ELECTROPHYSIOLOGY & PHARMACOLOGY OF SLEEP-WAKEFULNESS

电生理学

• 批准号: 6627581
• 负责人: MAHESH M THAKKAR
• 金额: $ 13万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-04 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6627581
• 关键词: REM sleep; adenosine; cats; electrical measurement; electrophysiology; microdialysis; neuropharmacology; neuroregulation; norepinephrine; preoptic areas; prosencephalon; single cell analysis; sleep disorders; wakefulness

DESCRIPTION (applicant's abstract): The broad objective of this program of research is to understand the physiological and pharmacological mechanisms controlling sleep, both the REM and nonREM phases, and thereby provide a sound basis for the understanding and treatment of human sleep disorders, both primary and secondary to medical and psychiatric conditions. The experiments described in this proposal focus on understanding of sleep and wakefulness at the cellular level. The key technique to be used is a novel combination of microdialysis and extracellular single unit recording in freely behaving cats. The nonREM sleep phase. Although data, including those from our laboratory, suggest adenosine is an endogenous sleep factor that acts on the brain to promote the nonREM phase of sleep, the specific cellular mechanisms of adenosine's actions are not known. Adenosine's powerful state-altering effects occur primarily via the basal forebrain cholinergic neurons' widespread and strategic efferent projections to the cortical and thalamic systems that are known to be important for the control of cortical activation. The basal forebrain/preoptic region of the forebrain is widely implicated in behavioral state control. The major hypothesis to be investigated is whether adenosine mediates sleep effect by the selective inhibition of the wake-active neurons in the basal forebrain/preoptic region, without having any effect of non-wake-active and/or sleep-related neurons. Our present preliminary data in cat support the hypothesis that the wake-active neurons of the basal forebrain/preoptic region mediate the sleep-promoting actions of adenosine, acting via A1 receptors. We will also evaluate the extent of noradrenergic control on the basal forebrain regulation of arousal. Preliminary data indicate that norepinephrine increases the discharge activity of basal forebrain wake-active neurons. The REM sleep phase. The hypothesis that norepinephrine-containing locus coeruleus neurons disinhibit cholinergic neurons and allow REM sleep to occur when these locus coeruleus neurons slow discharge during slow wave and REM sleep will also be evaluated. We will test the hypothesis the locus coeruleus input acting through the alpha-2 receptor inhibits discharge of the mesopontine cholinergic zone neurons that have been behaviorally identified to be preferentially active during REM sleep. In contrast, we predict neurons active in both wakefulness and REM sleep will be minimally or not at all affected by microdialysis application of norepinephrine. Finally, using the same unit recording/microdialysis technique, we will examine the degree to which serotonin acts to control the sleep-related slowing of dorsal raphe nucleus neuronal discharge via the 5-HT1A somato-dendritic receptors. Preliminary data suggest a strong suppressive effect of microdialysis-applied 8-OH-DPAT on state-related discharge activity of the dorsal raphe nucleus, and we will also investigate the effects of 5HT1A antagonists.

描述（申请人的摘要）：本计划的广泛目标是 研究是为了了解生理和药理机制 控制睡眠，REM和非REM阶段，从而提供声音 了解和治疗人类睡眠障碍的基础， 主要和次要的医疗和精神状况。实验 在这个建议中描述的重点是了解睡眠和觉醒， 细胞水平。要使用的关键技术是一种新的组合， 微透析和细胞外单个单位记录在自由行为的猫。 非REM睡眠阶段尽管数据，包括我们实验室的数据， 腺苷是一种内源性睡眠因子，作用于大脑， 促进睡眠的非快速眼动阶段， 腺苷的作用尚不清楚。腺苷强大的状态改变作用 主要通过基底前脑胆碱能神经元的广泛和 向皮质和丘脑系统的战略传出投射， 已知对控制皮层激活很重要。基底 前脑/前脑的视前区广泛涉及行为 国家控制。需要研究的主要假设是腺苷是否 通过选择性抑制脑内的觉醒神经元介导睡眠效应， 基底前脑/视前区，没有任何影响， 非唤醒活跃和/或睡眠相关神经元。我们目前的初步数据， 猫支持这一假设，即唤醒活跃的神经元的基底 前脑/视前区介导腺苷的睡眠促进作用， 通过A1受体起作用。我们还将评估去甲肾上腺素能 控制基底前脑对觉醒的调节。初步数据显示 去甲肾上腺素增加基底前脑的放电活动 唤醒活跃神经元。 REM睡眠阶段假设含有去甲肾上腺素的位点 蓝斑神经元解除胆碱能神经元的抑制，并允许REM睡眠发生 当这些蓝斑神经元在慢波和REM期间减慢放电时， 睡眠也将被评估。我们将检验蓝斑 通过α-2受体作用的输入抑制中脑脑桥的放电 胆碱能区神经元已被行为学鉴定为 在快速眼动睡眠时更活跃。相反，我们预测神经元活跃 在清醒和快速眼动睡眠中， 去甲肾上腺素的微透析应用。最后，使用相同的单位 记录/微透析技术，我们将检查 5-羟色胺控制睡眠相关的中缝背核减慢 通过5-HT 1A体细胞-树突受体的神经元放电。初步数据 表明微透析应用8-OH-DPAT对 状态相关的放电活动中缝背核，我们也将 研究5 HT 1A拮抗剂的作用。