Cytokine and Neurotransmitter Interactions in Sleep Regulation

描述(申请人提供)：睡眠是神经生物学的一个难题：我们不知道睡眠对大脑(或身体)有什么功能(S)。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，睡眠障碍导致的睡眠不足或睡眠障碍可能是多种疾病的一个促成因素，包括但不限于高血压、冠状动脉疾病、脑血管疾病和高血糖。大量研究表明，睡眠不足会损害免疫功能，而感染引起的免疫激活会改变睡眠。对感染的反应差异很大：在极端情况下，一些人会活下来，另一些人会因为对同一病原体的反应而死亡(S)。大量系统的临床前研究表明，感染会导致睡眠改变。大多数感染增加了非快速眼动睡眠(NREMS)，减少了快速眼动睡眠(REMS)。我们的功能假设是，感染期间睡眠改变的方式是决定临床结果的关键因素。事实上，一项回溯性研究表明，兔子的特定睡眠模式与感染后的存活率有关。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介素1作为免疫激活过程中睡眠改变的一个中介。数据表明，IL-1增加了NREMS，抑制了REMS。在本申请中，我们建议将工作重点放在IL-1诱导的对REMS的抑制上，这一效应已被普遍忽视。IL-1抑制ACh的合成和释放。被盖外侧背侧核(LDT)和桥脚核(PPT)的胆碱能神经元参与了REMS时脑电的去同步化和丘脑皮质的激活。RMS的生成结构受到GABA能抑制：IL-1在多个水平上增强了GABA的抑制作用。这项申请中提出的研究将检验IL-1通过对脑干胆碱能和GABA能系统相反但互补的作用来抑制REMS的机制假说。我们的初步数据表明：IL-1微量注射到LDT可降低大鼠的RMS；IL-1可降低LDT切片中胆碱能神经元的放电频率；IL-1可增加腹外侧导水管周围灰质(VlPAG)中c-Fos+神经元的数量，vlPAG是投射到脑桥网状结构和LDT的富含GABA的区域。在这一应用中，我们建议用免疫荧光技术来确定：1)脑干胆碱能/胆碱能核团内微量注射IL-1对睡眠的影响；2)IL-1对胆碱能神经元电生理特性的影响；3)IL-1对REMS相关脑干核团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感染期间抑制RMS的机制提供关键的新数据。只有当清楚地了解免疫反应针对感染的神经解剖和神经化学底物时，才可能确定睡眠变化是否有助于良好的临床结果。公共卫生相关性一些人因感染而活着，另一些人因感染而死亡。在感染期间，睡眠会发生巨大的变化。有证据表明，睡眠改变的方式可能有助于生存。该项目将确定免疫激活对负责调节疾病期间被抑制的一个睡眠阶段的大脑系统的影响。一旦我们了解了感染期间睡眠是如何改变的(通过什么方法)，我们就能够研究为什么在感染期间睡眠会改变，也就是说，睡眠改变是否有助于恢复？

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?