The Influence of Estradiol on GABAergic Signaling in Perimenopausal-Onset Anhedonia
2026 Award: $59,326
Depression characterized by anhedonia—decreased interest or pleasure—during perimenopause is common, but our knowledge of how this arises and how to best treat it remains understudied. In this project, we will examine how hormonal variability and signals in the brain linked to mood respond to estradiol treatment. Findings will provide the first step towards development of novel treatments and inform the use of existing treatments to alleviate depressive symptoms during perimenopause.
Need/Problem: Anhedonia, the loss of interest or pleasure, that arises during perimenopause is prevalent and associated with marked distress and reduced functioning. Improved understanding of the biological basis of perimenopausal-onset anhedonia and its treatment with estradiol is needed to shape intervention and alleviate suffering.
Grant Summary:To examine a potential biomarker of perimenopausal-onset anhedonia, we will measure levels of the neurotransmitter GABA and estradiol variability before and after three weeks of estradiol or placebo administration.
Goals & Projected Outcomes: This study will provide data on how estradiol variability and GABA levels are associated with perimenopausal-onset anhedonia and its response to estradiol treatment. Data derived from this study will support future NIH proposals to further delineate the neurobiological impact of hormonal change during perimenopause and the association with depressive symptoms and their treatment.
Erin Bondy, PhD
Grant Details: A defining feature of perimenopausal-onset (PO) depression is anhedonia, which prior work has demonstrated is triggered by rapidly fluctuating estradiol (E2) characteristic of perimenopause. A growing body of literature indicates that gamma-aminobutyric acid (GABA)—the brain’s primary inhibitory neurotransmitter—plays a key role in mood alterations during reproductive hormone change. Treatment with estradiol (E2) has been shown to alleviate PO anhedonia, although it remains unclear if E2 reduces PO symptoms by targeting GABA pathways. Therefore, the goal of the current study is to examine the effects of variability in E2 and the effects of E2 treatment on GABA in women with PO anhedonia.
