Novel technologies for nontoxic transsynaptic tracing

无毒跨突触追踪新技术

基本信息

批准号：
8822590
负责人：
IAN R WICKERSHAM
金额：
$ 69.99万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-26 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8822590
关键词：
Acute Address Alzheimer&apos s Disease Animals Area Behavior Behavioral Behavioral Paradigm Brain Cognition Cognitive Complex Engineering Epilepsy Flow Cytometry Gene Expression Gene Expression Profile Generations Genes Genetic Huntington Disease Image In Situ Individual Infection Label Left Lentivirus Vector Mental disorders Modeling Monitor Mus Neurons Neurosciences Parkinson Disease Physiological Population Presynaptic Terminals Primates Problem Solving Rabies Rabies virus Rattus Reporter Research Personnel Resolution Rodent Role Slice Synapses System Techniques Technology Testing Time Toxic effect Transgenes Transgenic Organisms Viral Viral Genes Viral Genome Viral Vector Virus Whole-Cell Recordings autism spectrum disorder base calcium indicator env Gene Products genetic technology in vivo killings mutant nervous system disorder neural circuit new technology novel operation optical imaging optogenetics particle public health relevance recombinase relating to nervous system research study tool transgene expression vector virus envelope

项目摘要

DESCRIPTION (provided by applicant): Genetic tools have dramatically increased the power and resolution of neuroscientific experiments, allowing monitoring and perturbation of specific neuronal populations within the brain, often in the context of complex cognitive and behavioral paradigms. However, the usefulness of these tools is limited by the available means of delivering them in circuit-specific ways, a major drawback in view of the critical importance of specific connectivity between individual neurons and between neuronal classes. The primary available means of achieving transgene expression based on neurons' synaptic connections is virus-based transsynaptic tracing, which allows identification, activity imaging, optogenetic control, and perturbation of gene expression in networks of synaptically connected neurons in vivo. The required viruses, however, are toxic within a few days, precluding longer-term experiments that are needed to address many central questions in neuroscience. We will solve this problem by engineering viral transsynaptic tracing systems with either greatly reduced or entirely eliminated toxicity, so that the role of neuronal networks of known connectivity in cognition and behavior. The result will be a set of tools that will allow optical imaging, physiological recording, and manipulation of the activity and gene expression of neuronal networks of known synaptic connectivity in the context of behavioral and other experimental paradigms lasting weeks, months, or years, in any mammalian model species. This will greatly enhance our understanding of the neural bases of normal cognition as well as neurological and mental disorders.

描述（适用提供）：遗传工具大大提高了神经科学实验的功能和分辨率，从而使大脑内特定的神经元种群的监测和扰动通常是在复杂的认知和行为范式的背景下。但是，这些工具的有用性受到以特定电路方式传递它们的可用手段，这是一个主要缺点，这是单个神经元和神经元类之间特定连通性的至关重要性。基于神经元的突触连接实现转基因表达的主要方法是基于病毒的透射性跟踪，它允许在体内识别，活性成像，光遗传学控制和基因表达扰动在体内突触连接神经元网络中的基因表达。但是，所需的病毒在几天之内有毒，排除了解决神经科学中许多中心问题所需的长期实验。我们将通过工程性的具有大大降低或完全消除毒性的病毒透射性跟踪系统来解决这一问题，从而使已知连通性的神经元网络在认知和行为中的作用。结果将是一组工具，这些工具将允许在任何哺乳动物模型物种中持续数周，几个月或几年的行为和其他实验范式的背景下，在行为和其他实验范式的背景下，已知合成连通性的神经元网络的活性和基因表达操纵。这将大大增强我们对正常认知以及神经和精神疾病的神经元基础的理解。