Rosinger Zachary J, De Guzman Rose M, Jacobskind Jason S, Saglimbeni Brianna, Malone Margaret, Fico Danielle, Justice Nicholas J, Forni Paolo E, Zuloaga Damian G
Department of Psychology, University at Albany, Albany, NY 12222, United States.
Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, University of Texas Health Sciences Center, Houston, TX, United States.
Physiol Behav. 2020 May 15;219:112847. doi: 10.1016/j.physbeh.2020.112847. Epub 2020 Feb 18.
Anxiety and depression are strikingly more prevalent in women compared with men. Dysregulation of corticotropin-releasing factor (CRF) binding to its cognate receptor (CRFR1) is thought to play a critical role in the etiology of these disorders. In the present study, we investigated whether there were sex differences in the effects of chronic variable stress (CVS) on CRFR1 cells using CRFR1-GFP reporter mice experiencing a 9-day CVS paradigm. Brains were collected from CVS and stress naïve female and male mice following exposure to the open field test. This CVS paradigm effectively increased anxiety-like behavior in female and male mice. In addition, we assessed changes in activation of CRFR1 cells (co-localization with c-Fos and phosphorylated CREB (pCREB)) in stress associated brain structures, including two sexually dimorphic CRFR1 cell groups in the anteroventral periventricular nucleus (AVPV/PeN; F>M) and paraventricular hypothalamus (PVN; M>F). CVS increased CRFR1-GFP cell number as well as the number of CRFR1/pCREB co-expressing cells in the female but not male AVPV/PeN. In the PVN, the number of CRFR1/pCREB co-expressing cells was overall greater in males regardless of treatment and CVS resulted in a male-specific reduction of CRFR1/c-Fos cells. In addition, CVS induced a female-specific reduction in CRFR1/c-Fos cells within the anteroventral bed nucleus of the stria terminalis and both sexes exhibited a reduction in CRFR1/c-Fos co-expressing cells following CVS within the ventral basolateral amygdala. Overall, these sex-specific effects of CVS on CRFR1 populations may have implications for sex differences in stress-induction of mood disorders.
与男性相比，焦虑和抑郁在女性中更为普遍。促肾上腺皮质激素释放因子（CRF）与其同源受体（CRFR1）结合失调被认为在这些疾病的病因中起关键作用。在本研究中，我们使用经历9天慢性可变应激（CVS）范式的CRFR1-GFP报告基因小鼠，研究了CVS对CRFR1细胞的影响是否存在性别差异。在暴露于旷场试验后，从经历CVS和未经历应激的雌性和雄性小鼠中收集大脑。这种CVS范式有效地增加了雌性和雄性小鼠的焦虑样行为。此外，我们评估了应激相关脑区中CRFR1细胞激活的变化（与c-Fos和磷酸化CREB（pCREB）共定位），包括室旁前腹核（AVPV/PeN；雌性>雄性）和下丘脑室旁核（PVN；雄性>雌性）中的两个性别二态性CRFR1细胞群。CVS增加了雌性而非雄性AVPV/PeN中CRFR1-GFP细胞数量以及CRFR1/pCREB共表达细胞数量。在PVN中，无论治疗如何，雄性中CRFR1/pCREB共表达细胞的数量总体上更多，且CVS导致雄性特异性的CRFR1/c-Fos细胞减少。此外，CVS诱导终纹床核前腹侧CRFR1/c-Fos细胞出现雌性特异性减少，并且在腹侧基底外侧杏仁核中，两性在CVS后均表现出CRFR1/c-Fos共表达细胞减少。总体而言，CVS对CRFR1群体的这些性别特异性影响可能对情绪障碍应激诱导中的性别差异具有影响。
