Sleep: a synchrony of cell activity‐driven small network states

Abstract

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 brain we posit that small networks of highly interconnected neurons and glia, e.g. 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 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 (SRS) 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.

Sleep Homeostasis, Metabolism, and Adenosine

“…Adenosine can also be produced directly in the extracellular space through hydrolysis and dephosphorylation of ATP by ecto-nucleotidases [12,16]. The ATP is released from γ-amino-butyric acid (GABA)ergic, cholinergic, monoaminergic, and glutamatergic neurons as a consequence of cellular activity [17,18]. It may be noteworthy that, in rodents, the final step to release adenosine by dephosphorylation of AMP, occurs primarily in the striatum and olfactory bulb [19].…”

“…These data challenge a causal role for adenosine in the BF as the regulator of sleep homeostasis. Furthermore, ATP and adenosine in the extracellular space are rapidly metabolized and removed and are, therefore, unlikely to be involved in long-term sleep-wake regulation [18]. The available evidence rather suggests that extracellular adenosine provides a global feedback signal on neuronal networks, including subcortical and cortical structures [23•, 63] and contributes to wake-sleep transitions and the regulation of important functional aspects of sleep such as sleep intensity.…”

“…It has, therefore, been questioned whether adenosine alone can be responsible for long-term sleepwake regulation [18]. Adenosine is released in response to neuronal activity and may modulate sleep-wake regulatory processes indirectly via ATP.…”

Perchance to dream? Primordial motor activity patterns in vertebrates from fish to mammals: their prenatal origin, postnatal persistence during sleep, and pathological reemergence during REM sleep behavior disorder

“…The present paper reviews the evidence that MAS, with its defining multi-second spontaneous rhythms [13] , far from being a phylogenetic 'end point' (e.g, Rattenborg [14] ; Siegel [8] ), in fact represents the persistence of a primordial developmental state that is characteristic for animal behavior from the very onset of multicellular animal evolution. More generally, sleep may well be a fundamental manifestation of many simple neuronal networks [1,[15][16][17] .…”

Sleep and Addictions

“…Among these hypotheses are the adenosine hypothesis, according to which use-dependent dephosphorylation of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) during wakefulness causes the accumulation of adenosine; which, in turn, hyperpolarizes cortical neurons resulting in slow oscillations and neural synchrony (Benington & Heller, 1995;Thakkar, Winston, & McCarley, 2003). The somnogenic trophic factor hypothesis postulates that increases in somnogenic trophic factors, over time, modify levels of activity in neural circuits involved in sleep regulation, causing a transition to sleep (Krueger, Huang, Rector, & Buysse, 2013). Metabolic perspective links metabolic demand with molecular circadian signaling, to regulate rest-activity cycles (Franken, 2013).…”