REM SLEEP DEPRIVATION, HYPOXIA, AND HIPPOCAMPAL FUNCTION

快速眼动睡眠剥夺、缺氧和海马功能

• 批准号: 6192272
• 负责人: David Gozal
• 金额: $ 30.38万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6192272
• 关键词: REM sleep; apoptosis; behavior test; behavioral /social science research tag; fos protein; gene induction /repression; glutamate receptor; hippocampus; hypoxia; immunocytochemistry; laboratory rat; learning; long term potentiation; memory; neural plasticity; neurophysiology; sleep deprivation

Obstructive sleep apnea syndrome (OSAS) is a frequent condition affecting up to 5 percent of the population, and is characterized by repeated episodes of hypoxia and recurrent EEG/behavioral arousal, particularly during REM sleep. When untreated, OSAS is associated with significant neurocognitive morbidities such as excessive daytime sleepiness and diminished intellectual performance, attention span, learning and vigilance. However, the relative contributions of REM sleep deprivation (REMSD) and episodic hypoxia to OSAS-associated neurocognitive dysfunction remain unclear. To test the hypothesis that REM sleep deprivation and episodic hypoxia affect learning and memory in an additive fashion, four major specific aims will be examined in a young adult rat model as follows: (1) The acquisition and retention of Morris water maze task paradigms will be assessed in conscious 55-60-day old male rats after either 4-day REMSD using the inverted flower pot technique, 14-day episodic daytime hypoxia (EHYP), or the combination thereof (REMSD-EHYP); (2) The effect of such exposure paradigms on long-term potentiation (LTP) within the CA1 region of the hippocampus will be examined using neurophysiological extracellular recordings of the in vitro hippocampal slice preparation; (3) Changes in ionotropic glutamate receptor distribution and in apoptosis within the hippocampal formation and neocortex will be determined using immunohistochemical and wester blot approaches in naive and maze trained animals following REMSD, EHYP, or both; (4) Alterations in early gene induction (c-fos) elicited by maze learning procedures will be further assessed in the hippocampus of REMSD, EHYP, and REMSD-EHYP by immunohistochemistry and AP-1 electromobility shift assays. These e xperiments will extend our understanding on potential mechanisms and interactions underlying the decreased performance that occurs in particular neurocognitive functions of untreated OSAS patients. In this context, REMSD, EHYP, or both would lead to either up-regulation or down-regulation of specific ionotropic glutamate receptor complexes, induce apoptosis, and thereby modify early gene activation patterns associated with learning or retention of newly learned tasks. Such alterations in receptor-signal transduction pathways could also lead to both short- and long- term changes in neuronal excitability and synaptic transmission within brain regions with important and defined roles in memory formation and learning such as the hippocampus.

阻塞性睡眠呼吸暂停综合征（OSA）是一种频繁的疾病，影响了多达5％的人群，其特征是反复发作缺氧和复发性脑电图/行为唤醒，尤其是在REM睡眠期间。 如果不进行治疗，OSA会与明显的神经认知性病有关，例如白天过度嗜睡和智力表现，注意力跨度，学习和警惕性降低。 然而，REM睡眠剥夺（REMSD）和发作性缺氧对与OSAS相关的神经认知功能障碍的相对贡献尚不清楚。 为了测试以下假设：REM睡眠剥夺和情节性低氧影响学习和记忆的方式，将在年轻的成年大鼠模型中检查四个主要的特定目标，如下所示：（1）以下内容：（1）Morris Water Maze Maze Taskms的获取和保留将在有意识的55-60天的年龄在4-Aday Day Day Tay Tay Tay Day Tody Potls-depay Polls ted Pots中进行评估。 （EHYP）或其组合（REMSD-EHYP）； （2）将使用神经生理学的体外海马切片制剂中的神经生理学外记录来检查这种暴露范式对海马CA1区域内长期增强（LTP）的影响； （3）将使用REMSD，EHYP或两者兼有免疫组织化学和Wester训练的动物中的免疫组织化学和Wester blot方法来确定海马形成和新皮层内海马形成和新皮层中凋亡的变化； （4）将通过免疫组织化学和AP-1电动性转移测定法进一步评估通过迷宫学习程序的早期基因诱导（C-FOS）的改变。 这些e xperiment将扩展我们对潜在的机制和相互作用的理解，从而降低了未经治疗的OSAS患者的神经认知功能的降低。 在这种情况下，REMSD，EHYP或两者都会导致特定离子型谷氨酸受体复合物的上调或下调，诱导凋亡，从而改变与新学习任务的学习或保留相关的早期基因激活模式。 受体信号转导途径的这种改变也可能导致在大脑区域内神经元兴奋性和突触传播的短期和长期变化，在记忆形成和学习中具有重要和定义的作用，例如海马。