Evans Maggie C, Stowe Shaun M, Sawyer India L, Decourt Caroline, Lee Frank, Kauffman Alexander S, Anderson Greg M
Centre for Neuroendocrinology and Department of Anatomy, University of Otago School of Biomedical Sciences, Dunedin 9016, New Zealand.
Department of OBGYN and Reproductive Sciences and the Center for Chronobiology, University of California, San Diego, CA 92093, USA.
Endocrinology. 2025 Jun 10;166(8). doi: 10.1210/endocr/bqaf106.
The association between perceived stress and reproductive dysfunction is known, yet the underlying mechanisms remain incompletely determined. We previously demonstrated that RF-amide related (RFRP) peptide 3-expressing neurons, putative inhibitors of the central regulation of fertility, are required for both acute restraint stress- and glucocorticoid-induced suppression of LH pulsatility in female mice. The present study complemented this by testing the role of RFRP neurons in the stress-induced suppression of the estrogen-induced preovulatory-like LH surge. We first established a reliable model of acute restraint stress in mice that stimulates glucocorticoid secretion, suppresses a late afternoon estrogen-induced LH surge, and inhibits corresponding kisspeptin neuronal activation in the anteroventral periventricular brain region. Two hours of restraint stress initiated 2 to 6 hours prior to lights off met these criteria. We then ablated RFRP neurons in adult female mice by expressing a diphtheria toxin receptor specifically in these cells and exposing them to diphtheria toxin. RFRP neuron-ablated and control mice that were ovariectomized and estrogen-treated were exposed to the acute, mid-afternoon restraint stress protocol and assessed for their peak LH concentrations several hours later at the expected time of the LH surge. Control mice exhibited stress-induced suppression of the LH surge, as expected, whereas RFRP-ablated mice did not. No differences in peak LH concentrations were observed between nonstressed controls and stressed RFRP-ablated mice. These data suggest that acute psychosocial stress occurring several hours prior to preovulatory LH surge induction invokes RFRP neuron-mediated blockade of the surge. The neural circuitry involved remains to be fully characterized.
感知压力与生殖功能障碍之间的关联是已知的，但其潜在机制仍未完全明确。我们之前证明，表达RF酰胺相关肽3（RFRP）的神经元是生育力中枢调节的假定抑制因子，对于急性束缚应激和糖皮质激素诱导的雌性小鼠促黄体生成素（LH）脉冲性抑制都是必需的。本研究通过测试RFRP神经元在应激诱导的雌激素诱导的排卵前样LH峰抑制中的作用对这一点进行了补充。我们首先在小鼠中建立了一种可靠的急性束缚应激模型，该模型可刺激糖皮质激素分泌，抑制傍晚雌激素诱导的LH峰，并抑制室前腹中脑区域相应的吻素神经元激活。在熄灯前2至6小时开始的两小时束缚应激符合这些标准。然后，我们通过在成年雌性小鼠的这些细胞中特异性表达白喉毒素受体并使其暴露于白喉毒素来消融RFRP神经元。将接受卵巢切除术并经雌激素处理的RFRP神经元消融小鼠和对照小鼠暴露于急性午后束缚应激方案，并在数小时后的LH峰预期时间评估它们的LH峰值浓度。正如预期的那样，对照小鼠表现出应激诱导的LH峰抑制，而RFRP消融小鼠则没有。在未应激的对照小鼠和应激的RFRP消融小鼠之间未观察到LH峰值浓度的差异。这些数据表明，在排卵前LH峰诱导前数小时发生的急性心理社会应激会引发RFRP神经元介导的LH峰阻断。所涉及的神经回路仍有待充分表征。
