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: 8297756
• 负责人: Robert W Greene
• 金额: $ 33.49万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297756
• 关键词: Adenosine; Adenosine A1 Receptor; Adenosine Kinase; Adult; Affect; Affinity; Animals; Attenuated; Behavior; Behavior Control; Brain; Brain Stem; Cerebrum; Data; Electroencephalography; Engineering; Enzymes; Extracellular Protein; Fourier Transform; Frequencies; Gene Deletion; Genes; Genetic; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Sleep is an important and necessary behavior; however, control of sleep drive in response to sleep loss, is not well understood. This project investigates a possible mechanism for this control mediated by brain adenosine. Further, the control of this adenosine by adenosine kinase in glia (non-neuronal supporting cells) will be characterized.

描述（由申请人提供）：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。睡眠稳态，基于先前清醒时间的睡眠驱动，通过延长清醒后慢波活动（SWA，脑电图活动中的0.5-4.5 Hz振荡）增加和SWS后SWA减少来反映。在人、大鼠和小鼠中已经证明了SWS期间SWA的这种消散和长时间清醒后SWA的积累。此外，已经在野生型和突变啮齿动物中模拟了SWA积累和消散，并且已知SWA积累和消散受遗传控制。在当前的项目中，腺苷在SWA体内平衡中的作用进行了研究，首先通过使用腺苷A1受体（ADA 1 R）的基因敲除，腺苷通过其影响SWA的主要腺苷受体，其次通过使用腺苷激酶（AdK）的诱导性敲除，其将腺苷转化为AMP，并且由于平衡转运蛋白，在很大程度上控制腺苷的细胞外水平。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稳态，正如我们假设的那样，这将证明神经胶质控制SWA稳态。该项目使用3个具体目标：1）表征在基线和从睡眠剥夺条件恢复下SWA积累和消散中的CANA 1 R的作用，2）表征胶质AdK在CANA 1 R介导的哺乳动物皮层神经元抑制性紧张中的作用，和3）表征在基线和从睡眠剥夺条件恢复下SWA积累和消散中胶质AdK的作用。总的来说，这些特定的目标调查一个潜在的神经生物学底物，腺苷，这可能会影响SWA的积累和消散，这是睡眠驱动的指示。已知腺苷影响SWA，因此将该化合物作为控制SWA稳态的神经生物学底物进行测试是合理的。初步的数据支持的作用，SWA的体内平衡，并建议神经胶质介导的AdK敲除，这增加腺苷水平，也改变SWA的体内平衡，但在相反的方向作为SWA 1 R敲除。这些发现将为胶质细胞控制对胶质代谢状态敏感的行为状态相关SWA提供一种机制。 公共卫生关系：睡眠是一种重要且必要的行为;然而，对睡眠不足的睡眠驱动的控制还没有得到很好的理解。该项目调查 一种可能的机制，这种控制介导的脑腺苷。此外，将表征神经胶质（非神经元支持细胞）中腺苷激酶对该腺苷的控制。