open field (OF) or explored the open arm of an elevated plus-maze (EPM). Moreover, AHNVgat+ neuron activity foreshadowed behavioral retreats and correlated with object and open-arm avoidance. Crucially, exploration-triggered optogenetic inhibition of AHNVgat+ neurons dramatically reduced avoidance behaviors. Furthermore, retrograde viral tracing identified the ventral subiculum (vSub) of the hippocampal formation as a significant input to AHNVgat+ neurons in driving avoidance behaviors. Thus, the activity of the hippocampal-hypothalamic pathway promotes idiosyncratic anxiety-related behavioral avoidance.