Top-down control of flight by a non-canonical cortico-amygdala pathway

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 behaviour, including panic-like flight, is controlled by neuronal circuits in the central amygdala (CeA)2; however, the source of neuronal excitation to the CeA that contributes to these high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping, in-vivo calcium imaging, functional manipulations, and slice physiology 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. 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 for both avoidance behaviour and flight. Furthermore, we found that DP projections preferentially target distinct medial CeA neuronal populations linked to flight. These results are the first demonstration that the prefrontal cortex exerts direct, top-down control of the CeA and elucidate a non-canonical pathway regulating panic-like fear responses.

The prelimbic prefrontal cortex mediates the development of lasting social phobia as a consequence of social threat conditioning

“…Upon visual inspection of representative videos, it was evident that other defensive mechanisms also emerged during the STC task (Supp Fig 2). These included stretched postures which are associated with risk assessment and avoidance-approach ambivalence [30,31], and darting moves which represent escape and flight-like responses [32,33]. These findings are consistent with the effectiveness of the STC task to produce social phobia states.…”

The mouse dorsal peduncular cortex encodes fear memory

“…During the revision of this manuscript, an additional study was published that points towards a role for DP excitatory projections to the central amygdala in the control of fight or flight 13 . The authors observed that neurons in layer 2/3 project to central amygdala whereas those in layer 5/6 project to the dorsal medial hypothalamus, a circuit implicated in mediating sympathetic responses to psychosocial stress 10 .…”

“…Following social defeat stress, the DP, along with the region immediately ventral, the dorsal tenia tecta (DTT), have been implicated in driving physiological sympathetic responses, including thermoregulation and cardiac responses [10][11][12] . Moreover, recent studies have also implicated the DP/DTT in driving anxiety-like behaviors 9 and circuits of fight or flight 13 . Given the central role for autonomic responses in fear, we hypothesized that the DP may be playing a role in fear memory processes rather than in extinction.…”