Cellular and Neurochemical Mechanisms of REM Sleep

快速眼动睡眠的细胞和神经化学机制

• 批准号: 8247816
• 负责人: Subimal Datta
• 金额: $ 34.19万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247816
• 关键词: Address; Adenylate Cyclase; Adult; Alzheimer' s Disease; Animals; Antibodies; Appearance; Architecture; Behavioral; Behavioral Mechanisms; Biological Assay; Brain Stem; Calcium/calmodulin-dependent protein kinase; Catalytic Domain; Cataplexy; Cells; Choline O-Acetyltransferase; Clinical; Computer software; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Disease; Dose; Drops; Endogenous depression; Enzyme-Linked Immunosorbent Assay; Equilibrium; Event; FOS gene; Future Generations; GABA Receptor; GABA-B Receptor; Generations; Glutamate Receptor; Glutamates; Goals; Health; Homeostasis; Huntington Disease; Image; Image Analysis; Kainic Acid Receptors; Label; Laboratories; Lead; Light; Link; Malignant Neoplasms; Measures; Mediating; Medical; Methods; Microinjections; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Molecular; Monitor; N-Methylaspartate; Narcolepsy; Nature; Neurobiology; Neurodegenerative Disorders; Neurons; Neurotransmitters; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Physiological Processes; Platelet aggregation; Process; Protein Kinase A Inhibitor; REM Sleep; Radioactive; Rattus; Receptor Activation; Regulation; Research; Research Design; Restless Legs Syndrome; Role; Schizophrenia; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Sleep Apnea Syndromes; Sleep Architecture; Sleep Deprivation; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Slow-Wave Sleep; Staging; System; Techniques; Testing; Therapeutic; Time; U-0126; Wakefulness; Western Blotting; awake; base; calmodulin-dependent protein kinase II; cancer therapy; cell type; cholinergic; cholinergic neuron; design; experience; gamma-Aminobutyric Acid; inhibitor/antagonist; interdisciplinary approach; kainate; natural hypothermia; neurobiological mechanism; neurochemistry; novel; pedunculopontine tegmentum; rapid eye movement; receptor; receptor sensitivity; research study; sleep regulation

DESCRIPTION (provided by applicant): The long-term objective of this research is to further our understanding of brainstem cellular, molecular, and network mechanisms of REM sleep regulation. Specifically, the goal of this renewal application is to investigate the involvement of pedunculopontine tegmentum (PPT) intracellular signaling mechanisms in the regulation of REM sleep. The central hypothesis of this proposal is that REM sleep is regulated by a balance of cellular mechanisms in the PPT; specifically, in the PPT, REM sleep is induced by the activation of cAMP- dependent protein kinase A (PKA), and REM sleep is suppressed by the induction of wakefulness caused by activation of Ca2????dependent protein kinase II (CaMKII) and/or mitogen-activated protein kinase (MAPK). Three specific aims have been designed to systematically test this hypothesis: 1. Identify the neurotransmitter phenotype(s) of cells in the PPT whose activation induces REM sleep. To achieve this goal, state-dependently activated PPT cells will be identified by c-fos and pCREB expression, and their neurochemical identity will be determined by the immunocytochemical labeling of choline acetyltransferase (ChAT) and GABA. 2. Test the hypothesis that the activation of PKA in the PPT induces REM sleep. This goal will be achieved by quantifying the levels of PPT PKA activity after different amounts of REM sleep and by microinjecting a selective cAMP-PKA activation inhibitor into the PPT to block the homeostatic drive for REM sleep. 3. Test the hypothesis that CaMKII and MAPK activation in the PPT terminates REM sleep by inducing wakefulness. This goal will be achieved by measuring the levels of PPT CaMKII and MAPK activity at varying amounts of wakefulness and REM sleep and by applying inhibitors of CaMKII and MAPK activation into the PPT while quantifying their effects on the architecture of spontaneous as well as rebound REM sleep. All of these experiments will be performed on adult, freely moving rats. Preliminary data provide a rationale for each specific aim and demonstrate feasibility. This proposal addresses, at the mechanistic level, the general question in basic neurobiology: how is REM sleep regulated? Importantly, identification of the intracellular signaling molecules involved in the regulation of REM sleep may lead to the design of a future generation of drugs to treat REM sleep disorders as well as a variety of serious medical conditions that are exacerbated by disrupted REM sleep, such as narcolepsy/cataplexy, restless legs syndrome, endogenous depression, schizophrenia, Alzheimer's, and Huntington's disease. PUBLIC HEALTH RELEVANCE The goal of this research is to identify the intracellular signaling molecules involved in the normal regulation of rapid eye movement (REM) sleep. Recent evidence indicates that novel compounds designed to modify intracellular transduction pathways have therapeutic potential for endogenous depression, cancer, hypothermia, and pathological aggregation of platelets. Similarly, identification of the intracellular molecules involved in normal regulation of REM sleep may lead to the design of a future generation of drugs to treat REM sleep disorders as well as a variety of serious medical conditions that are exacerbated by disrupted REM sleep, such as narcolepsy/cataplexy, restless legs syndrome, endogenous depression, schizophrenia, Alzheimer's, and Huntington's disease.

描述（由申请人提供）：这项研究的长期目标是进一步了解REM睡眠调节的脑干细胞，分子和网络机制。具体而言，这种更新应用的目的是研究Pedunculopontine Teggmentum（PPT）在REM睡眠调节中的细胞内信号传导机制的参与。该提议的中心假设是REM睡眠受PPT中细胞机制的平衡来调节。具体而言，在PPT中，REM睡眠是由cAMP依赖性蛋白激酶A（PKA）的激活引起的，并且REM睡眠受到Ca2激活引起的醒目的抑制？已经设计了三个特定的目标来系统地检验以下假设：1。识别PPT中细胞的神经递质表型，其激活诱导REM睡眠。为了实现这一目标，将通过C-FOS和PCREB表达来鉴定状态依赖性活化的PPT细胞，其神经化学身份将通过胆碱乙酰基转移酶（CHAT）和GABA的免疫细胞化学标记确定。 2。检验以下假设：PPT中PKA的激活诱导REM睡眠。将通过在不同量的REM睡眠后量化PPT PKA活性的水平，并将选择性的Camp-PKA激活抑制剂量化以阻止REM睡眠的稳态驱动器来实现此目标。 3。检验以下假设：PPT中CaMKII和MAPK激活通过诱导清醒终止REM睡眠。通过以不同量的清醒和REM睡眠来测量PPT CAMKII和MAPK活性的水平，并通过将CAMKII和MAPK激活的抑制剂应用于PPT，同时量化其对自发性和REM睡眠的影响。所有这些实验将对成人自由移动的大鼠进行。初步数据为每个特定目标提供了理由，并证明了可行性。该建议在机械层面上解决了基本神经生物学中的一般问题：如何调节REM睡眠？ Importantly, identification of the intracellular signaling molecules involved in the regulation of REM sleep may lead to the design of a future generation of drugs to treat REM sleep disorders as well as a variety of serious medical conditions that are exacerbated by disrupted REM sleep, such as narcolepsy/cataplexy, restless legs syndrome, endogenous depression, schizophrenia, Alzheimer's, and Huntington's disease.这项研究的目标是确定与快速眼运动（REM）睡眠正常调节有关的细胞内信号传导分子。最近的证据表明，旨在改变细胞内转导途径的新型化合物具有内源性抑郁症，癌症，体温过低和血小板病理聚集的治疗潜力。 Similarly, identification of the intracellular molecules involved in normal regulation of REM sleep may lead to the design of a future generation of drugs to treat REM sleep disorders as well as a variety of serious medical conditions that are exacerbated by disrupted REM sleep, such as narcolepsy/cataplexy, restless legs syndrome, endogenous depression, schizophrenia, Alzheimer's, and Huntington's disease.