Tao Long, Li Xiao-Xiao, Tu Xin-Ru, Liu Rui, Xu Jia-Wen, Lv Yi-Li, Yao Yu-You
School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China; Nanjing Jiangning District Center for Disease Control and Prevention, Nanjing 211100, China.
School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China.
Behav Brain Res. 2024 Aug 24;472:115139. doi: 10.1016/j.bbr.2024.115139. Epub 2024 Jul 3.
Numerous studies have demonstrated that chronic stress during pregnancy (CSDP) can induce depression and hippocampal damage in offspring. It has also been observed that high levels of corticotropin-releasing hormone (CRH) can damage hippocampal neurons, and intraperitoneal injection of a corticotropin releasing hormone receptor 1 (CRHR1) antagonist decreases depression-like behavior and hippocampal neuronal damage in a mouse depression model. However, whether CSDP causes hippocampal damage and depression in offspring through the interaction of CRH and hippocampal CRHR1 remains unknown and warrants further investigation. Therefore, hippocampal Crhr1 conditional gene knockout mice and C57/BL6J mice were used to study these questions. Depression-related indexs in male offspring mice were examined using the forced swim test (FST), sucrose preference test (SPT), tail suspension test (TST) and open field test (OFT). Serum CRH levels were measured by enzyme-linked immunosorbent assay (ELISA). Golgi-Cox staining was used to examine the morphological changes of hippocampal neuronal dendrites. Neuronal apoptosis in the hippocampal CA3 regions was detected by terminal deoxynucleotidy transferase dUTP nick end labeling (TUNEL) staining. The levels of mammalian target of rapamycin (mTOR), phosphorylated mTOR (p-mTOR) and protein kinase B (AKT) proteins were measured by Western blot analysis. This study showed that CSDP induces depression-like behavior, hippocampal neuronal dendrite damage and apoptosis in male offspring mice. Conditional gene knockout of hippocampal Crhr1 in mice reduced CSDP-induced depression-like behavior, hippocampal neuronal dendrite damage and apoptosis in male offspring, and counteracted the CSDP-induced decreased expression of p-Akt and mTOR activity in male offspring hippocampus. These findings demonstrated that CSDP might inhibit the Akt/mTOR pathway by increasing the levels of CRH, leading to increased CRH-mediated activation of hippocampal CRHR1, thereby inducing synaptic impairment and apoptosis in hippocampal neurons, which in turn leads to depression-like behavior in offspring.
大量研究表明，孕期慢性应激（CSDP）可导致子代出现抑郁和海马损伤。也有观察发现，高水平的促肾上腺皮质激素释放激素（CRH）会损害海马神经元，腹腔注射促肾上腺皮质激素释放激素受体1（CRHR1）拮抗剂可减少小鼠抑郁模型中的抑郁样行为和海马神经元损伤。然而，CSDP是否通过CRH与海马CRHR1的相互作用导致子代海马损伤和抑郁仍不清楚，值得进一步研究。因此，本研究使用海马Crhr1条件性基因敲除小鼠和C57/BL6J小鼠来探究这些问题。通过强迫游泳试验（FST）、蔗糖偏好试验（SPT）、悬尾试验（TST）和旷场试验（OFT）检测雄性子代小鼠的抑郁相关指标。采用酶联免疫吸附测定（ELISA）法检测血清CRH水平。运用高尔基-考克斯染色法观察海马神经元树突的形态变化。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色法检测海马CA3区的神经元凋亡情况。通过蛋白质免疫印迹分析检测雷帕霉素靶蛋白（mTOR）、磷酸化mTOR（p-mTOR）和蛋白激酶B（AKT）蛋白的水平。本研究表明，CSDP可诱导雄性子代小鼠出现抑郁样行为、海马神经元树突损伤和凋亡。小鼠海马Crhr1条件性基因敲除可减轻CSDP诱导的雄性子代抑郁样行为、海马神经元树突损伤和凋亡，并抵消CSDP诱导的雄性子代海马中p-Akt表达降低和mTOR活性下降。这些研究结果表明，CSDP可能通过提高CRH水平抑制Akt/mTOR通路，导致CRH介导的海马CRHR1激活增加，从而诱导海马神经元的突触损伤和凋亡，进而导致子代出现抑郁样行为。
