Neurotransmitter Interactionson Sub-Second Timescales

亚秒级时间尺度上的神经递质相互作用

• 批准号: 8691921
• 负责人: Michael A. Johnson
• 金额: $ 18.73万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691921
• 关键词: AMPA Receptors; Address; Agonist; Amino Acid Neurotransmitters; Animals; Behavior; Biogenic Amines; Biological; Brain; Caliber; Chemicals; Cognitive; Control Animal; Detection; Development; Disease Pathway; Dopamine; Event; Excitatory Amino Acids; Exposure to; Fiber Optics; Generations; Gilles de la Tourette syndrome; Glutamates; Goals; Huntington Disease; Hydrogen Peroxide; Knowledge; Laboratories; Life; Light; Measurement; Measures; Mental Depression; Mercury; Methodology; Methods; Microelectrodes; Mission; Modeling; Molecular Analysis; Movement Disorders; Nature; Nervous System Physiology; Neurobiology; Neuromodulator; Neurotransmitters; Nitric Oxide; Organism; Parkinson Disease; Pathway interactions; Physiologic pulse; Play; Rattus; Research; Research Personnel; Resolution; Rodent Model; Role; Scanning; Serotonin; Signal Transduction; Slice; Source; System; Techniques; Technology; Testing; Time; Tissues; Ultraviolet Rays; United States National Institutes of Health; Work; addiction; animal tissue; awake; base; brain tissue; burden of illness; carbon fiber; design; disability; empowered; extracellular; gamma-Aminobutyric Acid; human disease; in vivo; innovation; insight; irradiation; millisecond; photoactivation; receptor; research study; response; tool; uptake

Ttie particular mechanisms underlying the sub-second control of dopamine release by glutamate and other neurotransmitters/neuromodulators are not well-known largely because the analytical methodology required to address these important questions has not been sufficiently developed. Although one technique, fast-scan cyclic voltammetry at carbon-fiber microelectrodes, offers sufficient temporal resolution to measure the release and uptake of electroactive biogenic amines such as dopamine, its use in characterizing such sub-second neurotransmitter/neuromodulator interactions is lacking. This deficiency represents a serious roadblock because signaling events in the brain that influence outward physical responses and cognitive events occur within this sub-second time regime. Therefore, the central aim of this proposed research is to develop and apply tools that will allow for the quantitative study of these neurotransmitter/neuromodulator interactions in tissues and in vivo. Two temporally-compatible methods, fast-scan cyclic voltammetry and the photoactivation ofthe p-hydroxyphenyl caged form of glutamate (pHP-Glu), used here as a model caged system, will be applied to measure the sub-second response of dopamine release in response to millisecond timescale exposures to exogenous glutamate. The overall objective of this proposed research will be accomplished by successfully completing two specific aims: (1) integrate the sub-second measurement of electrically-evoked dopamine release with the photo-activation of caged compounds in brain slices and (2) optimize the construction and use of a combined probe/carbon-fiber microelectrode for measuring the impact of caged compound photoactivation on dopamine release events in vivo. This approach is innovative because it is among the first to simultaneously apply these two high temporal resolution techniques in living tissues and animals. The development and application of this proposed methodology is significant because it will enable laboratory researchers to measure sub-second timescale dopamine release in response to ¿mu¿s-timescale glutamate application. Moreover, this work should have a broad impact since the application of these techniques can be expanded to include the detection of other electroactive neurotransmitters and neuromodulators, such as serotonin, hydrogen peroxide (H{2}O{2}), and nitric oxide (NO), and the photoactivation of other bioactive molecules, such as GABA and specifically designed synthetic agonists/antagonists. Importantly, this research directly relates to the NIH mission of seeking fundamental knowledge about the nature and behavior of living systems and reducing the burdens of illness and disability in that applies to, but is not limited to: (1) fundamental neurobiological studies; (2) studies of dopamine-related movement disorders [e.g. Huntington's disease (HD), Parkinson's disease (PD), Tourette's syndrome (TS)]; (3) studies of addiction and depression; and (4) studies addressing the mechanisms of action of CNS-active pharmacological agents.

谷氨酸和其他神经递质/神经调节剂对多巴胺释放释放多巴胺释放的特定机制并不是众所周知的，因为解决这些重要问题所需的分析方法尚未得到充分发展。尽管一种技术，即在碳纤维微电极上的快速扫描环状伏安法提供了足够的临时分辨率，可以测量诸如多巴胺等电活性生物胺的释放和摄取，在表征这种次秒的神经递质/神经递质相互作用方面的用途缺乏。这种缺陷代表了一个严重的障碍，因为在这个次秒时，大脑中的信号事件会影响外向物理反应和认知事件。因此，这项拟议的研究的核心目的是开发和应用工具，以允许对这些神经递质/神经调节剂相互作用进行定量研究。两种暂时兼容的方法：快速扫描的环状伏安法和谷氨酸氧化苯基笼形式的光活化（php-GLU）（php-GLU）将用作模型笼子系统，可用于测量对毫秒量表量表的多巴胺释放响应的次要响应，以响应millisecond Timescale exposures exogenos glututamate to exogenos Glutamate to exogenos glutamate to exogenos glutamatores。 The overall objective of this proposed research will be accomplished by successfully completing two specific aims: (1) integrated the sub-second measurement of electronically-evoked dopamine release with the photo-activation of caged compounds in brain slices and (2) optimize the construction and use of a combined probe/carbon-fiber microelectrode for measuring the impact of caged compound photoactivation on dopamine release events in vivo.这种方法具有创新性，因为它是最早在生物组织和动物中轻松应用这两种高临时分辨率技术的人之一。这种提出的方​​法的开发和应用是重要的，因为它将使实验室研究人员能够测量响应``MU。s-timesscale谷氨酸盐）的次秒时间尺度释放。此外，这项工作应该具有广泛的影响，因为这些技术的应用可以扩展到包括对其他电活性神经递质和神经调节剂的检测，例如5-羟色胺，过氧化氢（H {2} o {2}），以及氧化物（no）和其他Bioecivation ins gioectivation ins gioective interivation ins gioecative ins giocativation及其光活性。激动剂/对手。重要的是，这项研究直接涉及NIH的使命，该任务是寻求有关生命系统的性质和行为的基本知识，并减少适用的疾病和混乱的伯氏，但不限于：（1）基本的神经生物学研究； （2）多巴胺相关运动障碍的研究[例如亨廷顿氏病（HD），帕金森氏病（PD），图雷特综合症（TS）]； （3）成瘾和抑郁症的研究； （4）研究CNS活性药剂的作用机理的研究。