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Review
. 2016 Aug;28:46-54.
doi: 10.1016/j.smrv.2015.08.005. Epub 2015 Aug 28.

Sleep Function: Toward Elucidating an Enigma

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Free PMC article
Review

Sleep Function: Toward Elucidating an Enigma

James M Krueger et al. Sleep Med Rev. .
Free PMC article

Abstract

Sleep function remains controversial. Individual perspectives frame the issue of sleep function differently. We briefly illustrate how sleep measurement and the evolution, tissue organization levels, molecular mechanisms, and regulation of sleep could influence one's view of sleep function. Then we discuss six viable theories of sleep function. Sleep serves host-defense mechanisms and conserves caloric expenditures, but these functions likely are opportunistic functions evolving later in evolution. That sleep replenishes brain energy stores and that sleep serves a glymphatic function by removing toxic byproducts of waking activity are attractive ideas, but lack extensive supporting experimental evidence. That sleep restores performance is experimentally demonstrated and has obvious evolutionary value. However, this hypothesis lacks experimentally verified mechanisms although ideas relating to this issue are presented. Finally, the ideas surrounding the broad hypothesis that sleep serves a connectivity/plasticity function are many and attractive. There is experimental evidence that connectivity changes with sleep, sleep loss, and with changing afferent input, and that those changes are linked to sleep regulatory mechanisms. In our view, this is the leading contender for the primordial function of sleep. However, much refinement of ideas and innovative experimental approaches are needed to clarify the sleep-connectivity relationship.

Keywords: Glymphatics; Homeostasis; Immune; Interleukin-1; Local sleep; Metabolism; Performance; Plasticity; Synapse; Tumor necrosis factor.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Cell activity-driven changes in sleep regulatory and neuronal connectivity related molecules. This simplified molecular network illustrates the principal of activity-driven changes in small neuronal networks. Adenosine triphosphate (ATP) is released as a consequence of action potentials in neurons and glial membrane potential changes into the extracellular space. ATP binds to purine type 2 receptors on glia causing the processing and release of multiple substances including interleukin-1 (IL1), tumor necrosis factor (TNF) (shown) and brain derived neurotrophic factor (not shown). These substances in turn alter neurotransmitter receptor populations and their location within the cell (called receptor trafficking). These actions change synaptic efficacy and thereby the input/output state of the neuronal network within which such synapses are located. Additional activity-dependent molecules, including NO, Ca++, neurotrophins and hormones, are also involved in small neuronal network state changes. For example, in order for IL1 to signal in neurons it requires the neuron-specific IL1 receptor accessory protein (AcPb); AcPb plays a role in sleep homeostasis and neuronal synaptogenesis. Abbreviations: P2R–purine type two receptor; R-receptor; NFkB-nuclear factor kappa B; A1AR-an adenosine type 1 R; AMPAR- a glutamate receptor. Figure from.
Figure 2
Figure 2
This figure illustrates how a small network, e.g. cortical column, is influenced by activity-dependent mechanisms involving cytokines and neurotrophins. The circle (left) and diamond (right) represent the same small network in the wake and sleep state receiving the same input 1 at two different times. The large square (center) shows molecular changes that drive the changes in state and connectivity (via Hebbian and scaling mechanisms). On the left, the wake state is illustrated with a particular input/output (I/O) relationship. The activity associated with waking induces activity-dependent molecular expressions that in turn alter connectivity and state. On the right, the sleep state is represented by a different I/O and the new output (O2) influences connectivity because O2 is different from O1 even though both receive the same input 1. Different synapses within the network are affected by O2 than those affected by O1 (left side). These actions set up an oscillation within the small network (cortical column). The actions set in motion by the cellular activities responsible for O1 and O2 can increase or decrease synaptic efficacy. The network’s connectivity and sensitivity to input signals never comes back to the initial condition as new experience is integrated into the network while old stimulus patterns are reinforced.

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