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Chronic stress, complement immune system and behavior

Chronic stress, complement immune system and behavior
慢性压力、补体免疫系统和行为
批准号:
10396335
负责人:
Anilkumar Pillai
金额:
$18.7万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-09-23 至 2022-06-30

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中文摘要
翻译
慢性应激是多种精神疾病发展的重要危险因素
英文摘要
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.
期刊论文(9)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1038/s41380-023-02189-7
发表时间: 2023-09
期刊: MOLECULAR PSYCHIATRY
影响因子: 11
作者: [Tripathi, Ashutosh, Bartosh, Alona, Whitehead, Carl, Pillai, Anilkumar]
通讯作者: Pillai, Anilkumar
DOI: 10.1038/s41380-021-01065-6
发表时间: 2021-07
期刊: Molecular psychiatry
影响因子: 11
作者: [Tripathi A, Whitehead C, Surrao K, Pillai A, Madeshiya A, Li Y, Khodadadi H, Ahmed AO, Turecki G, Baban B, Pillai A]
通讯作者: Pillai A
DOI: 10.1016/j.mito.2021.08.016
发表时间: 2021-11
期刊: Mitochondrion
影响因子: 4.4
作者: [Tripathi A, Scaini G, Barichello T, Quevedo J, Pillai A]
通讯作者: Pillai A
DOI: 10.1038/s41398-022-01794-4
发表时间: 2022-02-01
期刊: Translational psychiatry
影响因子: 6.8
作者: [Madeshiya AK, Whitehead C, Tripathi A, Pillai A]
通讯作者: Pillai A
Mitochondrial DNA, chronic stress, and inflammation
Complement system and suicidal behavior
Complement system and suicidal behavior
Complement system and suicidal behavior
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