Corticotropin-releasing factor and somatostatin neurons in the central amygdala mediate dynamic defensive behaviors during fear extinction

Traumatic experiences can result in heightened fear responses to trauma-associated stimuli. These symptoms can be difficult to extinguish, so identifying neuronal targets for facilitating fear extinction is critical. Many studies investigating fear learning in mice measure conditioned fear via freezing, but other defensive behaviors, such as flight, can also be present during conditioning. The central amygdala (CEA) mediates conditioned freezing and flight responses via corticotropin-releasing factor-positive (CRF+) and somatostatin-positive (SOM+) neuron populations. However, it is unknown how these populations regulate changes in freezing and flight responses as fear extinction is learned. Thus, we investigated the roles of CRF+ and SOM+ CEA neurons in modulating defensive behaviors during extinction. To elicit dynamic defensive responses in male and female mice, we used a modified Pavlovian conditioned flight paradigm that paired an aversive footshock with a serial compound stimulus (SCS) consisting of tone followed by white noise (WN), resulting in freezing during the tone that rapidly transitioned into flight (escape jumping and darting) during WN. We used optogenetics in CRF-Cre and SOM-Cre mice to selectively excite and inhibit CRF+ and SOM+ CEA populations during WN presentation within extinction. Within early extinction, CRF+ inhibition reduced WN-evoked jumping and led to subsequent context-specific reduction in tone-evoked freezing. During extinction, SOM+ excitation replaced early WN-evoked flight with freezing, and both SOM+ excitation and inhibition reduced WN-evoked darting. Collectively, these data demonstrate modulation of jumping and darting behaviors within extinction via CRF+ and SOM+ CEA activity. These findings suggest mechanisms of attenuating multiple defensive behaviors during extinction.<b>Significance Statement</b> Fear extinction is a critical process for recovery from trauma, but it is often impaired by persistent fear responses. We conducted these experiments to better understand how defensive behaviors involved in learned fear are modulated during fear extinction through activity in the central amygdala. We found that inhibiting corticotropin-releasing factor-positive neurons reduced escape jumping, exciting somatostatin-positive neurons replaced flight with freezing, and unbalancing somatostatin activity reduced darting behaviors. Overall, this work highlights modulatory roles of central amygdala neuron populations in selecting and directing defensive behaviors over the course of fear extinction, which can assist in future endeavors to reduce unwanted fear responses in those suffering from fear disorders with impaired fear extinction.