The Homeostatic Regulation of Sleep Need Is under Genetic Control

Abstract

Delta power, a measure of EEG activity in the 1-4 Hz range, in slow-wave sleep (SWS) is in a quantitative and predictive relationship with prior wakefulness. Thus, sleep loss evokes a proportional increase in delta power, and excess sleep a decrease. Therefore, delta power is thought to reflect SWS need and its underlying homeostatically regulated recovery process. The neurophysiological substrate of this process is unknown and forward genetics might help elucidate the nature of what is depleted during wakefulness and recovered during SWS. We applied a mathematical method that quantifies the relationship between the sleep-wake distribution and delta power to sleep data of six inbred mouse strains. The results demonstrated that the rate at which SWS need accumulated varied greatly with genotype. This conclusion was confirmed in a "dose-response" study of sleep loss and changes in delta power; delta power strongly depended on both the duration of prior wakefulness and genotype. We followed the segregation of the rebound of delta power after sleep deprivation in 25 BXD recombinant inbred strains by quantitative trait loci (QTL) analysis. One "significant" QTL was identified on chromosome 13 that accounted for 49% of the genetic variance in this trait. Interestingly, the rate at which SWS need decreases did not vary with genotype in any of the 31 inbred strains studied. These results demonstrate, for the first time, that the increase of SWS need is under a strong genetic control, and they provide a basis for identifying genes underlying SWS homeostasis. Key words: EEG delta power; slow-wave activity; sleep deprivation; homeostatic regulation of non-REM sleep; simulation of Process S; BXD recombinant-inbred mouse strains; QTL;Dps1; Dps2; Dps3; forward genetics Slow oscillations in the delta frequency range (1-4 Hz) are characteristic of the EEG during slow-wave sleep (SWS) (i.e., non-REM sleep in humans). Delta oscillations reflect synchronized burst-pause firing patterns of hyperpolarized thalamocortical and corticothalamic neurons (Steriade et al., 1993;McCormick and Bal, 1997;Steriade, 1999). Activity in the delta frequency range can be quantified as delta power by Fourier analysis. Delta power is negatively correlated with the response to arousing stimuli (Neckelmann and Ursin, 1993) and SWS fragmentation (Franken et al., 1991a) and thus can be seen as a measure of SWS intensity. Delta power is also in a quantitative and predictive relationship with prior sleep and wakefulness in mammals, including humans. Sleep loss evokes an increase in delta power during subsequent SWS that is proportional to the loss (Tobler and Borbély, 1986;Dijk et al., 1987), excess sleep results in an attenuation of delta power (Werth et al., 1996), and delta power decreases over the course of a sleep period, independent of the circadian phase at which sleep is initiated (Dijk and Czeisler, 1995). These and other observations have been interpreted as evidence that SWS is a restorative and homeostatically regulated behavior and that delta ...

Homeostatic Regulation of Sleep in a Genetic Model of Depression in the Mouse: Effects of Muscarinic and 5-HT1A Receptor Activation

“…These data confirm the results obtained in mice of other lines (Franken et al, 2001;Lena et al, 2004;Tobler et al, 1997), and are consistent with those in humans after one night of sleep deprivation (Borbely et al, 1981;Dijk and Beersma, 1989).…”

“…During recovery from sleep deprivation, this homeostatic drive notably causes an increase of slow wave activity (SWA) assessed by quantitative EEG measures, in humans (Borbely et al, 1981), rats (Borbely et al, 1981;Tobler and Borbely, 1990), as well as mice (Franken et al, 2001;Lena et al, 2004;Tobler et al, 1997). The magnitude of SWA depends on the duration of prior waking (Tobler and Borbely, 1990), which suggests that SWA is a marker for sleep intensity (Borbely et al, 1981).…”

Genetic determination of sleep EEG profiles in healthy humans

“…Consistent with these findings in humans, genetic studies in inbred mice revealed that a genomic region including Ada modifies the rate, at which NREM sleep need accumulates during wakefulness (Franken et al, 2001). Moreover, local pharmacological inhibition of ADA in rats increases extracellular adenosine concentration and the duration of deep NREM sleep (Okada et al, 2003).…”

“…Another region in the mouse genome affecting the accumulation of sleep propensity during wakefulness includes the gene encoding the neurotrophic receptor, tyrosine kinase B (TrkB) (Franken et al, 2001). This genetic locus explains almost 50 % of the variance in the rebound in delta activity after sleep deprivation.…”

Perchance to dream: Solving the mystery of sleep through genetic analysis

“…A quantifiable measure of NREM sleep intensity called delta power (i.e., EEG power in the 1-4-Hz range) is a reliable physiologic correlate of homeostasis, and is the regulated variable in the two-process model. However, the regulation of NREM sleep duration is not fully accounted for by the two-process model (Dijk and Beersma, 1989;Aeschbach et al, 1996;Dijk and Kronauer, 1999;Franken et al, 2001), and the regulation of REM sleep is not addressed. Although REM sleep is also governed by circadian and homeostatic processes, its regulation clearly differs from that of NREM sleep in that loss of REM sleep seems primarily compensated by increases in REM sleep duration (reviewed by Franken, 2002).…”