Sgk1 upregulation in hippocampus-projecting amygdala neurons underlies the delayed onset of PTSD-like avoidance behavior

Abstract Excessive avoidance is a core symptom of post-traumatic stress disorder (PTSD), yet its underlying circuit mechanisms remain poorly understood. Here, using a mouse model of PTSD induced by inescapable footshock, we observed a delayed and prolonged increase in avoidance behavior associated with selective activation of basolateral amygdala (BLA) projection neurons (PNs) targeting ventral hippocampus (BLA→vHPC PNs), but not nucleus accumbens, in both sexes. This projection-specific activation results from enhanced neuronal excitability and excitatory transmission driven by glucocorticoid receptor (GR) signaling. Among the cascade of GR signaling molecules, we identified serum- and glucocorticoid-regulated kinase 1 (Sgk1) as a key downstream mediator linking stress exposure to the hyperactivation of BLA→vHPC PNs and PTSD-like avoidance behavior. Manipulating Sgk1 expression bidirectionally regulates neuronal activity and susceptibility to stress-induced avoidance. These findings underscore the critical role of projection-specific upregulation of Sgk1 in BLA PNs in the pathogenesis of PTSD-like avoidance behavior.