# Synaptic and Genetic Mechanisms of Sex-Specific Effects of Stress

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2021 · $557,838

## Abstract

Summary
 Stress hormones elicit profound and complex effects throughout the lifespan, and adolescent brain is
particularly sensitive to stressors. One important but understudied question is the sexually dimorphic effects of
early life stress. Using mice exposed to prolonged post-weaning social isolation stress, we have found distinct
behavioral phenotypes that are reminiscent to human symptoms - elevated aggression in males, and
diminished sociability in females. The goal of this project is to understand the physiological and molecular
mechanisms underlying the sex-specific divergent effects of chronic adolescent isolation stress. We
hypothesize that circuit-specific alterations of neuronal functions in stressed males and females, which are
driven by circuit-specific changes in gene expression, mediate the sexually dimorphic consequences of early
life stress. To test this, we will use the combination of cutting-edge techniques to address three Specific Aims:
(1) To identify differential behavioral and physiological changes induced by stress in male and female mice. A
battery of behavioral assays will be made to identify stress-induced phenotypes in both sexes. Slice recordings
of synaptic currents and in vivo multichannel recordings of neuronal activity in behaving animals will be
performed to examine the involvement of prefrontal cortex (PFC), basolateral amygdala (BLA) and ventral
tegmental area (VTA) in the heightened aggression in stressed males and diminished sociability in stressed
females. (2) To determine neuronal circuits mediating differential effects of stress in male and female mice. By
combining chemogenetic technology to manipulate neuronal activity in specific brain circuits with in vivo
recordings of calcium signal and neuronal spikes in behaving animals, we will examine whether the disturbed
PFCBLA and PFCVTA pathway after chronic isolation stress plays a causal role in controlling the sexually
dimorphic behavioral effects of stress. (3) To investigate molecular mechanisms underlying the circuit-specific
effects of stress in male and female mice. We will perform RNAseq to analyze the alteration of mRNA profile in
PFC, BLA, and VTA from males and females exposed to adolescent isolation stress to determine molecular
basis for the sexually dimorphic effects of stress. We will also use viral-based gene transfer to manipulate key
molecules to determine their roles in different aspects of stress effects in both males and females. This
proposal will address important issues on neuronal underpinnings of the sex-specific diverse consequences of
adolescent stress. The identified mechanisms will offer insights into the development of novel precision therapy
to mitigate the distinct deficits in males and females after stress exposure.

## Key facts

- **NIH application ID:** 10225076
- **Project number:** 1R01MH126443-01
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Zhen Yan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $557,838
- **Award type:** 1
- **Project period:** 2021-04-05 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225076

## Citation

> US National Institutes of Health, RePORTER application 10225076, Synaptic and Genetic Mechanisms of Sex-Specific Effects of Stress (1R01MH126443-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10225076. Licensed CC0.

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