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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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  • Jia-Xin Zou,
  • Wei-Zhu Liu,
  • Ya-Qing Li,
  • Yuan-Yuan Li,
  • Wen-Jie You,
  • Han-Qing Pan,
  • Chun-Yan Wang,
  • Wen-Hua Zhang,
  • Bing-Xing Pan

摘要

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.