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，影响高达5%的人口，其特征是反复出现缺氧和反复的脑电/行为唤醒，特别是在快速眼动睡眠期间。如果不进行治疗，OSAS与严重的神经认知疾病有关，如白天过度嗜睡，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)和间歇性低氧对OSAS相关神经认知功能障碍的相对贡献仍不清楚。为了验证REM睡眠剥夺和间歇性低氧以相加的方式影响学习和记忆的假说，将在幼年大鼠模型中检验四个主要目标：(1)在55-60日龄清醒雄性大鼠中，采用倒置花盆技术、14d间歇性白天低氧(EHYP)或其组合(REMSD-EHYP)，评估清醒雄性大鼠对Morris水迷宫任务范式的习得和保持；(2)这种暴露范式对海马区CA1区长时程增强(LTP)的影响将通过体外海马片制备的神经生理学细胞外记录来检测；(3)在REMSD、EHYP或两者兼而有之的幼稚动物和迷宫训练动物中，将采用免疫组织化学和Wester印迹法检测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电迁移率分析进一步评估迷宫学习过程诱导的早期基因诱导(c-fos)在REMSD、EHYP和REMSD-EHYP模型中的变化。这些实验将扩大我们对未经治疗的OSAS患者尤其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的离子型谷氨酸受体复合体的上调或下调，诱导细胞凋亡，从而改变与学习或保持新学习任务相关的早期基因激活模式。受体-信号转导通路的这种变化也可能导致神经元兴奋性和突触传递的短期和长期变化，这些区域在记忆形成和学习中具有重要和明确的作用，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.