Running exercise has been shown to alleviate depressive symptoms. However, the mechanism underlying the antidepressant effects of running exercise is not fully understood. The imbalance of M1/M2 microglia phenotype/polarization and concomitant dysregulation of neuroinflammation play crucial roles in the pathogenesis of depression. Running exercise increases circulating levels of adiponectin which is known to cross the blood‒brain barrier and suppress inflammatory responses. AdipoR1 is an adiponectin receptor that is involved in regulating microglial phenotypes and activation states. However, whether running exercise regulates hippocampal microglial phenotypes and neuroinflammation through adiponectin/AdipoR1 to exert its antidepressant effects remains unclear. In the current study, 4 weeks of running exercise significantly alleviated the depressive-like behaviors of chronic unpredictable stress (CUS)-exposed mice. Moreover, running exercise decreased the microglial numbers and altered microglial morphology in three subregions of the hippocampus to restore the M1/M2 balance; these effects were accompanied by regulation of pro-/anti-inflammatory cytokine production and secretion in CUS-exposed mice. These effects may involve elevation of peripheral tissue (adipose tissue and muscle) and plasma adiponectin levels, and hippocampal AdipoR1 levels as well as activation of the AMPK-NF-κB/STAT3 signaling pathway by running exercise. When an adeno-associated virus was used to knock down hippocampal AdipoR1, mice showed depressive-like behaviors and alterations in microglia and inflammatory factor expression in the hippocampus that were similar to those observed in CUS-exposed mice. Together, these results suggest that running exercise maintains the M1/M2 balance and inhibits neuroinflammation in the hippocampus of CUS-exposed mice. These effects might occur via adiponectin/AdipoR1-mediated activation of the AMPK-NF-κB/STAT3 signaling pathway.

跑步运动已被证明可以缓解抑郁症状。然而，跑步运动的抗抑郁作用的潜在机制尚不完全清楚。M1/M2 小胶质细胞表型/极化的失衡和伴随的神经炎症失调在抑郁症的发病机制中起着至关重要的作用。跑步运动会增加脂联素的循环水平，脂联素已知可以穿过血液\u2012脑屏障并抑制炎症反应。AdipoR1 是一种脂联素受体，参与调节小胶质细胞表型和激活状态。然而，跑步运动是否通过脂联素/AdipoR1 调节海马小胶质细胞表型和神经炎症以发挥其抗抑郁作用仍不清楚。在目前的研究中，4 周的跑步运动显着缓解了慢性不可预测的压力 （CUS） 暴露小鼠的抑郁样行为。此外，跑步运动减少了海马体三个亚区的小胶质细胞数量并改变了小胶质细胞形态，以恢复 M1/M2 平衡;这些作用伴随着 CUS 暴露小鼠促炎/抗炎细胞因子产生和分泌的调节。这些影响可能涉及外周组织 （脂肪组织和肌肉） 和血浆脂联素水平、海马 AdipoR1 水平的升高，以及通过跑步运动激活 AMPK-NF-κB/STAT3 信号通路。当使用腺相关病毒敲除海马 AdipoR1 时，小鼠表现出类似抑郁的行为以及海马体中小胶质细胞和炎症因子表达的改变，这与在 CUS 暴露小鼠中观察到的相似。 总之，这些结果表明，跑步运动可维持 M1/M2 平衡并抑制 CUS 暴露小鼠海马体的神经炎症。这些作用可能通过脂联素/AdipoR1 介导的 AMPK-NF-κB/STAT3 信号通路激活而发生。