ELECTROPHYSIOLOGY & PHARMACOLOGY OF SLEEP-WAKEFULNESS

描述（申请人的摘要）：该计划的总体目标 研究是为了了解生理和药理机制 控制睡眠，包括快速眼动阶段和非快速眼动阶段，从而提供声音 理解和治疗人类睡眠障碍的基础 原发性和继发性医疗和精神疾病。实验 该提案中描述的重点是对睡眠和觉醒的理解 细胞水平。所使用的关键技术是一种新颖的组合 自由行为猫的微透析和细胞外单单位记录。 非快速眼动睡眠阶段。尽管数据，包括来自我们实验室的数据， 表明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，具体的细胞机制 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分布和 对皮质和丘脑系统的战略传出投射 已知对于控制皮质激活很重要。基础的 前脑/前脑的视前区广泛涉及行为 国家控制。要研究的主要假设是腺苷是否 通过选择性抑制唤醒活性神经元来介导睡眠效应 基底前脑/视前区，没有任何影响 非唤醒活动和/或睡眠相关神经元。我们目前的初步数据 猫支持这样的假设：基底层的唤醒活跃神经元 前脑/视前区介导腺苷的促进睡眠作用， 通过A1受体发挥作用。我们还将评估去甲肾上腺素能的程度 控制基础前脑的唤醒调节。初步数据表明 去甲肾上腺素增加基底前脑的放电活动 唤醒活跃的神经元。 快速眼动睡眠阶段。含有去甲肾上腺素的基因座的假设 蓝核神经元抑制胆碱能神经元并允许快速眼动睡眠发生 当这些蓝斑神经元在慢波和快速眼动期间缓慢放电时 睡眠也会受到评估。我们将检验蓝斑假设 通过 α-2 受体作用的输入抑制中桥脑的放电 胆碱能区神经元已被行为识别为 在快速眼动睡眠期间优先活跃。相反，我们预测神经元活跃 在清醒和快速眼动睡眠中，受到的影响很小或根本不受影响 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，我们将检查其程度 血清素可控制中缝背核与睡眠相关的减慢 神经元通过 5-HT1A 体细胞树突受体放电。初步数据 表明微透析应用的 8-OH-DPAT 对 中缝背核的状态相关放电活动，我们还将 研究 5HT1A 拮抗剂的作用。

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.