Sleep as an Essential Modulator for Plasticity and Cognition During Atypical Neurodevelopment

Abstract

Sleep is thought to be a critical regulator of neural circuitry during neurodevelopment. Under conditions where postnatal neurodevelopment is modified - either by altered sensory experience, or in the context of genetically-mediated neurodevelopmental disorders - sleep is commonly altered or disrupted. However, the precise role sleep plays in promoting brain plasticity is still unknown, and it is unclear whether normalizing sleep could help normalize brain functions in atypical neurodevelopment. My dissertation work addresses this gap, by measuring how sleep loss affects recovery of disrupted visual cortex function in a mouse model of amblyopia (a form of vision loss caused by altered experience during postnatal development) and testing how normalizing sleep behavior affects memory disruptions in a model of Fragile X syndrome (FXS; a genetic disorder). My electrophysiological, behavioral, and molecular data suggest that sleep not only is critical for recovery mechanisms in disrupted neurodevelopment, but is also a useful target for therapeutic intervention.

The first part of this dissertation (Chapter 2) examines the relationship between sleep and recovery of disrupted cortical dynamics in early neurodevelopment. Here, I examined the relative impacts of visual experience and sleep on recovery of cortical visual responses in a mouse model of amblyopia. Using monocular deprivation (MD) to disrupt vision for one eye during early postnatal development, we used in vivo single-unit recordings and immunohistochemistry (IHC) to measure how binocular and monocular visual experience influenced recovery of deprived eye responses after MD. We found that binocular experience during recovery from MD vastly improved restoration of visual responses to the deprived eye. Furthermore, this recovery was dependent on sleep. Together, both binocular visual experience and subsequent sleep could be important factors mediating recovery of visual cortical responses in amblyopia.

The second part of this dissertation assesses the intersection of sleep and recovery of hippocampal-cognitive dysfunction in neurodevelopmental disorders. Here, I tested how a novel hypnotic, ML297, which acts via activation of G-protein inward rectifying potassium (GIRK) channels can rescue sleep loss and subsequent memory consolidation in a mouse model of FXS. First (Chapter 3), using C57BL/6 mice, we determined how ML297 affects memory consolidation using EEG/EMG recordings, contextual fear conditioning and IHC. We found that ML297 reversed reductions in NREM and REM spectral power, along with REM sleep amount and led to improved contextual fear memory. In a second study using Fmr1-/y mice (Chapter 4), we characterized sleep architecture and oscillatory activity for the first time in the FXS mouse model. We found deficits in NREM sleep architecture, spectral power, and inter-cortical coherence that were restored with ML297. Restoration of sleep via ML297 also showed improved cognition via fear learning and spatial memory tasks. Lastly, we found hippocampal activation patterns associated with memory formation change with ML297 to facilitate improved cognition. Overall, rescue of abnormal sleep could help with cognitive dysfunction in FXS and possibly other neurodevelopment disorders.

Together, these findings enlighten us on the contributions of sleep to cortical development and hippocampal cognition in the context of neurodevelopment. While both have been extensively measured in past studies, the role of sleep remains vastly understudied. Further research into the underlying mechanisms by which sleep facilities recovery in these domains may lead to future and targeted therapeutic intervention for the diverse number of developmental and neurological disorders where sleep loss impacts plasticity and cognition.