Melatonin and Aging in Non-human Primates

项目描述（由申请人提供）：该项目旨在确定非人灵长类动物下丘脑视交叉上核（SCN）的睡眠、温度调节、激素分泌和形态完整性的年龄相关变化，以及褪黑素对老年猴子夜间巩固睡眠、体温调节和认知表现的贡献。使用病变替代方法，我们还将确定褪黑激素促进睡眠和降低体温的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年轻对照动物和接受松果体（Px）、SCN （SCNx）或松果体和SCN （Px/SCNx）损伤的年轻猴子的睡眠数量和质量、认知表现、昼夜节律的幅度和时间模式（温度、激素分泌）以及褪黑激素治疗的效果来完成。研究对象为年轻的（5.9岁）和年老的（20-24岁）恒河猴。将测试五个实验组（每组9只猴子，共45只），包括：(1)老年“手术”动物；(2)青壮年伴Px；(3)患有SCNx的年轻人；(4)年轻成人合并Px/SCNx病变；(5)年轻的成年“手术”对照猴子。睡眠（多导睡眠图）和核心体温将通过植入的遥测探针来测量，活动节律将通过活动图来记录，血浆褪黑激素和皮质醇水平将通过放射免疫测定来测量，认知能力将通过神经心理学任务来评估。SCN的形态学完整性和手术病变的质量将通过术前和术后MRI和死后脑组织形态学分析来记录。比较不同的猴群(年老与年轻、年老或年轻、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值），同时记录每只动物中SCN和松果体的形态完整性，将使我们能够确定松果体或SCN中与年龄相关的变化对睡眠、认知功能和体温和激素分泌的昼夜节律的维持的贡献。这种方法还可以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降体温作用是否通过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.