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-?)-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-? in microglia-mediated synaptic loss in inflammatory disease conditions. Increased IFN-? expression has been reported in the blood of depressed subjects, and long-term IFN-? treatment frequently triggers a variety of neuropsychiatric symptoms. Our preliminary studies found a significant increase in IFN-? mRNA levels in the spleen, but not in mPFC of mice exposed to CUS. Also, treatment of mice with anti-IFN-? 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-? 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.

Public Health Relevance

The proposed project is relevant to public health because identification of the pathophysiological mechanisms underlying chronic stress-induced behavioral abnormalities will lead to novel interventions, including complement-based inhibitors or antibody strategies in stress-related mental health disorders. Thus, the project is relevant to the mission and priorities of the National Institute of Mental Health of the National Institute of Health that pertains to advancing mechanistic approaches to understand fundamental processes relevant to emotional and cognitive disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH121959-02
Application #
10021726
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Tonelli, Leonardo H
Project Start
2019-09-23
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Augusta University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912