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

> **NIH NIH U54** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $79,202

## Abstract

This application is a request for diversity supplemental funding for Ms. Emily Castellanos to initiate her
graduate studies in the laboratory of Dr. Stuart Tobet at Colorado State University. This project examines
the fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis, an important system for regulating
and coordinating adrenal glucocorticoid (GC) secretion to allow for proper adaptation to stressors and
maintain physiological homeostasis. As part of the U54 program that oversees this project, Ms. Castellanos
will be a member of the training program and be exposed to the educational mission that the SCORE
program is developing. Ms. Castellanos will also work closely with the other PIs in the SCORE program.
This includes Dr. Jill Goldstein who is PI of the Program and the PI of Project 1, and Drs. Vitaly Napadow
and Ronald Garcia who are PIs of Project 2 and Dr. Taben Hale who is a co-investigator in project 3.
During development, increased exposure to GCs through prenatal stress or inflammation can disrupt fetal
brain programming and increase risk for long-term health consequences. The foundation for this hypothesis
is that the in utero environment programs the brain and increases the risk developing long-term complex
diseases in adulthood. Diseases with fetal origins include depression and anxiety-like disorders, social
impairments, schizophrenia, and metabolic disorders. The overarching goal of Ms Castellanos’ project is to
examine the effects of in utero overexposure to GCs on hypothalamic development resulting in co-morbid
anxiety and feeding behaviors, metabolism and neuroendocrine stress responses. Preliminary data has
shown that rodents display neuroendocrine, behavioral and metabolic changes after in utero exposure to
the synthetic GC, dexamethasone (DEX). It has also been shown that the hypothalamic paraventricular
nucleus (PVN), a known body weight-regulating region, houses a key group of stress-responsive neurons
expressing corticotropin-releasing hormone (CRH). These CRH neurons are part of the feeding circuitry and
also impact anxiety and depressive like behaviors. Therefore, this proposal hypothesizes that excess GC
exposure in utero organizes metabolic circuitry to coincidently alter feeding behavior, anxiety and
depressive like behaviors and neuroendocrine stress responses. Aim 1 will map CRH circuitry involved in
metabolism / feeding using a CRH-Ires-cre driver mouse line. Aim 2 will identify changes in CRH neurons
that may underlie comorbid changes in feeding and stress using novel transgenic mouse lines to identify a
common subpopulation of CRH neurons and their projections to brainstem autonomic areas. Aim 3 will
utilize transcutaneous Vagal Nerve Stimulation to reverse the long-term effects of prenatal GC exposure on
adult hypothalamic function. These studies will have implications for how the fetal environment affects adult
hypothalamic function and how it contributes to susceptibility for increased risk for ...

## Key facts

- **NIH application ID:** 10527864
- **Project number:** 3U54MH118919-03S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JILL M GOLDSTEIN
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $79,202
- **Award type:** 3
- **Project period:** 2020-02-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10527864

## Citation

> US National Institutes of Health, RePORTER application 10527864, Sex Differences in Major Depression: Impact of Prenatal Stress-Immune and Autonomic Dysregulation (3U54MH118919-03S1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10527864. Licensed CC0.

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