Chronic intermittent hypoxia sensitizes acute hypothalamic-pituitary-adrenal stress reactivity and Fos induction in the rat locus coeruleus in response to subsequent immobilization stress
Chronic intermittent hypoxia sensitizes acute hypothalamic-pituitary-adrenal stress reactivity and Fos induction in the rat locus coeruleus in response to subsequent immobilization stress
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DOI：
10.1016/j.neuroscience.2008.04.068
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发表时间：
2008-07-17
期刊：
影响因子：
3.3
通讯作者：
Morilak, D. A.
中科院分区：
文献类型：
--
作者：
Ma, S.;Mifflin, S. W.;Morilak, D. A.
阻塞性睡眠呼吸暂停（OSA）与几种病理生理学状况相关，包括高血压、肥胖、胰岛素抵抗、下丘脑-垂体-肾上腺（HPA）失调以及包括"代谢综合征"的其他内分泌和代谢紊乱。"OSA中反复发作的缺氧可能代表慢性间歇性应激，导致HPA失调。HPA反应性的改变可能会导致或加剧其他病理生理过程。我们以前表明，另一种代谢应激，慢性间歇性冷应激，增强去甲肾上腺素促进急性HPA应激反应。在这项研究中，我们调查是否慢性间歇性缺氧（CIH），动脉低氧血症，伴随OSA的大鼠模型，同样敏感的HPA对新的急性应激反应。将大鼠暴露于CIH（常氧[在21%O-2下3分钟]和缺氧[在10%O-2下3分钟]的交替循环，在循环的光照部分连续重复8小时/天，持续7天）。在最后一次CIH暴露后的第二天，基线血浆促肾上腺皮质激素（ACTH）没有差异，但对30分钟急性制动应激的峰值ACTH反应在CIH应激大鼠中大于对照组。急性制动应激诱导Fos表达在CIH后的几个HPA调节脑区，包括室旁核，终纹床核和杏仁核。Fos诱导在下丘脑外侧区（HPA抑制区）减弱。相比之下，急性Fos诱导增强去甲肾上腺素能神经元在蓝斑CIH曝光。因此，类似于慢性冷应激，CIH敏化急性HPA和去甲肾上腺素能应激反应。急性应激反应中的可塑性对于长期适应是重要的，但也可能导致与慢性或重复应激状态相关的病理生理状况，如OSA。确定这些适应背后的神经机制可能有助于我们更好地了解这些疾病的病因，并为开发更有效的治疗方法提供信息。(C)2008年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Obstructive sleep apnea (OSA) is associated with several pathophysiological conditions, including hypertension, obesity, insulin resistance, hypothalamic-pituitary-adrenal (HPA) dysregulation, and other endocrine and metabolic disturbances comprising the "metabolic syndrome." Repeated episodes of hypoxia in OSA may represent a chronic intermittent stress, leading to HPA dysregulation. Alterations in HPA reactivity could then contribute to or exacerbate other pathophysiological processes. We showed previously that another metabolic stressor, chronic intermittent cold stress, enhanced noradrenergic facilitation of acute HPA stress reactivity. In this study, we investigated whether chronic intermittent hypoxia (CIH), a rat model for the arterial hypoxemia that accompanies OSA, similarly sensitizes the HPA response to novel acute stress. Rats were exposed to CIH (alternating cycles of normoxia [3 min at 21% O-2] and hypoxia [3 min at 10% O-2], repeated continuously for 8 h/day during the light portion of the cycle for 7 days). On the day after the final CIH exposure, there were no differences in baseline plasma adrenocorticotropic hormone (ACTH), but the peak ACTH response to 30 min acute immobilization stress was greater in CIH-stressed rats than in controls. Induction of Fos expression by acute immobilization stress was comparable following CIH in several HPA-modulatory brain regions, including the paraventricular nucleus, bed nucleus of the stria terminalis, and amygdala. Fos induction was attenuated in lateral hypothalamus, an HPA-inhibitory region. By contrast, acute Fos induction was enhanced in noradrenergic neurons in the locus coeruleus following CIH exposure. Thus, similar to chronic cold stress, CIH sensitized acute HPA and noradrenergic stress reactivity. Plasticity in the acute stress response is important for long-term adaptation, but may also contribute to pathophysiological conditions associated with states of chronic or repeated stress, such as OSA. Determining the neural mechanisms underlying these adaptations may help us better understand the etiology of such disorders, and inform the development of more effective treatments. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.