REM SLEEP DEPRIVATION, HYPOXIA, AND HIPPOCAMPAL FUNCTION

阻塞性睡眠呼吸暂停综合征（OSAS）是一种常见的疾病，影响了多达5%的人口，其特征是反复发作的缺氧和反复的脑电图/行为唤醒，特别是在快速眼动睡眠期间。如果未经治疗，OSAS与显著的神经认知疾病相关，如白天过度嗜睡和智力表现、注意力持续时间、学习能力和警觉性下降。然而，快速眼动睡眠剥夺（REMSD）和间歇性缺氧对osas相关神经认知功能障碍的相对影响尚不清楚。为了验证快速眼动睡眠剥夺和短暂性缺氧以一种累加的方式影响学习和记忆的假设，我们将在一个年轻的成年大鼠模型中检验四个主要的具体目标，如下：(1)在55-60天的有意识雄性大鼠进行4天的倒立花盆快速眼动睡眠剥夺和14天的短暂性日间缺氧（EHYP）或两者结合（REMSD-EHYP）后，评估莫里斯水迷宫任务范式的习得和保留；(2)这些暴露模式对海马CA1区域内长期增强（LTP）的影响将通过体外海马切片制备的神经生理学细胞外记录进行检查；(3)采用免疫组织化学和western blot方法，在未进行REMSD、EHYP或两者同时进行的小鼠和迷宫训练的小鼠中，测定海马和新皮层内嗜离子性谷氨酸受体分布和细胞凋亡的变化；(4)在REMSD、EHYP和REMSD-EHYP的海马中，迷宫学习过程引发的早期基因诱导（c-fos）的改变将通过免疫组织化学和AP-1电迁移转移实验进一步评估。这些实验将扩展我们对未经治疗的OSAS患者特定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或两者都会导致特异性嗜离子性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习任务相关的早期基因激活模式。这种受体信号转导通路的改变也可能导致神经元兴奋性和突触传递的短期和长期变化，这些变化发生在大脑中对记忆形成和学习有重要作用的区域，如海马体。

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.