Cellular and Molecular Mechanisms of REM Sleep

快速眼动睡眠的细胞和分子机制

• 批准号: 8874292
• 负责人: Subimal Datta
• 金额: $ 28.33万
• 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/8874292
• 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）：本研究的长期目标是进一步了解快速眼动睡眠调节的脑干细胞、分子和网络机制。具体来说，这项更新应用的目标是研究桥脚被盖 (CCC-PPT) 和背蓝下核 (SubCD) 胆碱能细胞区室中的分子机制，以及它们在快速眼动睡眠稳态调节中的作用。该提案的中心假设是，REM 睡眠和相性脑桥波 (P 波) 活动的稳态调节是通过脑源性神经营养因子 (BDNF) 受体（原肌球蛋白相关激酶 B [TrkB]）之间的相互作用主动调节的。 CCC-PPT 和 SubCD 中的细胞外信号调节激酶 1/2 (ERK1/2) 信号传导。我们设计了三个具体目标来系统地检验这一假设： 1. 检验以下假设：在选择性 REM 睡眠剥夺期间，慢波睡眠的增加和 CCC-PPT 中 BDNF 表达的增加对于 REM 睡眠稳态驱动的发展至关重要，并且在相同条件下，SubCD 中 BDNF 表达的增加对于 P 波活动的稳态调节至关重要。这一目标将通过测量 CCC-PPT、SubCD 和许多控制区域在不同强度的 REM 睡眠稳态驱动增加时与稳态驱动相关的 BDNF 水平变化来实现。 2. 检验以下假设：CCC-PPT 中 BDNF TrkB 受体与 ERK1/2 信号传导之间的相互作用对于 REM 睡眠的稳态调节至关重要，而 SubCD 中的相同相互作用对于 P 波的稳态调节至关重要活动。为了检验这一假设，在选择性 REM 睡眠剥夺期开始时，我们将 BDNF TrkB 受体抑制剂、ERK1/2 激活抑制剂或载体对照应用到大鼠的 CCC-PPT 或 SubCD 中，以阻止增加的快速眼动睡眠的稳态驱动。 3. 检验以下假设：在杂合 BDNF 敲除 (BDNF+/-) 大鼠中，CCC-PPT 中 BDNF 产生的减少会减弱 REM 睡眠的稳态调节，而 SubCD 中 BDNF 产生的减少会减弱 P 波活动的稳态调节。为了检验这一假设，在选择性 REM 睡眠剥夺期开始时，我们将 BDNF 应用于 BDNF+/- 大鼠的 CCC-PPT 或 SubCD。所有这些实验都将在成年、自由活动的老鼠身上进行。我们相信，这些研究的结果将扩展有关快速眼动睡眠调节的基本神经生物学机制的前沿知识。此外，这些结果将首次启动一个新的研究领域，旨在了解快速眼动睡眠个体生理迹象的稳态调节的局部细胞和分子机制。我们相信，这些研究的结果将揭示许多精神和神经系统疾病（例如内源性抑郁症、精神分裂症、阿尔茨海默氏症、亨廷顿氏症、帕金森氏症和中风）中快速眼动睡眠稳态调节功能障碍的神经病理机制，以及将帮助我们设计治疗干预措施来消除这些功能障碍。