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Abstract
Accumulation of waste in cortical tissue and glymphatic waste clearance via extracellular voids partly drives the sleep-wake cycle and modeling has reproduced much of its dynamics. Here, new modeling incorporates higher void volume and clearance in sleep, multiple waste compounds, and clearance obstruction by waste. This model reproduces normal sleep-wake cycles, sleep deprivation effects, and performance decreases under chronic sleep restriction (CSR). Once fitted to calibration data, it successfully predicts dynamics in further experiments on sleep deprivation, intermittent CSR, and recovery after restricted sleep. The results imply a central role for waste products with lifetimes similar to tau protein. Strong tau buildup is predicted if pathologically enhanced production or impaired clearance occur, with runaway buildup above a critical threshold. Predicted tau accumulation has timescales consistent with the development of Alzheimer’s disease. The model unifies a wide sweep of phenomena, clarifying the role of glymphatic clearance and targets for interventions against waste buildup.
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1 University of Sydney, School of Physics, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); University of Sydney, Center of Excellence for Integrative Brain Function, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X)
2 University of Sydney, School of Physics, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); University of Sydney, Center of Excellence for Integrative Brain Function, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); University of Sydney, Woolcock Institute of Medical Research, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); University of Sydney, Sydney Nano, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X); University of Sydney, Charles Perkins Center, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X)