James M. Krueger, Yanhua H. Huang, David M. Rector, Daniel J. Buysse

We posit a bottom-up sleep-regulatory paradigm in which state changes are initiated within small networks as a consequence of local cell activity. Bottom-up regulatory mechanisms are prevalent throughout nature, occurring in vastly different systems and levels of organization. Synchronization of state without top-down regulation is a fundamental property of large collections of small semi-autonomous entities. We posit that such synchronization mechanisms are sufficient and necessary for whole-organism sleep onset. Within the brain we posit that small networks of highly interconnected neurons and glia, for example cortical columns, are semi-autonomous units oscillating between sleep-like and wake-like states. We review evidence showing that cells, small networks and regional areas of the brain share sleep-like properties with whole-animal sleep. A testable hypothesis focused on how sleep is initiated within local networks is presented. We posit that the release of cell activity-dependent molecules, such as ATP and nitric oxide, into the extracellular space initiates state changes within the local networks where they are produced. We review mechanisms of ATP induction of sleep-regulatory substances and their actions on receptor trafficking. Finally, we provide an example of how such local metabolic and state changes provide mechanistic explanations for clinical conditions, such as insomnia.