2023
In the modern world, our circadian clock is under constant attack. The circadian system, which keeps 24-hour time in our body to orchestrate complex biological processes, can be disrupted by many aspects of modern life, including exposure to light at night, digital screen exposure, shift work and travel across time zones. Disruption of sleep timing and circadian rhythms are common symptoms of Alzheimer’s disease (AD) and other neurodegenerative diseases. Accumulating evidence from human and mouse studies suggests that disrupted circadian rhythms may influence AD pathogenesis and increase AD risk, though this has not been definitely proven, and the mechanisms remain unclear. Circadian disruption comes in two major flavors: arrhythmicity (loss of amplitude) and desynchrony (misaligned circadian phase). The effects of circadian desynchrony, the more common of the two types of disruption, on the AD disease process are unknown. To address this, we propose to examine the effect of circadian desynchrony in AD mice, using a nongenetic, light-shifting model of jet lag. We will determine whether our jet-lag model, which simulates eastward travel through six time zones each week, can impact either amyloid plaque formation or alpha-synuclein spreading in mouse brain. We will investigate the role of glial cells in this process, to understand how these critical cells of the brain adapt to jet lag and influence pathology. Finally, we will determine whether we can prevent the negative effects of jet lag in the brain by enhancing the speed by which mice entrain to the jet-lag stimulus, either by weakening their central circadian clock or by providing time-restricted feeding that is synchronized to the light-dark cycle.