CART regulation of wakefulness

CART(可卡因和苯丙胺调节转录本)多肽似乎介导了相关的行为 使用精神刺激药物，包括：下丘脑介导的食物摄入抑制，激活 HPA轴、运动和奖励/动机。我们假设含有手推车的神经元 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) 以及参与调节觉醒的其他核团；即，也与 精神刺激剂。我们的初步研究表明：1)CART表现出昼夜节律 非人灵长类脊髓液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间产生深刻的、剂量依赖的觉醒增加；3) 对内源性CART信号的干扰增加了最初大发作的快速眼动睡眠 大鼠的活动期；4)非人灵长类动物和患有糖尿病的人的CART被抑制 帕金森症和其他以清醒障碍为特征的情况。我们建议进一步 表征CART多肽的尾迹促进作用，并探索其底物及其 潜在的临床意义。S.A.#1建议区分CART作为动态平衡的角色和 昼夜节律唤醒促进信号通过检查其每日振荡，对睡眠剥夺的反应， 以及与昼夜(觉醒活跃的)非人类灵长类动物(恒河猴)先前睡眠-觉醒的关系。S.A.#2 建议通过中心分娩来证明内源性手推车是正常觉醒所必需的 对大鼠的CART抗体进行检测，并表征CART/-和CART-/-小鼠的睡眠/觉醒状态。S.A.#3 建议从解剖学(大鼠、非人灵长类和人类)和行为学(大鼠)确定 CART促醒作用的区域、细胞和药理学基础。最后，S.A.#4提议 检查以保持清醒状态为特征的人体条件下的脊液车 (例如，发作性睡病、帕金森症、特发性睡眠过多和强直性肌营养不良)。这些加在一起， 这些发现将为在日益增长的环境中管理觉醒的机制提供新的见解 认识到关键的细胞机制还包括整合额外的、看似完全不同的 适应行为，如能量平衡、进食、奖励和动机。

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.