Mechanisms Governing Activity-dependent Postnatal Brain Development

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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.