# Projection-specific gene expression in resilience to chronic stress

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2024 · $605,658

## Abstract

SUMMARY
Stressful and traumatic experiences can contribute to mood disorders in some individuals while others are
resilient to this process, and pharmacological tools for treating major depression (MDD) are effective on only a
subset of patients. Moreover, MDD affects women nearly twice as often as men, but the neurobiological
underpinnings of this discrepancy are unclear. Over the past five years of the current funded project, we
demonstrated that lower excitability of ventral hippocampal glutamatergic projections to nucleus accumbens
(vHPC-NAc) drives increased resilience to stress-induced anhedonia in male mice compared to females, and
that this effect is caused directly by testosterone in males. However, the mechanisms by which testosterone
regulates excitability of the vHPC-NAc remain unknown. Testosterone produces many of its effects through
activation of the androgen receptor (AR) which can alter cell function through signaling cascades in the cytosol
or through directly binding to DNA and altering gene expression. We have shown that vHPC-NAc neurons
produce AR and respond to AR antagonists, and our preliminary data show that eliminating AR in vHPC-NAc
neurons increases excitability. This leads to our overarching hypothesis for years 6-10: that testosterone
activation of ARs in vHPC-NAc decreases excitability through changes in gene expression to drive behavioral
resilience to stress. This is significant, as identification of AR targets/mechanisms driving resilience may generate
novel therapeutic strategies that would be particularly beneficial in females, an unmet need due to the sexual
disparity in mood disorders. We will address this using three specific aims: 1) Uncover the mechanisms of
testosterone-driven reduction in vHPC-NAc excitability using novel transgenic mice and classical pharmacology;
2) Uncover the mechanisms of testosterone-driven resilience to stress using novel mouse lines and a circuit-
specific intersection dual viral vector approach; and 3) Determine circuit-specific gene expression driven by sex,
testosterone, and the androgen receptor using translating ribosome affinity purification. Given the established
role of vHPC circuitry in emotional regulation, the gene expression studies proposed here will meaningfully
impact basic psychiatric research and may elucidate novel treatment strategies for psychiatric disorders that
could be particularly beneficial to female patients. Moreover, our understanding of basal sex differences in brain
circuitry is lacking, so this work will inform not only stress studies, but will increase understanding of sex as a
biological variable in all behaviors that engage vHPC circuitry.

## Key facts

- **NIH application ID:** 10887620
- **Project number:** 5R01MH111604-08
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Michelle Suzanne Mazei-Robison
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $605,658
- **Award type:** 5
- **Project period:** 2016-09-08 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887620

## Citation

> US National Institutes of Health, RePORTER application 10887620, Projection-specific gene expression in resilience to chronic stress (5R01MH111604-08). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10887620. Licensed CC0.

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