REM SLEEP DEPRIVATION, HYPOXIA, AND HIPPOCAMPAL FUNCTION

快速眼动睡眠剥夺、缺氧和海马功能

基本信息

批准号：
6638587
负责人：
David Gozal
金额：
$ 32.4万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2005-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6638587
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

项目摘要

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 (OSAS) 是一种常见疾病，影响高达 5% 的人口，其特点是反复发作缺氧和反复出现脑电图/行为唤醒，尤其是在快速眼动睡眠期间。如果不治疗，OSAS 会导致严重的神经认知疾病，例如白天过度嗜睡以及智力表现、注意力持续时间、学习和警觉性下降。然而，REM 睡眠剥夺 (REMSD) 和阵发性缺氧对 OSAS 相关神经认知功能障碍的相对影响仍不清楚。为了检验快速眼动睡眠剥夺和间歇性缺氧以累加方式影响学习和记忆的假设，将在年轻成年大鼠模型中检查四个主要具体目标，如下所示：（1）莫里斯水迷宫任务范式的获取和保留将在使用倒置花盆技术进行 4 天 REMSD、14 天间歇性白天缺氧 (EHYP) 或其组合后，对意识清醒的 55-60 天雄性大鼠进行评估（REMSD-EHYP）； (2) 将使用体外海马切片制备物的神经生理学细胞外记录来检查此类暴露范例对海马 CA1 区域内的长时程增强 (LTP) 的影响； (3) 在 REMSD、EHYP 或两者后，在幼稚动物和迷宫训练动物中使用免疫组织化学和蛋白质印迹方法来确定海马结构和新皮质内离子型谷氨酸受体分布和细胞凋亡的变化； (4) 将通过免疫组织化学和 AP-1 电迁移率测定在 REMSD、EHYP 和 REMSD-EHYP 的海马中进一步评估迷宫学习程序引起的早期基因诱导 (c-fos) 的改变。这些实验将加深我们对未经治疗的 OSAS 患者特别是神经认知功能下降的潜在机制和相互作用的理解。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，诱导细胞凋亡，从而改变与学习或保留新学到的任务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大脑区域内神经元兴奋性和突触传递的短期和长期变化，这些区域在记忆形成和学习中发挥着重要和明确的作用，例如海马体。