Chronic stress, complement immune system and behavior

慢性应激是发展为多种精神障碍的重要危险因素 现有的治疗方法是不够的。慢性应激也会引起炎症加剧和夸大 然而，在人类和动物模型中，炎症反应与炎症有关的机制 对行为异常的了解还不是很清楚。我们假设慢性应激诱导的行为 外周干扰素-α介导的小胶质细胞活化和补体- 涉及认知、情绪和社会行为的大脑区域的依赖性突触丢失。最新研究 提示补体依赖途径和小胶质细胞介导突触消除 在包括精神障碍在内的某些疾病情况下，发育被不适当地激活。 补体成分3(C3)是所有补体激活途径的中枢，C3及其受体， C3aR1在不同疾病条件的小鼠模型中介导突触丢失。我们最近的研究发现，C3 慢性不可预测应激(CUS)后小鼠前额叶皮质(PFC)表达增加 在抑郁症自杀受试者中。此外，C3aR1缺乏改善了小鼠的抑郁样表型 暴露在CUS下。此外，最近的研究表明，外周干扰素-α在小胶质细胞介导的 炎症性疾病条件下的突触丢失。据报道，干扰素-α在血液中的表达增加 长期的干扰素-α治疗经常会引发各种神经精神疾病 症状。我们的初步研究发现，在脾组织中，干扰素-α基因水平显著增加，但在 CUS染毒小鼠的mPFC。此外，用抗干扰素-α受体(IFNAR)抗体治疗小鼠的效果也有所减弱 压力导致的社会缺陷和抑郁样行为。这些观察提出了一些重要的问题。 由于C3aR1在小胶质细胞和单核/巨噬细胞(Mo/MFS)中表达，目前尚不清楚 小胶质细胞或Mo/MFS中的C3aR1在慢性应激诱导的突触丢失和行为效应中起关键作用。 尽管用抗干扰素受体治疗是有保护作用的，但尚不清楚外周血干扰素-α是否激活。 小胶质细胞和补体系统促进突触丢失和慢性行为改变的观察 压力条件。在这个探索性应用程序中，我们将从以下两个具体方面解决这些问题 目标。使用条件突变小鼠，Aim 1将测试小胶质细胞C3aR1介导慢性 应激诱导的突触丢失和行为异常。利用抗干扰素受体抗体和干扰素受体1−/−嵌合体 小鼠，目标2将验证在慢性应激下I型干扰素信号增加促进小胶质细胞的假设 激活、补体激活、突触丢失和行为异常。如果成功，我们的项目将 在理解外周炎症和应激诱导的通路方面取得新进展 行为异常，从而允许开发新的治疗策略，包括 应激相关精神健康障碍中基于补体的抑制剂或抗体策略。

Chronic stress is an important risk factor for the development of multiple psychiatric disorders for which existing therapies are inadequate. Chronic stress can also provoke elevated inflammation and exaggerated inflammatory responses in both humans and animal models, however, the mechanisms that link inflammation to behavioral abnormalities are not well understood. We hypothesize that chronic stress-induced behavioral changes result from peripheral interferon alpha (IFN-α)-mediated microglia activation and complement- dependent synaptic loss in brain regions involved in cognition, mood and social behavior. Recent studies indicate that the complement-dependent pathway and microglia that mediate synapse elimination in development are inappropriately activated in some disease conditions including psychiatric disorders. Complement component 3 (C3) is the hub of all complement activation pathways, and C3 and its receptor, C3aR1 mediate synapse loss in mouse models of various disease conditions. Our recent study found that C3 expression is increased in the prefrontal cortex (PFC) of mice following chronic unpredictable stress (CUS) and in depressed suicide subjects. Also, C3aR1 deficiency improved the depression-like phenotype in mice exposed to CUS. Further, recent studies indicate an important role of peripheral IFN-α in microglia-mediated synaptic loss in inflammatory disease conditions. Increased IFN-α expression has been reported in the blood of depressed subjects, and long-term IFN-α treatment frequently triggers a variety of neuropsychiatric symptoms. Our preliminary studies found a significant increase in IFN-α mRNA levels in the spleen, but not in mPFC of mice exposed to CUS. Also, treatment of mice with anti-IFN-α receptor (IFNAR) antibody attenuated stress-induced social deficits and depressive-like behavior. These observations raise important questions. Because C3aR1 is expressed in microglia and monocytes/macrophages (Mo/MFs), it is not known whether C3aR1 in microglia or Mo/MFs is critical for chronic stress-induced effects on synapse loss and behavior. Although treatment with anti-IFNAR was protective, it is not known whether peripheral IFN-α activates microglia and the complement system to promote synaptic loss and behavioral changes observed in chronic stress conditions. In this exploratory application, we will address these questions in the following two specific aims. Using conditional mutant mice, Aim 1 will test the hypothesis that microglial C3aR1 mediates chronic stress-induced synapse loss and behavioral abnormalities. Using anti-IFNAR antibody and IFNAR1−/− chimera mice, Aim 2 will test the hypothesis that increased type I IFN signaling under chronic stress promotes microglia activation, complement activation, synaptic loss and behavioral abnormalities. If successful, our project will create new developments in understanding the pathways linking peripheral inflammation and stress-induced behavioral abnormalities, and thereby allow the development of novel strategies for treatment, including complement-based inhibitors or antibody strategies in stress-related mental health disorders.