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 distinct pathways, most prominently the blood glucose level, but also feedforward signals from motor circuits, and different neuromodulatory pathways. Here, we analyzed how neuromodulatory inputs control the activity of the main source of insulin in Drosophila — 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 for in-vivo recordings 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 show that the IPC population expresses a variety of receptors for neuromodulators and classical neurotransmitters. Interestingly, individual IPCs exhibit heterogeneous receptor profiles, suggesting they could be modulated differentially. This is supported by electrophysiological recordings of IPCs which 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 revealed 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 of Drosophila.

Nutritional state-dependent modulation of Insulin-Producing Cells inDrosophila

“…Hence, DH44Ns strongly and significantly inhibited IPCs. Notably, we also recorded from one IPC, which was excited during DH44N activation and inhibited immediately after cessation of activation (Supplementary Figure S4C), indicating heterogeneity in the IPC population 30 . Overall, our results indicate that acute activation of DH44Ns inhibits IPC activity, hence regulating insulin release.…”

“…For example, the line labels a subset of DH44Ns ascending from the VNC. A pair of these DH44Ns co-express the neuropeptide Leucokinin (LK) 69 , and LK expressing neurons inhibit most IPCs 30 .…”

“…In Drosophila , Insulin-Producing Cells (IPCs), which are analogous to human pancreatic beta cells, reside in the pars intercerebralis (PI) of the brain 22 . These IPCs secrete Drosophila insulin-like peptides (DILPs) and are sensitive to changes in the metabolic state 23–26 , the behavioral state 27,28 , the circadian time 25,29 , aminergic and peptidergic inputs 30 , and other peripheral signals 31 . Consequently, they play a key role in orchestrating the metabolic demands of behaving animals.…”

Synaptic connectome of theDrosophilacircadian clock

“…Consistent with our prediction, our analysis indicated that multiple receptors for clock peptides are indeed expressed in NSC. Modulatory inputs to m-NSC DILP have been examined extensively and our analysis is in agreement with previous expression and functional studies (Kapan et al ., 2012, Nässel and Vanden Broeck, 2016, Nagy et al ., 2019, Oh et al ., 2019, Held et al ., 2023). Taken together, our analysis uncovers the molecular substrates of paracrine signaling between clock neurons and NSC.…”