Polymnia Georgiou, Abagail F. Postle, Ta-Chung M. Mou, Liam E. Potter, Xiaoxian An, Panos Zanos, Michael S. Patton, Katherine J. Pultorak, Sarah M. Clark, Vien Ngyuyen, Chris F. Powels, Katalin Prokai-Tatrai, Antonis Kirmizis, Istvan Merchenthaler, Laszlo Prokai, Margaret M. McCarthy, Brian N. Mathur, Todd D. Gould
{"title":"Estradiol, via estrogen receptor β signaling, mediates stress-susceptibility in the male brain","authors":"Polymnia Georgiou, Abagail F. Postle, Ta-Chung M. Mou, Liam E. Potter, Xiaoxian An, Panos Zanos, Michael S. Patton, Katherine J. Pultorak, Sarah M. Clark, Vien Ngyuyen, Chris F. Powels, Katalin Prokai-Tatrai, Antonis Kirmizis, Istvan Merchenthaler, Laszlo Prokai, Margaret M. McCarthy, Brian N. Mathur, Todd D. Gould","doi":"10.1038/s41380-025-03027-8","DOIUrl":null,"url":null,"abstract":"<p>Dysregulation 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 abundant conversion 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 the role of the most prevalent and potent estrogen, 17β-estradiol, in male stress-induced reward processing dysfunction. We found that absence of estrogen receptor (ER) β renders male but not female mice susceptible to stress-induced maladaptive reward-processing behaviors. We demonstrated that activation of ERβ-projecting neurons from the basolateral amygdala to nucleus accumbens induced rewarding effects in male, but not female mice. Moreover, we show that the activity of ERβ-expressing neurons projecting from the basolateral amygdala to nucleus accumbens is reduced in hypogonadal male mice subjected to stress, while activation of this circuit reverses stress-induced maladaptive reward processing behaviors and inhibition induces stress susceptibility. We identified that absence of estradiol, but not testosterone per se, underlies susceptibility to stress-mediated dysfunction of rewarding behaviors and that brain-selective delivery of estradiol and intra-basolateral amygdala administration of an ERβ-specific agonist prevent maladaptive reward-processing behaviors in hypogonadal male mice. These findings delineate an estrogen-based mechanism underlying stress susceptibility and provide a novel therapeutic strategy for the treatment of reward-related disorders associated with hypogonadal conditions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"70 1","pages":""},"PeriodicalIF":9.6000,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41380-025-03027-8","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Dysregulation 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 abundant conversion 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 the role of the most prevalent and potent estrogen, 17β-estradiol, in male stress-induced reward processing dysfunction. We found that absence of estrogen receptor (ER) β renders male but not female mice susceptible to stress-induced maladaptive reward-processing behaviors. We demonstrated that activation of ERβ-projecting neurons from the basolateral amygdala to nucleus accumbens induced rewarding effects in male, but not female mice. Moreover, we show that the activity of ERβ-expressing neurons projecting from the basolateral amygdala to nucleus accumbens is reduced in hypogonadal male mice subjected to stress, while activation of this circuit reverses stress-induced maladaptive reward processing behaviors and inhibition induces stress susceptibility. We identified that absence of estradiol, but not testosterone per se, underlies susceptibility to stress-mediated dysfunction of rewarding behaviors and that brain-selective delivery of estradiol and intra-basolateral amygdala administration of an ERβ-specific agonist prevent maladaptive reward-processing behaviors in hypogonadal male mice. These findings delineate an estrogen-based mechanism underlying stress susceptibility and provide a novel therapeutic strategy for the treatment of reward-related disorders associated with hypogonadal conditions.
期刊介绍:
Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.