In vivo Profiling of Glial and Neuronal Activities in Psychostimulant Abuse

精神兴奋剂滥用中神经胶质和神经元活动的体内分析

• 批准号: 7851185
• 负责人: Philip K Liu
• 金额: $ 62.78万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851185
• 关键词: Abstinence; Actins; Affect; Amphetamine Addiction; Amphetamines; Animals; Autopsy; Blood - brain barrier anatomy; Brain; Brain Diseases; Cell Culture Techniques; Cells; Cerebrum; Chronic; Chronic Disease; Contrast Media; Data; Detection; Development; Discrimination; Doctor of Philosophy; Dose; Drug Addiction; Drug Exposure; Drug abuse; Event; Exposure to; Eyedrops; FOS gene; Gene Activation; Gene Expression; Genes; Glial Fibrillary Acidic Protein; Goals; Imaging Techniques; Immunohistochemistry; In Situ; In Situ Hybridization; Individual; Intraperitoneal Injections; Knockout Mice; Life; Link; Longitudinal Studies; Magnetic Resonance Imaging; Maps; Mediating; Messenger RNA; Methods; Modification; Molecular; Molecular Profiling; Monitor; Mus; Neuroglia; Neurons; Neurosciences; Neurosciences Research; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Polymerase Chain Reaction; Preparation; Productivity; Proteins; RNA Probes; Resolution; Reverse Transcription; Role; Route; Sampling; Sensitivity and Specificity; Signal Transduction; Slice; Societies; Staging; Staining method; Stains; Substance abuse problem; Techniques; Time; Toxin; Up-Regulation; Wild Type Mouse; addiction; base; behavioral sensitization; dosage; drug of abuse; imaging probe; in vivo; iron oxide; member; nanoparticle; novel; nutrition; protein expression; psychostimulant; public health relevance; receptor; response; segregation; spatiotemporal; stimulant abuse

DESCRIPTION (provided by applicant): In vivo profiling of glial and neuronal activities in psychostimulant abuse (PI: Christina H Liu, PhD) Drug addiction is a chronic brain disorder that severely hampers productivity of many members of our society. One of the most used drugs of abuse is amphetamine. Most neuroscience studies on amphetamine have focused on the morphological and molecular adaptations of neurons in response to chronic drug exposure. Electrophysiological data from cell cultures or brain slice preparations show that an important component of drug abuse is the interaction that occurs between glia and neurons during neuronal activations arising from repeat exposure to amphetamine. Although we know that glial cells are essential to the survival of neurons, providing critical support, nutrition, and toxin clearance to the neurons, our understanding of the role of glia in drug addiction is very limited. To overcome this limitation, we have developed a novel in vivo probe to visualize the changes in gene activities in neurons and glia, using magnetic resonance imaging (MRI) in live brains after exposure to amphetamine. We have demonstrated the utility of this method for discrimination of cells that express different but specific gene activities; i.e., neuronal-based elevation of cfos messenger RNA (mRNA) from glia-based GFAP mRNA. Because our detection technique does not require the use of postmortem samples, we are able to study the longitudinal profiles of different cerebral gene activities during and after exposure to drugs. Here, we aim to study gene activation during amphetamine sensitization in living C57Black6 mice, which involves repeated usage of, abstinence from, and re-exposure to the drug. We will utilize our novel technique that uses mRNA-targeted MR contrast probes to detect altered endogenous gene activities that result from amphetamine exposure in neurons and glia. The targets to be investigated in this project are mRNAs of glial fibrillary acidic protein (GFAP) and neuronal cFos protein. Our goals for this project are to use this novel MRI technique to enhance current understanding of the interactions between glial and neuronal cells at different stages of amphetamine exposure. We propose the following specific aims: (1) determine the optimal dosage and retention profiles of MRI probes in live brains; (2) determine the gene activity profiles of glial and neuronal cells in mouse brains in vivo after amphetamine, at different stages of exposure; and (3) explore the neuron-mediated glial response in the development of the amphetamine addiction phenotype. PUBLIC HEALTH RELEVANCE: In this project, we will utilize a novel Magnetic Resonance Imaging (MRI) technique that we have developed to detect altered gene expression in neurons and glia of live animal affected by addictive drugs. The goals of this project are to enhance current understanding of the interaction between glial and neuronal cells at different stages of amphetamine exposure. Such enhancement will bring a step closer to real-time analysis of neurophysiologic events that occur in patients with substance abuse and addiction.

描述（由申请人提供）：神经胶质和神经元活动在精神兴奋剂滥用的体内分析（PI：Christina H Liu，博士）药物成瘾是一种慢性脑部疾病，严重阻碍了我们社会许多成员的生产力。最常用的滥用药物之一是安非他明。大多数关于安非他明的神经科学研究都集中在神经元对慢性药物暴露的形态和分子适应上。从细胞培养或脑切片制备的电生理数据表明，药物滥用的一个重要组成部分是神经胶质细胞和神经元之间的相互作用，在神经元激活引起的重复接触安非他明。虽然我们知道神经胶质细胞对神经元的存活至关重要，为神经元提供关键的支持，营养和毒素清除，但我们对神经胶质细胞在药物成瘾中的作用的理解非常有限。为了克服这一局限性，我们已经开发出一种新的体内探针可视化的神经元和神经胶质细胞中的基因活性的变化，使用磁共振成像（MRI）在活的大脑暴露于安非他明后。我们已经证明了这种方法用于区分表达不同但特定基因活性的细胞的实用性;即，基于神经元的cfos信使RNA（mRNA）从基于胶质细胞的GFAP mRNA升高。由于我们的检测技术不需要使用尸检样本，我们能够研究暴露于药物期间和之后不同大脑基因活动的纵向分布。在这里，我们的目标是研究苯丙胺致敏过程中的基因激活在生活C57 Black 6小鼠，其中包括重复使用，禁欲，并重新暴露于药物。我们将利用我们的新技术，使用mRNA靶向的MR对比探针来检测神经元和神经胶质细胞中安非他明暴露导致的内源性基因活性改变。本课题研究的靶点是胶质细胞酸性蛋白（GFAP）和神经元cFos蛋白的mRNA。我们这个项目的目标是使用这种新的MRI技术，以提高目前的理解神经胶质细胞和神经元细胞之间的相互作用，在不同阶段的安非他明暴露。我们提出了以下具体目标：（1）确定活体脑中MRI探针的最佳剂量和保留曲线;（2）确定安非他明后小鼠脑中胶质细胞和神经元细胞在体内不同暴露阶段的基因活性曲线;（3）探索安非他明成瘾表型发展中神经元介导的胶质反应。公共卫生相关性：在这个项目中，我们将利用一种新的磁共振成像（MRI）技术，我们已经开发出检测受成瘾药物影响的活体动物的神经元和神经胶质细胞中改变的基因表达。该项目的目标是提高目前的理解神经胶质细胞和神经元细胞之间的相互作用，在不同阶段的安非他明曝光。这种增强将使对药物滥用和成瘾患者发生的神经生理事件的实时分析更近一步。