CART regulation of wakefulness

描述（由申请人提供）：CART（可卡因和安非他明调节转录本）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、下丘脑轴的激活、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有额外的解剖/行为关系（间接或直接）；也就是说，一种行为“状态”也与精神兴奋剂有关。我们的初步研究表明：1)非人类灵长类动物脊髓液中的CART表现出昼夜节律，在清晨达到峰值；2)大鼠在主要睡眠期间的脑室内分娩会产生明显的、剂量依赖性的醒觉增加；3)内源性CART信号的干扰增加了大鼠主活动初期的快速眼动睡眠；4)在非人类灵长类动物和患有帕金森病和其他以清醒障碍为特征的疾病的人类中，CART被抑制。我们建议进一步表征CART肽的尾流促进作用，并探索其潜在的底物及其潜在的临床意义。s.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白天（清醒活跃）的非人灵长类动物（猕猴）先前睡眠-觉醒的关系，来区分CART作为稳态信号与昼夜节律觉醒促进信号的作用。s.s.a. #2建议通过向大鼠中枢递送CART抗体，并表征CART和CART -/-小鼠的睡眠/清醒状态，证明内源性CART是正常清醒所必需的。s.s.a. #3提出了解剖学（大鼠、非人灵长类动物和人类）和行为学（大鼠）对CART唤醒作用的区域、细胞和药理基础的确定。最后，sa #4建议检查以保持清醒受损为特征的人类条件下的脊髓液CART（例如，嗜睡症、帕金森病、特发性嗜睡症和肌强直性营养不良）。综上所述，这些发现将为清醒的控制机制提供新的见解，因为人们越来越认识到关键的细胞机制也涉及额外的、看似不同的适应性行为的整合，如能量稳态、喂养、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.