Mechanism and function of transient adenosine signaling in the brain

描述(申请人提供)：腺苷是一种神经调节剂，调节神经传递和脑血流，但腺苷信号在大脑中的性质尚未得到很好的描述。大多数研究都描述了腺苷受体激活或腺苷基础水平改变的长期影响。最近，人们发现了腺苷的快速变化，但这些短暂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。本项目的目的是研究瞬时腺苷信号的形成和功能。这项研究具有创新性，因为它挑战了腺苷神经调节缓慢的范式，并通过使用新型电化学传感器来克服时间分辨率低和灵敏度低的关键仪器障碍，从而推动了技术的进步。中心假说是，短暂的腺苷释放在整个大脑中发生，由腺苷受体调节，并在快速的时间尺度上调节神经传递和血流。这一假设将通过三个目标进行检验。在目标1中，电刺激的腺苷释放将在多个脑区表现为特征。药理学实验将在脑片中进行，以测试腺苷的形成机制和每个区域的细胞来源。在目标2中，将研究麻醉大鼠的自发性腺苷瞬变。这些瞬变在没有药物的情况下发生，但在给予A1受体拮抗剂后更频繁。这项研究将更好地理解腺苷受体是如何调节瞬时腺苷释放的。目标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液流动。外源性应用腺苷对多巴胺神经传递的影响将在脑片中进行测试。此外，暂时性腺苷释放对血流的影响将在体内进行研究。这项研究将有助于更好地了解暂时性腺苷释放的形成和功能。基于腺苷的疗法已被提议作为治疗神经疾病的可能方法，如疼痛、帕金森病、亨廷顿病和药物滥用。对神经调节时间进程的新见解可能会导致更好地处理短暂的腺苷变化，以减轻神经传递受损引起的疾病。 公共卫生相关性：拟议的研究与公共健康相关，因为对大脑中腺苷信号形成和功能的表征最终有望导致更好地理解作用于腺苷系统的药物如何用于治疗神经传递受损引起的疾病。因此，这项拟议的研究与NIH的使命相关，即发展可用于减轻疾病负担的生命系统性质的基本知识。

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the characterization of the formation and function of adenosine signaling in the brain is ultimately expected to lead to a better understanding of how drugs that act on the adenosine system can be used to treat diseases that result from impaired neurotransmission. Thus, the proposed research is relevant to the NIH's mission to develop fundamental knowledge about the nature of living systems that can be applied to reduce the burdens of illness.