Mechanism and function of transient adenosine signaling in the brain

描述（由申请人提供）：腺苷是一种调节神经传递和脑血流的神经调质，但腺苷在脑中信号传导的性质尚未得到很好的表征。大多数研究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，腺苷的快速变化最近被发现，但这些短暂的变化的功能是未知的。该实验室的长期目标是开发新的微电极方法来了解大脑神经调节的快速动态。本课题的目的是研究腺苷信号的形成和功能。这项研究是创新的，因为它挑战了腺苷神经调节缓慢的范式，并通过采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来推进技术。核心假设是短暂的腺苷释放发生在整个大脑中，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，电刺激腺苷释放将在多个脑区域中表征。将在脑切片中进行药理学实验，以测试腺苷形成的机制和每个区域的细胞来源。在目标2中，将在麻醉大鼠中研究自发腺苷瞬变。这些瞬变在没有药物的情况下发生，但在A1受体拮抗剂给药后更频繁。这项研究将提供一个更好的了解腺苷受体如何调节短暂的腺苷释放。目的3的目标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。将在脑切片中测试外源性腺苷对多巴胺神经传递的影响。此外，将在体内研究瞬时腺苷释放对血流的影响。本研究将有助于更好地了解腺苷释放的形成和功能。已经提出基于腺苷的治疗剂作为神经系统疾病如疼痛、帕金森病、亨廷顿病和药物滥用的可能治疗。对神经调节的时间过程的新见解可能会导致更好地操纵短暂的腺苷变化，以减轻由神经传递受损引起的疾病。 公共卫生相关性：拟议的研究与公共卫生有关，因为腺苷信号在大脑中的形成和功能的表征最终有望导致更好地了解作用于腺苷系统的药物如何用于治疗神经传递受损导致的疾病。因此，拟议中的研究与NIH的使命相关，即开发有关生命系统性质的基础知识，以减少疾病负担。

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.