Cytokine and Neurotransmitter Interactions in Sleep Regulation

描述（由申请人提供）：睡眠给神经生物学提出了一个难题：我们不知道睡眠对大脑（或身体）有什么作用。然而，我们确实知道，充足的睡眠对身心健康至关重要。除了对认知和表现的影响外，睡眠不足或睡眠障碍导致的睡眠中断可能是多种病理的促成因素，包括但不限于高血压、冠状动脉疾病、脑血管疾病和高血糖症。大量研究表明，睡眠不足会损害免疫功能，感染引起的免疫激活会改变睡眠。对感染的反应性差异很大：在极端情况下，对同一种病原体的反应有些人会活下来，有些人会死亡。许多系统的临床前研究证实了感染引起的睡眠改变。大多数感染增加非快速眼动睡眠（NREMS）和减少快速眼动睡眠（REMS）。我们的功能假设是，在感染期间睡眠改变的方式是临床结果的关键决定因素。事实上，一项回顾性研究表明，兔子的特定睡眠模式与感染存活率有关。为了进一步了解导致良好临床结果的中枢神经系统反应，我们将重点放在细胞因子白细胞介素(IL)-1作为免疫激活过程中睡眠改变的一个中介。数据显示IL-1增加NREMS，抑制REMS。在本研究中，我们建议将重点放在il -1诱导的REMS抑制上，这一效应一直被普遍忽视。IL-1抑制乙酰胆碱合成和释放。眼动期脑电失同步和丘脑皮层激活与脑侧背侧被盖核（LDT）和桥脚核（PPT）的胆碱能神经元有关。REMS生成结构受到GABA能抑制：IL-1在多个水平上增强GABA抑制作用。本申请中提出的研究将检验IL-1通过对脑干胆碱能和gaba能系统的相反但互补的作用来抑制REMS的机制假设。我们的初步数据表明：IL-1微注射LDT可降低大鼠的rem；IL-1降低LDT切片制备中胆碱能神经元的放电率；IL-1增加了腹外侧导水管周围灰质（vlPAG）中c-Fos+神经元的数量，vlPAG是一个富含gaba的区域，投射到脑桥网状结构和LDT。在这项应用中，我们打算确定：1)将IL-1显微注射到脑干胆碱能/胆碱感受核中对睡眠的影响，2)IL-1对胆碱能神经元电生理特性的体外影响，以及3)IL-1对rem相关脑干核和神经递质系统的影响。这些目标的成功完成将为我们理解REMS在感染期间被抑制的机制提供关键的新数据。只有当对感染免疫反应的神经解剖学和神经化学底物有了明确的了解后，才能确定睡眠的改变是否有助于良好的临床结果。一些人因感染而存活，另一些人因感染而死亡。在感染期间，睡眠会发生显著变化。有证据表明，改变睡眠的方式可能有助于生存。该项目将确定免疫激活对大脑系统的影响，该系统负责调节在疾病期间被抑制的睡眠阶段。一旦我们了解了感染期间睡眠是如何（通过什么方式）改变的，我们就能够研究为什么感染期间睡眠会改变，也就是说，改变的睡眠是否有助于恢复？

DESCRIPTION (provided by applicant): Sleep presents a conundrum for neurobiology: we do not know what function(s) sleep serves for the brain (or the body). We do know, however, that adequate sleep is essential for physical and mental health. In addition to effects on cognition and performance, lack of sleep, or sleep disruption due to sleep disorders may be a contributing factor to multiple pathologies, including but not limited to hypertension, coronary artery disease, cerebrovascular disease, and hyperglycemia. Numerous studies demonstrate that sleep loss impairs immune function and that immune activation from infection alters sleep. Responsiveness to infection varies widely: in the extreme, some will live and others will die in response to the same pathogen(s). Numerous systematic pre- clinical studies demonstrate infection-induced alterations in sleep. Most infections increase non-rapid eye movements sleep (NREMS) and decrease rapid eye movements sleep (REMS). Our functional hypothesis is that the manner in which sleep is altered during infection is a critical determinant of clinical outcome. Indeed, one retrospective study demonstrates that specific sleep patterns of rabbits are associated with survival from infection. To further our understanding of central nervous system responses that result in good clinical outcome, we focus on the cytokine interleukin (IL)-1 as one mediator of altered sleep during immune activation. Data indicate IL-1 increases NREMS and suppresses REMS. We propose in this application to focus effort on IL-1-induced suppression of REMS, an effect that has been universally ignored. IL-1 inhibits ACh synthesis and release. Cholinergic neurons of the laterodorsal tegmental (LDT) and pedunculopontine (PPT) nuclei are involved in EEG desynchronization and thalamocortical activation during REMS. REMS- generating structures are under GABAergic inhibition: IL-1 enhances GABA inhibitory effects at multiple levels. Studies proposed in this application will test the mechanistic hypothesis that IL-1 suppresses REMS by opposed, yet complementary actions on brainstem cholinergic and GABAergic systems. Our preliminary data indicate: IL-1 microinjected into the LDT reduces REMS of rats; IL-1 reduces firing rates of cholinergic neurons in LDT slice preparations; and IL-1 increases the number of c-Fos+ neurons in the ventrolateral periaqueductal grey (vlPAG), a GABA-rich area that projects to the pontine reticular formation and the LDT. In this application, we propose to determine: 1) the impact on sleep of IL-1 microinjection into brainstem cholinergic/cholinoceptive nuclei, 2) in vitro effects of IL-1 on electrophysiological properties of cholinergic neurons, and 3) the impact of IL-1 on REMS-relevant brainstem nuclei and neurotransmitter systems using immuno- fluorescence techniques. Successful completion of these aims will provide novel data critical for our understanding of mechanisms by which REMS is suppressed during infection. Determination of whether alterations in sleep contribute to good clinical outcome will only be possible when the neuroanatomic and neurochemical substrates targeted by immune responses to infection are clearly understood. PUBLIC HEALTH RELEVANCE Some individuals live and others die in response to infections. Sleep is dramatically altered during infection. Evidence suggests the manner in which sleep is altered may contribute to survival. This project will determine effects of immune activation on brain systems responsible for regulating one phase of sleep that is suppressed during sickness. Once we understand how (by what means) sleep is altered during infection, we will be able to study why sleep is altered during infection, i.e., does altered sleep facilitate recovery?