Optical montoring of modulatory neurotransmitter levels using new infrared nanonsensors

项目总结 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，与广泛的 各种精神和神经障碍，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态变化不像我们人类那样快速、灵敏、直接或干净 会想要。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，方法是将 近红外(NIR)纳米传感器技术从纳米科学家的长凳上转移到神经生物学家的试验台上。为 容易校准和与成瘾有很强的相关性，我们将从多巴胺纳米传感器开始。我们会 在脑片和完整小鼠中将新的近红外纳米传感器工具与现有的成像和记录方法相结合 以便更好地了解调节性神经传递的生物学。在具体目标1中，我们计划 体外检测诱发多巴胺的多巴胺敏感纳米传感器的研制和校准 在纹状体和额叶皮质脑片中释放。在具体目标2中，我们将测试使用这些工具的可行性 感应器可以长时间在活体内进行测量。在特定的目标3中，我们将成像纳米传感器对诱发的 在完整和潜在清醒行为的小鼠体内释放多巴胺。我们的目标是把舞台搭建成光学的 监测体内的多巴胺和其他神经递质水平，以响应条件下的提示和奖励 这会在健康和疾病的小鼠模型中导致奖励预测错误。发展和传播 单是多巴胺纳米传感器就能极大地帮助我们理解具有滥用潜力的物质。 以及多种药理制剂的作用。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。我们的 最终目标是开发测量大脑皮质中多巴胺、去甲肾上腺素和5-羟色胺的方法。 活体同时进行。新的红外纳米传感器有可能极大地促进我们对 大脑，给了我们新的眼睛来实时看到调节性的神经传递。

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.