Sleep, Light, Circadian, Central Oxidative Stress

Non-visual Effects of Light, Chronic Variable Sleep Deficiency

Sleep, Circadian, Light exposure, Oxidative Stress

Irregular sleep timing and sleep deficiency are pervasive in society despite evidence that sleep deficiency impairs cognition and is linked to neurodegenerative disease. Potential pathways underlying the adverse cognitive function and brain health associated with irregular insufficient sleep include misalignment of sleep from the internal \ 24-hour body clock and brain oxidative stress. This research will investigate these putative pathways and inform future interventions to mitigate the impact of sleep loss on cognition and brain health.

Millions of adults in the US vary their day-to-day sleep timing to accommodate social and work demands. These irregular sleep schedules promote poor and insufficient sleep. Chronic insufficient sleep increases the risk of errors, accidents and developing various health disorders including neurodegenerative disease. The underlying mechanistic pathways by which irregular sleep schedules promote cognitive impairment and neurodegenerative disease remains poorly understood, and the proposed work will address this critical knowledge gap. Our preliminary data indicate that irregular sleep schedules induce circadian misalignment which we hypothesize is caused by irregular patterns of light exposure. Supporting this hypothesis, our pilot data show that implementing sleep- and circadian-informed lighting (SCIL) attenuated circadian misalignment and improved cognitive function, even in the presence of irregular sleep timing. Additionally, our pilot studies show that more sleep disturbance correlated with more oxidative stress (OS) in brain regions that are associated with cognitive function in humans, and consequently more OS in these regions correlated with poorer cognitive performance. Taken together, our results suggest that circadian misalignment and OS associated with insufficient sleep may be in the causal pathway for cognitive impairment due to irregular sleep schedules and SCIL may be a potential countermeasure. Therefore, the objective of this project is to determine the impact of chronic variable sleep deficiency (CVSD), as a model of irregular sleep schedules, on circadian misalignment, OS and cognition. Additionally, we will explore the role of ambient light exposure and the impact of SCIL conditions in a CVSD paradigm (2 cycles of two consecutive nights of 3 h of sleep followed by one 8-h recovery sleep) on neurophysiologic and neurocognitive outcomes. In a 7-night inpatient study, young healthy adults will be randomized to one of four conditions: dim-light control (8 h sleep each night), dim-light CVSD, room-light CVSD, and SCIL CVSD. The primary outcomes include circadian phase resetting, OS via central glutathione measured by magnetic resonance spectroscopy, and cognitive performance. The aims of the study are to: (1) Determine the causal role of light exposure in circadian phase resetting in CVSD, (2) evaluate the impact of SCIL in CVSD on circadian phase resetting, sleep and cognition, (3) evaluate the impact of sleep deficiency and circadian phase resetting in CVSD on OS, and (4) evaluate the association between cognition and central OS in CVSD. Our work will be a comprehensive evaluation of two mechanistic pathways - circadian misalignment and OS -that can contribute to cognitive impairment associated with irregular sleep schedules. We expect our experimental and analytic paradigm to be a foundational resource that can be extended to future studies examining mechanisms of cognitive impairment and neurodegenerative diseases associated with sleep loss and irregular sleep schedules, and have a positive public health impact by guiding therapeutic strategies for patients with sleep disorders and the general population at large who experience chronic variable sleep deficiency.

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