Effects of Sleep Fragmentation on Adult Neurogenesis

描述（由申请人提供）：拟议的研究将评估与基本生物学问题相关的假设，即睡眠如何影响大脑结构和可塑性。我们将研究成人海马神经发生（AN）的过程和促进AN的基因和蛋白质的表达。我们表明，睡眠剥夺强烈抑制新细胞的增殖以及显示成熟神经元特性的新细胞的百分比。我们现在建议研究睡眠片段化和REM剥夺对AN的影响，并评估睡眠片段化的延迟功能影响的预测。AN受一系列蛋白质调控，包括磷酸化环AMP反应元件结合蛋白（pCREB）和脑源性神经营养因子（BDNF）。我们的初步数据显示，48小时睡眠剥夺抑制海马BDNF的表达以及突触蛋白-1，一种由BDNF诱导的囊泡蛋白。在新皮层中，可塑性相关基因在清醒时表达。大脑蛋白质的合成在睡眠中增加。这些发现表明，清醒和睡眠状态在支持大脑功能和可塑性方面发挥着不同的作用。我们将评估以下模型：光/睡眠阶段为基因翻译和蛋白质合成提供环境，包括细胞增殖。快速眼动睡眠是蛋白质对接和稳定所必需的。然而，唤醒和睡眠的相互作用以及睡眠片段化和REM剥夺对海马增殖基因表达和蛋白质合成的影响尚未得到研究。我们将分别分析亮相睡眠和暗相觉醒期，并确定睡眠片段化和REM剥夺的影响。将通过溴脱氧尿苷（BrdU）方法研究细胞增殖。通过RT-PCR评估海马中的基因表达。我们建议恢复增殖，在睡眠片段和抑制增殖在睡眠中的局部变化BDNF。我们的研究采用了一种新的、控制良好的、无压力的睡眠剥夺方法，即间歇性跑步机。因变量将与睡眠参数和睡眠期间的δ EEG活动相关。许多证据表明，AN的抑制可能与衰老和流行的人类疾病（包括重度抑郁症和阻塞性睡眠呼吸暂停）相关的神经和认知病理学密切相关。慢性睡眠碎片和限制是常见的这些条件。

DESCRIPTION (provided by applicant): Proposed studies will assess hypotheses related to a fundamental biological problem, how sleep affects brain structure and plasticity. We will examine the processes of adult hippocampal neurogenesis (AN) and the expression of genes and proteins facilitating AN. We showed that sleep deprivation strongly inhibits proliferation of new cells and the percentage of new cells showing mature neuronal properties. We now propose to study effects of sleep fragmentation and REM deprivation on AN and to evaluate a prediction of delayed functional effects of sleep fragmentation. AN is regulated by a cascade of proteins, including phosphorylated cyclic AMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF). Our pilot data shows that 48 hrs sleep deprivation depresses hippocampal expression of BDNF as well as synapsin-1, a vesicular protein induced by BDNF. In neocortex plasticity-related genes are expressed during wake. Brain protein synthesis is increased during sleep. These findings suggest that wake and sleep states play distinct roles in support of brain functions and plasticity. We will assess the following model: The light/sleep phase provides the milieu for gene translation and protein synthesis, including cell proliferation. REM sleep is required for protein docking and stabilization. However, the interactions of wake and sleep and the effects of sleep fragmentation and REM deprivation on proliferation gene expression and protein synthesis in hippocampus have not been studied. We will separately analyze the light phase sleep arid dark phase wake periods and determine effects of sleep fragmentation and REM deprivation. Cell proliferation will be studied by the bromodeoxyuridine (BrdU) method. Gene expression in hippocampus is assessed by RT-PCR. We propose to restore proliferation, during sleep fragmentation and to suppress proliferation during sleep by local changes in BDNF. Our studies utilize a new, well-controlled, non-stressful method of sleep deprivation, the intermittent treadmill. Dependent variables will be correlated with sleep parameters and delta EEG activity during sleep. Much evidence shows that suppression of AN could be critically involved in the neuro- and cognitive pathology associated with aging and with prevalent human diseases, including major depressive disorder, and obstructive sleep apnea. Chronic sleep fragmentation and restriction are common to these conditions.