Mechanisms Governing Activity-dependent Postnatal Brain Development

项目摘要 迫切需要全面了解大脑发育的基本机制 在出生后的早期，这是建立正确的大脑布线的关键时期， 行为和认知功能，并在此期间，毫不奇怪，许多症状， 神经发育障碍（NDD）开始显现。出生后大脑的功能成熟是高度 受神经元活动的影响，但神经元活动驱动突触和电路的机制 成熟度知之甚少。获得整个大脑的成熟视图特别具有挑战性， 这是因为，除了神经元群体内的巨大异质性外， 成熟在整个大脑中是高度可变的，不同的区域在不同的时间经历成熟， 速度.为了应对这一挑战，我们开发了一种遗传工具来捕获神经元群体，因为它们 经历活动依赖性回路成熟。有了这个工具结合组织清理和整个大脑 体积成像，我们建议构建，为第一次，出生后全脑回路的时空地图 成熟我们还将研究发育干预对整个大脑的影响，为以下方面铺平道路： 创建一个发现平台来研究NDD。最后，利用我们区分神经元的能力， 经历了活动依赖的成熟，从他们的不太成熟的同行，我们建议揭示 活动依赖性大脑发育的分子机制。我们的研究将提供 出生后大脑发育急需的知识，并最终告知未来的治疗设计 干预措施，以改善NDD的症状。

PROJECT SUMMARY There is an urgent need to fully understand the fundamental mechanisms governing brain development during the early postnatal period, a period that is critical in establishing the correct brain wiring for lifelong behavioral and cognitive functions and a period during which, unsurprisingly, symptoms of many neurodevelopmental disorders (NDDs) start to manifest. The functional maturation of the postnatal brain is highly influenced by neuronal activity, but the mechanisms by which neuronal activity drives synaptic and circuit maturation are poorly understood. It is particularly challenging to gain a whole brain view of the maturation process because, in addition to the tremendous heterogeneity within the neuronal population, activity-dependent maturation is highly variable across the brain, with different regions undergoing maturation at different times and speeds. To meet this challenge, we have developed a genetic tool to capture the neuronal populations as they undergo activity-dependent circuit maturation. With this tool combined with tissue clearing and whole brain volume imaging, we propose to construct, for the first time, a spatiotemporal map of postnatal whole brain circuit maturation. We will also examine the whole brain impact of developmental interventions, paving the way to creating a discovery platform to study NDDs. Finally, taking advantage of our ability to distinguish neurons that have undergone activity-dependent maturation from their less mature counterparts, we propose to uncover molecular mechanisms underlying activity-dependent brain development. Our proposed research will provide much-needed knowledge of postnatal brain development, and ultimately inform the design of future therapeutic interventions to ameliorate symptoms of NDDs.