Sleep as a fundamental property of neuronal assemblies

Abstract

Sleep is vital to cognitive performance, productivity, health and well-being. Earlier theories of sleep presumed that it occurred at the level of the whole organism and that it was governed by central control mechanisms. However, evidence now indicates that sleep might be regulated at a more local level in the brain: it seems to be a fundamental property of neuronal networks and is dependent on prior activity in each network. Such local-network sleep might be initiated by metabolically driven changes in the production of sleep-regulatory substances. We discuss a mathematical model which illustrates that the sleep-like states of individual cortical columns can be synchronized through humoral and electrical connections, and that whole-organism sleep occurs as an emergent property of local-network interactions.

Figure 1. Molecular networks of sleep-regulatory substances make up the NREMS homeostat

The sleep-regulatory substances (SRSs) illustrated are produced in response to cellular activity and metabolism. These SRSs, as well as others not illustrated, are influenced by positive- and negative-feedback signals including transcription-enhancer substances such as nuclear factor kappa B (NFkB). The fruit fly homolog of NFkB, relish, is implicated in state control of those insects. The transcription and translation events that are needed to produce the proteins illustrated in this figure occur over periods of hours or longer. As such they offer a mechanism by which the brain can track its sleep/wake history. SRSs with direct sleep-promoting actions are labile substances with short half lives such as nitric oxide (NO) and adenosine. In the two-process model of sleep it is the output of this homeostat, as estimated from electroencephalogram (EEG) delta-wave power, that is modeled as process S. Several of the SRSs enhance EEG delta-wave power, e.g. interleukin-1 (IL1), tumor necrosis factor (TNF), and adenosine. A variety of experimental manipulations affects the homeostat and sleep in predictable ways. For instance, acute mild increases in ambient temperature enhance sleep duration and TNF levels. Infection enhances sleep duration and increases the concentration in the brain of almost every SRS. Excessive food intake enhances brain IL1 levels and sleep duration. Sleep loss increases levels of IL1, TNF, and adenosine, whereas administration of antagonists of these substances before sleep deprivation attenuates the expected non-rapid eye movement sleep (NREMS) rebound. We propose that this biochemical network operates within cortical columns and other neuronal assemblies to affect state. Many of these substances also promote whole-organism sleep if they are applied directly to sleep-regulatory networks in subcortical networks, suggesting that the homeostat operates at every level of the neural axis. Such findings also suggest that there is a high degree of evolutionary conservation of this fundamental mechanism.

Figure 2. Translation of neurotransmission into sleep-regulatory substances

The mechanism for the translation of synaptic activity into signals that act as sleep regulatory substances such as tumor necrosis factor alpha (TNF) and interleukin-1 beta (IL1), may involve ATP-enhanced release of these cytokines from glia. Thus, within the brain– and the immune system ATP induces the release of cytokines via purine P2 receptors. During neurotransmission, ATP is released from presynaptic neurons. This extracellular ATP acts rapidly via its breakdown into adenosine on postsynaptic purine P1 receptors (the adenosine A1 receptor-A1R). The ATP-P2R-released TNF and IL1 act more slowly on postsynaptic neurons via activation of nuclear factor kappa B (NFkB) and its promotion of receptors such as the A1R and the glutamate AMPA receptor to change sensitivity of the postsynaptic neuron over longer periods (see Figure 3 and Box 3).

Figure 3

Illustration of activity-driven changes in sleep regulatory substances regulate sleep at the local level. The same substances are involved in other cellular processes such as neuronal connectivity. These substances are induced by changes in ATP and adenosine and they affect sleep via their immediate actions on receptors and by longer-term actions on the synthesis of receptors. During waking environmental input to a neuronal assembly induces environmental relevant outputs. During sleep, due to the SRS-induced changes in receptor activation, the same environmental inputs result in a different output, one not directly relevant to the environment. This establishes the need for unconsciousness.

Box 2 Figure