Tenorio-Lopes L, Henry M S, Marques D, Tremblay M-È, Drolet G, Bretzner F, Kinkead R
Department of Pediatrics, Centre de Recherche de l'Institut Universitaire de Cardiologie et Pneumologie de Québec, Université Laval, Québec, QC, Canada.
Department of Molecular Medicine, Centre de Recherche du CHU de Québec-Université Laval, Axe Neurosciences, Université Laval, Québec, QC, Canada.
J Neuroendocrinol. 2017 Dec;29(12). doi: 10.1111/jne.12550.
Respiratory manifestations of panic disorder (PD) include a greater respiratory instability and enhanced responsiveness to CO compared to normal individuals. Although the prevalence of PD is approximately three times greater in women compared to men, the origins of this sexual dimorphism remain poorly understood. Similar to PD patients, adult female rats previously subjected to neonatal maternal separation (NMS) show an increase in their ventilatory response to CO . Because this effect of NMS is not observed in males, we hypothesised that testosterone prevents NMS-induced hyper-responsiveness to CO . Pups subjected to NMS were placed in an incubator for 3 h d from postnatal days 3-12. Control pups remained undisturbed. At adulthood (8-10 weeks of age), rats were then subjected either to sham surgery or castration. Fourteen days later, breathing was measured at rest (room air) and during acute exposure to hypercapnia (5 and 10% CO for 10 minutes each) using plethysmography. To gain insight into the mechanisms involved, c-fos expression was used as an indicator of neuronal activation. Brains were collected following air or CO exposure for quantification of c-fos positive cells by immunohistochemistry in selected regions, including the paraventricular nucleus of the hypothalamus, the dorsomedial hypothalamus and the amygdalar complex. Castration produced a 100% increase of hyperventilatory response to 10% CO in control rats. Unexpectedly, castration had no effect on the hyperventilatory response of NMS rats. The intensity of the hypercapnic response was inversely correlated with c-fos expression in the medial amygdala. We conclude that testosterone prevents the hyper-responsiveness to CO , whereas NMS attenuates sensitivity to hormone withdrawal. We propose that an inhibitory influence from the medial amygdala contributes to this effect.
惊恐障碍（PD）的呼吸表现包括与正常个体相比，呼吸稳定性更高以及对二氧化碳（CO）的反应性增强。尽管女性中PD的患病率约为男性的三倍，但这种性别差异的根源仍知之甚少。与PD患者类似，先前经历过新生期母婴分离（NMS）的成年雌性大鼠对CO的通气反应增强。由于在雄性大鼠中未观察到NMS的这种效应，我们推测睾酮可预防NMS诱导的对CO的高反应性。从出生后第3天至12天，将经历NMS的幼崽每天置于培养箱中3小时。对照幼崽则不受干扰。成年后（8至10周龄），对大鼠进行假手术或去势手术。十四天后，使用体积描记法测量大鼠在静息状态（室内空气）下以及急性暴露于高碳酸血症（分别为5%和10%的CO，每次10分钟）期间的呼吸情况。为深入了解其中涉及的机制，使用c-fos表达作为神经元激活的指标。在空气或CO暴露后收集大脑，通过免疫组织化学对包括下丘脑室旁核、下丘脑背内侧核和杏仁复合体在内的选定区域中的c-fos阳性细胞进行定量。去势使对照大鼠对10% CO的过度通气反应增加了100%。出乎意料的是，去势对NMS大鼠的过度通气反应没有影响。高碳酸血症反应的强度与内侧杏仁核中的c-fos表达呈负相关。我们得出结论，睾酮可预防对CO的高反应性，而NMS会减弱对激素撤除的敏感性。我们提出内侧杏仁核的抑制性影响促成了这种效应。
