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，其特征是反复发作的缺氧和反复发作的EEG/行为觉醒，特别是在REM睡眠期间。 如果不进行治疗，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、注意力广度、学习和警惕性下降。 然而，快速眼动睡眠剥夺（REMSD）和间歇性缺氧对阻塞性睡眠呼吸暂停综合征相关的神经认知功能障碍的相对作用尚不清楚。 为了检验REM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的具体目标，如下所示：（1）在使用倒置花盆技术的4天REMSD后，14天间歇性日间缺氧（EHYP）或其组合（2）使用体外海马切片制备的神经生理学细胞外记录来检查这种暴露模式对海马CA 1区内的长时程增强（LTP）的影响;（3）在REMSD、EHYP或两者之后，在未处理和迷宫训练的动物中，使用免疫组织化学和wester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）通过免疫组织化学和AP-1电迁移率改变分析进一步评估迷宫学习程序引起的REMSD、EHYP和REMSD-EHYP海马早期基因诱导（c-fos）的改变。 这些实验将加深我们对未经治疗的OSAS患者的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，或两者都将导致上调或下调特定的离子型谷氨酸受体复合物，诱导细胞凋亡，从而修改与学习或保留新学习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在记忆形成和学习中具有重要和确定作用的脑区域（如海马）内神经元兴奋性和突触传递的短期和长期变化。

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.