# Chronic stress, complement immune system and behavior

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $186,999

## Abstract

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 a...

## Key facts

- **NIH application ID:** 10396335
- **Project number:** 7R21MH121959-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Anilkumar Pillai
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $186,999
- **Award type:** 7
- **Project period:** 2019-09-23 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396335

## Citation

> US National Institutes of Health, RePORTER application 10396335, Chronic stress, complement immune system and behavior (7R21MH121959-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10396335. Licensed CC0.

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