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

描述(申请人提供)：睡眠障碍影响10%到20%的总人口，是一个重大的公共卫生挑战。揭示参与睡眠调节的新型神经递质系统和结构将极大地扩展我们对这一重要生理功能的理解。此外，它还将成为治疗各种睡眠障碍或干扰的潜在靶点，如失眠、白天过度困倦、睡眠呼吸暂停和嗜睡症。神经肽S及其受体是新近发现的一种促进觉醒和觉醒的神经肽系统。我们之前的研究表明，中枢给予NPS显著地诱导觉醒，抑制睡眠的所有阶段，并减少睡眠和觉醒不同阶段之间的转换。我们的核心假设是神经肽S是睡眠和觉醒的重要内源性调节因子，调节觉醒中枢的活动。长期目标是进一步研究NPS系统在睡眠和觉醒调节中的作用。在这项提案中，我们将调查三个具体目标。(1)测定光/暗周期和睡眠剥夺后NPS多肽、前体和受体mRNA的浓度。我们将在不同的昼夜节律、持续黑暗和睡眠剥夺条件下监测NPS多肽、NPS前体和受体mRNA的表达。(2)确定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)下丘脑外侧核(B)结节乳头核(TMN)和(C)背外侧被盖核(LDTg)局部注射微克分子剂量的NPS是否也会引起觉醒并抑制REM和NREM睡眠？之所以提出这三个脑区，是因为它们都表达高水平的NPSR mRNA，并接受强烈的NPS纤维神经支配。此外，它们是大脑中在调节警觉状态方面发挥重要作用的区域。这些实验将确定NPS是否作用于涉及觉醒和REM睡眠的神经元回路，并将增加我们对NPS与其他唤醒网络相互作用的理解。(3)确定NPS受体缺陷对睡眠结构的影响。最近产生了NPS受体KO小鼠。我们将对NPSR KO小鼠在基线条件下和睡眠剥夺后的睡眠参数进行表征。正如我们从其他肽能系统中了解到的那样，在这个目标下获得的数据，如果成功，将明确证明NPS系统是调节睡眠和清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.