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：该项目研究了对腺苷水平的神经胶质控制及其在睡眠体内平衡中的作用。 睡眠体内平衡是基于先前醒来时间睡眠的动力，反映了慢波活动 （SWA，脑电图活动中的0.5-4.5 Hz振荡）长时间醒来并减少 SWA遵循SWS。长时间醒来后，SWS和SWA的积累中的SWA发生了这种耗散 在人类，大鼠和小鼠中被证明。此外，已经对SWA的积累和耗散进行了建模 在野生型和突变啮齿动物中，众所周知，SWA的积累和耗散处于遗传控制之下。 在当前的项目中，研究腺苷在SWA稳态中的作用，首先是使用遗传 敲除腺苷A1受体（ADOA1R）的敲除，这是主要腺苷受体的腺苷。 影响SWA，其次使用腺苷激酶（ADK）的诱导型敲除它的影响 腺苷至AMP，由于平衡转运蛋白，在很大程度上控制了腺苷的细胞外水平。 腺苷激酶主要在成年动物的神经胶质中表达，因此，如果腺苷影响SWA 正如我们假设的那样，稳态会表现出对SWA稳态的神经胶质控制。项目 使用3个特定目的：1）表征ADOA1RS在SWA积累和耗散中的作用 基线和从睡眠剥夺条件中恢复，2）表征神经胶质ADK在ADOA1R中的作用 在哺乳动物皮质神经元上介导的抑制性张力，3）表征神经胶质ADK在 SWA在基线下的积累和耗散以及从睡眠剥夺条件中恢复。全面的， 这些具体目的研究了一种潜在的神经生物学底物腺苷，这可能会影响 SWA积累和耗散表示睡眠驱动器。已知腺苷会影响SWA 因此，可以合理地测试该化合物作为控制SWA稳态的神经生物学底物。 初步数据支持ADOA1R在SWA稳态中的作用，并建议使用Glial介导的ADK敲除， 这增加了腺苷水平，也改变了SWA稳态，但在相反的方向上与ADOA1R相反 昏死。这些发现将为行为状态相关的SWA提供神经胶质控制的机制，这是 对神经胶质代谢状态敏感。