Aminergic signaling pathways have been implicated in a variety of neuropsychiatric illnesses, but the mechanisms by which these pathways influence complex behavior remain obscure. Vesicular monoamine transporters (VMATs) have been shown to regulate the amount of monoamine neurotransmitter that is stored and released from synaptic vesicles in mammalian systems, and an increase in their expression has been observed in bipolar patients. The model organism Drosophila melanogaster provides a powerful, but underutilized genetic system for studying how dopamine (DA) and serotonin (5HT) may influence behavior. We show that a Drosophila isoform of VMAT (DVMAT-A) is expressed in both dopaminergic and serotonergic neurons in the adult Drosophila brain. Overexpression of DVMAT-A in these cells potentiates stereotypic grooming behaviors and locomotion and can be reversed by reserpine, which blocks DVMAT activity, and haloperidol, a DA receptor antagonist. We also observe a prolongation of courtship behavior, a decrease in successful mating and a decrease in fertility, suggesting a role for aminergic circuits in the modulation of sexual behaviors. Finally, we find that DMVAT-A overexpression decreases the fly's sensitivity to cocaine, suggesting that the synaptic machinery responsible for this behavior may be downregulated. DVMAT transgenes may be targeted to additional neuronal pathways using standard Drosophila techniques, and our results provide a novel paradigm to study the mechanisms by which monoamines regulate complex behaviors relevant to neuropsychiatric illness.

Multicellular organisms employ concurrent gene regulatory programs to control development and physiology of cells and tissues. The Drosophila melanogaster model system has a remarkable history of revealing the genes and mechanisms underlying fundamental biology yet much remains unclear. In particular, brain xenobiotic protection and endobiotic regulatory systems that require transcriptional coordination across different cell types, operating in parallel with the primary nervous system and metabolic functions of each cell type, are still poorly understood. Here we use the unsupervised machine learning method independent component analysis (ICA) on majority freshfrozen, bulk tissue microarrays to define biologically pertinent gene expression signatures which are sparse, i.e. each involving only a fraction of all fly genes. We optimize the gene expression signature definitions partly through repeated application of a stochastic ICA algorithm to a compendium of 3,346 microarrays from 221 experiments provided by the Drosophila research community. Our optimized ICA model of pan fly gene expression consists of 850 modules of co-regulated genes that map to tissue developmental stages, disease states, cell-autonomous pathways and presumably novel processes. Importantly, we show biologically relevant gene modules expressed at varying amplitudes in whole brain and isolated adult blood-brain barrier cell levels.Thus, whole tissue derived ICA transcriptional signatures that transcend single cell type boundaries provide a window into the transcriptional states of difficult to isolate cell ensembles maintaining delicate brain physiologies. We believe the fly ICA gene expression signatures set, by virtue of the success of ICA at inferring robust often low amplitude patterns across large datasets and the quality of the input samples, to be an important asset for analyzing compendium and newly generated microarray or RNA-seq expression datasets.