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Insulin plays a critical role in maintaining metabolic homeostasis. Since metabolic demands are highly dynamic, insulin release needs to be constantly adjusted. These adjustments are mediated by different pathways, most prominently the blood glucose level, but also by feedforward signals from motor circuits and different neuromodulatory systems. Here, we analyze 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 for in vivo recordings in intact animals. We characterized functional inputs to IPCs using single-nucleus RNA sequencing analysis, anatomical receptor expression mapping, connectomics, 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, IPCs exhibit heterogeneous receptor profiles, suggesting that the IPC population can be modulated differentially. This is supported by electrophysiological recordings from IPCs, which we performed while activating different populations of modulatory neurons. Our analysis revealed that some modulatory inputs have heterogeneous effects on the IPC activity, such that they inhibit one subset of IPCs, while exciting another. Monitoring calcium activity across the IPC population uncovered that these heterogeneous responses occur simultaneously. Certain neuromodulatory populations shifted the IPC population activity towards an excited state, while others shifted it towards inhibition. Taken together, we provide a comprehensive, multi-level analysis of neuromodulation in the insulinergic system ofDrosophila.
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Bistable State Switch Enables Ultrasensitive Feedback Control in Heterogeneous Microbial Populations
Ultrasensitive feedback control can improve robust gene expressions in cell populations, yet it usually requires large chemical productions that cause severe burden to cells. Inspired by `division-of-labor' in heterogeneous populations, we propose a bistable switch circuit that utilizes quorum sensing systems to coordinate heterogeneous phenotypes' behaviors. We show that ultrasensitivity emerges from a collection of parallel bistable switches in individual cells. When applied to feedback control of population level expressions, it can achieve robust reference tracking and adaptation to disturbances. In particular, we demonstrate that molecular sequestration enables tunable hysteresis in single switches, leading to a wide range of stable population level expressions.
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- Award ID(s):
- 2020039
- PAR ID:
- 10274112
- Date Published:
- Journal Name:
- Proceedings of the American Control Conference
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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