Chronic stress, complement immune system and behavior

慢性压力、补体免疫系统和行为

基本信息

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
项目类别：
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

项目摘要

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生的重要危险因素。现有的治疗方法不足，慢性压力也会引起炎症升高和加剧。然而，人类和动物模型中的炎症反应，将炎症联系起来的机制我们对慢性压力引起的行为异常还没有很好的了解。外周干扰素α（IFN-α）介导的小胶质细胞激活和补体引起的变化涉及认知、情绪和社会行为的大脑区域的依赖性突触损失。表明补体依赖性途径和小胶质细胞介导突触消除在某些疾病（包括精神疾病）中，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，我们最近的研究发现，C3aR1 介导各种疾病小鼠模型中的突触损失。慢性不可预测应激（CUS）后小鼠前额皮质（PFC）中的表达增加此外，C3aR1 缺陷改善了小鼠的抑郁样表型。此外，最近的研究表明外周 IFN-α 在小胶质细胞介导中发挥重要作用。据报道，在炎症性疾病中，血液中 IFN-α 的表达增加。抑郁症受试者的长期 IFN-α 治疗经常引发各种神经精神疾病我们的初步研究发现，脾脏中的 IFN-α mRNA 水平显着增加，但脾脏中的 IFN-α mRNA 水平却没有显着增加。此外，用抗 IFN-α 受体 (IFNAR) 抗体治疗小鼠的 mPFC 也减弱。这些观察结果提出了重要的问题。由于 C3aR1 在小胶质细胞和单核细胞/巨噬细胞 (Mo/MF) 中表达，因此尚不清楚是否小胶质细胞或 Mo/MF 中的 C3aR1 对于慢性应激引起的突触损失和行为影响至关重要。尽管抗 IFNAR 治疗具有保护作用，但尚不清楚外周 IFN-α 是否会激活小胶质细胞和补体系统促进慢性疾病中观察到的突触损失和行为变化在这个探索性应用中，我们将在以下两个具体问题中解决这些问题。目标 1 将使用条件突变小鼠来检验小胶质细胞 C3aR1 介导慢性疾病的假设。使用抗 IFNAR 抗体和 IFNAR1−/− 嵌合体导致应激诱导的突触丧失和行为异常。小鼠，目标 2 将测试慢性应激下 I 型干扰素信号传导增强促进小胶质细胞的假设如果成功，我们的项目将包括激活、激活补体、突触丢失和行为异常。在理解外周炎症和压力诱发的关联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治疗与压力相关的精神健康障碍。