Cognitive impairment, a core symptom of psychiatric disorders, is frequently observed in adolescents exposed to early-life stress (ES). However, the underlying neural mechanisms are unclear, and therapeutic efficacy is limited. Targeting parvalbumin-expressing interneurons (PVIs) in the medial prefrontal cortex (mPFC), we report that ES reduces mPFC PVI activity, which causally mediated ES-induced cognitive deficits in adolescent male mice through chemogenetic and optogenetic experiments. To understand the possible causes of PVI activity reduction following ES, we then demonstrated that ES upregulated corticotropin-releasing hormone (CRH) receptor 1 [CRHR1, mainly expressed in pyramidal neurons (PNs)] and reduced activity of local pyramidal neurons (PNs) and their excitatory inputs to PVIs. The subsequent genetic manipulation experiments (CRHR1 knockout, CRH overexpression, and chemogenetics) highlight that ES-induced PVI activity reduction may result from CRHR1 upregulation and PN activity downregulation and that PVIs play indispensable roles in CRHR1- or PN-mediated cognitive deficits induced by ES. These results suggest that ES-induced cognitive deficits could be attributed to the prefrontal CRHR1-PN-PVI pathway. Finally, treatment with antalarmin (a CRHR1 antagonist) and environmental enrichment successfully restored the PVI activity and cognitive deficits induced by ES. These findings reveal the neurobiological mechanisms underlying ES-induced cognitive deficits in adolescent male mice and highlight the therapeutic potentials of PVIs in stress-related cognitive deficits in adolescent individuals.

认知障碍是精神疾病的核心症状，经常在暴露于早期生活压力 （ES） 的青少年中观察到。然而，潜在的神经机制尚不清楚，治疗效果有限。针对内侧前额叶皮层 （mPFC） 中表达细小白蛋白的中间神经元 （PVI），我们报道 ES 降低 mPFC PVI 活性，这通过化学遗传学和光遗传学实验因果介导了 ES 诱导的青春期雄性小鼠认知缺陷。为了了解 ES 后 PVI 活性降低的可能原因，我们随后证明 ES 上调了促肾上腺皮质激素释放激素 （CRH） 受体 1 [CRHR1，主要在锥体神经元 （PNs） 中表达] 并降低了局部锥体神经元 （PNs） 的活性及其对 PVI 的兴奋性输入。随后的基因操作实验（CRHR1 敲除、CRH 过表达和化学遗传学）强调，ES 诱导的 PVI 活性降低可能是由 CRHR1 上调和 PN 活性下调引起的，并且 PVI 在 ES 诱导的 CRHR1 或 PN 介导的认知缺陷中起着不可或缺的作用。这些结果表明，ES 诱导的认知缺陷可归因于前额叶 CRHR1-PN-PVI 通路。最后，用 antalarmin （一种 CRHR1 拮抗剂） 和环境富集治疗成功恢复了 ES 诱导的 PVI 活性和认知缺陷。这些发现揭示了 ES 诱导的青少年雄性小鼠认知缺陷的神经生物学机制，并强调了 PVI 在青少年个体压力相关认知缺陷中的治疗潜力。