NEUROCHEMICAL BASIS OF SLEEP HOMEOSTASIS

睡眠稳态的神经化学基础

基本信息

批准号：
6390134
负责人：
WILLIAM C DEMENT
金额：
$ 28.67万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-05-25 至 2003-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (adapted from applicant's abstract): Compensatory sleep responses (CSR) following extended prior waking constitute a central tenet of sleep physiology-- that sleep is "homeostatically" regulated. NonREM sleep time, sleep episode duration, and EEG delta power normally increase proportional to prior wake duration. Waking from stimulants (methamphetamine and methylphenidate) also induce CSR. However, waking induced by pemoline or selective dopamine reuptake blockers (DARBs) produces no CSR, suggesting that dopamine-induced wakefulness can uncouple the sleep homeostatic mechanism. The cholinergic neurons in the nucleus basalis (NBM) and adjacent basal forebrain regions that diffusely project to the cerebral cortex have been extensively characterized in promotion of wakefulness. Because the NBM receives dopaminergic input directly from the ventral tegmental area (VTA), wakefulness produced by DARBs is likely to be mediated directly in this region. Given the hypothetical role of adenosine as an endogenous sleep factor, it is possible that adenosine levels in this region may interact with dopaminergic influences on the NBM. The research proposed investigates dopaminergic interaction with sleep homeostasis in terms of its generality, involvement of the basal forebrain, DA receptor subtypes involved, interaction with sleep deprivation, and interaction with adenosinergic mechanisms that also modulate sleep-wakefulness. Six interrelated specific aims will examine the role of DA in sleep homeostasis using computerized sleep recording, microinjection, and in vivo dialysis techniques in rats. The experiments will test the hypotheses that: 1.) Wakefulness induced by selective increase in DA neurotransmission is uncoupled from the sleep homeostatic process; 2.) Direct VTA dopaminergic projections to the NBM mediate DA waking without subsequent compensatory sleep; 3.) Specific DA receptor subtypes mediate the ability of DARBs to promote waking without subsequent compensatory hypersomnolence; 4.) DA-induced basal forebrain waking counteracts compensatory sleep drive following sleep deprivation; 5.) Elevated adenosine levels mediate hypersomnolence following sleep deprivation or waking induced by classic psychomotor stimulants (methamphetamine, methylphenidate); 6.) Adenosinergic agonists in the NBM can restore CSR after pemoline or DARB-induced wakefulness. Excessive sleepiness undermines the health and quality of life in millions of people including the elderly, sleep apnea sufferers, narcoleptics, and shift-workers. Sleep regulation is also highly disturbed in patients with abnormal DA production, such as in Parkinson's Disease. The proposed studies will advance our basic understanding of central mechanisms underlying compensatory sleep, with the hope that this basic knowledge will lead to better long-term treatments for excessive sleepiness.

描述（改编自申请人的摘要）：补偿性睡眠长时间提前醒来后的反应（CSR）构成了一个中心原则睡眠生理学——睡眠是“稳态”调节的。非快速眼动睡眠睡眠时间、睡眠持续时间和脑电图增量功率通常会增加与之前的唤醒持续时间成正比。从兴奋剂中醒来（甲基苯丙胺和哌醋甲酯）也能诱导企业社会责任。然而，醒来由匹莫林或选择性多巴胺再摄取阻滞剂 (DARB) 诱导产生没有 CSR，表明多巴胺引起的觉醒可以解开睡眠稳态机制。基底核 (NBM) 中的胆碱能神经元和邻近的基底前脑区域，广泛投射到大脑皮质在促进觉醒方面已被广泛表征。因为 NBM 直接从腹侧接收多巴胺能输入被盖区 (VTA)，DARB 产生的觉醒可能是介导的直接在这个区域。鉴于腺苷作为内源性睡眠因素，该区域的腺苷水平可能可能与 NBM 的多巴胺能影响相互作用。研究提出研究多巴胺能与睡眠稳态的相互作用一般性、基底前脑的参与、DA 受体亚型涉及、与睡眠剥夺的相互作用以及与腺苷能机制也调节睡眠-觉醒。六相互关联的具体目标将检查 DA 在睡眠稳态中的作用使用计算机化睡眠记录、显微注射和体内透析大鼠技术。实验将检验以下假设：1.) 选择性增加 DA 神经传递诱导的觉醒是与睡眠稳态过程脱钩； 2.) 直接 VTA 多巴胺能对 NBM 的预测会介导 DA 苏醒，而无需后续补偿睡觉; 3.) 特定的 DA 受体亚型介导 DARB 的能力促进清醒，而不会出现随后的代偿性嗜睡； 4.) DA诱导的基底前脑唤醒抵消补偿性睡眠驱动力睡眠不足后； 5.) 腺苷水平升高介导睡眠不足或醒来后诱发的嗜睡精神运动兴奋剂（甲基苯丙胺、哌醋甲酯）； 6.) 腺苷能 NBM 中的激动剂可以在匹莫林或 DARB 诱导后恢复 CSR 觉醒。过度嗜睡会损害健康和生活质量在包括老年人、睡眠呼吸暂停患者在内的数百万人中，嗜睡症患者和轮班工人。睡眠调节也受到严重干扰 DA 产生异常的患者，例如帕金森病患者。拟议的研究将增进我们对中央的基本理解补偿性睡眠的潜在机制，希望这一基本机制了解这些知识将有助于更好地长期治疗过度嗜睡。