CART regulation of wakefulness

描述(由申请人提供)：CART(可卡因和苯丙胺调节的转录本)多肽似乎介导与精神刺激药物相关的行为，包括：下丘脑介导的食物摄入抑制，HPA轴的激活，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其他参与调节觉醒的核团有额外的解剖/行为关系(间接或直接)；即，也与精神刺激剂相关的行为‘状态’。我们的初步研究支持证明：1)CART在非人灵长类脊髓液中显示出日节律，并在清晨达到峰值；2)在大鼠的主要睡眠期间，脑室内给药可产生深刻的、剂量依赖的、增加觉醒的反应；3)对内源性CART信号的干扰增加了大鼠在最初的主要活动期的快速眼动睡眠；4)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疾病的人类中，CART受到抑制。我们建议进一步表征CART多肽的促醒作用，并探索其潜在的底物及其潜在的临床意义。S.A.#1建议通过检查CART的日常振荡、对睡眠剥夺的反应以及与昼夜(清醒活动的)非人类灵长类(恒河猴)先前睡眠-觉醒的关系，来区分CART作为动态平衡信号和昼夜唤醒信号的作用。S.A.#2建议通过将CART抗体集中传递给大鼠并表征CART和CART-/-小鼠的睡眠/唤醒状态来证明内源性CART是正常觉醒所必需的。S.A.#3建议从解剖学(大鼠、非人灵长类动物和人类)和行为学(大鼠)确定CART促进觉醒作用的区域、细胞和药理学基础。最后，S.A.#4建议检查以保持清醒能力受损(例如，发作性睡病、帕金森症、特发性睡眠症和强直性肌营养不良)为特征的人类条件下的脊液CART。综上所述，这些发现将为人们对清醒的管理机制提供新的见解，因为人们越来越认识到，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，如能量稳态、进食、奖励和动机。

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.