Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Hungarian Research Network, 1083 Budapest, Hungary.
Nikon Center of Excellence, Institute of Experimental Medicine, Hungarian Research Network, 1083 Budapest, Hungary.
Int J Mol Sci. 2024 Nov 8;25(22):12004. doi: 10.3390/ijms252212004.
Corticotropin-releasing hormone (CRH) neurons within the paraventricular hypothalamic nucleus (PVH) play a crucial role in initiating the neuroendocrine response to stress and are also pivotal in coordination of autonomic, metabolic, and behavioral stress reactions. Although the role of parvocellular CRH neurons in activation of the hypothalamic-pituitary-adrenal (HPA) axis is well established, the distribution and function of CRH-expressing neurons across the whole central nervous system are less understood. Stress responses activate complex neural networks, which differ depending on the type of stressor and on the sex of the individual. Because of the technical difficulties of localizing CRH neurons throughout the rodent brain, several CRH reporter mouse lines have recently been developed. In this study, we used Crh-IRES-Cre;Ai9 reporter mice to examine whether CRH neurons are recruited in a stressor- or sex-specific manner, both within and outside the hypothalamus. In contrast to the clear sexual dimorphism of CRH-mRNA-expressing neurons, quantification of CRH-reporting, tdTomato-positive neurons in different stress-related brain areas revealed only subtle differences between male and female subjects. These results strongly imply that sex differences in CRH mRNA expression occur later in development under the influence of sex steroids and reflects the limitations of using genetic reporter constructs to reveal the current physiological/transcriptional status of a specific neuron population. Next, we compared the recruitment of stress-related, tdTomato-expressing (putative CRH) neurons in male and female Crh-IRES-Cre;Ai9 reporter mice that had been exposed to predator odor. In male mice, fox odor triggered more c-Fos in the CRH neurons of the paraventricular hypothalamic nucleus, central amygdala, and anterolateral bed nucleus of the stria terminalis compared to females. These results indicate that male mice are more sensitive to predator exposure due to a combination of hormonal, environmental, and behavioral factors.
促肾上腺皮质激素释放激素 (CRH) 神经元位于室旁下丘脑核 (PVH) 内，在启动应激的神经内分泌反应中发挥着关键作用，并且在协调自主神经、代谢和行为应激反应方面也起着关键作用。尽管副室旁核 CRH 神经元在激活下丘脑-垂体-肾上腺 (HPA) 轴中的作用已得到充分证实，但整个中枢神经系统中 CRH 表达神经元的分布和功能了解较少。应激反应会激活复杂的神经网络，这些网络因应激类型和个体性别而异而有所不同。由于在整个啮齿动物大脑中定位 CRH 神经元存在技术困难，因此最近开发了几种 CRH 报告小鼠品系。在这项研究中，我们使用 Crh-IRES-Cre;Ai9 报告小鼠来检查 CRH 神经元是否以应激源或性别特异性的方式募集，无论是在下丘脑内还是外。与 CRH-mRNA 表达神经元的明显性别二态性形成鲜明对比的是，在不同与应激相关的脑区中量化报告的 CRH 表达，tdTomato 阳性神经元仅显示出雄性和雌性个体之间的细微差异。这些结果强烈暗示，CRH mRNA 表达的性别差异是在性激素的影响下在发育后期出现的，反映了使用遗传报告构建体来揭示特定神经元群体当前生理/转录状态的局限性。接下来，我们比较了暴露于捕食者气味的雄性和雌性 Crh-IRES-Cre;Ai9 报告小鼠中与应激相关的，tdTomato 表达（推定的 CRH）神经元的募集情况。与雌性相比，雄性小鼠的 fox 气味会导致室旁下丘脑核、中央杏仁核和终纹床核的前外侧床核中的 CRH 神经元中的 c-Fos 更多。这些结果表明，由于激素、环境和行为因素的综合作用，雄性小鼠对捕食者暴露更为敏感。
