# Sex Differences in Major Depression: Impact of Prenatal Stress-Immune and Autonomic Dysregulation

> **NIH NIH U54** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $1,723,891

## Abstract

OVERALL SUMMARY. Major depressive disorder (MDD) topped heart disease as the number one cause of
disability worldwide, and women have twice the risk of men. MDD is associated with abnormalities in the stress
response circuitry, areas that are among the most sexually dimorphic in the brain. These areas are dense in
sex steroid and glucocorticoid receptors coupled with cytokine receptors. Further, activity in these areas has
been associated with cortisol response, autonomic dysfunction, and immune responses, which we showed
differed by sex. This is important since autonomic dysregulation is significantly associated with cardiovascular
disease. In fact, women are at twice the risk for the co-occurrence of MDD, autonomic dysregulation and heart
disease, leading to a 3-5-fold risk of death in women from heart disease, often with unrecognized and
untreated MDD. Thus, understanding early biomarkers for sex differences in MDD and autonomic
dysregulation will provide knowledge for early intervention, attenuating later life disability, in particular for
women who are at higher risk. The scientific mission of this SCORE is to identify stress-immune pathway
abnormalities, beginning in fetal development, that have shared consequences for sex differences in brain
circuitry regulating mood and lifelong recurrent MDD and dysregulation of hormone and immune responses to
stress, and autonomic and neurovascular dysfunction in early midlife. We aim to facilitate transdisciplinary,
translational collaboration among basic and clinical investigators to enhance our understanding of the impact of
sex on MDD and central and peripheral autonomic function and provide the groundwork for translating this
knowledge into sex-selective therapeutics. Further, we aim to serve as an interdisciplinary resource to train
and disseminate findings about sex differences in MDD and autonomic dysregulation to the scientific and
medical communities, policy makers, and the public. To accomplish this, three integrated studies are proposed:
1) a clinical population neuroscience study relating prenatal risk biomarkers to sex differences in brain circuitry
and physiologic deficits in response to stress in MDD in early midlife; 2) clinical study using direct
transcutaneous neuromodulatory stimulation of the vagus nerve, auricular branch (or taVNS) to target the
circuitry associated with stress-immune function and map its neuroanatomic, physiologic and clinical effects in
MDD by sex, in the same subjects as in project 1; and 3) rodent model studies that will map out the central
mechanistic pathways involved in projects 1 and 2. In addition, three cores will contribute to the success of this
SCORE: 1) Leadership Administration Core to administer and oversee the administrative integration of the
studies and cores; 2) Resources Core to provide shared technical expertise across studies; and 3) Career
Enhancement Core, to supplement the training of junior faculty and others on the topic of our SCORE, a...

## Key facts

- **NIH application ID:** 9853480
- **Project number:** 1U54MH118919-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JILL M GOLDSTEIN
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,723,891
- **Award type:** 1
- **Project period:** 2020-02-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853480

## Citation

> US National Institutes of Health, RePORTER application 9853480, Sex Differences in Major Depression: Impact of Prenatal Stress-Immune and Autonomic Dysregulation (1U54MH118919-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9853480. Licensed CC0.

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