University at Albany, Department of Psychology, Albany, NY 12222, United States of America.
Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, University of Texas Health Sciences Center, Houston, TX, USA.
Neuroscience. 2019 Jun 15;409:195-203. doi: 10.1016/j.neuroscience.2019.04.045. Epub 2019 May 2.
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.
一般认为，神经结构的性别差异是导致焦虑、抑郁和下丘脑-垂体-肾上腺轴性别差异的基础，尽管具体涉及的特定回路在很大程度上仍不清楚。使用促肾上腺皮质释放因子受体 1 (CRFR1)报告小鼠品系，我们报告了下丘脑室旁核 (PVN) 中 CRFR1 表达细胞的性别二态性分布（男性>女性）。与成年水平相比，PVN CRFR1 表达细胞在出生后第 0、4 或 21 天稀疏且无性别二态性。这表明 PVN 细胞可能以性别特异性的方式在青春期或成年早期募集 CRFR1。PVN CRFR1 的成年性别差异在老年小鼠（20-24 个月）中持续存在。成年去势（6 周）导致雄性而非雌性 PVN 中 CRFR1 免疫反应性细胞显著减少。CRFR1 细胞与雌激素受体 alpha (ERα) 中度共表达，与雄激素受体高度共表达，表明循环性腺激素可能通过潜在的机制调节 CRFR1 表达和功能。最后，我们证明了一种心理应激源，束缚应激，通过与转录/神经激活标志物磷酸化 CREB 的共定位，诱导 PVN CRFR1 细胞中性别二态性的神经激活模式（男性>女性）。鉴于 CRFR1 在调节与应激相关的行为和激素反应中的已知作用，这种 PVN CRFR1 的性别差异可能有助于这些功能的性别差异。
