Transgenic Probes of Active Circuits

有源电路转基因探针

• 批准号: 8532870
• 负责人: MARK R MAYFORD
• 金额: $ 42.89万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532870
• 关键词: Allatostatin; Area; Biochemical; Boxing; Brain; Brain region; Cell Separation; Cells; Cognitive; Color; Complex; Discipline; Disease; Disease model; Dominant-Negative Mutation; Enterobacteria phage P1 Cre recombinase; Episodic memory; Event; Gene Expression Regulation; Genes; Genetic; Goals; Grant; Health; Hippocampus (Brain); Human; Knowledge; Lead; Learning; Ligands; Light; Memory; Mind; Modeling; Molecular; Mus; Mutant Strains Mice; Neurologic; Neurons; Neurophysiology - biologic function; Neurosciences; Nuclear; Pattern; Perception; Plastics; Process; Regulation; Resolution; Retrieval; Sensory; Series; Signal Transduction; Specific qualifier value; Stimulus; Structure; Synapses; System; Techniques; Tetracyclines; Time; Toxin; Transgenic Mice; Transgenic Organisms; base; brain cell; cell type; design; genetic manipulation; improved; information processing; memory retrieval; mouse model; neural circuit; neuropsychiatry; promoter; receptor; relating to nervous system; response; tool

DESCRIPTION (provided by applicant): A key question in attempts to understand brain function is how does the electrical activity of neurons give rise to specific perceptions or memories? What is the neural representation of the external world or of past events? While there is a basic understanding of brain circuits at the macroscopic level between defined anatomical regions and to a lesser extent locally within brain regions, there are currently no techniques that allow the identification or manipulation of neuronal ensembles that represent a specific external stimulus or event. The primary goal of this proposal is to improve and extend upon a genetic approach that we have developed that uses the cfos promoter and the tetracycline system to allow the introduction of long lasting genetic tags into active neuronal ensembles (Reijmers et al. 2007; Matsuo et al. 2008). We will develop and validate transgenic mouse lines that allow the direct electrical and biochemical manipulation of environmentally activated neuronal ensembles. If successful, these mice will provide a tool that should be generally useful throughout a wide range of neuroscience disciplines. PUBLIC HEALTH RELEVANCE: The human mind is made up of specific bits of knowledge and memories that are integrated within a relational network. Many neurological and neuropsychiatric disorders lead to a disruption of memories or of the cognitive framework in which these memories exists. In this proposal we develop mouse models that allow us to genetically alter, and thus manipulate electrically and molecularly, neurons that make up specific memories. These tools should be useful in dissecting the underlying circuit structure of specific memories, how they are accessed, and how they are disrupted in disease models.

描述（由申请人提供）：试图理解大脑功能的一个关键问题是神经元的电活动是如何产生特定的感知或记忆的？外部世界或过去事件的神经表征是什么？虽然在宏观层面上对确定的解剖区域之间的脑回路有了基本的了解，并且在较小程度上对局部脑区域内的脑回路有了基本的了解，但目前还没有技术允许识别或操纵代表特定外部刺激或事件的神经元集合。本提案的主要目标是改进和扩展我们已经开发的遗传方法，该方法使用cfos启动子和四环素系统，允许将持久的遗传标签引入活跃的神经元集合（Reijmers等人，2007；Matsuo等人，2008）。我们将开发和验证转基因小鼠系，允许对环境激活的神经元集合进行直接的电和生化操作。如果成功，这些小鼠将提供一个工具，在广泛的神经科学学科中普遍有用。公共卫生相关性：人类的大脑是由特定的知识和记忆组成的，这些知识和记忆被整合在一个关系网络中。许多神经和神经精神疾病会导致记忆或记忆存在的认知框架的破坏。在这个提议中，我们开发了小鼠模型，使我们能够从基因上改变，从而在电和分子上操纵构成特定记忆的神经元。这些工具应该有助于剖析特定记忆的潜在电路结构，它们是如何被访问的，以及它们如何在疾病模型中被破坏。