Aminergic and peptidergic modulation of Insulin-Producing Cells inDrosophila

Abstract

Insulin plays a critical role in maintaining metabolic homeostasis. Since metabolic demands change momentarily, insulin release needs to be constantly adjusted. These adjustments are mediated via various pathways, most prominently the blood glucose level, but also by feedforward signals from motor circuits and different neuromodulatory pathways. Here, we analyzed how neuromodulatory inputs control the activity of the main source of insulin inDrosophila– a population of Insulin-Producing Cells (IPCs) located in the brain. IPCs are functionally analogous to mammalian pancreatic beta cells, but their location makes them accessible forin vivorecordings in intact animals. We characterized the functional inputs to IPCs using single-nucleus RNA sequencing analysis, anatomical receptor expression mapping, and an optogenetics-based “intrinsic pharmacology” approach. Our results showed that the IPC population expressed a variety of receptors for neuro-modulators and classical neurotransmitters. Interestingly, individual IPCs exhibited heterogeneous receptor profiles, suggesting that they could be modulated differentially. This was supported by electrophysiological recordings of IPCs that we performed while activating different populations of modulatory neurons. Our analysis revealed that some modulatory inputs had heterogeneous effects on the IPC activity, such that they inhibited one subset of IPCs, while exciting another. Monitoring calcium activity across the IPC population uncovered that these heterogeneous responses occurred simultaneously. Certain neuromodulatory populations shifted the IPC population activity towards an excited state, while others shifted the IPCs towards inhibition. Taken together, we provide a comprehensive, multi-level framework of neuromodulation in the insulinergic system ofDrosophila.