Major depressive disorder (MDD) is a highly pervasive, severe psychological condition for which the precise underlying pathophysiology is incompletely understood, although microglial activation is known to play a role in this context. In this study we analyzed the association between neuroinflammation and depressive-like behaviors in a lipopolysaccharide (LPS)-induced mouse model system using 10-12-week-old male C57BL/6 mice. Microglial activation and associated neuroinflammatory activity were monitored via positron emission tomography (PET) imaging. Animals were assessed at three time points, including 24 h prior to LPS injection, 24 h post-LPS injection, and 72 h post-LPS injection. Analyses of microglial activation and hippocampal neuroinflammation were conducted through [18]F DPA-714 PET imaging and immunohistochemical staining for ionized calcium-binding adapter molecule 1 (Iba-1) and translocator protein (TSPO). Moreover, NOD-like receptor protein 3 (NLRP3) inflammasome activity and interleukin-1β (IL-1β) levels were assessed at 24 h post-LPS injection. We found that LPS treatment was associated with a marked increase in depressive-like behavior at 24 h post-injection time point, and that it was less pronounced at the 72 h post-injection time point. These changes coincided with enhanced [18F] DPA-714 PET uptake in the whole brain, hippocampus, cortex and amygdala together with increased hippocampal microglial activation as evidenced by immunofluorescent staining. By 72 h post-injection, however, these PET and immunofluorescence phenotypes had returned to baseline levels. Furthermore, increased NLRP3 inflammasome activation and IL-1β expression were evident at 24 h post-LPS injection. These data demonstrate that dynamic microglial activation is associated with LPS-induced depressive-like behaviors and hippocampal neuroinflammation in a mouse model system.

中文翻译：

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动态小胶质细胞激活与 LPS 诱导的小鼠抑郁样行为相关：[18F] DPA-714 PET 成像研究。

重度抑郁症 (MDD) 是一种高度普遍、严重的心理状况，其确切的潜在病理生理学尚不完全清楚，尽管已知小胶质细胞激活在这种情况下发挥作用。在这项研究中，我们使用 10-12 周大的雄性 C57BL/6 小鼠分析了脂多糖 (LPS) 诱导的小鼠模型系统中神经炎症和抑郁样行为之间的关联。通过正电子发射断层扫描 (PET) 成像监测小胶质细胞活化和相关的神经炎症活动。在三个时间点评估动物，包括 LPS 注射前 24 小时、LPS 注射后 24 小时和 LPS 注射后 72 小时。通过 [18] F DPA-714 PET 成像和离子化钙结合接头分子 1 (Iba-1) 和转运蛋白 (TSPO) 的免疫组织化学染色对小胶质细胞活化和海马神经炎症进行分析。此外，在注射 LPS 后 24 小时评估 NOD 样受体蛋白 3 (NLRP3) 炎症小体活性和白细胞介素 1β (IL-1β) 水平。我们发现 LPS 治疗与注射后 24 小时的抑郁样行为显着增加有关，并且在注射后 72 小时的时间点不太明显。这些变化与整个大脑、海马、皮层和杏仁核的 [18F] DPA-714 PET 摄取增加以及免疫荧光染色所证明的海马小胶质细胞活化增加相吻合。然而，到注射后 72 小时，这些 PET 和免疫荧光表型已恢复到基线水平。此外，在 LPS 注射后 24 小时，NLRP3 炎性体激活和 IL-1β 表达增加是明显的。这些数据表明，动态小胶质细胞激活与小鼠模型系统中 LPS 诱导的抑郁样行为和海马神经炎症有关。