# Sex differences in fetal programming by glucocorticoids: Adult hypothalamus and Autonomic Nervous System

> **NIH NIH U54** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $463,470

## Abstract

PROJECT SUMMARY / ABSTRACT
The overarching goal, and ultimate impact, of this project is to identify the cellular and physiological pathways
whereby developmental overexposure to glucocorticoids cause long-term, sex-selective programming of adult
anxiety- and depressive-like behaviors, neuroendocrine function and autonomic nervous system responses to
stress. Developmental programming, the permanent adaptation of the fetus to maternal environmental signals
can elevate fetal glucocorticoids to program neurodevelopment. Preliminary data in mice and rats show sex-
biased changes following late-gestation exposure to the synthetic glucocorticoid, dexamethasone. These
include increased anxiety- and depressive-like behaviors, and hyperreactive neuroendocrine and autonomic
nervous system responses to stress and changes in gene expression in the hypothalamus. In all cases, adult
females showing a greater change than males. We hypothesize that these adult dysfunctions have a common
mechanism related to programmed changes in the hypothalamic paraventricular n. (PVN), a brain region that
has been shown to influence all of these physiological endpoints. Our studies show similar responses in both
rats and mice allowing these studies to exploit the well-described physiology of the rat as well as the power of
mouse genetic approaches. 3 specific aims are described. Aim 1 will determine the causal factors for long-
term alterations in anxiety-and depressive-like behaviors, neuroendocrine response to stress and an imbalance
of the autonomic nervous system. Moreover, this aim will examine the central renin-angiotensin system as a
central mediator of the observed changes in brain function following prenatal glucocorticoid overexposure.
Aim 2 will determine the impact of prenatal glucocorticoid exposure on connectivity between hypothalamic
preautonomic and brainstem autonomic nuclei and use mouse genetic approaches and viral vectors to
specifically activate neuron populations in the PVN. Aim 3 will use transcutaneous vagal nerve stimulation to
modulate autonomic nervous system balance and reverse the effects of prenatal glucocorticoid exposure on
adult behaviors, neuroendocrine, and autonomic responses to stress. The results of these studies will identify,
not only the brain circuitry underlying the sex-biased developmental programming of behavioral, endocrine and
autonomic responses in adulthood, but also reveal potential therapeutic mechanisms whereby these changes
can be reversed in adulthood.

## Key facts

- **NIH application ID:** 10089495
- **Project number:** 5U54MH118919-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Robert J Handa
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $463,470
- **Award type:** 5
- **Project period:** 2020-02-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089495

## Citation

> US National Institutes of Health, RePORTER application 10089495, Sex differences in fetal programming by glucocorticoids: Adult hypothalamus and Autonomic Nervous System (5U54MH118919-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10089495. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*