Ontogenesis of the molecular response to sleep loss

Abstract

Sleep deprivation (SD) results in profound cellular and molecular changes in the adult mammalian brain. Some of these changes may result in, or aggravate, brain disease. However, little is known about how SD impacts gene expression in developing animals. We examined the transcriptional response in the prefrontal cortex (PFC) to SD across postnatal development in male mice. We used RNA sequencing to identify functional gene categories that were specifically impacted by SD. We find that SD has dramatically different effects on PFC genes depending on developmental age. Gene expression differences after SD fall into 3 categories: present at all ages (conserved), present when mature sleep homeostasis is first emerging, and those unique to certain ages in adults. Developmentally conserved gene expression was limited to a few functional categories, including Wnt-signaling which suggests that this pathway is a core mechanism regulated by sleep. In younger ages, genes primarily related to growth and development are affected while changes in genes related to metabolism are specific to the effect of SD in adults.

Developing forebrain synapses are uniquely vulnerable to sleep loss

“…Recent mathematical modeling (12) and our current findings strongly indicate that sleep plays a unique role in shaping brain/synapse development in early life, transitioning to homeostatic functions with maturation. Distinct responses to SD between juvenile and adult mice is also supported by recently reported RNAseq analysis (39). The majority of neuronal synapses in the forebrain are formed after birth, during a period of profound synaptogenesis, followed by a period of activity dependent synapse pruning before synapse densities finally stabilize during maturation to adulthood (Fig.…”

“…Finally, our findings, together with a prior systematic EEG analysis show that juveniles lack well characterized adaptations to SD: increased NREM-SWA 37 , dark phase sleep rebound, induction of Homer1a, and accumulation of synaptic protein phosphorylation, potentially exposing the developing brain to greater vulnerabilities of SD. A recent RNAseq analysis from frontal cortex also shows almost no overlap in SD-induced gene expression changes between juvenile and adult mice 53 . Taken together, our findings suggest sleep plays a distinct and important role supporting brain maturation and highlight the developing synapse as a major node of vulnerability to sleep loss relevant for childhood onset forms of neurodevelopmental disorders.…”

“…Contrasting reports between developmental and adult time points has driven controversy on the synaptic basis of sleep function 26 . Indeed, very few studies have engaged in systematic analysis of sleep function or response to SD across developmental and adult time points 37,53 . Forebrain synapses undergo well characterized dynamics during postnatal development, beginning with a period of synaptogenesis, followed by experience-dependent pruning 17 .…”