Early life stress exerts detrimental effects on cognitive function, but the mechanism by which this occurs is unknown. The NLRP3 inflammasome-mediated inflammatory response has emerged as a prominent contributor to cognitive impairment induced by chronic stress. In the present study, we showed that 8-week chronic social isolation (SI) led to cognitive impairment in mice, remarkably increasing expression of the hippocampal NLRP3 inflammasome. Furthermore, the 8-week SI procedure significantly increased the levels of hippocampal IL-1β and IL-18 without significant alteration of the level of serum IL-1β, suggesting a central mechanism for IL-1β-related CNS inflammation. Moreover, inflammatory microglial and expression of AMPAR were reduced in the hippocampus of SI mice. Minocycline is an antibiotic that limits microglia responses, and previous study also showed that minocycline could prevent stress-induced pro-inflammatory cytokine expression in the brain. Our experiment found that minocycline improved cognitive behavior in SI mice. Minocycline also prevented expression of the hippocampal NLRP3 inflammasome, indicating that microglia might be the primary contributor to SI-induced hippocampal NLRP3 inflammasome activation. Furthermore, alterations in SI mice were also restored by chronic treatment with the NLRP3 inhibitor MCC950. These results indicate that the microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to social isolation and that specific NLRP3 inflammasome inhibition using MCC950 may represent a promising therapeutic approach for early stress induced cognitive impairment.

早期生活压力对认知功能产生不利影响，但发生这种情况的机制尚不清楚。NLRP3 炎症小体介导的炎症反应已成为慢性压力引起的认知障碍的主要因素。在本研究中，我们发现 8 周的慢性社会隔离 (SI) 导致小鼠认知障碍，海马 NLRP3 炎症小体的表达显着增加。此外，为期 8 周的 SI 程序显着增加了海马 IL-1β 和 IL-18 的水平，而没有显着改变血清 IL-1β 的水平，表明 IL-1β 相关的中枢神经系统炎症的中心机制。此外，SI 小鼠海马中的炎性小胶质细胞和 AMPAR 的表达降低。米诺环素是一种限制小胶质细胞反应的抗生素，之前的研究还表明，米诺环素可以防止大脑中压力诱导的促炎细胞因子表达。我们的实验发现米诺环素改善了 SI 小鼠的认知行为。米诺环素还阻止海马 NLRP3 炎症小体的表达，表明小胶质细胞可能是 SI 诱导的海马 NLRP3 炎症小体激活的主要贡献者。此外，用 NLRP3 抑制剂 MCC950 长期治疗也恢复了 SI 小鼠的改变。这些结果表明，小胶质细胞衍生的 NLRP3 炎症小体可能主要参与对社会隔离的炎症反应，并且使用 MCC950 的特定 NLRP3 炎症小体抑制可能代表了一种有前途的治疗早期压力引起的认知障碍的方法。