# Exploring the Effects of Corticosteroids on the Human Hippocampus using Neurocognitive Testing and High-Resolution Brain Imaging

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $735,974

## Abstract

Abstract
 Chronic corticosteroid (CS) exposure is associated with changes in memory and the hippocampus in
both humans and in animal models. The hippocampus has a high concentration of glucocorticoid receptors
(GCRs), and the pre-clinical literature demonstrates shortening of apical dendrites in the CA3 region of the
hippocampus and decreased neurogenesis in the dentate gyrus (DG) following CS administration. In humans,
both stress and CS exposure are associated with a decline in declarative memory performance (a process
mediated by the hippocampus). Impairment in declarative memory and hippocampal atrophy are reported in
patients with excessive CS release due to Cushing's disease, and, by our group, in patients receiving
prescription CS therapy. These findings have important implications for patients with mood disorders, as a
large subset of people with major depressive disorder (MDD) show evidence of HPA axis activation, elevated
cortisol and, importantly, resistance to the effects of CSs on both the HPA axis and on declarative memory.
Thus, resistance to corticosteroids appears to be a consequence of MDD.
 Our prior work has shown memory deficits in persons receiving prescription CSs (e.g., prednisone) or
healthy controls briefly administered hydrocortisone (cortisol). Our pilot data suggest that 3-day administration
of hydrocortisone is associated with reversible decline in declarative memory, decrease in task-related
hippocampal activation, and a significant, but reversible, decrease in hippocampal volume. Decrease in
hippocampal volume was greater in women and correlated with increases in serum cortisol levels. Based on
these data, we propose to examine changes in declarative memory, as well as use state-of-the-art high-
resolution multimodal neuroimaging, including structural and functional (i.e., task-based and resting state) MRI,
in both men and women healthy controls, and, as an exploratory aim, a depressed group, given 3-day
exposures to hydrocortisone (160 mg/day) or placebo. The study will translate preclinical findings to humans,
provide valuable data on possible sex differences in the response to cortisol and, for the first time, identify
specific hippocampal subfields (e.g., CA3/DG) in humans that are most sensitive to acute CS effects. Using
resting state fMRI data and whole brain connectomics using graph theoretical approaches, we will determine
the effects of cortisol exposure on functional brain networks. Furthermore, this will be the first study to use
neuroimaging to compare the brain's response to CSs in people with depression vs. controls, and determine
whether depressed people demonstrate glucocorticoid resistance within the hippocampus. We hypothesize
that hippocampal response to acute CSs will be greatest in the CA3/DG subfield, greater in women than in
men, and that depressed people will show a blunted hippocampal response to CSs compared to controls. A
multidisciplinary research team with extensive experience in CS ef...

## Key facts

- **NIH application ID:** 10333336
- **Project number:** 5R01MH115932-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** E SHERWOOD BROWN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $735,974
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333336

## Citation

> US National Institutes of Health, RePORTER application 10333336, Exploring the Effects of Corticosteroids on the Human Hippocampus using Neurocognitive Testing and High-Resolution Brain Imaging (5R01MH115932-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10333336. Licensed CC0.

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