A sexually dimorphic distribution of corticotropin-releasing factor receptor 1 in the paraventricular hypothalamus

• Published in: Neuroscience 2019-06, Vol.409, p.195-203
• Main Authors: Rosinger, Zachary J., Jacobskind, Jason S., De Guzman, Rose M., Justice, Nicholas J., Zuloaga, Damian G.
• Format: Article
• Language: English
• Subjects: androgen; Animals; corticotropin releasing factor; Cyclic AMP Response Element-Binding Protein - metabolism; Estrogen Receptor alpha - metabolism; Female; Hypothalamo-Hypophyseal System - metabolism; Male; Mice; Mice, Transgenic; Paraventricular Hypothalamic Nucleus - metabolism; Phosphorylation; Pituitary-Adrenal System - metabolism; Receptors, Corticotropin-Releasing Hormone - metabolism; Restraint, Physical; Sex Characteristics; sex difference; stress; Stress, Psychological - metabolism
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2019.04.045

Sex differences in neural structures are generally believed to underlie sex differences reported in anxiety, depression, and the hypothalamic–pituitary–adrenal axis, although the specific circuitry involved is largely unclear. Using a corticotropin-releasing factor receptor 1 (CRFR1) reporter mouse line, we report a sexually dimorphic distribution of CRFR1 expressing cells within the paraventricular hypothalamus (PVN; males > females). Relative to adult levels, PVN CRFR1-expressing cells are sparse and not sexually dimorphic at postnatal days 0, 4, or 21. This suggests that PVN cells might recruit CRFR1 during puberty or early adulthood in a sex-specific manner. The adult sex difference in PVN CRFR1 persists in old mice (20–24 months). Adult gonadectomy (6 weeks) resulted in a significant decrease in CRFR1-immunoreactive cells in the male but not female PVN. CRFR1 cells show moderate co-expression with estrogen receptor alpha (ERα) and high co-expression with androgen receptor, indicating potential mechanisms through which circulating gonadal hormones might regulate CRFR1 expression and function. Finally, we demonstrate that a psychological stressor, restraint stress, induces a sexually dimorphic pattern of neural activation in PVN CRFR1 cells (males >females) as assessed by co-localization with the transcription/neural activation marker phosphorylated CREB. Given the known role of CRFR1 in regulating stress-associated behaviors and hormonal responses, this CRFR1 PVN sex difference might contribute to sex differences in these functions. •Male mice have a greater number of CRFR1 cells in the paraventricular hypothalamus.•This sex difference appears after postnatal day 21 and persists through the lifespan.•Gonadectomy decreases CRFR1 cell number in the male paraventricular hypothalamus.•Males show a greater activation of paraventricular CRFR1 cells following restraint stress.