Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes. To study the roles of microglial GR under normal homeostatic conditions and following chronic stress, we generated a mouse model in which the GR gene is depleted in microglia specifically at adulthood to prevent developmental confounds. We first confirmed that microglia were depleted in GR in our model in males and females among the cingulate cortex and the hippocampus, both stress-sensitive brain regions. Then, cohorts of microglial-GR depleted and wild-type (WT) adult female mice were housed for 3 weeks in a standard or stressful condition, using a chronic unpredictable mild stress (CUMS) paradigm. CUMS induced stress-related behavior in both microglial-GR depleted and WT animals as demonstrated by a decrease of both saccharine preference and progressive ratio breakpoint. Nevertheless, the hippocampal microglial and neural mechanisms underlying the adaptation to stress occurred differently between the two genotypes. Upon CUMS exposure, microglial morphology was altered in the WT controls, without any apparent effect in microglial-GR depleted mice. Furthermore, in the standard environment condition, GR depleted-microglia showed increased expression of pro-inflammatory genes, and genes involved in microglial homeostatic functions (such as Trem2, Cx3cr1 and Mertk). On the contrary, in CUMS condition, GR depleted-microglia showed reduced expression levels of pro-inflammatory genes and increased neuroprotective as well as anti-inflammatory genes compared to WT-microglia. Moreover, in microglial-GR depleted mice, but not in WT mice, CUMS led to a significant reduction of CA1 long-term potentiation and paired-pulse ratio. Lastly, differences in adult hippocampal neurogenesis were observed between the genotypes during normal homeostatic conditions, with microglial-GR deficiency increasing the formation of newborn neurons in the dentate gyrus subgranular zone independently from stress exposure. Together, these findings indicate that, although the deletion of microglial GR did not prevent the animal’s ability to respond to stress, it contributed to modulating hippocampal functions in both standard and stressful conditions, notably by shaping the microglial response to chronic stress.

慢性心理压力是神经精神障碍最重要的诱因和环境危险因素之一。慢性压力可以通过分泌压力激素（包括肾上腺分泌的糖皮质激素）影响所有器官，肾上腺协调全身的压力反应。在大脑中，糖皮质激素受体 (GR) 由包括小胶质细胞在内的各种细胞类型表达，小胶质细胞是其常驻免疫细胞，可调节压力诱导的炎症过程。为了研究小胶质细胞 GR 在正常稳态条件下和慢性应激后的作用，我们生成了一个小鼠模型，其中 GR 基因在成年期特别是在小胶质细胞中被耗尽，以防止发育混淆。我们首先证实，在我们的模型中，男性和女性的扣带回皮层和海马体中的小胶质细胞在 GR 中耗尽，这两个区域都是压力敏感的大脑区域。然后，使用慢性不可预测的轻度压力 (CUMS) 范式，将小胶质细胞 GR 耗尽和野生型 (WT) 成年雌性小鼠在标准或压力条件下饲养 3 周。CUMS 在小胶质细胞 GR 耗竭和 WT 动物中诱导应激相关行为，如糖精偏好和渐进比率断点的降低所证明的。然而，适应压力的海马小胶质细胞和神经机制在两种基因型之间发生不同。在 CUMS 暴露后，WT 对照中的小胶质细胞形态发生了改变，对小胶质细胞-GR 耗竭的小鼠没有任何明显影响。此外，Trem2 , Cx3cr1和Mertk）。相反，在 CUMS 条件下，与 WT 小胶质细胞相比，GR 耗尽的小胶质细胞显示促炎基因的表达水平降低，神经保护和抗炎基因的表达水平增加。此外，在小胶质细胞 GR 耗竭的小鼠中，而不是在 WT 小鼠中，CUMS 导致 CA1 长期增强和配对脉冲比显着降低。最后，在正常稳态条件下，在基因型之间观察到成年海马神经发生的差异，小胶质细胞 GR 缺陷增加了齿状回颗粒下区新生神经元的形成，而与压力暴露无关。总之，这些发现表明，虽然小胶质细胞 GR 的缺失并没有阻止动物应对压力的能力，