Cytokine and neurotransmitter interactions in sleep regulation

睡眠作为一种复杂的行为，给神经生物学提出了一个难题：我们不知道睡眠的功能是什么 为大脑服务。然而，我们知道充足的睡眠对身心健康至关重要。 睡眠和免疫系统之间的相互作用是双向的：免疫系统的激活会改变 睡眠不足会损害免疫功能。在上一个融资期间，我们专注于 研究一种细胞因子，白细胞介素-1（IL-1），和肾上腺素能系统之间的相互作用。数据表明 IL-1增加NREMS。我们证明了IL-1和肾上腺素能系统之间的相互作用是 与NREMS功能相关。在本申请中，我们建议将精力集中在IL-1对人白细胞介素1受体的作用的一个方面。 被普遍忽视的睡眠，抑制快速眼动睡眠。IL-1抑制ACh的合成和释放。 背外侧被盖核（LDT）和脚桥核（PPT）的胆碱能神经元参与了 快速眼动睡眠时的脑电图去兴奋化和丘脑皮质激活。REMS生成结构在 GABA能抑制：IL-1在多个水平上增强GABA抑制作用。本研究中提出的 应用将测试IL-1通过相反但互补的作用抑制REMS的总体假设 脑干胆碱能和γ-氨基丁酸能系统。我们的初步数据表明：IL-1微量注射到 LDT减少大鼠的REMS; IL-1减少LDT切片制备物中胆碱能神经元的放电率; IL-1减少LDT切片制备物中胆碱能神经元的放电率; 增加中脑导水管周围灰质（vlPAG）中c-Fos阳性神经元的数量， 投射到脑桥网状结构的区域，以及在LDT中，涉及REMS的脑干区域。在 本研究拟：1）确定脑干内微量注射IL-1对睡眠的影响 胆碱能/胆碱能感受核，2）确定IL-1对体外细胞电生理特性的影响， 脑干胆碱能神经元; 3）使用免疫组织化学定位IL-1的脑干作用部位 技术.成功完成这些目标将提供有关潜在机制的新数据， IL-1抑制REMS。这些信息对于我们理解 感染引起的睡眠改变了解IL-1改变REMS的机制将进一步促进我们的研究。 了解以REMS破坏和细胞因子失调为特征的精神障碍， 严重抑郁症

Sleep as a complex behavior presents a conundrum for neurobiology: we do not know what function(s) sleep serves for the brain. We do know, however, that adequate sleep is essential for physical and mental health. Interactions between sleep and the immune system are bidirectional: activation of the immune system alters sleep, whereas sleep loss impairs immune function. During the previous funding period we focused our studies on interactions between one cytokine, interleukin-1 (IL-1), and the serotonergic system. Data indicate IL-1 increases NREMS. We demonstrated that interactions between IL-1 and the serotonergic system are of functional relevance to NREMS. We propose in this application to focus effort on one aspect of IL-1 effects on sleep that has been universally ignored, suppression of REMS. 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 overall 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 positive neurons in the ventrolateral periaqueductal grey (vlPAG), a GABA-rich area that projects to the pontine reticular formation, and in the LDT, brain stem regions implicated in REMS. In this application, we propose to: 1) determine the impact on sleep of IL-1 microinjection into brainstem cholinergic/cholinoceptive nuclei, 2) determine in vitro effects of IL-1 on electrophysiol-ogical properties of brainstem cholinergic neurons, and 3) localize brain stem sites of action for IL-1 using immunohistochemical techniques. Successful completion of these aims will provide novel data about potential mechanisms whereby IL-1 suppresses REMS. Such information is critical for our understanding of the functional consequences of infection-induced alterations in sleep. Knowledge of mechanisms by which IL-1 alters REMS will further our understanding of mental disorders characterised by disruptions to REMS and by cytokine dysregulation, such as major depressive disorders.