NEUROENDOCRINE ABNORMALITIES INDUCED BY SLEEP DEPRIVATIO

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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.