# Sex, Hormones and GABA in Stress Induced Anhedonia in Depression

> **NIH NIH R01** · MCLEAN HOSPITAL · 2020 · $637,596

## Abstract

Project Summary
Major depressive disorder (MDD) is the leading cause of disease burden worldwide and women have a 2-fold
risk higher than men. Despite this, little is known about the neurobiological mechanisms associated with the
sex-dependent emergence of MDD and in what form they persist after full remission. Preclinical studies have
demonstrated dysregulated hypothalamic pituitary adrenal (HPA) circuitry (i.e., stress circuitry) and gamma-
aminobutyric acid (GABA) in depression models. Critically, the stress circuitry houses some of the most highly
sexually dimorphic regions in the brain. Using an innovative multi-modal imaging approach, the proposed study
will investigate the role of GABA (assessed by proton magnetic resonance spectroscopy; MRS), functional
brain activity deficits within key stress circuitry regions, as well as gonadal and adrenal hormones in
understanding sex differences in MDD. Further, we will link these abnormalities to fundamental dimensions of
behaviors (anhedonia and stress sensitivity) that capture key MDD vulnerabilities. Goals are to investigate: (1)
functional and neurochemical features of sexually dimorphic regions within the stress circuitry irrespective of
clinical state; (2) moderating effects of steroid hormonal dysfunction on stress circuitry in MDD; and (3) sex
differences in anhedonic behavior and inability to regulate arousal under stress. To this end, 144 unmedicated
young adults ages of 18-25, 96 with current or remitted MDD (rMDD), will be recruited, equally divided by sex.
Capitalizing on a novel triple-voxel MRS technique affording improved temporal and spatial resolution, GABA
transmission will be simultaneously assessed from three sexually dimorphic regions implicated in stress
regulation (rostral anterior cingulate cortex (rACC), medial prefrontal cortex (mPFC), and hippocampus
(HIPP)). In addition, functional MRI will be collected during a well-established stress paradigm. Participants will
also undergo a probabilistic reward task under “no-stress” and “stressful” conditions. Gonadal and adrenal
hormones will be collected during baseline and stress/reward tasks to relate sex-dependent hormonal
abnormalities to task performance and imaging data. Based on our extensive preliminary data, we hypothesize
that: 1) Relative to healthy women, women with MDD will show dysregulated (1a) activation and (1b) functional
connectivity within the stress circuitry, and (1c) lower GABA signaling in HIPP, mPFC, and rACC. Further, we
expect that (1d) predicted sex differences will emerge irrespective of current vs. remitted MDD status. (2)
These neural abnormalities will be associated with physiological deficits in steroid hormone levels; and (3)
Reduced GABA and lower activity in HIPP, mPFC, and rACC will predict greater stress-induced anhedonia,
particularly among MDD women. Using categorical and dimensional analytic approaches, the proposed
integration of laboratory-based measures of reward and stress sensitivity,...

## Key facts

- **NIH application ID:** 9937839
- **Project number:** 5R01MH108602-05
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** JILL M GOLDSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $637,596
- **Award type:** 5
- **Project period:** 2016-08-10 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937839

## Citation

> US National Institutes of Health, RePORTER application 9937839, Sex, Hormones and GABA in Stress Induced Anhedonia in Depression (5R01MH108602-05). Retrieved via AI Analytics 2026-07-25 from https://api.ai-analytics.org/grant/nih/9937839. Licensed CC0.

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