# Projection-specific gene expression in resilience to chronic stress

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $372,379

## Abstract

Project Summary
Major depressive disorder (MDD) affects ~4% of the worldwide population, and these numbers
are continuously increasing. Moreover, MDD disproportionately affects women, who are twice
as likely as men to be diagnosed with the disease. Thus, uncovering the molecular, cellular, and
circuit-level mechanisms underlying susceptibility and resilience to depression is critical. Recent
work demonstrates that ventral hippocampal (vHPC) projections to nucleus accumbens (NAc)
regulate mood and susceptibility to stress. Our group has shown that the transcription factor
ΔFosB is crucial for hippocampal cell morphology and learning, and several lines of evidence
implicate hippocampal ΔFosB in depressive-like behaviors (e.g., FosB knockout mice have
hippocampal malformations and depressive behaviors, and current antidepressants induce
ΔFosB in vHPC). However, to date there is no study characterizing the role of hippocampal
ΔFosB in stress resilience and depression. To this end, we have produced a novel dual-virus
CRISPR-Cas9 system allowing knockout of FosB gene expression specifically in vHPC cells
projecting to the NAc. In combination with our many well-vetted molecular, physiological, and
behavioral tools and models, this will allow us to address the central hypothesis that ΔFosB
expression in vHPC neurons projecting to NAc mediates cell function and resilience to social
stress in male and female mice. To test this hypothesis, we propose two Specific Aims. In Aim I,
we will first characterize the epigenetic mechanisms of induction of the FosB gene in
hippocampus by chronic stress, determine its role in resilience to stress in both males and
females, and uncover its transcriptional targets in vHPC. Indeed, our preliminary data show that
inhibition of ΔFosB in vHPC induces susceptibility to depression-like symptoms. In Aim II, we
will examine the stress induction and cellular effects of ΔFosB in vHPC neurons with projections
to various brain regions, including NAc, then use our novel dual-virus system to knock down
FosB gene expression specifically in vHPC cells projecting to the NAc and observe the
behavioral results on stress responses. Here, too, we have strong preliminary data suggesting
that ΔFosB regulates the excitability of vHPC neurons, and that ΔFosB expression in the vHPC-
NAc projection cells regulates susceptibility to depression. Together, the proposed studies will
elucidate the critical role of ΔFosB in stress-induced changes in hippocampal control of limbic
circuitry of both males and females, as well as identify novel ΔFosB targets that could serve as
potential points for sex-specific therapeutic intervention in depression or PTSD.

## Key facts

- **NIH application ID:** 9967105
- **Project number:** 5R01MH111604-05
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** ALFRED J ROBISON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,379
- **Award type:** 5
- **Project period:** 2016-09-08 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967105

## Citation

> US National Institutes of Health, RePORTER application 9967105, Projection-specific gene expression in resilience to chronic stress (5R01MH111604-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9967105. Licensed CC0.

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