Synapses and Sleep in Neurodevelopment: A Crucial Interaction at a Critical Time

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DESCRIPTION (provided by applicant): During development, brain circuits undergo extensive remodeling, involving both synaptogenesis and pruning. Adolescence, in particular, is thought to be a sensitive period for synaptic pruning in cortical circuits involved in cognitive functions and emotional regulation. Adolescence is also a sensitive period for the pathophysiology of many psychiatric disorders, presumably due to this extensive synaptic remodeling. Thus, it would be useful to be able to track changes in the number and efficacy of synapses longitudinally and non-invasively during adolescence. New evidence suggests that changes in sleep slow wave activity (SWA), which can be assessed longitudinally and non-invasively using electroencephalography (EEG), may parallel neurodevelopmental changes in cortical synaptic density. To develop SWA as a potential marker of synaptic function during developmental sensitive periods requires an animal model in which: i) anatomical, molecular, and physiological changes in cortical synapses can be evaluated directly; ii) a point- to-point, intra-subject correlation can be established between sleep SWA and direct measures of synaptic number/molecular composition/efficacy. In Aim 1 of this project, we will pursue these goals by performing both chronic EEG recordings and repeated in vivo imaging with two-photon microscopy in transgenic mice that express yellow fluorescent protein in cortical neurons. Moreover, we will measure molecular and electrophysiological markers of synaptic strength in these mice throughout development. In addition to monitoring synaptic remodeling in vivo, it is important to begin investigating which factors can influence it during the sensitive period of adolescence. Since major changes in synaptogenesis/pruning during development are correlated with major changes in sleep/wake patterns, it has been hypothesized that changes in behavioral state may not only reflect, but also affect synaptic remodeling. Consistent with this notion, new evidence in animals and humans shows that, in the adult brain, waking is associated with a net increase in synaptic strength, and sleep with a net decrease, and that SWA reflects molecular and physiological changes in synaptic function brought about by wake and sleep. Aim 2 of this proposal will test the hypothesis that sleep/wake behavior affect synaptic structure/function also during development. Specifically, we will determine whether sleep and waking differentially affect synaptogenesis and synaptic pruning, consistent with their effects on synaptic strength in adults. If successful, Aim 1 will lead the foundation for EEG monitoring of synaptic efficacy during neurodevelopment in human subjects at risk or patient populations as an essential aid for both diagnosis and therapy. Aim 2 will open the way to preventive/therapeutic approaches for influencing synaptogenesis/pruning by stabilizing/adjusting sleep/wake patterns in children. PUBLIC HEALTH RELEVANCE: Adolescence is a sensitive period during which the brain undergoes massive elimination or "pruning" of synapses - the connections among neurons in the brain. Adolescence is also a sensitive period for the onset and progression of many psychiatric disorders. This project seeks to establish whether the slow waves that can be recorded with the electroencephalogram during sleep in children and adolescents can be used as a sensitive, well-tolerated indicator of the number and strength of synapses. Moreover, this project will establish whether sleep can affect synaptic pruning during development. If so, changes in sleep and waking routines could help both the prevention and the therapy of mental illness.