THE AGING OF CIRCADIAN AND HOMEOSTATIC PROCESSES CONTROLLING SLEEP

控制睡眠的昼夜节律和稳态过程的老化

• 批准号: 6098469
• 负责人: WILLIAM C DEMENT
• 金额: $ 13.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098469
• 关键词: age difference; aging; biological clocks; circadian rhythms; embryo /fetus cell /tissue; experimental brain lesion; homeostasis; laboratory rat; longitudinal animal study; nervous system transplantation; sleep; sleep deprivation; sleep regulatory center; suprachiasmatic nucleus

Aging is characterized by reductions in the amplitude of a wide variety of circadian rhythms in mammals. This is particularly evident in the daily patterns of sleep and wakefulness which becomes progressively fragmented in the later years of life. The ubiquity of age-related decrements in circadian timekeeping and evidence of morphological changes in the suprachiasmatic nuclei (SCN) with age have contributed to the current view that age-related sleep-wake cycle fragmentation is due to organic deterioration of the biological clock. There are, however, at least two processes involved in sleep-wake cycle regulation -- a circadian process that appears to promote wakefulness at specific times of the day, and a sleep homeostatic process responsible for compensatory sleep in response to clock-imposed prior wakefulness. Age-related deterioration in sleep-wake cycle regulation may therefore involve intrinsic oscillatory mechanisms of the SCN, SCN effector mechanisms responsible for promoting wakefulness, and/or the sleep homeostat. Our recent investigations lead us to believe that age-related fragmentation of the sleep/wake cycle may be due to both deterioration in the circadian and homeostatic process controlling sleep-wakefulness. Little is known about how the circadian clock modulates states of arousal. Within the framework of an Opponent Process Model of sleep/wake regulation, we plan to investigate both the circadian and homeostatic control of sleep as a function of aging primarily using longitudinal experimental designs. Experiments will involve much needed longitudinal sleep-wake recordings under constant environmental conditions to accurately characterize circadian rhythm decrements with aging. SCN- lesioned rats will be subjected to acute sleep deprivation to assay age- related decrements of the sleep homeostatic process independent of influences from the circadian clock. We will also employ fetal SCN- transplantation techniques to restore sleep-wake cycles in SCN-lesioned and aged rats to further characterize the functional role of the SCN in sleep-wake regulation, and to determine if attributes of the transplanted SCN can ameliorate age-related sleep-wake regulation, and to determine if attributes of the transplanted SCN can ameliorate age-related sleep- wake cycle fragmentation. Finally, we will microinject anesthetics, tetrodotoxin, and GABA agonists/antagonists into the SCN or transplanted SCN to better understand how the circadian clock communicates temporal information that enhances sleep-wake cycle consolidation. These experiments should greatly improve our understanding of circadian and homeostatic determinants of sleep-wakefulness and their roles in age- related fragmentation of the sleep-wake cycle.

衰老的特点是多种物质的振幅减少 哺乳动物的昼夜节律。 这一点在 日常睡眠和觉醒模式逐渐变得 在晚年的生活中支离破碎。 与年龄相关的现象普遍存在 昼夜节律的减少和形态变化的证据 随着年龄的增长，视交叉上核（SCN）中的 目前的观点认为，与年龄相关的睡眠-觉醒周期碎片化是由于 生物钟的有机退化。 然而，有在 至少有两个过程参与睡眠-觉醒周期调节—— 似乎在特定时间促进清醒的昼夜节律过程 一天中的时间，以及负责补偿的睡眠稳态过程 睡眠是对生物钟强加的先前觉醒的反应。 与年龄相关 因此，睡眠-觉醒周期调节的恶化可能涉及 SCN 的内在振荡机制、SCN 效应机制 负责促进觉醒和/或睡眠稳态。 我们的 最近的调查使我们相信，与年龄相关的分裂 睡眠/觉醒周期的变化可能是由于昼夜节律恶化造成的 和控制睡眠觉醒的稳态过程。 人们对生物钟如何调节生物钟的状态知之甚少 唤醒。 在睡眠/唤醒的对手过程模型的框架内 监管，我们计划调查昼夜节律和稳态 主要利用纵向控制睡眠作为衰老的函数 实验设计。 实验将涉及非常需要的纵向 持续环境条件下的睡眠-觉醒记录 准确地描述昼夜节律随衰老而减少的特征。 SCN- 受损大鼠将受到急性睡眠剥夺以测定年龄 睡眠稳态过程的相关减少独立于 生物钟的影响。 我们还将使用胎儿 SCN- 移植技术恢复 SCN 损伤的睡眠-觉醒周期 和老年大鼠，以进一步表征 SCN 在 睡眠-觉醒调节，并确定移植的属性是否 SCN 可以改善与年龄相关的睡眠-觉醒调节，并确定 移植的 SCN 的属性是否可以改善与年龄相关的睡眠 唤醒周期碎片。 最后，我们将显微注射麻醉剂， 河豚毒素和 GABA 激动剂/拮抗剂进入 SCN 或移植 SCN 更好地了解生物钟如何进行时间通讯 增强睡眠-觉醒周期巩固的信息。 这些 实验应该极大地提高我们对昼夜节律和 睡眠觉醒的稳态决定因素及其在年龄中的作用 睡眠-觉醒周期的相关碎片。