Elucidating Estradiol Variability’s Impact on Dopaminergic Reward Circuitry in Perimenopausal Anhedonia

PROJECT SUMMARY/ABSTRACT Perimenopausal women face an increased risk of developing major depressive disorder (MDD), with anhedonia as a central symptom. Anhedonia during perimenopause is linked to fluctuations in estradiol levels (“estradiol flux”), potentially influencing reward responsiveness through dopamine modulation in the mesolimbic pathway. No research has yet explored this relationship using simultaneous PET-MR, a tool uniquely suited for its molecular specificity. This proposal aims to bridge this knowledge gap by examining the neurobiological mechanisms connecting estradiol flux and anhedonia during perimenopause. Our objectives are 1) to examine the influence of estradiol flux on striatal dopamine binding using [11C]raclopride PET, 2) to study the relationship between estradiol flux and neural connectivity during reward processing via fMRI, 3) to assess the influence of estradiol flux on self-reported anhedonia symptoms, and 4) to explore the mediating roles of dopamine binding and brain connectivity between estradiol flux and anhedonia. This study complements an ongoing NIMH project (MH128238) by focusing on estradiol variability's effects on dopamine metabolism, brain reward response, and anhedonia in perimenopausal women.