Circuitry Underlying Sleep in Drosophila Melanogaster: Anatomy and the Role of Octopamine

Almost 20 years ago, the gene underlying fatal familial insomnia was discovered, first suggesting the concept that a single gene can regulate sleep. In the two decades since, there have been many advances in the field of behavioral genetics, but it is only in the past 10 years that the genetic analysis of sleep has emerged as an important discipline. Major findings include the discovery of a single gene underlying the sleep disorder narcolepsy, and identification of loci that make quantitative contributions to sleep characteristics. The sleep field has also expanded its focus from mammalian model organisms to Drosophila, zebrafish, and worms, which is allowing the application of novel genetic approaches. This thesis picks up on current sleep research to understand sleep, using Drosophila as our model organism. In Drosophila we have the unique opportunity to study at a single neuron level, how it regulates sleep and by doing this try to understand why we sleep. This work is devoted primarily to the neurotransmitter octopamine, which is the invertebrate homolog of norepinephrine. We show that octopamine is a wake-promoting signal in the fly, as is its counterpart in mammals. Behavioral changes in the animal are seen with modifications of a single octopamine-producing cell and this effect is used to understand both the anatomical and cellular pathways involved in this signal. We find that octopamine exerts its arousal properties through cAMP/PKA-dependent mechanisms in the Pars Intercerebralis (PI) neurons of the brain. Its actions are independent of the mushroom body, which we have also shown to be an important sleep regulating structure in the fly. This understanding of the anatomical circuitry driving wakefulness in the fly paves the way for finer dissection of the cellular and molecular mechanisms underlying sleep