The Roles of Neuropeptide S System in the Regulation of Sleep and Wakefulness

描述（由申请人提供）：睡眠障碍影响10%至20%的普通人群，是一项重大的公共卫生挑战。揭示参与睡眠调节的新的神经递质系统和结构将大大扩展我们对这一基本生理功能的理解。此外，它将导致潜在的治疗目标的各种睡眠障碍或干扰，如失眠，白天过度嗜睡，睡眠呼吸暂停和嗜睡症。神经肽S（Neuropeptide S，NPs）及其受体是新近发现的一种促进觉醒的神经肽系统。我们以前的研究表明，中枢给药显著诱导觉醒，抑制睡眠的所有阶段，并减少睡眠和觉醒的不同阶段之间的过渡。我们的核心假设是，神经肽S是一个重要的内源性调节睡眠和觉醒，并调节唤醒中心的活动。长期的目标是进一步研究睡眠调节系统在睡眠和觉醒调节中的作用。在本建议中，我们将探讨三个具体目标。(1)测定光/暗周期和睡眠剥夺后的β肽、前体和受体mRNA浓度。我们将在不同的昼夜节律时间和持续黑暗条件下以及睡眠剥夺后，监测β肽、β肽前体和受体mRNA的表达。(2)确定在不同脑区局部注射神经肽S是否影响睡眠结构和稳态。在三个脑区（A）外侧下丘脑、（B）结节乳头核（TMN）和（C）外侧背侧被盖核（LDTg）局部注射皮摩尔剂量的多巴胺是否也诱导觉醒并抑制REM和NREM睡眠？提出这三个脑区是因为它们都表达高水平的NPSR mRNA，并接受强烈的神经纤维支配。此外，它们是在警觉状态调节中起重要作用的脑区。这些实验将确定是否在涉及清醒和REM睡眠的神经元回路中起作用，并将增加我们对睡眠与其他唤醒网络相互作用的理解。(3)确定睡眠结构中β受体缺陷的后果。最近已经产生了β受体KO小鼠。我们将描述NPSR KO小鼠在基线条件下和睡眠剥夺后的睡眠参数。正如我们从其他肽能系统中所了解到的那样，根据这一目标获得的数据，如果成功的话，将明确地证明睡眠调节系统是调节睡眠和觉醒的电路的重要组成部分。

DESCRIPTION (provided by applicant): Sleep disturbances affect 10 to 20 percent of the general population and represent a major public health challenge. Revealing novel neurotransmitter systems and structures that are involved in sleep regulation will significantly extend our understandings to this essential physiological function. In addition, it will lead to potential therapeutic targets for various sleep disorders or disturbances such as insomnia, excessive daytime sleepiness, sleep apnea and narcolepsy. Neuropeptide S (NPS) and it receptor are a newly discovered neuropeptide system that promotes arousal and wakefulness. Our previous studies have shown that central administration of NPS dramatically induces wakefulness, suppresses all stages of sleep and reduces the transitions between different stages of sleep and wakefulness. Our core hypothesis is that neuropeptide S is an important endogenous regulator of sleep and wakefulness and modulates the activity of arousal center. The long term objective is to further investigate the roles of NPS system in the regulation of sleep and wakefulness. In this proposal, we will investigate three specific aims. (1) To determine NPS peptide, precursor and receptor mRNA concentrations during the light/dark cycle and after sleep deprivation. We will monitor the expressions of NPS peptide, NPS precursor and receptor mRNA contents at different circadian times and in conditions of constant darkness and after sleep deprivation. (2) To determine whether local injection of Neuropeptide S in different brain areas affects sleep architecture and homeostasis. Does local injection of NPS at picomolar doses in three brain regions (A) lateral hypothalamus, (B) tuberomammillary nucleus (TMN) and (C) laterodorsal tegmental nuclei (LDTg) also induce wakefulness and suppress REM and NREM sleep? These three brain regions are proposed because they all express high level of NPSR mRNA and receive intense NPS fiber innervations. In addition, they are brain regions that play important roles in the regulation of vigilance state. These experiments will determine whether NPS acts in neuronal circuits involved in waking and REM sleep, and will increase our understanding on the interaction of NPS with other arousal networks. (3) To determine the consequences of NPS receptor deficiency in sleep architecture. NPS receptor KO mice have recently been generated. We will characterize the sleep parameters of NPSR KO mice under baseline conditions and after sleep deprivation. As we have learned from other peptidergic systems, the data obtained under this aim, if successful, will unequivocally prove that the NPS system is an important component of the circuitry that modulates sleep and wakefulness.