Hotchkiss Brain Institute; Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.
Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec. Département de Pédiatrie. Université Laval, Québec, QC, Canada.
Transl Psychiatry. 2020 Nov 10;10(1):394. doi: 10.1038/s41398-020-01076-x.
Panic disorder (PD) is ~2 times more frequent in women. An excessive ventilatory response to CO inhalation is more likely during the premenstrual phase. While ovarian hormones appear important in the pathophysiology of PD, their role remains poorly understood as female animals are rarely used in pre-clinical studies. Using neonatal maternal separation (NMS) to induce a "PD-like" respiratory phenotype, we tested the hypothesis that NMS disrupts hormonal regulation of the ventilatory response to CO in female rats. We then determined whether NMS attenuates the inhibitory actions of 17-β estradiol (E) on orexin neurons (ORX). Pups were exposed to NMS (3 h/day; postnatal day 3-12). The ventilatory response to CO-inhalation was tested before puberty, across the estrus cycle, and following ovariectomy. Plasma E and hypothalamic ORX were measured. The effect of an ORX antagonist (SB334867; 15 mg/kg) on the CO response was tested. Excitatory postsynaptic currents (EPSCs) were recorded from ORX neurons using whole-cell patch-clamp. NMS-related increase in the CO response was observed only when ovaries were functional; the largest ventilation was observed during proestrus. SB334867 blocked this effect. NMS augmented levels of ORX in hypothalamus extracts. EPSC frequency varied according to basal plasma E levels across the estrus cycle in controls but not NMS. NMS reproduces developmental and cyclic changes of respiratory manifestations of PD. NMS disrupts the inhibitory actions of E on the respiratory network. Impaired E-related inhibition of ORX neurons during proestrus is a novel mechanism in respiratory manifestations of PD in females.
惊恐障碍（PD）在女性中更为常见，约为男性的两倍。在月经前期，对 CO 吸入的过度通气反应更有可能发生。虽然卵巢激素在 PD 的病理生理学中很重要，但由于很少在临床前研究中使用雌性动物，因此其作用仍知之甚少。我们使用新生期母体分离（NMS）来诱导“PD 样”呼吸表型，以检验 NMS 是否破坏了 CO 通气反应的激素调节在雌性大鼠中的假说。然后，我们确定 NMS 是否会减弱 17-β 雌二醇（E）对食欲素神经元（ORX）的抑制作用。将幼仔暴露于 NMS（每天 3 小时；出生后第 3-12 天）。在青春期前、发情周期和卵巢切除术后测试 CO 吸入的通气反应。测量血浆 E 和下丘脑 ORX。测试了 ORX 拮抗剂（SB334867；15mg/kg）对 CO 反应的影响。使用全细胞膜片钳记录 ORX 神经元的兴奋性突触后电流（EPSC）。仅当卵巢功能正常时，NMS 相关的 CO 反应增加；最大通气发生在发情前期。SB334867 阻断了这种作用。NMS 增加了下丘脑提取物中的 ORX 水平。在对照组中，EPSC 频率根据发情周期中的基础血浆 E 水平而变化，但在 NMS 中则没有。NMS 再现了 PD 呼吸表现的发育和周期性变化。NMS 破坏了 E 对呼吸网络的抑制作用。在发情前期，E 相关的 ORX 神经元抑制受损是女性 PD 呼吸表现的新机制。
