Adrenergic transmission properties and implication

项目总结 去甲肾上腺素(NE)和肾上腺素(Epi)与复杂的认知功能有关， 例如感觉处理、睡眠-觉醒/觉醒状态转换和注意力 在各种组织和器官中的生物过程，包括心脏、胰腺和脾。 肾上腺素能传递的失调与许多神经系统疾病有关，包括 阿尔茨海默氏症、抑郁障碍和精神分裂症，以及许多其他健康问题， 包括心血管疾病、免疫缺陷和肿瘤发生。 尽管NE/Epi可能参与多种生理和病理情况， 肾上腺素能传递的精确调节和确切的功能作用仍然不清楚，因为 主要是由于可用于监测NE/EPI的工具的局限性。我们最近发展了一个家庭 基于强度的G蛋白偶联受体(GPCR)激活基于遗传编码的NE 环状置换绿色荧光蛋白(CpGFP)与人 肾上腺素能受体。当这些GRABNE传感器允许首次看到肾上腺素能 传输，传感器在确定肾上腺素能突触特性方面是次优的。 变速箱。为了促进NE/EPI的研究，我们最近设计了高性能的GRABNE 允许高灵敏度和高分辨率可视化肾上腺素能传递事件的传感器 在单一的释放地点。新的传感器和初步数据增强了我们测试 高性能GRABNE传感器可能解决肾上腺素能传递的假说 可以推断肾上腺素能功能作用的性质。此应用程序遵循两个特定的 目的：目的1是确定高性能的GRABNE传感器是否可以分解肾上腺素能 传递特性，目标2是测试肾上腺素能传递是否在 要求精确度和注意力的行为。我们预计拟议中的实验将 描述一种新形式的神经元传递的第一组基本突触属性和 为肾上腺素能传递定义一个新的、独特的功能角色。

PROJECT SUMMARY Norepinephrine (NE) and epinephrine (Epi) have been implicated in complex cognitive functions, such as sensory processing, sleep-wake/arousal state transition and attention, in the brain, and other biological processes in various tissues and organs, including the heart, pancreas and spleen. Dysregulation of adrenergic transmission is linked to a number of neurological diseases, including Alzheimer’s disease, depressive disorders and schizophrenia, as well as many other health problems, including cardiovascular diseases, immune-deficiency and tumorigenesis. Despite the potential involvement of NE/Epi in myriad physiological and pathological conditions, the precise regulation and exact functional role of adrenergic transmission remain poorly defined, due primarily to limitations of available tools for monitoring NE/Epi. We have recently developed a family of intensity-based G-protein-coupled receptor (GPCR) activation-based genetically encoded NE (GRABNE) sensors by coupling a circular permutated green fluorescent protein (cpGFP) with a human adrenergic receptor. While these GRABNE sensors allowed the first visualization of adrenergic transmission, the sensors were suboptimal in determining synaptic properties of adrenergic transmission. To facilitate NE/Epi research, we recently engineered high-performance GRABNE sensors that allowed high-sensitivity and high-resolution visualization of adrenergic transmission events at single release sites. The new sensors and preliminary data build up our confidence to test the hypothesis that high-performance GRABNE sensors may resolve the adrenergic transmission properties that could deduce the adrenergic functional role. This application follows two specific aims: Aim 1 is to determine whether high-performance GRABNE sensors may resolve adrenergic transmission properties, and Aim 2 is to test whether adrenergic transmission plays an essential role in the precision- and attention-demanding behaviors. We expect the proposed experiments to characterize the first set of fundamental synaptic properties of a new form of neuronal transmission and define a novel, unique functional role for adrenergic transmission.