腹外侧视前区腺苷及其A1受体对睡眠觉醒的调节作用及机制研究

Sleep is regulated by circadian rhythm and homeostasis. Adenosine is a critical endogenous sleep-promoting substance, which is involved in the regulation of sleep. There are four subtypes of adenosine receptors (R), including A1R, A2AR, A2BR and A3R. Among them, A1R and/or A2AR subtypes have been reported to mediate the sleep-promoting effect of adenosine. Several lines of evidence suggest that adenosine acts via A1R at the wake-promoting areas of cholinergic basal forebrain, histaminergic tuberomammillary nucleus (TMN), and/or orexinergic lateral hypothalamus to promote sleep. However, systemical or intracerebroventricular administration of an A1R agonist has no clear effects on sleep promotion. In addition, A1R knockout mice do not show any phenotypes on sleep under baseline conditions. Thus, we hypothesize that the effect of adenosine is site-dependent and activation of A1R in some brain regions may inhibit sleep. The ventrolateral preoptic nucleus (VLPO) has been considered to be a critical region for sleep induction. We hypothesize that activation of A1R may inhibit the sleep active neurons in the VLPO, and thus promote wakefulness, counteracting the effect caused by inhibition of wake-promoting systems. In this study, we will investigate the role of A1R in the VLPO on the regulation of spontaneous sleep-wake cycle and homeostatic sleep by employing a highly automatic recording and analysis system for sleep-wake profiles, neuropharmacology, immunohistochemistry, microdialysis, high performance liquid chromatography (HPLC) and H1R knockout mice.

睡眠受昼夜节律和内稳态因素的调控。腺苷是重要的内源性促眠物质，腺苷受体（Receptor, R）有四种亚型：A1R、A2AR、A2BR和A3R，大量研究显示: A1R和A2AR介导腺苷的促眠效应。研究表明：腺苷可通过A1R抑制基底前脑胆碱能神经元、结节乳头核（TMN）组胺能神经元、和/或下丘脑外侧部orexin能神经元，促进睡眠。但全身或脑室内给予A1R激动剂对睡眠觉醒行为无明显影响。因此我们推测，腺苷作用呈现脑区依赖性，可能激活某些脑区的A1R，抑制睡眠。下丘脑腹外侧视前区（VLPO）是重要的睡眠中枢，我们推测激活VLPO区A1R可能抑制睡眠中枢，促进觉醒，抵消全脑内给药抑制觉醒系统引起的睡眠。本研究将利用高度自动化睡眠觉醒生物解析系统，结合药理学、免疫组化、微透析、高效液相色谱分析及H1R基因敲除小鼠，研究VLPO区A1R对睡眠-觉醒行为及睡眠内稳态的调节作用及神经通路和机制。