Development of Fluorescent False Neurotransmitters

荧光假神经递质的开发

基本信息

批准号：
8976879
负责人：
DALIBOR SAMES
金额：
$ 62.74万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-18 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8976879
关键词：
Action Potentials Acute Address Amphetamines Anxiety Area Arousal Attention Attention deficit hyperactivity disorder Axon Behavioral Biological Biological Assay Brain Brain Diseases Calcium Cell Culture Techniques Cells Central Nervous System Diseases Characteristics Cognition Collaborations Corpus striatum structure Coupled Data Development Disease Disease model Dopamine Dorsal Drug Addiction Drug abuse Electric Stimulation Emotions Fiber Fluorescence Future Health Hippocampus (Brain)Image Imagery Individual Interdisciplinary Study Kinetics Label Laboratories Lead Learning Libraries Life Measures Mental Depression Mental disorders Methods Microscopic Microscopy Molecular Probes Monitor Mood Disorders Mus Neurobiology Neurologic Neurons Neurosciences Neurotransmitters Norepinephrine Operative Surgical Procedures Optics Organic Chemistry Parkinson Disease Pathology Pharmaceutical Preparations Phase Physiological Play Preparation Presynaptic Terminals Process Property Regulation Research Rewards Rodent Rodent Diseases Role Schizophrenia Sensory Serotonin Signal Transduction Slice Somatosensory Cortex Staging Stress Substantia nigra structure Synapses Synaptic Vesicles Synaptic plasticity System Time Tracer Varicosity Ventral Tegmental Area area striata barrel cortex calcium indicator density design dopamine system dopamine transporter dopaminergic neuron imaging agent imaging modality in vivo in vivo imaging median forebrain bundle method development monoamine multi-photon nervous system disorder neural circuit neurochemistry neuronal cell body neuropsychiatry neurotransmission neurotransmitter release noradrenaline transporter novel novel strategies optical imaging optogenetics presynaptic programs public health relevance receptor research study sensor serotonin transporter somatosensory synaptic function tool tool development treatment effect vesicular monoamine transporter 2 voltage

项目摘要

DESCRIPTION (provided by applicant): Monoamine neurotransmitters (dopamine, norepinephrine, and serotonin) play important roles in modulating the strength of both excitatory and inhibitory neurotransmission via activation of the corresponding receptors. Monoamine neurons project their axons throughout the brain and regulate diverse brain functions including arousal, stress, emotion, reward, learning, and cognition. On a cellular level, monoamines modulate responsiveness of the target cells and synapses. Aberrations in monoamine neurotransmission have been implicated in numerous neurological and neuropsychiatric disorders including Parkinson's disease, schizophrenia, ADHD, drug addiction, depression, and anxiety. However, due to methodological limitations, monoamine neurotransmission have only been studied on the bulk level of large ensembles of monoaminergic synapses. There have been no experimental tools to examine the monoamine release characteristics of individual presynaptic boutons, a fundamental physiological parameter. Drs. Dalibor Sames (PI-1) and David Sulzer (PI-2) established an interdisciplinary research program focused on addressing this challenge. Specifically, optical probes termed "Fluorescent False Neurotransmitters" (FFNs) were designed as tracers of dopamine. This new application aims to expand the scope of the FFN concept to the entire monoamine system, many different brain areas, and living rodents. We propose to develop FFN probes selective for norepinephrine and serotonin synapses, and in vivo microscopic imaging methods applicable in living rodents. The proposed new imaging methods will enable, for the first time, visualization of synaptic content release at individual presynaptic terminals of specific neurochemical types in vivo in several brain areas (striatum, somatosensory cortex, hippocampus). These new probes and associated imaging methods will unlock the possibility of addressing many long-standing questions about release properties of single synapses and their physiological regulation and deregulation in rodent disease models. The FFN probes are compatible with the existing calcium and voltage sensors and thus jointly these tools will provide a more complete readout of synaptic function and plasticity in intact circuitry.

描述（由申请人提供）：单胺神经递质（多巴胺、去甲肾上腺素和血清素）通过激活相应的受体将其轴突投射到整个大脑并调节不同的大脑功能，在调节兴奋性和抑制性神经传递的强度方面发挥着重要作用。包括唤醒、压力、情绪、奖励、学习和认知。在细胞水平上，单胺调节靶细胞的反应性。单胺神经传递的异常与许多神经和神经精神疾病有关，包括帕金森病、精神分裂症、注意力缺陷多动症、药物成瘾、抑郁症和焦虑症，然而，由于方法学的限制，单胺神经传递仅在大量水平上进行了研究。单胺能突触的集合还没有实验工具来检查单个突触前突触的单胺释放特征，这是一个基本的生理参数。 Dalibor Sames 博士 (PI-1) 和 David Sulzer (PI-2) 建立了一个跨学科研究计划，专注于解决这一挑战，具体而言，称为“荧光假神经递质”(FFN) 的光学探针被设计为多巴胺的示踪剂。该应用旨在将 FFN 概念的范围扩展到整个单胺系统、许多不同的大脑区域和活体啮齿动物。我们建议开发对去甲肾上腺素和去甲肾上腺素具有选择性的 FFN 探针。血清素突触和适用于活体啮齿动物的体内显微成像方法将首次实现体内多个大脑区域（纹状体、体感）特定神经化学类型的单个突触前末端释放的突触内容释放的可视化。这些新的探针和相关的成像方法将解决许多长期存在的问题的可能性，这些问题涉及单个突触的释放特性及其生理调节和放松管制。 FFN 探针与现有的钙和电压传感器兼容，因此这些工具将共同提供完整电路中突触功能和可塑性的更完整的读数。