Transgenic Probes of Active Circuits

描述（由申请人提供）：试图了解大脑功能的一个关键问题是神经元的电活动如何引起特定的感知或记忆？外部世界或过去事件的神经表征是什么？虽然在定义的解剖区域之间的宏观水平上以及在较小程度上局部地在脑区域内存在对脑回路的基本理解，但是目前还没有允许识别或操纵表示特定外部刺激或事件的神经元集合的技术。该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，以允许将持久的遗传标签引入活性神经元集合（Reijmers等人，2007; Matsuo等人，2008）。我们将开发和验证转基因小鼠品系，允许环境激活的神经元合奏的直接电气和生化操纵。如果成功的话，这些小鼠将提供一种在广泛的神经科学学科中普遍有用的工具。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导致记忆或这些记忆存在的认知框架的破坏。在这项提议中，我们开发了小鼠模型，使我们能够从遗传上改变，从而以电子和分子方式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底层电路结构，它们是如何被访问的，以及它们在疾病模型中是如何被破坏的。

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.