# Amygdala hyper-connectivity in a mouse model of unpredictable early life stress

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $678,912

## Abstract

Abstract
Childhood maltreatment increases the risk for anxiety and other psychopathologies in a dose-dependent
manner. The mechanisms by which multiple adverse events early in life synergize to affect anxiety is poorly
understood in humans and little effort has been made to clarify this issue in animal models of early life stress
(ELS). We recently showed that exposure to UPS, which is a complex and unpredictable mouse model of ELS,
leads to robust increase in anxiety that was not seen in mice exposed to a simple and predictable paradigm of
ELS known as the limited bedding (LB). Interestingly, exposure to LB or UPS did not affect anxiety-like
behavior in female mice. Since amygdala connectivity with fronto-limbic brain regions such as the
hippocampus (HPC) and the prefrontal cortex (PFC) play an important role in anxiety-like behavior and
exposure to childhood maltreatment leads to abnormal connectivity between these brain regions we used
resting state fMRI (rsfMRI) to compare amygdala connectivity with the HPC and the PFC in UPS and control
male mice. We found increased connectivity between the amygdala and the PFC and between the amygdala
and the HPC in UPS males. Importantly, the strength of theses connections was highly correlated with anxiety-
like behavior. In this application we hypothesize that amygdala connectivity with the PFC and the HPC
undergo microglial-mediated pruning during the perinatal period. In males, more severe forms of ELS, such as
UPS, lead to greater reduction in the expression of the master regulator PU.1 in postnatal microglia. This in
turn causes a dose-dependent impairment in the refinement of fronto-limbic connections that regulate anxiety.
Exposure to LB or UPS has no effect on PU.1 levels and microglial function in females. As a result, females
show normal amygdala connectivity and anxiety when exposed to LB or UPS. Work in aim 1 will use rsfMRI
and high resolution DTI to test how different types of ELS (UPS and LB) interact with sex to alter fronto-limbic
connectivity. In aim 2 we will use optogenetics and chemogenetics viruses to label and manipulate basolateral
amygdala (BLA) projections to the PFC and HPC. This approach will allow us to precisely map the size of
these projections, determine their contribution to anxiety, and assess their ability to induce c-fos activation and
to alter BOLD signal using fMRI. Studies proposed in aim 3 will use rsfMRI and high resolution DTI to
characterize functional and structural connectivity in PU.1-hets mice. The strength of this approach lies in the
diverse expertise of our team. This multidisciplinary effort allows us to use microglial specific genetic
manipulations, rigorously test causality using optogenetic and chemogenetic tools, and utilize human imaging
tools to assess brain connectivity in a mouse model of ELS.

## Key facts

- **NIH application ID:** 9990890
- **Project number:** 5R01MH118332-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** ARIE KAFFMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $678,912
- **Award type:** 5
- **Project period:** 2019-08-07 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990890

## Citation

> US National Institutes of Health, RePORTER application 9990890, Amygdala hyper-connectivity in a mouse model of unpredictable early life stress (5R01MH118332-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990890. Licensed CC0.

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