Characterization and gonadal hormone regulation of a sexually dimorphic corticotropin‐releasing factor receptor 1 cell group

• Published in: Journal of comparative neurology (1911) 2019-04, Vol.527 (6), p.1056-1069
• Main Authors: Rosinger, Zachary J., Jacobskind, Jason S., Bulanchuk, Nicole, Malone, Margaret, Fico, Danielle, Justice, Nicholas J., Zuloaga, Damian G.
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; anteroventral periventricular nucleus; Anxiety; Cell number; Corticotropin-releasing hormone; corticotropin‐releasing factor receptor 1; Cyclic AMP response element-binding protein; estrogen receptor alpha; Females; glucocorticoid receptor; Glucocorticoids; gonadal hormones; Gonadectomy; Green fluorescent protein; Hydroxylase; Kiss1 protein; Localization; Mental depression; Mood; Periventricular nucleus; Propionic acid; RRID: AB_2155786; RRID: AB_2296529; RRID: AB_2561044; RRID: AB_300798; RRID: AB_390204; RRID: AB_631470; Sex; sexual differentiation; Sexual dimorphism; Stress response; Testosterone; Testosterone propionate; Tyrosine 3-monooxygenase
• ISSN: 0021-9967; 1096-9861
• DOI: 10.1002/cne.24588

Corticotropin‐releasing factor binds with high affinity to CRF receptor 1 (CRFR1) and is implicated in stress‐related mood disorders such as anxiety and depression. Using a validated CRFR1‐green fluorescent protein (GFP) reporter mouse, our laboratory recently discovered a nucleus of CRFR1 expressing cells that is prominent in the female rostral anteroventral periventricular nucleus (AVPV/PeN), but largely absent in males. This sex difference is present in the early postnatal period and remains dimorphic into adulthood. The present investigation sought to characterize the chemical composition and gonadal hormone regulation of these sexually dimorphic CRFR1 cells using immunohistochemical procedures. We report that CRFR1‐GFP‐ir cells within the female AVPV/PeN are largely distinct from other dimorphic cell populations (kisspeptin, tyrosine hydroxylase). However, CRFR1‐GFP‐ir cells within the AVPV/PeN highly co‐express estrogen receptor alpha as well as glucocorticoid receptor. A single injection of testosterone propionate or estradiol benzoate on the day of birth completely eliminates the AVPV/PeN sex difference, whereas adult gonadectomy has no effect on CRFR1‐GFP cell number. These results indicate that the AVPV/PeN CRFR1 is regulated by perinatal but not adult gonadal hormones. Finally, female AVPV/PeN CRFR1‐GFP‐ir cells are activated following an acute 30‐min restraint stress, as assessed by co‐localization of CRFR1‐GFP cells with phosphorylated (p) CREB. CRFR1‐GFP/pCREB cells were largely absent in the male AVPV/PeN. Together, these data indicate a stress and gonadal hormone responsive nucleus that is unique to females and may contribute to sex‐specific stress responses. A newly discovered sex difference in corticotropin‐releasing factor receptor 1 containing cells within the preoptic area (females > males) is largely distinct from other sexually dimorphic cell populations in this region. This sex difference is regulated by neonatal exposure to estrogen and testosterone but is unaffected by adult gonadal hormones.