Mechanisms Governing Activity-dependent Postnatal Brain Development

项目总结 我们迫切需要充分了解大脑发育的基本机制 在出生后的早期阶段，这一时期对建立终身正确的大脑连接至关重要 行为和认知功能，在此期间，不出所料，许多 神经发育障碍(NDDS)开始显现。出生后大脑的功能成熟度很高。 受神经元活动的影响，但神经元活动驱动突触和回路的机制 人们对成熟期知之甚少。尤其具有挑战性的是，要对成熟度有一个完整的认识。 这是因为，除了神经元群体内的巨大异质性外，活动依赖于 成熟在整个大脑中是高度不同的，不同的区域在不同的时间和 速度。为了迎接这一挑战，我们开发了一种遗传工具来捕获神经元群体 经历依赖活动的回路成熟。用这个工具结合组织清理和整个大脑 体积成像，我们首次提出构建出生后全脑回路的时空图 成熟。我们还将研究发育干预对整个大脑的影响，为 创建一个研究NDD的发现平台。最后，利用我们区分神经元的能力 经历了不太成熟的同龄人的依赖活动的成熟，我们建议揭示 依赖活动的大脑发育的分子机制。我们提议的研究将提供 出生后大脑发育急需的知识，并最终为未来治疗方案的设计提供信息 改善新陈代谢综合征症状的干预措施。

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.