Chronic stress, complement immune system and behavior

慢性压力、补体免疫系统和行为

• 批准号: 9905204
• 负责人: Anilkumar Pillai
• 金额: $ 19.09万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905204
• 关键词: Address; Animal Model; Antibodies; Anxiety; Attenuated; Behavior; Behavioral; Blood; Bone Marrow; Brain; Brain region; C3AR1 gene; Cells; Chimera organism; Chronic; Chronic stress; Cognition; Cognition Disorders; Complement; Complement 3; Complement Activation; DLG4 gene; Depressed mood; Development; Disease; Elements; Emotional disorder; Exposure to; Fatigue; Fc Receptor; Functional disorder; IFNAR1 gene; Immune system; Impaired cognition; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon-alpha; Interferons; Intervention; Knockout Mice; Link; Medial; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Messenger RNA; Microglia; Mission; Moods; Mus; Mutant Strains Mice; National Institute of Mental Health; Pathway interactions; Peripheral; Phagocytes; Phenotype; Prefrontal Cortex; Process; Public Health; Receptor Signaling; Regulation; Reporting; Risk Factors; Role; Signal Transduction; Social Behavior; Spleen; Stress; Suicide; Synapses; Testing; United States National Institutes of Health; base; complement pathway; complement system; conditional mutant; depressive symptoms; experience; human model; improved; in vivo; inhibitor/antagonist; macrophage; mental health related disorder; monocyte; mouse model; neuropsychiatric symptom; novel; novel strategies; receptor; recombinase-mediated cassette exchange; social deficits; treatment strategy

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.

慢性压力是多种精神疾病发展的重要危险因素， 现有的治疗方法是不够的。慢性压力也会引起炎症升高， 然而，人类和动物模型中的炎症反应， 行为异常的原因还不太清楚我们假设慢性压力引起的行为 外周干扰素-α（IFN-α）介导的小胶质细胞活化和补体- 在涉及认知、情绪和社会行为的大脑区域中的依赖性突触损失。最近的研究 表明介导突触消除的补体依赖性途径和小胶质细胞 在一些疾病状况中，包括精神障碍，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枢纽，C3及其受体， C3 aR 1介导各种疾病状况的小鼠模型中的突触丧失。我们最近的研究发现，C3 在慢性不可预测的应激（CUS）后，小鼠的前额叶皮层（PFC）中的表达增加， 抑郁症自杀者的研究此外，C3 aR 1缺陷改善了小鼠的抑郁样表型 暴露于CUS。此外，最近的研究表明，外周IFN-α在小胶质细胞介导的 炎性疾病条件下的突触损失。据报道，血液中IFN-α表达增加 长期IFN-α治疗经常引发各种神经精神疾病， 症状我们的初步研究发现，IFN-α mRNA水平在脾脏中显著增加，但在 暴露于CUS的小鼠的mPFC。此外，用抗IFN-α受体（IFNAR）抗体治疗小鼠， 压力引起的社交缺陷和抑郁样行为。这些意见提出了重要的问题。 因为C3 aR 1在小胶质细胞和单核细胞/巨噬细胞（Mo/MFs）中表达，所以不知道C3 aR 1是否在小胶质细胞和单核细胞/巨噬细胞中表达。 小胶质细胞或Mo/MFs中的C3 aR 1对于慢性应激诱导的突触丧失和行为效应至关重要。 虽然抗IFNAR治疗具有保护作用，但外周IFN-α是否激活IFN-α受体尚不清楚。 小胶质细胞和补体系统促进突触丢失和行为改变， 应力条件在这个探索性的应用程序中，我们将在以下两个具体的 目标。使用条件突变小鼠，Aim 1将检验小胶质细胞C3 aR 1介导慢性炎症的假设。 压力引起的突触丧失和行为异常。使用抗IFNAR抗体和IFNAR 1 −/−嵌合体 目的2将检验在慢性应激下增加的I型IFN信号传导促进小胶质细胞增殖的假设。 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 在了解外周炎症和应激诱导的途径方面取得新进展 行为异常，从而允许开发新的治疗策略，包括 基于补体的抑制剂或抗体策略在压力相关的心理健康障碍。