MINI REVIEW article
Front. Behav. Neurosci.
Sec. Behavioral Endocrinology
Volume 19 - 2025 | doi: 10.3389/fnbeh.2025.1655725
This article is part of the Research TopicAnimal Models of Anxiety and Depression: Exploring the Underlying Mechanisms of Sex Differences - Volume IIView all 9 articles
Sex differences in G protein-coupled estrogen receptor (GPER)-mediated mechanisms in preclinical models of anxiety and fear
Provisionally accepted
- University of Massachusetts Boston, Boston, United States
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Sex differences are well-documented in the prevalence of psychiatric disorders, with anxiety and stress-related conditions more common in women. Growing evidence highlights the role of sex hormones, particularly estradiol (E2), and its receptor mechanisms as contributing factors to this disparity. Estrogen exerts its effects through three main receptors: estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and the G protein-coupled estrogen receptor (GPER). While the classical receptors ERα and ERβ have been widely studied in the context of fear and anxiety, the role of GPER remains less understood. Moreover, estrogen receptors themselves may be sexually dimorphic, adding complexity to their functional roles. Preclinical research has been valuable in advancing our understanding of these mechanisms; therefore, this review mostly focuses on findings from rodent studies. Here we discuss the influence of sex and E2 on anxiety and fear-related behavior, highlight emerging research on sex differences in GPER modulation of fear and anxiety in mice, rats, and humans, and explore GPER as a potential therapeutic target for anxiety and stress-related disorders.
Keywords: GPER, Estradiol, GPR30, Fear, Anxiety, stress, sex differences
Received: 28 Jun 2025; Accepted: 14 Oct 2025.
Copyright: © 2025 Tran and Maeng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Lisa Y. Maeng, lisa.maeng@umb.edu
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