Yu Qingying, Li Huan, Cui Xulan, Zhou Liuchang, Xie Zedan, Wang Shanshan, Deng Di, Zhao Jinlan, Sun Peng, Shi Yafei, Zhang Rong
Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
Front Pharmacol. 2025 May 21;16:1508037. doi: 10.3389/fphar.2025.1508037. eCollection 2025.
Early-life stress (ELS) is a well-established risk factor for adolescent depression, yet the underlying neurobiological mechanisms remain incompletely understood. The dorsal raphe nucleus (DRN), a key serotonergic center, demonstrates stress-induced synaptic impairments that may underlie depressive phenotypes. Sinisan (SNS), a classical Chinese herbal formula, shows clinical efficacy against mood disorders, but its effects on adolescent stress-induced DRN synaptic damage are unknown.
Using a maternal separation plus chronic unpredictable mild stress (MSCUMS) model in adolescent rats, we integrated behavioral tests with various neurobiological analyses. Depressive-like behaviors were evaluated, synaptic ultrastructure in the DRN was examined via electron microscopy, and CaSR expression was measured. The therapeutic effects of SNS and the mechanistic role of CaSR were investigated through pharmacological activation (GdCl3).
MS-CUMS induced: (1) depressive-like behaviors, (2) DRN synaptic ultrastructural damage, and (3) Calcium-sensing receptor (CaSR) downregulation. SNS treatment normalized depression/anxiety behaviors, restored CaSR expression and ameliorated synaptic damage. CaSR activation (GdCl3) reversed these deficits, confirming its mechanistic role.
These results demonstrate that CaSR mediates ELS-induced DRN synaptic impairment, and SNS exerts rapid antidepressant effects via CaSR upregulation.
早年生活应激（ELS）是青少年抑郁症公认的风险因素，但其潜在的神经生物学机制仍未完全明确。中缝背核（DRN）是一个关键的血清素能中心，表现出应激诱导的突触损伤，这可能是抑郁表型的基础。四逆散（SNS）是一种经典的中药配方，对情绪障碍具有临床疗效，但其对青少年应激诱导的DRN突触损伤的影响尚不清楚。
我们在青春期大鼠中采用母婴分离加慢性不可预测轻度应激（MSCUMS）模型，将行为测试与各种神经生物学分析相结合。评估抑郁样行为，通过电子显微镜检查DRN中的突触超微结构，并测量钙敏感受体（CaSR）的表达。通过药物激活（GdCl3）研究SNS的治疗效果和CaSR的机制作用。
MS-CUMS诱导：（1）抑郁样行为，（2）DRN突触超微结构损伤，以及（3）钙敏感受体（CaSR）下调。SNS治疗使抑郁/焦虑行为恢复正常，恢复CaSR表达并改善突触损伤。CaSR激活（GdCl3）逆转了这些缺陷，证实了其机制作用。
这些结果表明，CaSR介导ELS诱导的DRN突触损伤，而SNS通过上调CaSR发挥快速抗抑郁作用。
