Visualizing development of neuronal circuits in the brain using multicolor mice

使用多色小鼠可视化大脑中神经元回路的发育

• 批准号: 7480755
• 负责人: Tamily A Weissman
• 金额: $ 4.42万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480755
• 关键词: Adult; Brain; Brain region; Cerebellar Ataxia; Cerebellum; Child; Childhood; Classification; Complex; Condition; Development; Disease; Goals; Human; Individual; Investigation; Laboratories; Lead; Maps; Modeling; Mus; Neuraxis; Neurons; Peripheral Nervous System; Process; Property; Research; Research Proposals; Resolution; Staging; Synapses; Techniques; Three-Dimensional Imaging; Transgenic Organisms; Work; digital; granule cell; human disease; mossy fiber; motor control; motor learning; mouse model; programs; reconstruction; systems research; tool

DESCRIPTION (provided by applicant): The goal of this research proposal is to understand how complex neuronal circuits form in the developing brain. The precise mechanisms that underlie this developmental program, and how it can go awry in certain disorders, are not well-understood. It seems clear that a certain amount of reorganization occurs as neuronal circuits progress from nascent to highly specific and mature. The process of synaptic reorganization has been studied extensively in relatively simple circuits of the peripheral nervous system, but is poorly understood for more complex circuits in the central nervous system. New tools recently developed in the laboratory provide clear identification of many individual circuit components and allow one to begin to ask detailed questions about complex circuitry in the central nervous system. This research proposal focuses on the cerebellum, a region of the brain crucial for motor learning and coordination. The cerebellum provides an ideal model for circuitry analysis due to the presence of several different circuits at progressive stages of complexity. In newly developed Brainbow transgenic multicolor fluorescent mice, high-resolution imaging and three-dimensional digital reconstruction techniques will be used to construct detailed circuitry maps at various stages throughout development, including the adult. Analysis will involve the quantification of the convergent and divergent properties within the mossy fiber-to-granule cell circuit. These investigations will help determine what mechanisms underlie the development of this cerebellar circuit, and precisely when circuit maturation is complete. Also planned is an investigation of a mouse model of the human disease developmental cerebellar ataxia, a devastating condition in which children progressively lose motor control and coordination. A systematic comparison of the development of circuitry within the ataxic and normal brain will be done in order to investigate how the process of circuit development may go awry in the disease state. This research will help to provide a better understanding of how neuronal circuits form in the mammalian brain. The goal of this work is to understand how complex circuits form in the developing brain. There are a great deal of human disorders that arise when development goes awry (e.g., in childhood cerebellar ataxia); a better understanding of brain circuitry can lead to appropriate treatments for disease. This research will help to delineate the developmental mechanisms that lead to normal and abnormal connectivity within the brain.

描述（由申请人提供）：本研究计划的目标是了解发育中的大脑中复杂的神经元回路是如何形成的。这一发育程序背后的确切机制，以及它在某些疾病中如何出错，目前尚不清楚。似乎很清楚，随着神经元回路从新生发展到高度特异性和成熟，会发生一定程度的重组。突触重组过程已在周围神经系统相对简单的回路中进行了广泛研究，但对于中枢神经系统中更复杂的回路却知之甚少。实验室最近开发的新工具可以清楚地识别许多单独的电路组件，并允许人们开始提出有关中枢神经系统中复杂电路的详细问题。 这项研究计划的重点是小脑，这是大脑中对于运动学习和协调至关重要的区域。小脑为电路分析提供了理想的模型，因为在复杂性的渐进阶段存在几种不同的电路。在新开发的 Brainbow 转基因多色荧光小鼠中，高分辨率成像和三维数字重建技术将用于构建整个发育各个阶段（包括成年）的详细电路图。分析将涉及苔藓纤维到颗粒细胞回路内收敛和发散特性的量化。这些研究将有助于确定小脑回路发育的机制，以及回路成熟的确切时间。还计划对人类疾病发育性小脑共济失调的小鼠模型进行研究，这是一种破坏性的疾病，儿童逐渐失去运动控制和协调能力。我们将对共济失调和正常大脑内的回路发育进行系统比较，以研究回路发育过程在疾病状态下如何出错。这项研究将有助于更好地了解哺乳动物大脑中神经元回路的形成方式。 这项工作的目标是了解发育中的大脑中复杂的电路是如何形成的。当发育出现问题时，就会出现许多人类疾病（例如，儿童小脑性共济失调）；更好地了解大脑回路可以导致疾病的适当治疗。这项研究将有助于描述导致大脑内正常和异常连接的发育机制。