Intestine-to-neuronal signaling alters risk-taking behaviors in food-deprived Caenorhabditis elegans

Animals integrate changes in external and internal environments to generate behavior. While neural circuits detecting external cues have been mapped, less is known about how internal states like hunger are integrated into behavioral outputs. Here, we use the nematode C. elegans to examine how changes in internal nutritional status affect chemosensory behaviors. We show that acute food deprivation leads to a reversible decline in repellent, but not attractant, sensitivity. This behavioral change requires two conserved transcription factors MML-1 (MondoA) and HLH-30 (TFEB), both of which translocate from the intestinal nuclei to the cytoplasm during food deprivation. Next, we identify the insulin-like peptide INS-31 as a candidate ligand relaying food-status signals from the intestine to other tissues. Further, we show that neurons likely use the DAF-2 insulin receptor and AGE-1/PI-3 Kinase, but not DAF-16/FOXO to integrate these intestine-released peptides. Altogether, our study shows how internal food status signals are integrated by transcription factors and intestine-neuron signaling to generate flexible behaviors via the gut-brain axis. Author summaryWe have all experienced behavioral changes when we are hungry-the pang in our stomach that can cause us to behave erratically. In particular, animals, including humans, are known to pursue more risky behaviors when they are hungry as compared to when they are well-fed. Here we explore the molecular details of this behavior in the invertebrate animal model C. elegans. We show that C. elegans displays reduced copper sensitivity when hungry. As copper is toxic and repellant to C. elegans, this reduced avoidance suggests that these animals employ riskier food search strategies when food-deprived. Moreover, we find that this hunger-induced behavioral change is reversible upon re-feeding and is not caused by an increased attraction to food or depletion of fat stores, but rather insulin signaling between the intestine and neurons. We use genetic tools, microscopy, and behavioral tests to determine that this risky behavior involves a sensation of "lack of food" in the intestine, release of signaling molecules, and engagement with neurons. Our work highlights new and potentially evolutionarily conserved ways in which intestinal cells and neurons communicate and produce behavioral changes, highlighting the importance of the gut-brain-axis.