Sex differences in androgen receptor, estrogen receptor alpha, and c-Fos co-expression with corticotropin releasing factor expressing neurons in restrained adult mice

• Published in: Hormones and behavior Vol. 156; p. 105448
• Main Authors: Rybka, Krystyna A., Lafrican, Jennifer J., Rosinger, Zachary J., Ariyibi, Deborah O., Brooks, Mecca R., Jacobskind, Jason S., Zuloaga, Damian G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2023
• Subjects: Androgen receptor; Animals; Corticotropin releasing factor; Corticotropin-Releasing Hormone - genetics; Corticotropin-Releasing Hormone - metabolism; Estrogen receptor alpha; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; Gonadal Hormones; Hypothalamo-Hypophyseal System - metabolism; Male; Mice; Neurons - metabolism; Paraventricular Hypothalamic Nucleus - metabolism; Pituitary-Adrenal System - metabolism; Proto-Oncogene Proteins c-fos; Receptors, Androgen - genetics; Receptors, Corticotropin-Releasing Hormone - metabolism; Sex Characteristics; Sex differences; Sex differences; Estrogen receptor alpha; Mice; Corticotropin releasing factor; Androgen receptor
• ISSN: 0018-506X; 1095-6867
• DOI: 10.1016/j.yhbeh.2023.105448

Gonadal hormone actions through androgen receptor (AR) and estrogen receptor alpha (ERα) regulate sex differences in hypothalamic-pituitary-adrenal (HPA) axis responsivity and stress-related behaviors. Here we tested whether corticotropin releasing factor (CRF) expressing neurons, which are widely known to regulate neuroendocrine and behavioral stress responses, co-express AR and ERα as a potential mechanism for gonadal hormone regulation of these responses. Using Crh-IRES-Cre::Ai9 reporter mice we report high co-localization of AR in CRF neurons within the medial preoptic area (MPOA), bed nucleus of the stria terminalis (BST), medial amygdala (MeA), and ventromedial hypothalamus (VMH), moderate levels within the central amygdala (CeA) and low levels in the paraventricular hypothalamus (PVN). Sex differences in CRF/AR co-expression were found in the principal nucleus of the BST (BSTmpl), CeA, MeA, and VMH (males>females). CRF co-localization with ERα was generally lower relative to AR co-localization. However, high co-expression was found within the MPOA, AVPV, and VMH, with moderate co-expression in the arcuate nucleus (ARC), BST, and MeA and low levels in the PVN and CeA. Sex differences in CRF/ERα co-localization were found in the BSTmpl and PVN (males>females). Finally, we assessed neural activation of CRF neurons in restraint-stressed mice and found greater CRF/c-Fos co-expression in females in the BSTmpl and periaqueductal gray, while co-expression was higher in males within the ARC and dorsal CA1. Given the known role of CRF in regulating behavioral stress responses and the HPA axis, AR/ERα co-expression and sex-specific activation of CRF cell groups indicate potential mechanisms for modulating sex differences in these functions. •Various populations of CRF neurons in the mouse brain highly co-express androgen receptor.•CRF co-expression with estrogen receptor alpha is generally lesser than with androgen receptor.•Sex differences in CRF co-expression with these receptors are found throughout the brain.•Stress-induced activation of CRF neurons also differed by sex in select brain areas.•These findings have implications for understanding how sex hormones regulate stress responses.