Mechanism and function of transient adenosine signaling in the brain

描述（申请人提供）：腺苷是一种调节神经传递和脑血流量的神经调节剂，但腺苷信号在大脑中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。最近发现了腺苷的快速变化，但这些短暂变化的功能尚不清楚。本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态。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，并通过采用新型电化学传感器克服了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。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液流动。这一假设将通过三个目标来验证。在Aim 1中，电刺激的腺苷释放将在多个脑区被表征。药理实验将在脑切片上进行，以测试腺苷形成的机制和每个区域的细胞来源。在第二阶段，将研究麻醉大鼠的自发性腺苷瞬态。这些症状在没有药物的情况下发生，但在使用A1受体拮抗剂后更为常见。这项研究将更好地了解腺苷受体如何调节瞬时腺苷释放。Aim 3的目的是确定瞬时腺苷释放的功能。两种假设是腺苷调节神经传递和血液流动。外源性腺苷对多巴胺神经传递的影响将在脑切片中进行测试。此外，将在体内研究瞬时腺苷释放对血流的影响。这项研究将有助于更好地理解瞬时腺苷释放的形成和功能。以腺苷为基础的治疗方法已被提出作为神经系统疾病如疼痛、帕金森病、亨廷顿氏病和药物滥用的可能治疗方法。对神经调节时间过程的新见解可能导致更好地操纵短暂的腺苷变化，以减轻神经传递受损引起的疾病。

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.