Interpeduncular GABAergic neuron function controls threat processing and innate defensive adaptive learning

The selection of appropriate defensive behaviors in the face of potential threat is fundamental to survival. Equally important is learning to adjust and optimize defensive behaviors when there is no real danger. Despite extensive research on innate threat processing, little is known about the mechanisms by which individuals adapt their defensive behaviors in response to repeated threats that lack real danger. Insight into this process is critical as its dysregulation may contribute to neuropsychiatric conditions, such as anxiety disorders. Here, we used the visual looming stimulus (VLS) paradigm in mice to investigate innate threat processing and adaptive defensive learning. Repeated exposure to VLS over consecutive sessions reduced immediate freezing responses and time spent inside a sheltered area upon VLS events, leading to an increase in exploratory behaviors. Fiber photometry recordings and optogenetic manipulations revealed that VLS innate adaptive defensive learning is associated with reduced recruitment of the midbrain interpeduncular nucleus (IPN), a structure associated with fear and anxiety-related behaviors. Functional circuit-mapping identified a role for select IPN projections to the laterodorsal tegmental nucleus in gating defensive learning. Finally, we uncovered a subpopulation of IPN neurons that express the neuropeptide somatostatin and encode avoidance signals in response to VLS. These results identify critical behavioral signatures of innate defensive responses and a circuit that regulates the essential features of threat processing.