Chen Junyu, Huang Jiacheng, Han Taolei, Kojima Nobuhiko
Laboratory of Molecular Neurobiology, Faculty of Life Sciences, Toyo University, Saitama 351-8510, Japan.
Super-Network Brain Physiology, Graduate School of Life Sciences, Tohoku University, Sendai 980-8577, Japan.
Brain Sci. 2025 May 21;15(5):534. doi: 10.3390/brainsci15050534.
(1) Background: The high recurrence rate and individual differences in stress susceptibility contribute to the diverse symptoms of depression, making full recovery and relapse prevention challenging. Emerging evidence suggests that fluctuations in microglial activity are closely linked to depression progression under chronic stress exposure. Changes in the brain microenvironment can elicit microglial priming, enhancing their sensitivity to external stimuli. However, few studies have longitudinally examined how microglial characteristics evolve throughout depression progression. (2) Methods: In this study, we investigated microglial morphological changes and their responses to acute stress at different stages of depression using the chronic unpredictable mild stress (CUMS) paradigm in mice. (3) Results: Our findings reveal that in the dentate gyrus, microglial activation indices, including cell number and morphology, exhibit distinct dynamic patterns depending on CUMS exposure duration. Notably, after 2 and 4 weeks of CUMS exposure followed by acute stress re-exposure, microglia display opposing response patterns. In contrast, after 6 weeks of CUMS exposure, primed microglia exhibit dysfunction, failing to respond to acute stress. Notably, depressive behaviors are not prominent after 2 weeks of CUMS exposure but become more pronounced after 4 and 6 weeks of exposure. Additionally, regardless of CUMS duration, body weight demonstrates an intrinsic capacity to normalize after stress cessation. (4) Conclusions: These findings suggest that microglial priming responses are state-dependent, either enhancing or suppressing secondary stimulus responses, or exceeding physiological limits, thereby preventing further activation. This study provides novel insights into the role of microglial priming in stress vulnerability and its contribution to depression progression.
(1) 背景：高复发率以及应激易感性的个体差异导致了抑郁症症状的多样性，使得完全康复和预防复发具有挑战性。新出现的证据表明，在慢性应激暴露下，小胶质细胞活性的波动与抑郁症进展密切相关。脑微环境的变化可引发小胶质细胞致敏，增强其对外部刺激的敏感性。然而，很少有研究纵向考察小胶质细胞特征在抑郁症进展过程中的演变情况。(2) 方法：在本研究中，我们使用慢性不可预测轻度应激（CUMS）范式，在小鼠抑郁症的不同阶段研究了小胶质细胞的形态变化及其对急性应激的反应。(3) 结果：我们的研究结果表明，在齿状回中，包括细胞数量和形态在内的小胶质细胞激活指标，根据CUMS暴露持续时间呈现出不同的动态模式。值得注意的是，在暴露于CUMS 2周和4周后再进行急性应激重新暴露，小胶质细胞表现出相反的反应模式。相比之下，在暴露于CUMS 6周后，致敏的小胶质细胞表现出功能障碍，对急性应激无反应。值得注意的是，在暴露于CUMS 2周后抑郁行为并不突出，但在暴露4周和6周后变得更加明显。此外，无论CUMS持续时间如何，体重在应激停止后都具有恢复正常的内在能力。(4) 结论：这些发现表明，小胶质细胞致敏反应是状态依赖性的，要么增强要么抑制二次刺激反应，要么超过生理极限，从而阻止进一步激活。本研究为小胶质细胞致敏在应激易感性中的作用及其对抑郁症进展的贡献提供了新的见解。
