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）：该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，即基于先前醒来时间的睡眠驱动力，反映在长时间醒来后慢波活动（SWA，脑电图活动中的 0.5-4.5 Hz 振荡）增加和 SWS 后 SWA 减少。这种在 SWS 期间 SWA 的消散和长时间清醒后 SWA 的积累已在人类、大鼠和小鼠身上得到证实。此外，已经在野生型和突变型啮齿动物中模拟了 SWA 的积累和消散，并且已知 SWA 的积累和消散受到遗传控制。在当前的项目中，首先通过使用腺苷 A1 受体 (AdoA1R)（腺苷影响 SWA 的主要腺苷受体）的基因敲除来研究腺苷在 SWA 稳态中的作用，其次通过使用腺苷激酶的诱导敲除来研究腺苷在 SWA 稳态中的作用。 AdK），它将腺苷转化为 AMP，并且由于平衡转运蛋白，在很大程度上控制细胞外腺苷水平腺苷。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 稳态，正如我们假设的那样，这将证明神经胶质细胞对 SWA 稳态的控制。该项目有 3 个具体目标：1) 表征 AdoA1R 在基线下 SWA 积累和消散以及睡眠剥夺条件下恢复中的作用，2) 表征神经胶质 AdK 在 AdoA1R 介导的哺乳动物皮质神经元抑制音中的作用，以及 3)描述了神经胶质 AdK 在基线下 SWA 积累和消散以及从睡眠剥夺条件下恢复中的作用。总体而言，这些具体目标研究了一种潜在的神经生物学底物——腺苷，它可能会影响表明睡眠驱动力的 SWA 积累和消散。已知腺苷会影响 SWA，因此测试该化合物作为控制 SWA 稳态的神经生物学底物是合理的。初步数据支持 AdoA1R 在 SWA 稳态中的作用，并表明神经胶质介导的 AdK 敲除会增加腺苷水平，也会改变 SWA 稳态，但方向与 AdoA1R 敲除相反。这些发现将为神经胶质控制行为状态相关的 SWA 提供一种机制，该机制对神经胶质代谢状态敏感。 公共卫生相关性：睡眠是一种重要且必要的行为；然而，针对睡眠不足而控制睡眠驱动力的情况尚不清楚。本项目调查 这种控制的可能机制是由脑腺苷介导的。此外，还将表征神经胶质细胞（非神经元支持细胞）中腺苷激酶对这种腺苷的控制。