中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (1): 126-140.doi: 10.4103/NRR.NRR-D-24-00742

• 综述:神经损伤修复保护与再生 • 上一篇    下一篇

小胶质细胞在多巴胺能系统发育中的新作用：早期生活压力的干扰

  

  • 出版日期:2026-01-15 发布日期:2025-04-19
  • 基金资助:
    本研究得到国家自然科学基金 82304990 号、81973748 号、82174278 号；国家重点研发计划 2023YFE0209500 号；中国博士后科学基金 2023M732380 号；广州市公式图形重点实验室；中国科学院广州化学物理研究所；中国科学院广州化学物理研究所。中国博士后科学基金，编号：2023YFE0209500；中国博士后科学基金，编号：2023M732380；广州市中药方剂重点实验室、第 202102010014 号；暨南大学黄振东中医药研究基金，第 201911 号；国家大学生创新创业训练计划项目，第 201911 号。国家级大学生创新创业训练计划项目，编号：202310559128；暨南大学大学生创新创业训练计划暨南大学本科生创新创业训练计划，编号：CX24380、CX24381

Emerging role of microglia in the developing dopaminergic system: Perturbation by early life stress

Kaijie She1, #, Naijun Yuan1, 2, #, Minyi Huang1 , Wenjun Zhu1 , Manshi Tang1 , Qingyu Ma1, *, Jiaxu Chen1, 3, *   

  1. 1 Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong Province, China;  2 Shenzhen People’s Hospital, The 2nd Clinical Medical College, Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Shenzhen, Guangdong Province, China;  3 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
  • Online:2026-01-15 Published:2025-04-19
  • Contact: Qingyu Ma, PhD, tmaqingyu@jnu.edu.cn; Jiaxu Chen, PhD, chenjiaxu@hotmail.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82304990 (to NY), 81973748 (to JC), 82174278 (to JC); the National Key R&D Program of China, No. 2023YFE0209500 (to JC); China Postdoctoral Science Foundation, No. 2023M732380 (to NY); Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, No. 202102010014 (to JC); Huang Zhendong Research Fund for Traditional Chinese Medicine of Jinan University, No. 201911 (to JC); National Innovation and Entrepreneurship Training Program for Undergraduates in China, No. 202310559128 (to NY and QM); Innovation and Entrepreneurship Training Program for Undergraduates at Jinan University, Nos. CX24380, CX24381 (both to NY and QM).

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摘要：

早期生活压力与自闭症、注意力缺陷/多动障碍、精神分裂症、抑郁症和帕金森病等神经系统疾病的高发病率相关，主要涉及多巴胺能系统的异常发育和损伤，给公共健康带来了巨大的问题。作为大脑的主要免疫细胞，小胶质细胞对调节神经元回路的发育和存活至关重要。从胚胎期到成年期，小胶质细胞表现出特定阶段的基因表达谱、转录组特征和功能表型，从而提高了对早期生活压力的易感性。此综述认为，早期生活压力会破坏小胶质细胞的功能表型，从而导致巴胺能系统紊乱。具体来说，小胶质细胞活动受损会减少神经营养支持(如胰岛素样生长因子1)，从而损害巴胺能神经元，并通过缺陷吞噬和突触修剪阻碍巴胺能轴突生长。此外，小胶质细胞免疫反应迟钝会抑制纹状体巴胺能电路的发育，并削弱神经元的传导。另一方面，活化的小胶质细胞诱导的炎症和氧化应激可直接损伤巴胺能神经元，抑制多巴胺的合成、再摄取和受体活性。小胶质细胞吞噬功能的增强会抑制多巴胺轴突的延伸。小胶质细胞扰动的这些持久影响可能是由早期生活压力诱导的小胶质细胞表观遗传重编程直接驱动的。间接地，早期生活压力可能通过各种途径，如星形胶质细胞激活、下丘脑-垂体-肾上腺轴、肠道-大脑轴和母体免疫信号，进一步调节小胶质细胞的功能。最后，文章总结并讨论了针对小胶质细胞以恢复巴胺能系统的各种治疗策略和分子机制，包括经典的抗抑郁药和抗精神病药、抗生素和抗炎药以及中草药。结合药物干预和遗传策略的进一步研究对于阐明小胶质细胞表型和功能扰动在早期生活压力干扰的巴胺能系统中的因果关系至关重要。

https://orcid.org/0000-0002-4208-5634 (Qingyu Ma); https://orcid.org/0000-0002-5570-6233 (Jiaxu Chen)

关键词: 中药, 多巴胺, 早期生活压力, 表观遗传学, 肠脑轴, 下丘脑-垂体-肾上腺轴, 先天性免疫记忆, 小胶质细胞, 神经炎症, 帕金森病, 吞噬作用, 奖赏

Abstract: Early life stress correlates with a higher prevalence of neurological disorders, including autism, attention-deficit/hyperactivity disorder, schizophrenia, depression, and Parkinson’s disease. These conditions, primarily involving abnormal development and damage of the dopaminergic system, pose significant public health challenges. Microglia, as the primary immune cells in the brain, are crucial in regulating neuronal circuit development and survival. From the embryonic stage to adulthood, microglia exhibit stage-specific gene expression profiles, transcriptome characteristics, and functional phenotypes, enhancing the susceptibility to early life stress. However, the role of microglia in mediating dopaminergic system disorders under early life stress conditions remains poorly understood. This review presents an up-to-date overview of preclinical studies elucidating the impact of early life stress on microglia, leading to dopaminergic system disorders, along with the underlying mechanisms and therapeutic potential for neurodegenerative and neurodevelopmental conditions. Impaired microglial activity damages dopaminergic neurons by diminishing neurotrophic support (e.g., insulin-like growth factor-1) and hinders dopaminergic axon growth through defective phagocytosis and synaptic pruning. Furthermore, blunted microglial immunoreactivity suppresses striatal dopaminergic circuit development and reduces neuronal transmission. Furthermore, inflammation and oxidative stress induced by activated microglia can directly damage dopaminergic neurons, inhibiting dopamine synthesis, reuptake, and receptor activity. Enhanced microglial phagocytosis inhibits dopamine axon extension. These long-lasting effects of microglial perturbations may be driven by early life stress–induced epigenetic reprogramming of microglia. Indirectly, early life stress may influence microglial function through various pathways, such as astrocytic activation, the hypothalamic–pituitary–adrenal axis, the gut–brain axis, and maternal immune signaling. Finally, various therapeutic strategies and molecular mechanisms for targeting microglia to restore the dopaminergic system were summarized and discussed. These strategies include classical antidepressants and antipsychotics, antibiotics and anti-inflammatory agents, and herbal-derived medicine. Further investigations combining pharmacological interventions and genetic strategies are essential to elucidate the causal role of microglial phenotypic and functional perturbations in the dopaminergic system disrupted by early life stress.

Key words: Chinese herbal drugs, dopamine, early life stress, epigenetics, gut-brain axis, hypothalamo–pituitary–adrenal axis, innate immune memory, microglia, neuroinflammation, Parkinson disease, phagocytosis, reward