Investigating the role of dSERT activity in Drosophila Sleep

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Abstract: Sleep is a critical process essential for life and is conserved across many species. Although sleep disruption has been linked to a variety of neurological and psychiatric disorders, the cellular mechanisms and neural circuitry involved in sleep regulation are not well understood. The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) functions as a key neuromodulator of sleep behavior from insects to mammals. The relationship between serotonergic signaling and sleep has been studied for several decades, however its complex role in sleep regulation remains uncertain, with many studies showing it to play a role in both wakefulness and conversely sleep propensity. These complexities are further compounded by the fact that many antidepressants and antianxiety medications that work through selective inhibition of serotonin reuptake (SSRIs) have been shown to produce contradicting and various effects on sleep, ranging from insomnia to daytime somnolence. In both Drosophila and mammals reuptake of serotonin from the synaptic cleft is mediated via the Serotonin Transporter (SERT). The relationships between sleep, neurological disorders, and SSRI medications strongly suggest that variations in extracellular serotonin levels as a result of increased or decreased SERT activity could play a key role in modulating sleep behaviors. The molecular mechanisms underlying this process, however, are not well understood in either humans or model systems. To address these questions, I propose to use Drosophila as a model system to study the mechanisms by which altering Drosophila SERT (dSERT) activity may impact sleep behavior. I will first generate cutting edge genetic tools to probe the function of dSERT, and then I will implement these tools to interrogate sleep behavior. My training will take place in the Krantz and Donlea Laboratories at UCLA, a world-renowned center for neuroscience research. In order to accomplish these aims, I will train under neuroscience experts and collaborate with local specialists. In addition, I will utilize the ample resources of classes, seminars, journal clubs and workshops offered by UCLA and external sources. These experiments will elucidate the role of extracellular serotonin signaling in sleep physiology and identify the serotonergic circuitry involved in this behavior. This work investigates the molecular mechanisms of neuromodulation in the context of sleep and will enhance our understanding of how serotonergic signaling is involved in sleep behavior.