Region-Specific, Inducible Axonal Tract-Tracing in the Brain

大脑中区域特异性、可诱导的轴突束追踪

• 批准号: 9116301
• 负责人: David J Anderson
• 金额: $ 41.63万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116301
• 关键词: Amygdaloid structure; Anatomy; Animal Model; Behavior; Behavior Control; Behavioral; Behavioral Assay; Brain; Brain Diseases; Brain region; Canine Adenoviruses; Cells; Complex; Decision Making; Development; Diagnosis; Dissection; ESR1 gene; Emotions; FLP recombinase; Gene Expression; Genetic; Genetic Recombination; Goals; Health; Heterogeneity; Human; Hypothalamic structure; Instinct; Joints; Knowledge; Label; Lead; Light; Maps; Mediating; Mental disorders; Methods; Mission; Molecular; Mus; Nature; Neurobiology; Neurons; Neurophysiology - biologic function; Neurosciences; Organism; Outcome; Population; Process; Public Health; Reading; Recombinant adeno-associated virus (rAAV); Reporter; Reproductive Behavior; Research; Social Behavior; Specificity; Structure; System; Techniques; Technology; Tetracyclines; Transgenic Mice; Virus; Work; base; behavior test; cell type; combinatorial; innovation; insight; mind control; neural circuit; neurobiological mechanism; neuroregulation; novel; novel strategies; optogenetics; presynaptic; promoter; recombinase; tool

DESCRIPTION (provided by applicant): How neural circuits control complex behaviors is a fundamental problem in neuroscience. Revolutionary new tools, such as optogenetics, and the ability to express such tools in molecularly defined neuronal cell types, have transformed our ability to dissect neural function in genetically tractable model organisms such as the mouse. However, a gap remains between the ability to mark, map and manipulate neuronal populations defined by "Cre driver" transgenic mouse lines, and potential anatomic and functional heterogeneity within those populations. This gap limits our ability to dissect neural circuit function at an appropriate level of cellular specificity. To fill this gap, combinatorial approache will be developed to express optogenetic effectors and other genetically encoded tools in neuronal subpopulations defined by the intersection of their molecular identity, and their activity or connectional specificity. The long-term goal is to elucidate the neural circuits that control decisions between complex, innate social behaviors controlled by the hypothalamus, amygdala and other limbic structures. The overall objective of this application is to develop new methods for identifying and genetically targeting heterogeneous neural cell types contained within populations defined by the expression of a given Cre driver. Proof-of-principle for these methods will be obtained by dissecting hypothalamic circuits that govern behavioral decisions, using innate social behaviors as a robust read-out of targeted optogenetic manipulations. The central objective of this proposal is to develop intersectional methods that combine the expression of a specific Cre driver with orthogonal genetic methods that mark neurons based on their activity during particular behaviors, or their connectivity, in a contingent (logical 'AND') manner. The rationale for this research is that solving this general problem is essential to making forward progress in mapping the circuitry that governs complex behaviors. In this proposal, methods will be developed to mark neurons based on their expression of a specific Cre driver and: their activity during different innate behaviors (Aim 1); their projections to a specific target (Aim 2); and their presynaptic inputs and behavior-specific activation (Aim 3). The contribution will be to create new intersectional tools for marking and manipulating specific neuronal subpopulations that will be generally applicable, and to use them to gain new insights into the functional organization of hypothalamic circuits controlling behavioral decision-making. This contribution is significant because it will create new tools that allow dissection of neural circuit function at an unprecedented level of cellular specificity, and shed new light on an important problem in the neural control of complex behaviors. The approach is innovative, because it will provide intersectional approaches to genetically targeting specific neuronal cell types that have not yet been implemented in mice. The work proposed in this application will, therefore, both advance knowledge in this specific field and, by developing and disseminating novel methods, will also advance knowledge in other fields of neuroscience.

描述（由申请人提供）：神经回路如何控制复杂行为是神经科学中的基本问题。革命性的新工具（例如光遗传学）以及在分子定义的神经元细胞类型中表达此类工具的能力，已经改变了我们在遗传上可触及的模型生物（如小鼠）中剖析神经功能的能力。然而，在标记，映射和操纵由“ CRE驱动器”转基因小鼠线定义的神经元种群的能力与这些人群中潜在的解剖和功能异质性之间存在差距。该差距限制了我们在适当的细胞特异性水平上剖析神经回路功能的能力。为了填补这一空白，将开发组合方法来表达光学遗传效应子和其他遗传编码的工具在神经元亚群中，由其分子身份的相交和活性定义 或连接特异性。长期的目标是阐明由下丘脑，杏仁核和其他边缘结构控制复杂，先天社会行为之间决策的神经回路。该应用程序的总体目的是开发新的方法来识别和遗传靶向由给定CRE驱动器表达定义的种群中包含的异质神经细胞类型。这些方法的原则证明将通过解剖管理行为决策的下丘脑回路，使用先天的社会行为作为对靶向光遗传学操纵的强大读取。该提案的核心目的是开发相互选择的方法，将特定的CRE驱动器的表达与正交遗传方法相结合，这些方法以神经元在特定行为或其连通性（逻辑'and'和'）方式标记神经元的活性标记神经元。这项研究的理由是，解决这个总体问题对于在映射控制复杂行为的电路方面取得进步至关重要。在此提案中，将开发方法来根据其表达特定的CRE驱动程序来标记神经元，以及它们在不同的先天行为中的活动（AIM 1）；他们对特定目标的预测（AIM 2）； 及其突触前的输入和特定于行为的激活（AIM 3）。贡献将是创建新的交叉工具，用于标记和操纵通常适用的特定神经元亚群，并利用它们来获得对控制行为决策的下丘脑电路的功能组织的新见解。这种贡献很重要，因为它将创建新的工具，使神经电路功能在 史无前例的细胞特异性水平，并为复杂行为的神经控制中的一个重要问题提供了新的启示。该方法具有创新性，因为它将提供相交方法来靶向尚未在小鼠中实施的特定神经元细胞类型。因此，在本应用程序中提出的工作将在这个特定领域中提高知识，并且通过开发和传播新方法，也将推进神经科学其他领域的知识。