NEUROENDOCRINE ABNORMALITIES INDUCED BY SLEEP DEPRIVATIO

描述(根据申请者的摘要改编)：睡眠是一种重要的生物 保持认知能力和身体健康所必需的过程。深刻 人类的睡眠障碍/剥夺几乎总是与 疾病，患者睡眠不足被认为是高血压的高危因素 死亡率。在睡眠剥夺的动物模型中，发病率与 一系列神经内分泌变化后的败血症，大多数 特别值得一提的是甲状腺素血症。初步数据显示，神经内分泌 异常可延伸到生长激素(GH)和催乳素缺乏 (PRL)，并有可能解释睡眠引起的大部分病理 剥夺。有强有力的证据表明，神经内分泌的变化 集中调停。以下三个具体目标旨在测试 睡眠不足会导致下丘脑功能障碍的主要假设： 目的1：确定中枢介导性低甲状腺素血症是否由 睡眠剥夺动物的前TRH表达和TRH分泌不足。 拟议的研究将确定TRH mRNA在血管内皮细胞中的表达 室旁核和正中隆起的TRH含量受到抑制 对低T4无反应，表明甲状腺激素调节受损 下丘脑的水平。T3反馈到PVN神经元的通路将 接受检查以确定对低T4的反应上调的程度。 促甲状腺激素释放激素的潜在反应性将通过评估促甲状腺激素释放激素来评估。 受体mRNA在脑垂体中的表达。 目标2：确定生长激素减少的调节机制 以及睡眠剥夺大鼠的催乳素水平。拟议的研究将审查 大鼠睡眠过程中催乳素和生长激素的调节 通过研究刺激和抑制机制以及 可能是下丘脑和脑垂体部缺陷的原因 级别。 目的3：描述睡眠剥夺对甲状腺激素分泌的影响 在大脑里。睡眠剥夺大鼠甲状腺激素水平低提示 T4输入大脑的可用性降低，并随之而来 临床甲状腺功能减退状态常见的中枢调节功能障碍。 拟议的研究将检查碘甲腺原氨酸的含量和调节 睡眠不足的大脑。 这些研究将描绘出大脑内分泌调节的异常。 并确定导致睡眠不足的机制 外周内分泌变化是其相关全身病理的基础。

DESCRIPTION (adapted from applicant's abstract): Sleep is a vital biological process necessary to maintain cognitive ability and physical health. Profound sleep disturbance/deprivation in humans is nearly always associated with disease, and sleep deprivation in patients is considered a high risk factor for mortality. In animal models of sleep deprivation, morbidity is associated with septicemia subsequent to a constellation of neuroendocrine changes, most notably hypothyroxinemia. Preliminary data have shown that neuroendocrine abnormalities extend to deficiencies in growth hormone (GH) and prolactin (PRL), and have the potential to explain most of the pathology induced by sleep deprivation. There is strong evidence that the neuroendocrine changes are centrally mediated. The following three specific aims are intended to test the main hypothesis that sleep deprivation results in hypothalamic dysfunction: Aim 1: To determine whether centrally-mediated hypothyroxinemia is due to deficient proTRH expression and TRH secretion in sleep-deprived animals. Proposed studies will determine whether TRH mRNA expression in the paraventricular nucleus and TRH content in the median eminence are suppressed and unresponsive to low T4, indicating impaired thyroid hormone regulation at the level of the hypothalamus. The pathway of T3 feedback to PVN neurons will be examined to determine the degree of up-regulation in response to low T4. Potential TRH responsiveness of thyrotrophs will be assessed by evaluating TRH receptor mRNA expression in the pituitary. Aim 2: To identify regulatory mechanisms responsible for reduced growth hormone and prolactin levels in sleep-deprived rats. Proposed studies will examine the regulation of PRL and GH in individual rats during the course of sleep deprivation by studying stimulatory and inhibitory mechanisms and response that could be responsible for the deficiency at the hypothalamic and pituitary levels. Aim 3: To delineate effects of sleep deprivation on thyroid hormone processing in the brain. Low thyroid hormone concentrations in sleep-deprived rats imply decreased T4 availability for import to the brain and ensuing centrally-mediated dysfunction common to the clinical hypothyroid state. Proposed studies will examine the content and regulation of iodothyronines in the sleep deprived brain. These studies will delineate the abnormalities in brain endocrine regulation resulting from sleep deprivation and determine the mechanisms responsible for peripheral endocrine changes that underlie its associated systemic pathologies.