Glial Control of CNS State-related Activity

神经胶质细胞对中枢神经系统状态相关活动的控制

• 批准号: 8788072
• 负责人: Robert W Greene
• 金额: $ 34.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788072
• 关键词: Adenosine; Adenosine A1 Receptor; Adenosine Kinase; Adult; Affect; Affinity; Animals; Attenuated; Behavior; Behavior Control; Brain; Brain Stem; Cerebrum; Data; Electroencephalography; Enzymes; Extracellular Protein; Fourier Transform; Frequencies; Gene Deletion; Genes; Genetic; Genetic Engineering; Genotype; Glial Fibrillary Acidic Protein; Homeostasis; Human; Interneurons; Knock-out; Liquid substance; Mediating; Messenger RNA; Metabolic; Metabolism; Modeling; Mus; Neurobiology; Neuroglia; Neurons; Process; Proteins; Purinergic P1 Receptors; Rattus; Receptor Activation; Recovery; Rodent; Role; Signal Transduction; Sleep; Sleep Deprivation; Slow-Wave Sleep; Supporting Cell; Tamoxifen; Testing; Time; adenosine transporter; awake; base; extracellular; falls; mature animal; mutant; receptor; response; sleep regulation; vesicular release

Project summary: This project investigates glial control of adenosine levels and its role in sleep homeostasis. Sleep homeostasis, the drive to sleep based on prior waking time, is reflected by increased slow wave activity (SWA, 0.5-4.5 Hz oscillation in electroencephalographic activity) following prolonged waking and decreased SWA following SWS. This dissipation in SWA during SWS and buildup of SWA following prolonged waking has been demonstrated in humans, rats, and mice. Further, SWA accumulation and dissipation has been modeled in wildtype and mutant rodents and it is known that SWA accumulation and dissipation is under genetic control. In the current project, the role of adenosine in SWA homeostasis is investigated, first by using a genetic knockout of adenosine A1 receptors (AdoA1R), the main adenosine receptor through which adenosine influences SWA, and secondly by using an inducible knockout of adenosine kinase (AdK), which converts adenosine to AMP and, due to equilibrative transporters, largely controls the extracellular level of adenosine. Adenosine kinase is expressed primarily in glia in adult animals and therefore, if adenosine influences SWA homeostasis, as we hypothesize it does, this would demonstrate glial control of SWA homeostasis. The project uses 3 specific aims to: 1) characterize the role of AdoA1Rs in SWA accumulation and dissipation under baseline and recovery from sleep deprivation conditions, 2) characterize the role of glial AdK in AdoA1R mediated inhibitory tone on mammalian cortical neurons, and 3) characterize the role of glial AdK in accumulation and dissipation of SWA under baseline and recovery from sleep deprivation conditions. Overall, these specific aims investigate one potential neurobiological substrate, adenosine, which may influence the SWA accumulation and dissipation that is indicative of the sleep drive. Adenosine is known to influence SWA so it is reasonable to test this compound as a neurobiological substrate that controls SWA homeostasis. Preliminary data support a role of AdoA1R in SWA homeostasis and suggest glial-mediated AdK knockout, which increases adenosine levels, also alters SWA homeostasis but in the opposite direction as AdoA1R knockout. These findings will provide a mechanism for glial control of behavioral state related SWA that is sensitive to glial metabolic state.

项目摘要：本项目研究神经胶质细胞对腺苷水平的控制及其在睡眠稳态中的作用。 睡眠动态平衡，即基于先前清醒时间的睡眠动力，反映在慢波活动的增加上 (SWA，脑电活动的0.5-4.5赫兹振荡)觉醒时间延长后下降 紧随SWS之后的SWA。SWS期间SWA中的这种消散，以及在长时间清醒后SWA的积聚 已经在人类、大鼠和小鼠身上得到证实。此外，还模拟了SWA的积累和消散。 在野生型和突变型啮齿动物中，SWA的积累和消散是受基因控制的。 在目前的项目中，腺苷在SWA动态平衡中的作用被研究，首先通过使用一种基因 腺苷A1受体(ADOA1R)的敲除，腺苷主要通过腺苷受体 影响SWA，其次是通过使用可诱导的腺苷激酶(ADK)基因敲除，它可以将 腺苷到AMP，由于平衡的转运体，在很大程度上控制着腺苷的胞外水平。 腺苷激酶主要在成年动物的神经胶质细胞中表达，因此，如果腺苷影响SWA 动态平衡，正如我们假设的那样，这将证明胶质细胞控制SWA动态平衡。该项目 使用3个具体目标：1)描述ADOA1Rs在以下情况下SWA积累和消散中的作用 睡眠剥夺条件下的基线和恢复，2)胶质细胞ADK在Adobe A1R中的作用 3)神经胶质细胞ADK在中枢神经系统中的作用 基础状态下SWA的积累和消散以及睡眠剥夺条件下的恢复。总的来说， 这些特定的目的是研究一种潜在的神经生物学底物，腺苷，它可能影响 SWA的积累和消散，这是睡眠驱动力的标志。已知腺苷可影响SWA 因此，将该化合物作为控制SWA动态平衡的神经生物底物进行测试是合理的。 初步数据支持ADOA1R在SWA动态平衡中的作用，并提示胶质细胞介导的ADK基因敲除， 它增加了腺苷水平，也改变了SWA的动态平衡，但方向与ADOA1R相反 淘汰赛。这些发现将为行为状态相关的SWA的神经胶质控制提供一种机制，即 对神经胶质代谢状态敏感。