CART regulation of wakefulness

CART 觉醒调节

• 批准号: 7541731
• 负责人: DAVID B RYE
• 金额: $ 33.47万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-20 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541731
• 关键词: Adaptive Behaviors; Antibodies; Arousal; Awareness; Behavior; Behavioral; Brain; CARTPT gene; Cell Nucleus; Cerebrospinal Fluid; Circadian Rhythms; Clinical; Disease; Dopamine; Dose; Eating; Endocrine; Excessive Daytime Sleepiness; Exhibits; Fostering; Genetic; Homeostasis; Human; Hypothalamic structure; Idiopathic Hypersomnolence; Impairment; Lateral; Lead; Locomotion; Macaca mulatta; Mediating; Metabolic; Midbrain structure; Motivation; Mus; Myotonic Dystrophy; Narcolepsy; Neurobiology; Neurons; Neuropeptides; Organism; Parkinsonian Disorders; Pathway interactions; Pattern; Peptides; Pharmaceutical Preparations; REM Sleep; Rattus; Regulation; Research Personnel; Rewards; Rodent; Role; Rye cereal; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; System; Wakefulness; alertness; base; brain pathway; cholinergic; clinically significant; depressed; feeding; hypocretin; insight; nonhuman primate; programs; psychostimulant; receptor

CART (Cocaine and Amphetamine-Regulated Transcript) peptides appear to mediate behaviors associated with psychostimulant drugs including: hypothalamically mediated suppression of food intake, activation of the HPA axis, locomotion, and reward/motivation. We hypothesized that CART-containing neurons have additional anatomical/behavioral relationships (indirect or direct) with mesolimbic dopaminergic pathways and other nuclei involved in mediating wakefulness; i.e.,a behavioral 'state' also associated with psychostimulants. Our preliminary studies are supportive in demonstrating that: 1) CART exhibits a diurnal rhythm in non-human primate spinal fluid that peaks in the early morning; 2) intracerebroventricular delivery in rats during their major sleep period produces profound, dose-dependent, increases in wake; 3) interference with endogenous CART signaling increases rapid-eye-movement sleep in the initial major active period of rats; and 4)and CART is depressed in non-human primates and humans afflicted with parkinsonism and other conditions characterized by impairments in wakefulness. We propose to further characterize the wake promoting effects of CART peptides, and explore the underlying substrates and their potential clinical significance. S.A. #1 proposes to differentiate between CART'S role as a homeostatic vs. circadian wake promoting signal by examining its daily oscillations, responsiveness to sleep deprivation, and relationship to prior sleep-wake in the diurnal (wake-active) non-human primate (rhesus). S.A. #2 proposes to demonostrate that endogenous CART is necessary for normal wakefulness by central delivery of CART antibodies to rats and characterizing sleep/wake state in Cart +/- and Cart -/- mice. S.A. #3 proposes anatomical (rat,non-human primate, and human) and behavioral (rat)determination of the regional, cellular, and pharmacologic bases of CART'S wake promoting actions. Finally, S.A. #4 proposes to examine spinal fluid CART in human conditions characterized by impairments in maintaining wakefulness (e.g., narcolepsy, parkinsonism, idiopathic hypersomnia, and myotonic dystrophy). Taken together, these findings will provide new insights into the mechanisms governing wakefulness in the context of a growing recognition that the key cellular mechanisms also involve integration of additional, seemingly disparate adaptive behaviors such as energy homeostatis, feeding, reward and motivation.

CART（辅氨酸和安非他明调节转录物）肽似乎介导相关行为 与精神兴奋剂药物，包括：下丘脑介导的抑制食物摄入，激活 HPA轴、运动和奖励/动机。我们假设含有CART的神经元 与中脑边缘多巴胺能通路的其他解剖/行为关系（间接或直接） 以及涉及介导觉醒的其它核团;即，一种行为“状态”， 精神兴奋剂我们的初步研究表明：1）CART表现出昼夜 非人类灵长类动物脊髓液中的节律，在清晨达到峰值; 2）脑室内分娩 在大鼠的主要睡眠期产生深刻的，剂量依赖性的，增加清醒; 3） 内源性CART信号的干扰增加了最初主要的快速眼动睡眠， 大鼠的活跃期;和4）CART在非人灵长类动物和患有 帕金森综合症和其他以觉醒障碍为特征的病症。我们建议进一步 表征CART肽的唤醒促进作用，并探索潜在的底物及其 潜在的临床意义。S.A. #1建议区分CART的作用，作为一个稳态与 通过检查昼夜节律唤醒促进信号的每日振荡，对睡眠剥夺的反应性， 以及与白天活动（觉醒活跃）的非人灵长类动物（恒河猴）中先前睡眠-觉醒的关系。S.A. #2 建议证明内源性CART是必要的正常清醒的中央交付 和表征Cart +/-和Cart -/-小鼠中的睡眠/觉醒状态。S.A. #3 提出了解剖学（大鼠，非人类灵长类动物和人类）和行为（大鼠）的确定， CART唤醒促进作用的区域、细胞和药理学基础。最后，S。#4提议 在以维持清醒障碍为特征的人类条件下检查脊髓液CART (e.g.,发作性睡病、帕金森综合征、特发性睡眠过度和肌强直性营养不良）。综上所述各项 研究结果将为在日益增长的 认识到关键的细胞机制还涉及整合额外的，看似不同的， 适应性行为，如能量稳态、进食、奖励和激励。