CART regulation of wakefulness

CART 觉醒调节

• 批准号: 7213767
• 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/7213767
• 关键词: Adaptive Behaviors; Antibodies; Arousal; Awareness; Behavior; Behavioral; Brain; CARTPT gene; Cell Nucleus; Cerebrospinal Fluid; Cholinergic Agents; Circadian Rhythms; Clinical; Condition; Daily; Depressed mood; Disease; Disruption; Dopamine; Dose; Eating; Endocrine; Excessive Daytime Sleepiness; Exhibits; Fostering; Genetic; HPSE gene; 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; day; feeding; hypocretin; hypothalamic-pituitary-adrenal axis; insight; nonhuman primate; programs; psychostimulant; receptor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：CART（可卡因和苯丙胺调节的转录物）肽似乎介导与精神兴奋剂药物相关的行为，包括：下丘脑介导的食物摄入抑制、HPA轴激活、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和参与介导觉醒的其他核团具有额外的解剖/行为关系（间接或直接）;即，一种与精神兴奋剂有关的行为状态。我们的初步研究支持性地证明：1）CART在非人灵长类动物脊髓液中表现出在清晨达到峰值的昼夜节律; 2）在大鼠的主要睡眠期期间，脑室内递送在大鼠中产生深度的、剂量依赖性的觉醒增加; 3）干扰内源性CART信号传导增加大鼠的初始主要活动期的快速眼动睡眠;和4）CART在非人灵长类动物和患有帕金森综合症和以觉醒障碍为特征的其他病症的人中被抑制。我们建议进一步表征CART肽的促醒作用，并探索潜在的底物及其潜在的临床意义。S.A. #1提出通过检查CART的每日振荡、对睡眠剥夺的响应性以及与昼夜（觉醒活跃）非人类灵长类动物（恒河猴）中先前睡眠-觉醒的关系来区分CART作为稳态与昼夜唤醒促进信号的作用。S.A. #2提出通过向大鼠中枢递送CART抗体并表征Cart和Cart -/-小鼠中的睡眠/觉醒状态来证明内源性CART对于正常觉醒是必需的。S.A. #3提出了CART唤醒促进作用的区域、细胞和药理学基础的解剖学（大鼠、非人类灵长类动物和人类）和行为学（大鼠）确定。最后，S。#4提出在以维持清醒的损伤为特征的人类状况中检查脊髓液CART（例如，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）。总之，这些发现将提供新的见解的机制管理清醒的背景下，越来越多的认识到，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，喂养，奖励和动机。