The Function of Sleep in Critical Period Plasticity

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Project Summary Although we spend a third of our lives sleeping, the function of this evolutionarily conserved behavior remains elusive. Most studies investigating the function of sleep have focused on sleep in adults. However, young animals spend an even greater proportion of their lives asleep, and their sleep is deeper and has distinct electrophysiological features. Sleep in young animals is thought to aid brain development by promoting plasticity. These plastic processes occur during critical periods in which neural circuits are shaped by experience. Yet, the molecular, cellular and circuit mechanisms by which sleep functions in critical period plasticity remains elusive. This proposal aims to address this question by using a simple neural circuit in a genetically tractable model organism. In Aim 1, I will define sleep substages using behavioral features and statistical modeling, as well as imaging methods, and then determine if critical period plasticity requires a specific form of sleep. In Aim 2, I will investigate the neurophysiological processes by which sleep promotes critical period plasticity using patch clamp electrophysiology and investigate the genes that are important for this process using single cell RNA sequencing. In Aim 3, I will perform a large-scale RNAi screen using a behavioral assay to find novel genes that are involved in sleep-dependent critical period plasticity. In addition, I will investigate whether sleep-related neural activity is generated by astrocytes to aid critical period plasticity. Overall, these aims will delineate the function of specific sleep states in young animals and identify cellular and molecular mechanisms underlying sleep-dependent critical period plasticity. Because sleep disturbances in early life are predictors of neurocognitive disorders such as autism and attention deficit disorders, this work may have implications for the treatment of neurodevelopmental conditions. To achieve these aims, I have brought together a mentoring team which includes experts in computational modeling, transcriptional profiling, and developmental neural plasticity. In addition, the proposed career development and research plan will capitalize on the exceptional environment, facilities, and resources that Johns Hopkins University provides. My overarching career goal is to obtain a tenure track faculty position and establish my own research program as an independent scientist, and the proposed work and training will form a strong foundation for achieving this goal.