Current pharmacotherapies for posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are ineffective for many patients, and often do not restore cognitive dysfunction associated with these disorders. Behavioral therapies, such as exposure therapy, can be effective for treatment-resistant patients. The mechanisms underlying exposure therapy are not well-understood. Fear extinction as an intervention after chronic stress can model the beneficial effects of exposure therapy in rats. Extinction requires neuronal activity and protein synthesis in the infralimbic (IL) cortex for its beneficial effects. We hypothesized that extinction requires Brain-Derived Neurotrophic Factor (BDNF) activity in the IL cortex to reverse stress-induced cognitive flexibility impairments. Extinction learning reversed set-shifting deficits induced by Chronic Unpredictable Stress (CUS), tested 24 h after extinction. Blocking BDNF signaling in the IL cortex during extinction by local administration of a neutralizing antibody prevented the beneficial effects of extinction on set shifting after stress. Extinction induced activation of the BDNF TrkB receptor, and signaling pathways associated with BDNF (Akt and Erk). Administration of exogenous BDNF into IL cortex in the absence of extinction was sufficient to reverse the effects of stress on set shifting. The effects of extinction were prevented by blocking either Erk or Akt signaling in the IL cortex, whereas the effects of exogenous BDNF were dependent on Erk, but not Akt, signaling. Our observations suggest that BDNF-Erk signaling induced by extinction underlies plastic changes that can reverse or counteract the effects of chronic stress in the IL cortex.

目前针对创伤后应激障碍 (PTSD) 和重度抑郁症 (MDD) 的药物疗法对许多患者无效，并且通常不能恢复与这些疾病相关的认知功能障碍。行为疗法，例如暴露疗法，对难治性患者可能有效。暴露疗法的潜在机制尚不清楚。恐惧消退作为慢性压力后的干预可以模拟大鼠暴露疗法的有益效果。灭绝需要下边缘 (IL) 皮层中的神经元活动和蛋白质合成才能发挥其有益作用。我们假设灭绝需要 IL 皮层中的脑源性神经营养因子 (BDNF) 活动来逆转压力引起的认知灵活性障碍。灭绝学习逆转了由慢性不可预测压力 (CUS) 引起的设置转移缺陷，在灭绝后 24 小时进行了测试。通过局部施用中和抗体在消退过程中阻断 IL 皮层中的 BDNF 信号传导可防止消退对应激后集合移位的有益影响。灭绝诱导了 BDNF TrkB 受体的激活，以及与 BDNF 相关的信号通路（Akt 和 Erk）。在没有消退的情况下将外源性 BDNF 管理到 IL 皮层足以逆转压力对设置移位的影响。通过阻断 IL 皮层中的 Erk 或 Akt 信号传导可以防止灭绝的影响，而外源性 BDNF 的影响依赖于 Erk 而不是 Akt 信号传导。