# Role of microglial IRF8 in the developmental consequences of early adversity

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $419,559

## Abstract

Project Abstract
Exposure to unpredictable and complex stress early in life increases the risk for developing anxiety disorder
and abnormal connectivity between the amygdala, the prefrontal cortex (PFC), and the hippocampus (HPC).
Exactly how early life stress (ELS) modifies fronto-limbic connectivity and how these changes contribute to
increased anxiety are questions that are difficult to investigate in humans. Specifically, the question of how
ELS interacts with sex to alter fronto-limbic connections and anxiety are not addressable with current human
studies. To clarify these issues we developed a mouse model of ELS that we have named Unpredictable
Postnatal Stress (UPS), in which mice are exposed to unpredictable and complex stress early in life. We found
that UPS caused robust increase in anxiety that was not seen in mice exposed to simple and predictable form
of ELS, known as limited bedding (LB). Moreover, we found that UPS and LB preferentially increased anxiety
in male mice. Using resting state fMRI (rsfMRI), high resolution diffusion MRI (dMRI), and retrograde tracing
we found increased connectivity in male UPS mice that was present during the juvenile period and adulthood
and was highly correlated with anxiety. Preliminary data with dMRI indicate that fronto-limbic connectivity is not
altered in females and that these sex specific effects are associated with abnormal synaptic pruning and
reduced levels of the transcription factor IRF8 in male microglial, but not female microglia. We hypothesize
that amygdala connectivity with the PFC and the HPC undergoes microglial-mediated pruning during the
postnatal period. This process requires high levels of the transcription factor IRF8 in postnatal microglia and is
critical for programming levels of anxiety during the juvenile period and adulthood. UPS reduces expression of
IRF8 in males, but not female mice. This in turn leads to increase fronto-limbic connectivity and anxiety in UPS
males, but not UPS females. Work in aim 1 will use rsfMRI, dMRI, and dual retrograde tracing to characterize
the effects of UPS, sex and age on fronto-limbic connectivity. Studies in aim 2 will test whether reducing IRF8
in postnatal microglia is sufficient to phenocopy the effects of UPS on anxiety, fronto-limbic connectivity,
microglial gene expression, and phagocytic activity. In aim 3 we ask whether overexpressing IRF8 in postnatal
microglia can normalize anxiety and fronto-limbic connectivity in UPS mice. Successful completion of this
application will define a novel role for microglial IRF8 in refining fronto-limbic connections and programming
anxiety in the mouse; an important finding given the conserved role that IRF8 plays in guiding immune
responses in humans and mice. In addition, this work will provide a new paradigm to explain how ELS
differentially affects microglial function, amygdala connectivity, and anxiety in mice.

## Key facts

- **NIH application ID:** 10297861
- **Project number:** 5R01MH119164-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** ARIE KAFFMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $419,559
- **Award type:** 5
- **Project period:** 2020-01-01 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10297861

## Citation

> US National Institutes of Health, RePORTER application 10297861, Role of microglial IRF8 in the developmental consequences of early adversity (5R01MH119164-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10297861. Licensed CC0.

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