The CircadianClockMutation Alters Sleep Homeostasis in the Mouse

Abstract

The onset and duration of sleep are thought to be primarily under the control of a homeostatic mechanism affected by previous periods of wake and sleep and a circadian timing mechanism that partitions wake and sleep into different portions of the day and night. The mouse Clock mutation induces pronounced changes in overall circadian organization. We sought to determine whether this genetic disruption of circadian timing would affect sleep homeostasis. The Clock mutation affected a number of sleep parameters during entrainment to a 12 hr light/dark (LD 12:12) cycle, when animals were free-running in constant darkness (DD), and during recovery from 6 hr of sleep deprivation in LD 12:12. In particular, in LD 12:12, heterozygous and homozygous Clock mutants slept, respectively, ϳ1 and ϳ2 hr less than wild-type mice, and they had 25 and 51% smaller increases in rapid eye movement (REM) sleep during 24 hr recovery, respectively, than wild-type mice. The effects of the mutation on sleep are not readily attributable to differential entrainment to LD 12:12 because the baseline sleep differences between genotypes were also present when animals were free-running in DD. These results indicate that genetic alterations of the circadian clock system and/or its regulatory genes are likely to have widespread effects on a variety of sleep and wake parameters, including the homeostatic regulation of sleep.

Circadian genes, rhythms and the biology of mood disorders

“…Their behavioral profile includes hyperactivity in response to novelty and over the light/dark cycle, reduced depression-like behavior in the forced swim test and learned helplessness tests, reduced anxiety or increased risk taking behavior in several measures, and an increase in the reward value of cocaine, sucrose and intracranial self-stimulation (McClung et al, 2005;Roybal et al, in press). Other laboratories have found that these mice sleep less and have increased exploratory activity, adding to their overall manic-like phenotype (Naylor et al, 2000;Easton et al, 2003). Importantly, when we treat these mice with the mood stabilizer, lithium, the majority of their behavioral responses return to wild-type levels (Roybal et al, in press).…”

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

“…For example, mice mutant for components for the circadian system including Albumin D-binding protein (Dpb) and Clock, show alterations in total sleep time and delta power during baseline conditions [ Fig. 3(C) and (D); see below] but do not compensate for lost REM; delta power during recovery was similar to genetic controls (Franken et al, 2000;Naylor et al,. 2000).…”

“…As described above, in the fly both Creb and Cycle are transcriptional regulators that play important roles in circadian rhythm generation, are widely expressed throughout the organism, and have been shown to modulate sleep homeostasis (Hendricks et al, 2001;Shaw et al, 2002). In the mouse, the Clock mutation has profound effects on circadian rhythmicity , but also decreases NREM sleep time, NREM delta power, and NREM sleep consolidation (Naylor et al, 2000). Opposite sleep changes were observed in mice lacking both Cryptochromes (Cry1,2 Ϫ/Ϫ ), consistent with Clock and Cry being positive and negative regulators, respectively.…”

Identification of a population of sleep-active cerebral cortex neurons

“…The proportion of nNOS-immunoreactive (nNOS-ir) neurons that are activated during sleep is correlated with a measure of SWA intensity known as ''delta energy'' (14,15). Because sleep-active, nNOS-ir neurons are innervated by neurotransmitter systems previously implicated in sleep/wake control, cortical nNOS-ir neurons may be a previously unrecognized cell type involved in SWA and part of the neurobiological substrate that underlies homeostatic sleep regulation.…”