A STIM dependent dopamine-insulin axis maintains the larval drive to feed and grow in Drosophila

Abstract

Appropriate nutritional intake is essential for organismal survival. In holometabolous insects such as Drosophila melanogaster, the quality and quantity of food ingested as larvae determines adult size and fecundity. Here we have identified a subset of dopaminergic neurons (THD) that maintain the larval motivation to feed. Dopamine release from these neurons requires the ER Ca2+ sensor STIM. Larvae with loss of STIM stop feeding and growing, whereas expression of STIM in THD neurons rescues feeding, growth and viability of STIM null mutants. Moreover STIM is essential for maintaining excitability and release of dopamine from THD neurons. Optogenetic stimulation of THD neurons activated neuropeptidergic cells, including median neuro secretory cells that secrete insulin-like peptides. Loss of STIM in THD cells alters the developmental profile of specific insulin-like peptides including ilp3. Loss of ilp3 partially rescues STIM null mutants and inappropriate expression of ilp3 in larvae affects development and growth. In summary we have identified a novel STIM-dependent function of dopamine neurons that modulates developmental changes in larval feeding behaviour and growth. Author summaryThe ability to feed appropriately when hungry is an essential feature for organismal survival and is under complex neuronal control. An array of neurotransmitters and neuropeptides integrate external and internal signalling cues to initiate, maintain and terminate feeding. In adult vertebrates and invertebrates dopamine serves as a reward cue for motor actions, including feeding. Larvae of holometabolous insects, including Drosophila melanogaster, feed and grow constantly followed by gradual cessation of feeding, once sufficient growth is achieved for transition to the next stages of development. Here we identified a subset of larval dopaminergic neurons in Drosophila melanogaster, activity in which maintains continuous feeding in larvae. By analysis of a null mutant we show that these neurons require the Stromal Interaction Molecule (STIM) an ER Ca2+ sensor, to maintain excitability. In turn they modulate activity of certain neuropeptidergic cells. Among these are the median neurosecretory cells (MNSc) that synthesize and secrete insulin-like peptides including ilp3. The identified dopaminergic neurons dysregulate the normal pattern of larval ilp3 expression leading to premature cessation of feeding and growth. Overall, our study identified a simple dopamine modulated mechanism for feeding and growth whose manipulation could be useful for model organism studies related to feeding disorders, obesity and diabetes.