“The main facts in human life are five: birth, food, sleep, love and death.” ― E.M. Forster, Aspects of the Novel
Discovery of novel sleep and circadian genes
Fly sleep is strikingly similar to human sleep. Since one of the strengths of the fly as a model system is that we can perform high-throughput genetic screens, our research strategy has been to find Drosophila mutants with strong and interesting sleep and circadian phenotypes and identify the genetic, molecular, and cellular basis for the phenotypes. From unbiased forward-genetic screens of several thousand mutant fly lines, we have discovered several novel genes and mutations that influence distinct aspects of sleep-wake cycles. sleepless (Koh et al, 2008; Wu et al, 2010) and taranis (Afonso et al, 2015) determine how much flies sleep, whereas wide awake (Sha et al, 2014) and dyschronic (Jepson et al, 2012, 2014; Lamaze et al, 2020) determine the timing of sleep. We are continuing to identify and characterize genes that affect sleep and circadian rhythms.
Sleep and Neurodegeneration
Circadian and sleep disorders are common in patients with neurodegenerative diseases, such as Alzheimer’s disease (AD) and ALS/FTD. Moreover, growing evidence suggests that circadian/sleep disruptions accelerate neurodegeneration, but the genetic basis of the link between circadian rhythms/sleep and neurodegeneration is poorly understood. We have recently discovered that Drosophila models of AD and ALS/FTD exhibit circadian and sleep phenotypes. We are performing a genome-wide search for genes that can modify (enhance or suppress) the circadian/sleep phenotypes. This work will form the basis of collaborative investigations in which Drosophila models are used to identify new genetic modifiers and generate novel mechanistic hypotheses that will be tested in patient-derived iPSCs and mouse disease models.
Sexually-dimorphic regulation of sleep
Whereas fly sleep is regulated by two main mechanisms, circadian and homeostatic, other motivational factors such as hunger and sex drive play critical roles in modulating sleep. We showed that when presented with a female partner, Drosophila males forgo nighttime sleep to engage in courtship, and identified a small number of octopaminergic neurons that act upstream of courtship-regulating P1 neurons to balance sleep and courtship (Machado et al, 2017). We recently found that the sleep-courtship balance is modulated by nutritional status. Protein deprived male flies sleep more than normally fed males in the female presence, suggesting that flies engage in a sophisticated cost-benefit analysis that takes nutritional status into account in deciding whether the potential benefit of pursuing female partners is worth the cost of losing sleep (Duhart et al, 2020). We are investigating the neural circuit underlying the integration of sleep drive, sex drive, and nutritional status. We are also investigating female-specific sleep regulation such as the post-mating changes in sleep patterns.
Sleep and synaptic plasticity
A substantial body of data suggests a complex relationship between sleep and synaptic plasticity. Several genes isolated in our screens for sleep and circadian mutants are known to be involved in synaptic development and plasticity. DYSCHRONIC (DYSC), which was discovered in our screen for arrhythmic mutants (Jepson et al, 2012), also plays a role in synaptic development and function (Jepson et al, 2014). We recently showed that JETLAG, an E3 ubiquitin ligase known for light entrainment of the circadian clock (Koh et al, 2006), is also involved in synaptic development (Lamaze et al, 2020). We found that DYSC and JETLAG antagonistically regulate circadian output and synaptic development. We are testing whether DYSC and JETLAG regulate circadian rhythms through its control of synaptic remodeling in adulthood.
Sleep induction by sensory stimulation
Babies liked to be rocked to sleep. We found that gentle vibration can also induce sleep in flies (Ozturk-Colak et al, 2020). Interestingly, sleep induction improves over multiple vibration sessions, which suggests that habituation, a form of simple learning, plays a significant role in vibration-induced sleep. We are investigating the neural mechanisms underlying this intriguing phenomenon.