Melatonin and Aging in Non-human Primates

描述(申请人提供)：该项目的目标是确定非人类灵长类动物睡眠、体温调节、激素分泌和下丘脑视交叉上核(SCN)形态完整性的年龄相关变化，以及褪黑素对维持老年猴子巩固的夜间睡眠、体温调节和认知能力的贡献。使用病变替代方法，我们还将确定褪黑素的促进睡眠和降温作用在多大程度上依赖于SCN的完整性。这将通过比较老年灵长类动物和接受松果体(Px)、SCN(SCNx)或松果体和SCN(Px/SCNx)损伤的年轻对照动物和幼猴的睡眠数量和质量、认知表现、昼夜节律(温度、激素分泌)的幅度和时间模式以及褪黑素治疗的效果来实现。受试者将是年轻的(5.9岁)和老年(20-24岁)恒河猴。将测试五个试验组(每组9只猴子，总共45只)，包括：(1)老年手术动物；(2)患有PX的年轻人；(3)患有SCNx的年轻人；(4)患有Px/SCNx联合皮损的年轻人；以及(5)年轻人的‘手术’对照猴子。将使用植入的遥测探头测量睡眠(多导睡眠图)和核心体温，活动记录仪将记录活动节律，使用放射免疫分析法测量血浆褪黑素和皮质醇水平，并使用神经心理任务评估认知表现。SCN的形态完整性和手术损伤的质量将通过手术前后的MRI和死后脑组织的形态分析来证明。比较不同的猴群(老猴与幼猴；老猴或幼猴与Px、SCNx或PxISCNx；Px或SCNx与Px/SCNx)并使用受试者内设计(比较基线和脑外科手术后收集的测量结果)，同时记录每种动物的SCN和松果体的形态完整性，将使我们能够确定松果体或SCN的年龄相关变化对维持睡眠、认知功能以及体温和激素分泌的昼夜身体节律的贡献。这种方法还可以确定褪黑素在灵长类睡眠中的作用，以及褪黑素的急性促进睡眠和降温作用是否通过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.