Developmental profiling of caspase-dependent refinement

摘要 在神经系统中建立适当的连接对于更高的 大脑功能包括感知、学习和记忆。神经元回路最初是 通过电路构建(渐进性)事件组装起来，比如轴突生长。后来， 许多大脑回路需要通过回归来精炼额外的连接 事件。轴突修剪和突触消除等退行性事件在 电路的成熟和完善。轴突修剪事件有助于移除 活跃的轴突分支，不一定会导致细胞死亡。扰乱正常 神经回路成熟期间的修剪事件与神经发育有关 精神障碍，从自闭症到精神分裂症。尽管在这两个方面都发挥了关键作用 这些疾病的病因和健康神经系统的成熟，潜在的 修剪事件背后的细胞机制在很大程度上仍不清楚。深入了解 这些机制有助于促进我们对 神经发育障碍。因此，该项目的长期目标是 阐明负责改善大脑连通性的分子机制， 特别强调对正常认知功能至关重要的神经元回路。要实现 这一长期目标，我们建议对caspase依赖的神经元进行定位和表征。 神经元中的细化事件，这些神经元存活下来，但修剪了它们的连接。建议数 研究将产生一个强大的新工具来研究caspase依赖的电路 精致。这一工具将具有广泛的适用性，以研究发展和疾病在 器官种类繁多。成功实现这些目标将具有重要的意义 定义依赖于caspase的修剪的位置和流行率的含义 活体--神经建立和完善所必需的发育过程 电路。在未来，我们将利用产生的创新方法 这项建议的一部分，是确定电路成熟所需的新分子成员。 好了！

SUMMARY Proper establishment of connectivity in the nervous system is essential for higher brain functions including perception, learning and memory. Neuronal circuits are initially assembled through circuit building (progressive) events, like axon growth. Subsequently, many brain circuits require refinement of supernumerary connections via regressive events. Regressive events like axon pruning and synapse elimination play key roles in circuit maturation and refinement. Axon pruning events facilitate the removal of exuberant axonal branches, without necessarily eliciting cell death. Disruption of normal pruning events during circuit maturation has been linked to neurodevelopmental disorders, ranging from autism to schizophrenia. Despite playing a key role in both the etiology of these disorders and maturation of a healthy nervous system, the underlying cellular mechanisms behind pruning events remain largely unknown. Gaining insight into these mechanisms is instrumental for advancing our understanding of neurodevelopmental disorders. Therefore the long-term goal of this project is to elucidate the molecular mechanisms responsible for refining brain connectivity, with a particular emphasis on neuronal circuits critical for normal cognitive function. To achieve this long-term goal, we propose to map and characterize caspase-dependent neuronal refinement events in neurons that survive but prune their connections. The proposed studies will generate a powerful new tool to investigate caspase-dependent circuit refinement. This tool will have broad applicability to study development and disease in a variety of organs. Successful accomplishment of these objectives will have important implications for defining the location and prevalence of caspase-dependent pruning in vivo, a developmental process essential for the establishment and refinement of neural circuits. In the future, we will take advantage of the innovative approaches generated as part of this proposal to identify novel molecular players required for circuit maturation. !