Cellular and Molecular Mechanisms of REM Sleep

快速眼动睡眠的细胞和分子机制

• 批准号: 9128059
• 负责人: Subimal Datta
• 金额: $ 34.63万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128059
• 关键词: Adult; Affect; Alzheimer' s Disease; Area; Attenuated; Basic Science; Behavioral; Biological Markers; Brain Stem; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cells; Clinical; Development; Disease; Dorsal; Drug Design; EKG P Wave; Endogenous depression; Event; Fibrinogen; Functional disorder; Generations; Goals; Health; Hippocampus (Brain); Homeostasis; Huntington Disease; Individual; Investigation; K 252a; Knock-out; Knowledge; Light; Measures; Mental disorders; Methods; Molecular; Muscle; Neurobiology; Neurotrophic Tyrosine Kinase Receptor Type 2; Parkinson Disease; Pedunculopontine Tegmental Nucleus; Phosphotransferases; Physiological; Pontine structure; Population; Preoptic Areas; Production; REM Sleep; Rattus; Recovery; Regulation; Research; Role; Schizophrenia; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Sleep; Sleep Deprivation; Slow-Wave Sleep; Sprague-Dawley Rats; Stroke; Techniques; Testing; Therapeutic Intervention; Theta Rhythm; Time; Tropomyosin; Work; cholinergic; design; extracellular; immunocytochemistry; inhibitor/antagonist; male; nervous system disorder; neurobiological mechanism; novel therapeutic intervention; pedunculopontine tegmentum; rapid eye movement; receptor; research study; sleep regulation; time interval

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 molecular mechanisms within the cholinergic cell compartment of the pedunculopontine tegmentum (CCC-PPT) and dorsal subcoeruleus nucleus (SubCD) with respect to their roles in homeostatic regulation of REM sleep. The central hypothesis of this proposal is that homeostatic regulation of REM sleep and phasic pontine- wave (P-wave) activity are actively regulated by the interaction between brain-derived neurotrophic factor (BDNF) receptors (tropomyosin-related kinase B [TrkB]) and extracellular signal-regulated kinase1/2 (ERK1/2) signaling in the CCC-PPT and SubCD. Three specific aims have been designed to systematically test this hypothesis: 1. Test the hypothesis that during selective REM sleep deprivation, increased slow-wave sleep and increased expression of BDNF in the CCC-PPT are critical for the development of homeostatic drive for REM sleep, and under the same conditions, increased BDNF expression in the SubCD is critical for the homeostatic regulation of P-wave activity. This goal will be achieved by measuring homeostatic drive-associated changes in BDNF levels in the CCC-PPT, SubCD, and in a number of control areas at different intensities of increased REM sleep homeostatic drive. 2. Test the hypothesis that the interaction between BDNF TrkB receptors and ERK1/2 signaling in the CCC-PPT is critical for the homeostatic regulation of REM sleep, and that this same interaction in the SubCD is critical for the homeostatic regulation of P-wave activity. To test this hypothesis, at the beginning of a selective REM sleep deprivation period we will apply a BDNF TrkB receptor inhibitor, ERK1/2 activation inhibitor, or vehicle control into either the CCC-PPT or SubCD of rats, in order to block the increased homeostatic drive for REM sleep. 3. Test the hypothesis that, in heterozygous BDNF knockout (BDNF+/-) rats, decreased BDNF production in the CCC-PPT attenuates homeostatic regulation of REM sleep, and decreased BDNF production in the SubCD attenuates homeostatic regulation of P-wave activity. To test this hypothesis, at the beginning of the selective REM sleep deprivation period we will apply BDNF either into the CCC-PPT or SubCD of BDNF+/- rats. All of these experiments will be performed on adult, freely moving rats. We believe that the results of these studies will extend the leading edge of knowledge on the basic neurobiological mechanisms of REM sleep regulation. Also, for the first time, these results will launch a new area of investigation aimed at understanding the localized cellular and molecular mechanisms of homeostatic regulation of individual physiological signs of REM sleep. We believe that the results of these studies will shed light on the neuro-pathological mechanisms of REM sleep homeostatic regulatory dysfunctions in a number of psychiatric and neurological disorders (e.g., endogenous depression, schizophrenia, Alzheimer's, Huntington's, Parkinson's, and stroke), and will help us to design therapeutic interventions to eliminate these dysfunctions.

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 temgentum（CCC-PPT）和背部亚焦点核（SubCD）中胆碱能细胞区室内的分子机制（subcd）在其在REM睡眠的稳态调节中的作用。该提议的中心假设是，对REM睡眠和阶段庞然波（P波）活性的体内平衡调节受到脑源性神经营养因子（BDNF）受体之间的相互作用的积极调节（tropomyososin相关的激酶B [TRKB]）和细胞内部信号的Kinase1/2（ERK-KINase1/2）（ERK-KINASE1/2）（ERK-KINASE 1/2）。已经设计了三个具体目标来系统地检验以下假设：1。检验以下假设：在选择性rem睡眠剥夺，慢波睡眠增加以及CCC-PPT中BDNF的表达增加对于开发REM睡眠的稳态驱动力至关重要，并且在相同条件下，对于subcd的BDNF表达至关重要，对于subcd的bdnf表达至关重要。该目标将通过测量CCC-PPT，SUBCD中BDNF水平的稳态驱动器相关的变化以及在REM睡眠增加增加的不同强度的许多控制区域中的变化来实现。 2。检验以下假设：CCC-PPT中BDNF TRKB受体与ERK1/2信号之间的相互作用对于REM睡眠的体内稳态调节至关重要，并且SUBCD中的这种相同相互作用对于P-WAVE活性的稳态调节至关重要。为了检验这一假设，在选择性REM睡眠剥夺期开始时，我们将应用BDNF TRKB受体抑制剂，ERK1/2激活抑制剂，或将媒介物控制到大鼠的CCC-PPT或子C中，以阻止增加的稳态驱动力的REM睡眠。 3。检验以下假设：在杂合BDNF敲除（BDNF +/-）大鼠中，CCC-PPT中的BDNF产生减少了REM睡眠的体内稳态调节，并降低了BDNF的生产，SubCD减毒了P-Wave活动的稳态调节。为了检验这一假设，在选择性REM睡眠剥夺期开始时，我们将将BDNF应用于BDNF +/-大鼠的CCC-PPT或SubCD中。所有这些实验将对成人自由移动的大鼠进行。我们认为，这些研究的结果将扩展有关REM睡眠调节基本神经生物学机制的知识的前沿。同样，这些结果将首次推出一个新的调查领域，旨在了解REM睡眠的单个生理迹象的稳态调节的局部细胞和分子机制。我们认为，这些研究的结果将揭示REM睡眠睡眠稳态调节性调节性功能障碍的神经病理学机制（例如，精神分裂症，精神分裂症，阿尔茨海默氏症，阿尔茨海默氏症，亨廷顿，亨廷顿，帕金森氏症和Stroke），并将其设计为这些间隔。