A two-process model ofDrosophilasleep reveals an inter-dependence between circadian clock speed and the rate of sleep pressure decay

Abstract

Sleep is largely controlled by two processes - a circadian clock that regulates its timing and a homeostat that regulates the drive to sleep. Drosophila has been a useful model for understanding the molecular and neuronal control of circadian rhythms, and more recently, also for the homeostatic control of sleep. Consequently, mechanisms underlying both the circadian and the homeostatic processes regulating sleep have been characterized. Borbely and Daan's two-process model has provided a powerful quantitative framework for understanding how circadian and homeostatic processes converge to regulate sleep for four decades. Despite the clear utility of this model for understanding mammalian sleep regulation, the field of fly sleep has not employed a formal two-process model as a framework for the investigation of sleep control. To this end, we have adapted the two-process model to fly sleep. In this study, we establish the utility of this model by showing that it can provide empirically testable predictions regarding both the circadian and homeostatic control of fly sleep. Using this model, we show that the ultradian rhythms previously reported for loss-of-function clock mutants are a predictable consequence of a functional sleep homeostat in the absence of a functioning circadian system. Though a two-process model in which the circadian and homeostatic components act independently captures most aspects of sleep remarkably well, we found that increasing the rates of sleep pressure changes when circadian clocks run faster produced better fits between predicted and observed sleep rhythms. Finally, our results indicate that longer sleep bouts reflect the homeostatic process better than the current unitary definition of sleep as any bout of inactivity lasting five minutes or more. This simple two-process model represents a powerful theoretical framework for future work on the molecular and physiological regulation of fly sleep.

Homeostatic Control of Deep Sleep inDrosophila: Implications for Discovering Correlates of Sleep Pressure

“…Physiological and metabolic signatures of deep sleep in the fly both suggest that they correspond to sleep bouts that are significantly longer than the standard sleep definition of five minutes of inactivity and multiple lines of evidence suggest that deeper sleep states are likely reached upon attaining 15-30 minutes of inactivity ( 51, 59 ). Finally, recent work from our lab has suggested that bouts of inactivity of between 30 and 60 minute are stronger reflections of the daily homeostatic control sleep than shorter bouts of sleep ( 26 ). How might such long bouts of inactivity relate to homoeostatic sleep rebound?…”

“…Recent work in our lab revealed that long-bout sleep (~30 minutes or more of inactivity) is a better reflection of sleep homeostat action than shorter bouts of inactivity (26) and such long-bout sleep appears to represent a deep sleep stage that is physiologically and metabolically distinct from shorter bouts of sleep (51)(52)(53). We therefore hypothesized that the extent of sleep rebound and payback of lost sleep might be more readily apparent if we focused our analysis on long-bout sleep, eliminating the contribution of shorter, presumably shallower, bouts of sleep.…”

“…The existence of a distinct deep sleep state in flies suggests that treating sleep as a unitary state might obscure homeostatic sleep responses, particularly if, as in mammals, deep sleep is more strongly linked to homeostatic sleep pressure than shallower stages of sleep. Furthermore, our recent analyses suggest that longer bouts of sleep are a better reflection of sleep homeostasis than short bouts of sleep in the fly ( 26 ).…”

“…Furthermore, such work in the fly has revealed mechanisms that also mediate sleep regulation in mammals (21,22). Just as in humans and other mammalian species, fly sleep is controlled by both a sleep homeostat and a circadian clock, which, during normal sleep cycles, largely account for the timing and amount of daily sleep (23)(24)(25)(26). Future work in the fly will undoubtedly continue to enrich our understanding of sleep regulation in all animals.…”

Stem cell-specific ecdysone signaling regulates the development and function of aDrosophilasleep homeostat

“…We did, however, observe a substantial impact on sleep fragmentation during night, with an increase in sleep bout number (Figure 6B) and a decrease in bout length (Figure 6C) in E93 RNAi flies compared to both controls. Recent evidence indicates that sleep in Drosophila is not a homogenous state and that deeper sleep occurs during periods of consolidated sleep consisting of long sleep bouts [128][129][130][131][132][133][134] . We next asked if long bouts of sleep (60 minutes or longer) might be selectively affected by E93 knockdown; our analysis focused on the night period since this is when deep sleep primarily occurs 128,130,131 .…”