Effects of Sleep Fragmentation on Adult Neurogenesis

睡眠碎片化对成人神经发生的影响

• 批准号: 7676371
• 负责人: DENNIS J MCGINTY
• 金额: $ 11.55万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676371
• 关键词: Adult; Affect; Aging; Animals; Biological; Biological Assay; Brain; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; CREB1 gene; Cell Cycle; Cell Proliferation; Cell division; Cells; Chronic; Cognitive; Condition; Corticosterone; Cyclic AMP-Responsive DNA-Binding Protein; Data; Depressed mood; Docking; Electroencephalography; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Goals; Hippocampus (Brain); Hormones; Immunoglobulin G; Lateral; Latex; Learning; Light; Major Depressive Disorder; Measures; Mediating; Methods; Microspheres; Modeling; Neocortex; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Obstructive Sleep Apnea; Pathology; Phase; Phenotype; Phosphoproteins; Physiology; Play; Primates; Process; Proliferating; Property; Protein Biosynthesis; Proteins; REM Sleep; Rattus; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep Stages; Sleep disturbances; Stem cells; Stress; Structure; Synapsins; Technology; Time; Translations; Traumatic Stress Disorders; Vesicle; dentate gyrus; deprivation; granule cell; human disease; lateral ventricle; neurogenesis; roentgen equivalent man

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.

描述（由申请人提供）：拟议的研究将评估与基本生物学问题有关的假设，睡眠如何影响脑结构和可塑性。我们将检查成年海马神经发生（AN）的过程以及促进AN的基因和蛋白质的表达。我们表明，睡眠剥夺强烈抑制了新细胞的增殖以及显示出成熟神经元特性的新细胞的百分比。现在，我们建议研究睡眠碎片化和REM剥夺对AN的影响，并评估睡眠破碎化功能效应的预测。 A受一组蛋白质的调节，包括磷酸化的环状AMP反应元件结合蛋白（PCREB）和脑衍生的神经营养因子（BDNF）。我们的试点数据表明，48小时的睡眠剥夺抑制了BDNF的海马表达以及Synapsin-1，这是BDNF诱导的囊泡蛋白。在新皮层中，与塑性相关的基因在唤醒过程中表达。在睡眠期间，脑蛋白合成增加。这些发现表明唤醒和睡眠状态在支持大脑功能和可塑性方面起着不同的作用。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了环境，包括细胞增殖。蛋白质对接和稳定需要REM睡眠。然而，尚未研究唤醒和睡眠的相互作用以及睡眠碎片化和REM剥夺对海马中增殖基因表达和蛋白质合成的影响。我们将分别分析光相睡眠干旱的暗相唤醒周期，并确定睡眠碎片和REM剥夺的影响。细胞增殖将通过溴脱氧尿苷（BRDU）方法研究。海马中的基因表达通过RT-PCR评估。我们建议通过BDNF的局部变化在睡眠期间恢复增生，睡眠碎片和抑制增殖。我们的研究利用了一种新的，有充分控制的，无压力的睡眠剥夺方法，即间歇性跑步机。因变量在睡眠期间将与睡眠参数和三角洲脑电图活动相关。大量证据表明，抑制可能与与衰老和普遍的人类疾病相关的神经和认知病理，包括重度抑郁症和阻塞性睡眠呼吸暂停。慢性睡眠破碎和限制是这些条件的共同点。