Department of Women and Children's Health, School of Life Course and Population Sciences, Faculty of Life Science and Medicine, King's College London, London, United Kingdom.
Department of Mathematics and Statistics, Faculty of Environment, Science and Economy, University of Exeter, Exeter, United Kingdom.
Front Endocrinol (Lausanne). 2024 Jan 9;14:1322662. doi: 10.3389/fendo.2023.1322662. eCollection 2023.
The impact of stress on reproductive function is significant. Hypothalamic paraventricular nucleus (PVN) corticotrophin-releasing hormone (CRH) plays a major role in regulating the stress response. Understanding how the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis interact is crucial for comprehending how stress can lead to reproductive dysfunction. However, whether stress influences reproductive function via modulating PVN CRH or HPA sequelae is not fully elucidated.
In this study, we investigated the impact of chemogenetic activation of PVN CRH neurons on reproductive function. We chronically and selectively stimulated PVN CRH neurons in female CRH-Cre mice using excitatory designer receptor exclusively activated by designer drugs (DREADDs) viral constructs, which were bilaterally injected into the PVN. The agonist compound-21 (C21) was delivered through the drinking water. We determined the effects of DREADDs activation of PVN CRH neurons on the estrous cycles, LH pulse frequency in diestrus and metestrus and LH surge in proestrus mice. The effect of long-term C21 administration on basal corticosterone secretion and the response to acute restraint stress during metestrus was also examined. Additionally, computer simulations of a mathematical model were used to determine the effects of DREADDs activation of PVN CRH neurons, simulating chronic stress, on the physiological parameters examined experimentally.
As a result, and consistent with our mathematical model predictions, the length of the estrous cycle was extended, with an increase in the time spent in estrus and metestrus, and a decrease in proestrus and diestrus. Additionally, the frequency of LH pulses during metestrus was decreased, but unaffected during diestrus. The occurrence of the preovulatory LH surge during proestrus was disrupted. The basal level of corticosterone during metestrus was not affected, but the response to acute restraint stress was diminished after long-term C21 application.
These data suggest that PVN CRH neurons play a functional role in disrupting ovarian cyclicity and the preovulatory LH surge, and that the activity of the GnRH pulse generator remains relatively robust during diestrus but not during metestrus under chronic stress exposure in accordance with our mathematical model predictions.
压力对生殖功能的影响是显著的。下丘脑室旁核（PVN）促肾上腺皮质释放激素（CRH）在调节应激反应中起着重要作用。了解下丘脑-垂体-肾上腺（HPA）轴和下丘脑-垂体-性腺（HPG）轴如何相互作用对于理解压力如何导致生殖功能障碍至关重要。然而，压力是否通过调节 PVN CRH 或 HPA 后果来影响生殖功能尚未完全阐明。
在这项研究中，我们研究了化学遗传激活 PVN CRH 神经元对生殖功能的影响。我们使用兴奋性设计受体专门激活设计药物（DREADDs）病毒构建体，将其双侧注射到 PVN 中，对雌性 CRH-Cre 小鼠的 PVN CRH 神经元进行慢性和选择性刺激。激动剂化合物-21（C21）通过饮用水输送。我们确定了 DREADDs 激活 PVN CRH 神经元对发情周期、发情期和间情期 LH 脉冲频率以及发情前期 LH 激增的影响。还检查了长期 C21 给药对基础皮质酮分泌和间情期急性束缚应激反应的影响。此外，使用数学模型的计算机模拟来确定 DREADDs 激活 PVN CRH 神经元，模拟慢性应激，对实验中检查的生理参数的影响。
结果与我们的数学模型预测一致，发情周期延长，发情期和间情期时间增加，发情前期和发情后期时间减少。此外，间情期 LH 脉冲频率降低，但发情期不受影响。发情前期的促黄体生成素峰出现障碍。间情期基础皮质酮水平不受影响，但长期 C21 应用后，急性束缚应激反应减弱。
这些数据表明，PVN CRH 神经元在破坏卵巢周期性和促黄体生成素峰方面发挥功能作用，并且 GnRH 脉冲发生器的活性在慢性应激暴露下仍相对较强，尽管根据我们的数学模型预测，在发情期不受影响，但在间情期不受影响。
