Early life stress induces a transient increase in hippocampal corticotropin releasing hormone in rat neonates that precedes the effects on hypothalamic neuropeptides

Early life stress (ELS) programs the hypothalamus-pituitary-adrenal (HPA) axis activity, affects synaptic plasticity, and cognitive performance in adult individuals; however, the effects of ELS during the vulnerability time window are poorly understood. This study aimed to thoroughly characterize the effects of ELS in the form of periodic maternal separation (MS180) during the time of exposure to stress. Hippocampal corticotropin releasing hormone (CRH) gene expression and baseline HPA axis activity were analyzed at postnatal (P) days 6, 12, 15, and 21, and in adulthood (P75); these factors were correlated with plasticity markers and adult behavior. Our results indicate that MS180 induces an increase in hippocampal CRH expression at P9, P12, and P15, whereas the increase in hypothalamic CRH expression was observed from P12 to P21. Increased arginine vasopressin expression and corticosterone levels were observed only at P21. Moreover, MS180 caused transient alterations in hypothalamic synaptophysin expression during early life. As adults, MS180 rats showed a passive coping strategy in the forced swimming test, cognitive impairments in the object location test, increased hypothalamic CRH expression, and decreased oxytocin (OXT) expression.早期生命应激（Early Life Stress, ELS）可程序化调控下丘脑-垂体-肾上腺（hypothalamus-pituitary-adrenal, HPA）轴活性，影响成年个体的突触可塑性与认知表现，但针对应激易感窗口期内ELS的效应，目前仍缺乏深入解析。本研究旨在系统性表征以周期性母婴分离（MS180）为造模方式的ELS在应激易感窗口期内的作用效应。研究团队分别在出生后（P）第6、12、15、21天及成年期（P75）检测海马促肾上腺皮质激素释放激素（CRH）基因表达与基础HPA轴活性，并将上述指标与突触可塑性标志物及成年期行为表现进行关联分析。结果表明，MS180可在P9、P12及P15阶段上调海马CRH基因表达，而下丘脑CRH表达的升高则出现于P12至P21阶段；仅在P21阶段可观察到精氨酸加压素表达与皮质酮水平的升高。此外，MS180可在早期生命阶段引发下丘脑突触素表达的一过性异常改变。成年后，经MS180处理的大鼠在强迫游泳实验中表现出被动应对策略，在物体位置实验中出现认知功能障碍，同时下丘脑CRH表达升高、催产素（OXT）表达降低。