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）：该计划的广泛目标 研究是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 理解和治疗人类睡眠障碍的基础 初级和继发于医学和精神病疾病。实验 在此提案中描述的是理解睡眠和清醒的理解 细胞水平。要使用的关键技术是一种新颖的组合 自由行为猫中的微透析和细胞外单个单位记录。 非REM睡眠阶段。尽管数据，包括我们实验室的数据，但 暗示腺苷是对大脑作用于大脑的内源性睡眠因子 促进睡眠的非REM阶段，这是特定的细胞机制 腺苷的作用尚不清楚。腺苷的强大改变状态的影响 主要是通过基底前脑胆碱能神经元广泛发生的 对皮质和丘脑系统的战略传递预测 已知对于控制皮质激活很重要。基础 前脑的前脑/前区域广泛与行为有关 国家控制。要研究的主要假设是腺苷是否是否 通过选择性抑制唤醒活性神经元中的睡眠效应 基础前脑/前区域，没有任何影响 非醒作和/或与睡眠有关的神经元。我们目前的初步数据 CAT支持基底的唤醒神经元的假设 前脑/前区域介导腺苷的促进睡眠作用， 通过A1受体起作用。我们还将评估去甲肾上腺素能的程度 控制唤醒的基础前脑调节。初步数据表示 去甲肾上腺素增加了基础前脑的排放活性 唤醒活跃的神经元。 REM睡眠阶段。含去甲肾上腺素的基因座的假设 凝结神经元抑制胆碱能神经元并允许REM睡眠发生 当这些基因座凝结神经元在慢波和REM期间缓慢放电时 睡眠也将评估。我们将检验假设核心位点 通过Alpha-2受体作用的输入抑制中桥的排出 胆碱能区域神经元在行为上被确定为 在REM睡眠期间优先活跃。相比之下，我们预测神经元活跃 在清醒和REM睡眠中，都会最小或不受任何影响 去甲肾上腺素的微透析应用。最后，使用相同的单元 记录/微透析技术，我们将研究 5-羟色胺起作用可控制与睡眠相关的背raphe核的放慢 神经元通过5-HT1A somato树突受体的放电。初步数据 提出对微透析的8-OH-DPAT对强烈的抑制作用 背侧raphe核与状态相关的排放活性，我们还将 研究5HT1A拮抗剂的作用。