Unpredictable chronic mild stress (UCMS) is one of the most commonly used, robust and translatable models for studying the neurobiological basis of major depression. Although the model currently has multiple advantages, it does not entirely follow the trajectory of the disorder, whereby depressive symptomology can often present months after exposure to stress. Furthermore, patients with depression are more likely to withdraw in response to their stressful experience, or as a symptom of their depression, and, in turn, this withdrawal/isolation can further exacerbate the stressful experience and the depressive symptomology. Therefore, we investigated the effect(s) of six weeks of UCMS followed by another six weeks of social isolation (referred to as UCMSI), on behaviour, corticosterone stress responsivity, immune system functioning, and hippocampal neurogenesis, in young adult male mice. We found that UCMSI induced several behavioural changes resembling depression but did not induce peripheral inflammation. However, UCMSI animals showed increased microglial activation in the ventral dentate gyrus (DG) of the hippocampus and astrocyte activation in both the dorsal and ventral DG, with increased GFAP immunoreactivity, GFAP positive cell hypertrophy and process extension, and increased s100β positive cell density. Moreover, UCMSI animals had significantly reduced neurogenesis in the DG and reduced levels of peripheral vascular endothelial growth factor (VEGF) - a trophic factor produced by astrocytes and that stimulates neurogenesis. Finally, UCMSI mice also had normal baseline corticosterone levels but a smaller increase in corticosterone following acute stress, that is, the Porsolt Swim Test. Our work gives clinically relevant insights into the role that microglial and astrocyte functioning, and hippocampal neurogenesis may play in the context of stress, social isolation and depression, offering a potentially new avenue for therapeutic target.

中文翻译：

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慢性压力和社会隔离会促进抑郁样行为，改变小胶质细胞和星形胶质细胞生物学，并减少雄性小鼠的海马神经发生

不可预测的慢性轻度压力​​ (UCMS) 是研究重度抑郁症的神经生物学基础的最常用、稳健和可翻译的模型之一。尽管该模型目前具有多种优势，但它并不完全遵循疾病的轨迹，因此抑郁症状通常会在暴露于压力后数月出现。此外，抑郁症患者更有可能因压力经历或抑郁症状而退出，反过来，这种退出/孤立会进一步加剧压力经历和抑郁症状。因此，我们调查了六周的 UCMS 以及另外六周的社会隔离（称为 UCMSI）对行为、皮质酮应激反应、免疫系统功能、和海马神经发生，在年轻的成年雄性小鼠中。我们发现 UCMSI 诱导了几种类似于抑郁的行为变化，但没有诱导外周炎症。然而，UCMSI 动物显示海马腹侧齿状回 (DG) 小胶质细胞活化增加，背侧和腹侧 DG 星形胶质细胞活化增加，GFAP 免疫反应性增加，GFAP 阳性细胞肥大和突起延伸，s100β 阳性细胞密度增加。此外，UCMSI 动物的 DG 中的神经发生显着降低，外周血管内皮生长因子 (VEGF) 水平降低——一种由星形胶质细胞产生并刺激神经发生的营养因子。最后，UCMSI 小鼠的基线皮质酮水平也正常，但急性应激后皮质酮的增加幅度较小，也就是说，波索尔特游泳测试。我们的工作为小胶质细胞和星形胶质细胞功能以及海马神经发生在压力、社会孤立和抑郁的背景下可能发挥的作用提供了临床相关的见解，为治疗靶点提供了潜在的新途径。