Optical montoring of modulatory neurotransmitter levels using new infrared nanonsensors

项目摘要 多巴胺、去甲肾上腺素和5-羟色胺是主要的调节性神经递质，它们与广泛的神经系统疾病有关。 各种精神和神经疾病，包括成瘾。我们现有的方法来量化 这些神经递质在细胞外空间的动力学不像我们一样快速，敏感，直接或干净。 会喜欢。在这里，我们建议利用纳米科学的最新进展来解决这个问题， 近红外（nIR）纳米传感器技术从纳米科学家的工作台到神经生物学家的钻机。为 易于校准和与成瘾的强相关性，我们将从多巴胺纳米传感器开始。我们将 将新的nIR纳米传感器工具与脑切片和完整小鼠中现有的成像和记录方法相结合 以使人们更好地理解调节性神经传递的生物学。在具体目标1中，我们计划 开发和校准多巴胺敏感纳米传感器用于诱发多巴胺的离体检测 纹状体和额叶皮层脑切片中的释放。在具体目标2中，我们将测试使用这些方法的可行性。 传感器在体内的长时间尺度。在具体目标3中，我们将对纳米传感器对诱发的 在完整的和潜在清醒的行为小鼠体内释放多巴胺。我们的目标是在视觉上 监测体内多巴胺和其他神经递质水平，以响应条件中的提示和奖励， 这在健康和疾病的小鼠模型中引起奖励预测误差。发展和传播 多巴胺纳米传感器将极大地告知我们对具有滥用潜力的物质的理解 以及多种药理学试剂的作用。使用多巴胺收集的实验数据 然后将应用纳米传感器来促进去甲肾上腺素和5-羟色胺传感器的开发。我们 最终目标是开发出测量大脑皮层中多巴胺、去甲肾上腺素和5-羟色胺的方法， vivo同时新的红外纳米传感器有可能极大地推进我们对 大脑，赋予我们新的眼睛看到调制神经传递在真实的时间。

PROJECT SUMMARY Dopamine, norepinephrine, and serotonin are major modulatory neurotransmitters that are implicated in a wide variety of psychiatric and neurological disorders, including addiction. Our available methods to quantify the dynamics of these neurotransmitters in extracellular space are not as fast, sensitive, direct or as clean as we would like. Here we propose to leverage recent progress in nanoscience to solve this problem by moving new near infrared (nIR) nanosensor technology from the nanoscientists' bench into the neurobiologists' rig. For ease of calibration and strong relevance to addiction, we will start with a dopamine nanosensor. We will integrate new nIR nanosensor tools with existing imaging and recording methods in brain slices and intact mice to enable greater understanding of the biology of modulatory neurotransmission. In Specific Aim 1, we plan to develop and calibrate the use of dopamine sensitive nanosensors for ex vivo detection of evoked dopamine release in striatal and frontal cortex brain slices. In Specific Aim 2 we will test the feasibility of using these sensors over long time scales in vivo. In Specific Aim 3, we will image nanosensor response to evoked dopamine release in vivo in intact and potentially awake behaving mice. Our goal is to set the stage to optically monitor dopamine and other neurotransmitter levels in vivo, in response to cues and rewards in conditions which induce reward prediction error in mouse models of health and disease. Development and dissemination of the dopamine nanosensor alone will greatly inform our understanding of substances with abuse potential and the effects of a broad variety of pharmacological agents. Experimental data collected using the dopamine nanosensor will then be applied to facilitate development of the norepinephrine and serotonin sensors. Our ultimate goal is to develop methods for measuring dopamine, norepinephrine, and serotonin in the cortex in vivo simultaneously. New infrared nanosensors have the potential to greatly advance our understanding of the brain, granting us new eyes to see modulatory neurotransmission in real time.