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的行为是神经科学的一个基本问题。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这些工具的能力，已经改变了我们在遗传易处理的模型生物（例如小鼠）中剖析神经功能的能力。然而，由“Cre驱动程序”转基因小鼠品系定义的标记、绘图和操作神经元群体的能力与这些群体内潜在的解剖和功能异质性之间仍然存在差距。这一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，将开发组合方法来在神经元亚群中表达光遗传学效应器和其他遗传编码工具，这些神经元亚群由其分子身份和活性的交叉定义 或连接特异性。长期目标是阐明控制下丘脑、杏仁核和其他边缘结构控制的复杂、先天社会行为之间决策的神经回路。该应用的总体目标是开发新方法，用于识别和遗传靶向由给定 Cre 驱动程序的表达定义的群体中包含的异质神经细胞类型。这些方法的原理验证将通过解剖控制行为决策的下丘脑回路来获得，使用先天社会行为作为目标光遗传学操作的稳健读数。该提案的中心目标是开发交叉方法，将特定 Cre 驱动程序的表达与正交遗传方法相结合，根据神经元在特定行为期间的活动或连接性，以偶然（逻辑“AND”）方式标记神经元。这项研究的基本原理是，解决这个普遍问题对于在绘制控制复杂行为的电路方面取得进展至关重要。在本提案中，将开发根据特定 Cre 驱动程序的表达来标记神经元的方法，以及： 它们在不同先天行为期间的活动（目标 1）；他们对特定目标（目标 2）的预测； 及其突触前输入和行为特异性激活（目标 3）。其贡献将是创建新的交叉工具来标记和操纵普遍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回路的功能组织的新见解。这一贡献意义重大，因为它将创建新的工具，允许在一定程度上剖析神经回路功能。 前所未有的细胞特异性水平，并为复杂行为的神经控制中的一个重要问题提供了新的线索。该方法具有创新性，因为它将提供交叉方法来基因靶向特定神经元细胞类型，而这些方法尚未在小鼠中实施。因此，本申请中提出的工作将不仅推进该特定领域的知识，而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。