社会行为与免疫系统密不可分。虽然已知IFN-γ参与社会行为,然而,它是否以及如何编码社会记忆仍不清楚。在目前的研究中,我们向雄性C57BL/6J小鼠的侧脑室注射IFN-γ,并采用三室社会测验来检验IFN-γ对其社会偏好和社会记忆的影响。海马小胶质细胞的形态,使用免疫组织化学检查前边缘皮质和杏仁核,用免疫组织化学和酶联免疫吸附试验检测小胶质细胞的表型。注射IFN-γ的小鼠用脂多糖治疗,并评估了IFN-γ对行为和小胶质细胞反应的影响。使用蛋白质印迹和免疫组织化学在体内或体外检查STAT1途径和小胶质细胞-神经元相互作用。最后,我们使用STAT1抑制剂或米诺环素来评估STAT1在介导小胶质细胞启动中的作用以及启动的小胶质细胞在IFN-γ诱导的社会功能障碍中的作用.我们证明,500ng的IFN-γ注射导致社会指数和社会新颖性识别指数显着下降,并在海马中诱导小胶质细胞启动,以扩大的细胞体为特征,缩短的树枝,CD68,CD86,CD74,CD11b的表达增加,CD11c,CD47,IL-33,IL-1β,IL-6和iNOS,MCR1、Arg-1、IGF-1和BDNF的表达降低。这种小胶质细胞亚群对LPS攻击更敏感,其特征是更显著的形态学变化和炎症反应,以及诱导小鼠疾病行为增加。IFN-γ上调pSTAT1和STAT1,并促进海马小胶质细胞和原发性小胶质细胞中STAT1的核转位。给予米诺环素或STAT1抑制剂氟达拉滨阻断IFN-γ诱导的海马小胶质细胞的启动,改善了海马小胶质细胞-神经元相互作用和小胶质细胞突触修剪的功能障碍,从而改善IFN-γ注射小鼠的社会记忆缺陷。IFN-γ启动STAT1通路诱导海马小胶质细胞启动,从而破坏海马小胶质细胞-神经元的相互作用和神经回路与社会记忆的联系。阻断STAT1途径或抑制小胶质细胞启动可能是减少IFN-γ对社会行为影响的策略。
Social behavior is inextricably linked to the immune system. Although IFN-γ is known to be involved in social behavior, yet whether and how it encodes social memory remains unclear. In the current study, we injected with IFN-γ into the lateral ventricle of male C57BL/6J mice, and three-chamber social test was used to examine the effects of IFN-γ on their social preference and social memory. The morphology of microglia in the hippocampus, prelimbic cortex and amygdala was examined using immunohistochemistry, and the phenotype of microglia were examined using immunohistochemistry and enzyme-linked immunosorbent assays. The IFN-γ-injected mice were treated with lipopolysaccharide, and effects of IFN-γ on behavior and microglial responses were evaluated. STAT1 pathway and microglia-neuron interactions were examined in vivo or in vitro using western blotting and immunohistochemistry. Finally, we use STAT1 inhibitor or minocycline to evaluated the role of STAT1 in mediating the microglial priming and effects of primed microglia in IFN-γ-induced social dysfunction. We demonstrated that 500 ng of IFN-γ injection results in significant decrease in social index and social novelty recognition index, and induces microglial priming in hippocampus, characterized by enlarged cell bodies, shortened branches, increased expression of CD68, CD86, CD74, CD11b, CD11c, CD47, IL-33, IL-1β, IL-6 and iNOS, and decreased expression of MCR1, Arg-1, IGF-1 and BDNF. This microglia subpopulation is more sensitive to LPS challenge, which characterized by more significant morphological changes and inflammatory responses, as well as induced increased sickness behaviors in mice. IFN-γ upregulated pSTAT1 and STAT1 and promoted the nuclear translocation of STAT1 in the hippocampal microglia and in the primary microglia. Giving minocycline or STAT1 inhibitor fludarabin blocked the priming of hippocampal microglia induced by IFN-γ, ameliorated the dysfunction in hippocampal microglia-neuron interactions and synapse pruning by microglia, thereby improving social memory deficits in IFN-γ injected mice. IFN-γ initiates STAT1 pathway to induce priming of hippocampal microglia, thereby disrupts hippocampal microglia-neuron interactions and neural circuit link to social memory. Blocking STAT1 pathway or inhibiting microglial priming may be strategies to reduce the effects of IFN-γ on social behavior.