Ma Yu-Nu, Yang Chao-Juan, Zhang Chen-Chen, Sun Ya-Xin, Yao Xing-Duo, Liu Xiao, Li Xue-Xin, Wang Hong-Li, Wang Han, Wang Ting, Wang Xiao-Dong, Zhang Chen, Su Yun-Ai, Li Ji-Tao, Si Tian-Mei
Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China.
Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing, China.
Mol Psychiatry. 2025 Jun;30(6):2407-2426. doi: 10.1038/s41380-024-02845-6. Epub 2024 Nov 22.
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，在经历过早期生活应激（ES）的青少年中经常观察到。然而，其潜在的神经机制尚不清楚，治疗效果也有限。针对内侧前额叶皮质（mPFC）中表达小白蛋白的中间神经元（PVIs），我们报告称，ES会降低mPFC中PVIs的活性，通过化学遗传学和光遗传学实验表明，这在因果关系上介导了青春期雄性小鼠中ES诱导的认知缺陷。为了了解ES后PVIs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PVIs的兴奋性输入。随后的基因操作实验（CRHR1基因敲除、CRH过表达和化学遗传学）表明，ES诱导的PVIs活性降低可能是由于CRHR1上调和PNs活性下调所致，并且PVIs在ES诱导的由CRHR1或PNs介导的认知缺陷中起不可或缺的作用。这些结果表明，ES诱导的认知缺陷可能归因于前额叶CRHR1-PN-PVI通路。最后，使用安他拉美（一种CRHR1拮抗剂）和环境富集疗法成功恢复了ES诱导的PVIs活性和认知缺陷。这些发现揭示了青春期雄性小鼠中ES诱导的认知缺陷的神经生物学机制，并突出了PVIs在青少年个体应激相关认知缺陷中的治疗潜力。
