Estradiol Via Estrogen Receptor î² Signaling Mediates Stresssusceptibility In The Male Brain Polymnia Georgiou 1 by Polymnia Georgiou 1, 2, 3, 4✉, Abagail F. Postle2, Ichael S. Patton6, Katherine J. Pultorak6, Sarantonis Kirmizis3, Istvan Merchenthaler8, 9, Laszl 101038/S41380025030278 instant download after payment.

Molecular Psychiatry, doi:10.1038/s41380-025-03027-8Dysregulation of normal reward processing via psychological stress contributes to the development of psychiatric disorders.Estrogen is involved in reward processing in females, but this effect has not been well studied in males despite the abundantconversion of androgens to estrogens in the male brain. Here, we used a combination of genetic deletions, behavioral assays,pharmacology, circuit dissection, electrophysiology, in vivo fiber photometry, and optogenetics/chemogenetics to determine therole of the most prevalent and potent estrogen, 17β-estradiol, in male stress-induced reward processing dysfunction. We found thatabsence of estrogen receptor (ER) β renders male but not female mice susceptible to stress-induced maladaptive reward1234567890();,:processing behaviors. We demonstrated that activation of ERβ-projecting neurons from the basolateral amygdala to nucleusaccumbens induced rewarding effects in male, but not female mice. Moreover, we show that the activity of ERβ-expressing neuronsprojecting from the basolateral amygdala to nucleus accumbens is reduced in hypogonadal male mice subjected to stress, whileactivation of this circuit reverses stress-induced maladaptive reward processing behaviors and inhibition induces stresssusceptibility. We identified that absence of estradiol, but not testosterone per se, underlies susceptibility to stress-mediateddysfunction of rewarding behaviors and that brain-selective delivery of estradiol and intra-basolateral amygdala administration ofan ERβ-specific agonist prevent maladaptive reward-processing behaviors in hypogonadal male mice. These findings delineate anestrogen-based mechanism underlying stress susceptibility and provide a novel therapeutic strategy for the treatment of rewardrelated disorders associated with hypogonadal conditions.Molecular Psychiatry;