Mechanism and function of transient adenosine signaling in the brain

大脑中瞬时腺苷信号传导的机制和功能

• 批准号: 8651955
• 负责人: B. JILL VENTON
• 金额: $ 33.46万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651955
• 关键词: Adenosine; Astrocytes; Blood Vessels; Blood flow; Brain; Brain region; Cerebrovascular Circulation; Couples; Disease; Dopamine; Drug Targeting; Drug abuse; Electric Stimulation; Energy Supply; Frequencies; Glutamates; Goals; Green Fluorescent Proteins; Huntington Disease; Ischemia; Knowledge; Label; Lead; Long-Term Effects; Long-Term Potentiation; Measures; Mental Depression; Methods; Microelectrodes; Mission; Monitor; Nature; Neuromodulator; Neuronal Plasticity; Neurons; Neurotransmitters; Organism; Outcome; Oxygen; Pain; Parkinson Disease; Pharmaceutical Preparations; Process; Public Health; Purinergic P1 Receptors; Rattus; Regulation; Research; Resolution; Signal Transduction; Slice; Source; Stimulus; System; Technology; Testing; Therapeutic; Thinking; Time; addiction; adenosine receptor activation; base; burden of illness; extracellular; in vivo; innovation; insight; instrumentation; nervous system disorder; neuroregulation; neurotransmission; novel; receptor; receptor function; research study; response; sensor; treatment strategy

DESCRIPTION (provided by applicant): Adenosine is a neuromodulator that regulates neurotransmission and cerebral blood flow but the nature of adenosine signaling in the brain is not well characterized. Most studies have described long-term effects of activation of adenosine receptors or changes in adenosine basal levels. Recently, rapid changes in adenosine have recently been discovered but the function of these transient changes is not known. The long-term goal of this lab is to develop new microelectrode methods to understand the rapid dynamics of neuromodulation in the brain. The objective of this project is to investigate the formation and function of transient adenosine signaling. This research is innovative because it challenges the paradigm that neuromodulation by adenosine is slow and advances technology by employing novel electrochemical sensors that overcome critical instrumentation barriers of slow temporal resolution and low sensitivity. The central hypothesis is that transient adenosine release occurs throughout the brain, is regulated by adenosine receptors, and functions to modulate neurotransmission and blood flow on a rapid time scale. This hypothesis will be tested with three Aims. In Aim 1, electrically-stimulated adenosine release will be characterized in multiple brain regions. Pharmacological experiments will be performed in brain slices to test the mechanism of adenosine formation and the cellular sources in each region. In Aim 2, spontaneous adenosine transients will be studied in anesthetized rats. These transients occur without drugs but are more frequent after administration of an A1 receptor antagonist. This study will provide a better understanding of how adenosine receptors regulate transient adenosine release. The goal of Aim 3 is to determine the function of transient adenosine release. The two hypotheses are that adenosine modulates neurotransmission and blood flow. The effect of exogenously applied adenosine on dopamine neurotransmission will be tested in brain slices. In addition, the effect of transient adenosine release on blood flow will be studied n vivo. This research will result in a better understanding of the formation and function of transien adenosine release. Adenosine based therapeutics have been proposed as possible treatments for neurological diseases such as pain, Parkinson disease, Huntington's disease, and drug abuse. New insight into the time course of neuromodulation could lead to better manipulation of transient adenosine changes to mitigate diseases caused by impaired neurotransmission.

描述（由申请人提供）：腺苷是一种神经调节剂，可调节神经传递和脑血流量，但脑中腺苷信号传导的性质尚未得到很好的特征。大多数研究都描述了腺苷受体激活或腺苷基础水平变化的长期影响。最近，最近发现了腺苷的快速变化，但是这些瞬时变化的功能尚不清楚。该实验室的长期目标是开发新的微电极方法，以了解大脑中神经调节的快速动力学。该项目的目的是研究瞬态腺苷信号传导的形成和功能。这项研究具有创新性，因为它挑战了腺苷的神经调节速度缓慢，并且通过采用新型的电化学传感器来推进技术，从而克服了缓慢的时间分辨率和低灵敏度的关键仪器障碍。中心假设是瞬时腺苷释放发生在整个大脑中，受腺苷受体的调节，以及在快速时间尺度上调节神经传递和血液流动的功能。该假设将以三个目标进行检验。在AIM 1中，将在多个大脑区域进行电刺激的腺苷释放。药理学实验将在大脑切片中进行，以测试每个区域中腺苷形成和细胞源的机制。在AIM 2中，将在麻醉大鼠中研究自发的腺苷瞬变。这些瞬态发生没有药物，但在给药A1受体拮抗剂后更为频繁。这项研究将更好地了解腺苷受体如何调节瞬态腺苷的释放。 AIM 3的目的是确定瞬时腺苷释放的功能。这两个假设是腺苷调节神经传递和血流。外源施用腺苷对多巴胺神经传递的影响将在脑切片中进行测试。另外，将研究瞬时腺苷对血流的影响。这项研究将使人们更好地了解跨性别腺苷释放的形成和功能。已经提出了基于腺苷的治疗剂，以作为疼痛，帕金森病，亨廷顿氏病和药物滥用等神经系统疾病的可能治疗。对神经调节时间过程的新见解可能会导致对瞬时腺苷变化对减轻神经传递造成的疾病的瞬间变化的操纵。