Abstract

Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as posttraumatic stress and panic disorder.1 Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA)2; however, the source of neuronal excitation to the CeA that contributes to high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping, in-vivo calcium imaging, functional manipulations, and electrophysiology to characterize a previously unknown projection from the dorsal peduncular (DP) prefrontal cortex to the CeA. DP-to-CeA neurons are glutamatergic and specifically target the medial CeA, the main amygdalar output nucleus. Using a behavioural paradigm that elicits both freezing and flight, we found that CeA-projecting DP neurons are activated by high-intensity threats in a context-dependent manner. Functional manipulations revealed that the DP-to-CeA pathway is necessary and sufficient for both avoidance behaviour and flight. Furthermore, we found that DP projections target distinct medial CeA neuronal populations projecting to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.