慢性心理社会应激触发小胶质细胞/巨噬细胞诱导的炎症反应,导致神经元功能障碍和抑郁相关行为

Chronic psychosocial stress triggers microglial-/macrophage-induced inflammatory responses leading to neuronal dysfunction and depressive-related behavior

慢性环境压力和创伤性社会经历会导致不良行为变化,是主要抑郁症(MDD)和各种焦虑相关精神障碍的危险因素。临床研究和慢性压力的动物模型研究结果显示,症状严重程度与先天免疫反应和情绪调节相关脑区(mPFC:内侧前额叶皮质)中神经炎症细胞因子信号上调有关。尽管越来越多的证据表明神经可塑性受损和突触信号传导缺陷是与应激相关精神障碍的病理生理学的一部分,但小胶质细胞如何调节神经元稳态以应对慢性压力尚未明确。本研究使用反复社交挫败应激(RSDS)小鼠模型证明小胶质细胞诱导的炎症反应可以调节与心理社会压力相关的神经元可塑性。具体来说,我们发现慢性压力会迅速激活并增殖mPFC中的小胶质细胞以及巨噬细胞浸润,并且这些过程与神经元激活的空间位置相关。此外,我们研究还发现小胶质细胞炎症反应与对慢性压力的敏感性或抗性之间存在显著关联;暴露于慢性压力会加剧突触成分的吞噬作用和神经元可塑性的缺陷。通过使用2种不同的CSF1R抑制剂(脑渗透性的PLX5622和非渗透性的PLX73086),我们证实了小胶质细胞(其次为巨噬细胞)在催化mPFC中与心理社会压力相关的病理表现以及在与抑郁症相关的常见行为缺陷方面的关键作用。

Chronic environmental stress and traumatic social experiences induce maladaptive behavioral changes and is a risk factor for major depressive disorder(MDD)and various anxiety-related psychiatric disorders.Clinical studies and animal models of chronic stress have reported that symptom severity is correlated with innate immune responses and upregulation of neuroinflammatory cytokine signaling in brain areas implicated in mood regulation(mPFC;medial Prefrontal Cortex).Despite increasing evidence implicating impairments of neuroplasticity and synaptic signaling defi-cits into the pathophysiology of stress-related mental disorders,how microglia may modulate neuronal homeostasis in response to chronic stress has not been defined.Here,using the repeated social defeat stress(RSDS)mouse model we demonstrate that microglial-induced inflammatory responses are regulating neuronal plasticity associated with psycho-social stress.Specifically,we show that chronic stress induces a rapid activation and proliferation of microglia as well as macrophage infiltration in the mPFC,and these processes are spatially related to neuronal activation.Moreover,we report a significant association of microglial inflammatory responses with susceptibility or resilience to chronic stress.In addition,we find that exposure to chronic stress exacerbates phagocytosis of synaptic elements and deficits in neuro-nal plasticity.Importantly,by utilizing two different CSF1R inhibitors(the brain penetrant PLX5622 and the non-pene-trant PLX73086)we highlight a crucial role for microglia(and secondarily macrophages)in catalyzing the pathological manifestations linked to psychosocial stress in the mPFC and the resulting behavioral deficits usually associated with depression.