Substance abuse and mental health disorders are a leading source of years lost to disability from medical causes worldwide. Unfortunately, for most neurological disorders it is unclear how underlying genetic predispositions govern behavioral response to environmental stressors. Owing to their convenience, genetic tractability, and small brains, the fruit fly, Drosophila melanogaster, has become an invaluable model in which to dissect the neurological basis of conserved complex behaviors. Here, I characterized the respective roles of two genes in alcohol response and sleep behavior.
Steroid hormones profoundly influence behavioral response to alcohol, yet the role of unconventional non-genomic steroid signaling in this process is unknown. I discovered that Drosophila DopEcR, a G-protein coupled receptor (GPCR) activated by dopamine or the major insect steroid hormone ecdysone, plays a critical role in ethanol-induced behaviors. DopEcR mutants took longer to sedate when exposed to ethanol vapor, and post-eclosion expression of DopEcR-RNAi phenocopied mutant resistance. DopEcR was necessary in particular neuronal subsets, including cholinergic and peptidergic neurons, and promoted ethanol sedation by suppressing epidermal growth factor/extracellular signal-regulated kinase signaling. In adult flies, ecdysone negatively regulated DopEcR-mediated ethanol-induced sedation. We also found that DopEcR inhibits ethanol-induced locomotion, a conserved dopaminergic behavior. Together, these findings provide novel insight into how an unconventional steroid GPCR interacts with multiple downstream signaling cascades to fine tune behavioral response to alcohol.
Despite an established link between epilepsy and sleep behavior, it remains unclear how epileptogenic mutations affect sleep and seizure susceptibility. To address this, I examined the rest/wake behavior of two fly models of epilepsy with paralytic voltage-gated sodium channel mutations known to cause human generalized epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS). GEFS+ and DS flies display heat-induced seizure susceptibility, but at normal temperatures I found that both mutants had exaggerated nighttime sleep behavior. GEFS+ sleep was more resistant to pharmacologic and genetic reduction of GABA transmission as compared to control’s response. This finding is consistent with augmented GABAergic suppression of wake-promoting pigment-dispersing factor (PDF) neurons in GEFS+ mutants. Contrastingly, DS sleep was almost completely resistant to pharmacologic GABA reduction, suggesting that PDF neurons are incapable of functioning despite disinhibition. The sleep of both GEFS+ and DS flies was largely suppressed, but not eliminated, by scotophase light, highlighting the importance of light stimulus and circadian signals in the manifestation of their phenotypes. Following sleep deprivation, GEFS+ and DS mutants failed show to homeostatic rebound. Sleep loss also unexpectedly reduced the seizure susceptibility of GEFS+ flies. This study revealed the sleep architecture of Drosophila voltage-gated sodium channel mutants and provides a unique platform in which to further study the sleep/epilepsy relationship.