# Investigating the role of glucocorticoid function in PTSD

> **NIH NIH F30** · YALE UNIVERSITY · 2020 · $40,316

## Abstract

Project Abstract: Investigating the role of glucocorticoid function in PTSD
Post-traumatic Stress Disorder (PTSD) develops in 8-10% of individuals following experience of a traumatic
event. First-line pharmacological interventions for PTSD are only 22% effective at treating the debilitating
symptoms, which include threat-related intrusive re-experiencing and hyperarousal, and loss-related emotional
numbing and anhedonia. These symptoms occur in the immediate aftermath of a trauma but persist in some
individuals as the “failure to contain the biological stress response” that characterizes PTSD. Dysregulation of
the biological stress response in PTSD is evidenced by 1) enhanced negative feedback cortisol onto the
hypothalamic-pituitary-adrenal (HPA) axis, and 2) a correlation between low levels of peripheral cortisol with
greater loss-related symptoms. Altered corticolimbic connectivity in PTSD, which has been related to increased
threat-related symptoms, has also been associated with HPA axis dysregulation. Specifically, low levels of
peripheral cortisol were correlated with reduced negative functional connectivity of medial prefrontal cortex
(mPFC) with the amygdala. Preclinical experiments have found that increasing local levels of glucocorticoids in
the brain recapitulated threat-related behavior and decreasing brain glucocorticoid production decreased this
PTSD-like behavior. Thus, I hypothesize that local levels of cortisol in corticolimbic regions of the brain are a
mechanism by which corticolimbic connectivity regulates negative feedback onto the HPA axis, resulting in
PTSD symptoms and associated HPA axis dysregulation. In Aim 1, I will measure brain glucocorticoid
function in vivo in individuals with PTSD. Equipped with a novel PET radiotracer [18F]MOZAT, I will be able
to measure local glucocorticoid levels in the brain. [18F]MOZAT binds to the enzyme 11-hydroxysteroid
dehydrogenase type 1 (11-HSD1), which regenerates cortisol in the brain and thus can be used as a marker
of brain glucocorticoid function. Preclinical manipulation of brain glucocorticoid function and clinical
neuroimaging studies indicate that 11-HSD1 levels will be higher in individuals with PTSD compared to
trauma-exposed controls. In Aim 2, I will relate in vivo brain glucocorticoid function to corticolimbic
connectivity. Previous work showed associations between altered mPFC-amygdala functional connectivity
and low peripheral cortisol. Thus, brain glucocorticoid function may regulate HPA axis activity via modulation
of corticolimbic connectivity. Investigating this possibility may provide a brain substrate for the extensive
observations of altered corticolimbic connectivity related to PSTD symptoms. In Aim 3, I will relate in vivo
brain glucocorticoid function to threat- and loss-related symptoms of PTSD. This line of investigation will
shed light on the potential of 11-HSD1 as a possible target for pharmacological re-tuning of brain
glucocorticoid levels and asso...

## Key facts

- **NIH application ID:** 9996787
- **Project number:** 5F30MH116607-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Shivani Bhatt
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,316
- **Award type:** 5
- **Project period:** 2018-09-16 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996787

## Citation

> US National Institutes of Health, RePORTER application 9996787, Investigating the role of glucocorticoid function in PTSD (5F30MH116607-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9996787. Licensed CC0.

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