Visualizing development of neuronal circuits in the brain using multicolor mice

描述（由申请人提供）：本研究提案的目标是了解复杂的神经元回路如何在发育中的大脑中形成。这种发展程序背后的确切机制，以及它在某些疾病中是如何出错的，还没有得到很好的理解。很明显，当神经元回路从新生发展到高度特异性和成熟时，会发生一定量的重组。突触重组的过程已经在相对简单的外周神经系统回路中得到了广泛的研究，但对于中枢神经系统中更复杂的回路却知之甚少。最近在实验室开发的新工具可以清楚地识别许多单独的电路组件，并允许人们开始询问有关中枢神经系统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个不同的电路。在新开发的Brainbow转基因荧光小鼠中，高分辨率成像和三维数字重建技术将用于构建整个发育过程中各个阶段（包括成年阶段）的详细电路图。分析将涉及苔藓纤维-颗粒细胞回路内的会聚和发散特性的量化。这些研究将有助于确定这种小脑回路发展的机制，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。将对共济失调和正常大脑内回路的发展进行系统的比较，以研究在疾病状态下回路发展的过程如何出错。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。 这项工作的目标是了解复杂的电路如何在发育中的大脑中形成。当发展出错时，会出现大量的人类疾病（例如，儿童小脑共济失调）;更好地了解大脑回路可以导致适当的治疗疾病。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。

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.