Melatonin and Aging in Non-human Primates

描述（由申请人提供）：拟议项目的目标是确定非人灵长类动物下丘脑视交叉上核（SCN）的睡眠、体温调节、激素分泌和形态完整性的年龄相关变化，以及褪黑激素对维持老年猴巩固夜间睡眠、体温调节和认知能力的贡献。使用病变替代方法，我们还将确定褪黑激素的睡眠促进和降温作用在多大程度上取决于SCN的完整性。这将通过比较老年灵长类动物与接受松果体（Px）、SCN（SCNx）或松果体和SCN（Px/SCNx）损伤的年轻对照动物和年轻猴的睡眠数量和质量、认知能力、昼夜节律（温度、激素分泌）的振幅和时间模式以及褪黑激素治疗的效果来实现。受试者将为年轻（5.9岁）和老年（20-24岁）恒河猴。将对5个实验组（每组9只猴，共45只）进行试验，包括：（1）老年“手术"动物;（2）年轻的Px成年猴;（3）年轻的SCNx成年猴;（4）年轻的Px/SCNx合并病变成年猴;和（5）年轻的”手术"对照猴。将使用植入式遥测探头测量睡眠（多导睡眠描记术）和核心体温，将通过活动记录仪记录活动节律，将使用放射免疫测定法测量血浆褪黑激素和皮质醇水平，并将使用神经心理学任务评估认知能力。将使用术前和术后MRI和脑组织尸检形态学分析记录SCN的形态完整性和手术病变的质量。比较不同的猴子群体（老年人与年轻人;老年人或年轻人与Px、SCNx或PxISCNx; Px或SCNx vs. Px/SCNx），还使用受试者内设计（比较在基线和脑手术后收集的测量值），同时记录每只动物中SCN和松果体的形态完整性，将允许我们确定松果体或SCN中与年龄相关的变化对睡眠维持的贡献，认知功能和体温和激素分泌的昼夜节律。这种方法也将允许确定褪黑激素在灵长类动物睡眠中的作用，以及褪黑激素的急性睡眠促进和体温降低作用是否通过SCN介导。

DESCRIPTION (provided by applicant): The goals of the proposed project are to determine the age-related changes in sleep, temperature regulation, hormonal secretion and morphological integrity of the suprachiasmatic nuclei (SCN) of the hypothalamus in non-human primates and the contribution of melatonin to the maintenance of consolidated nocturnal sleep, thermoregulation and cognitive performance in aged monkeys. Using a lesion-replacement approach, we will also determine the extent to which sleep-promoting and hypothermic effects of melatonin depend on the integrity of the SCN. This will be accomplished by comparing sleep quantity and quality, cognitive performance, the amplitude and temporal patterns of the circadian body rhythms (temperature, hormonal secretion), as well as the effects of melatonin treatment, in old primates to young control animals and young monkeys that receive lesions of the pineal gland (Px), SCN (SCNx) or both pineal and SCN (Px/SCNx). Subjects will be young (5.9 yrs of age) and old (20-24 yrs of age) rhesus monkeys. Five experimental groups (9 monkeys in each group, 45 total) will be tested, including: (1) aged 'operated-on' animals; (2) young adults with Px; (3) young adults with SCNx; (4) young adults with combined Px/SCNx lesions; and (5) young adult 'operated-on' control monkeys. Sleep (polysomnography) and core body temperature will be measured using implanted telemetric probes, activity rhythms will be recorded actigraphically, plasma melatonin and cortisol levels will be measured using radioimmunoassay and cognitive performance will be assessed using neuropsychological tasks. The morphological integrity of the SCN and quality of surgical lesions will be documented using pre- and post-surgery MRI and post-mortem morphological analysis of brain tissue. Comparing different groups of monkeys (old vs. young; old or young vs. Px, SCNx or PxISCNx; Px or SCNx vs. Px/SCNx) and also using within-subject design (comparing measures collected at baseline and after the brain surgery), while documenting morphological integrity of SCN and pineal in each animal, will allow us to determine the contribution of age-related changes in the pineal or SCN to the maintenance of sleep, cognitive functions and circadian body rhythms of temperature and hormonal secretion. This approach will also allow determining the role of melatonin in primate sleep and whether the acute sleep-promoting and hypothermic effects of melatonin are mediated via the SCN.