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Sufficient supply of oxygen (O₂) to tissue is essential for survival of aerobicanimals. In mammals, there are constant homeostatic regulation mechanisms that act on different time scales to maintain optimal O₂ delivery to tissues. The ability to detect and respond to acute oxygen shortages is indispensable to aerobic life. However, the molecular mechanisms and circuits underlying this capacity are poorly understood.

We characterize the locomotory response of feeding Caenorhabditis elegans (C. elegans) to 1% O₂. Acute hypoxia triggers a bout of turning maneuvers followed by a persistent switch to rapid forward movement as animals seek to avoid and escape hypoxia. Increasing cGMP signaling inhibits escape from 1% O₂, and that cGMP activates the protein kinase G, EGL-4, which in turn enhances neuroendocrine secretion to inhibit acute response to 1% O₂. A primary source of cGMP is the guanylyl cyclase, GCY-28. In addition, increasing mitochondrial reactive oxygen species (ROS), abrogate acute hypoxia response. Up-regulation of mitochondrial ROS increases cGMP levels, which contribute to the reduced hypoxia response. Our results implicate ROS and precise regulation of intracellular cGMP in the modulation of acute response to hypoxia by C. elegans.

In addition, we found that FMRFamide-related peptides FLP-1 plays a role in hypoxia evoked locomotory response. Our data showed that FLP-1 secretion from AVK interneurons acts on AVA and other neurons through DMSR-4, DMSR7, and DMSR-8 GPCR receptors to maintain baseline speed and to promote locomotory response to hypoxia.

We also found that hypoxia could induce food leaving behavior in C. elegans. Animals quickly escaped from the bacterial lawn when exposed to 1% O₂. The known O₂ response mechanisms cannot explain this phenotype, instead, neuropeptidergic signalling seems to be required for this behaviour.

It's known that pro-inflammatory cytokine ILC-17.1, the homologue of mammalian IL-17s, act as a neuromodulator involved in hyperoxia sensing in C. elegans. We found that it was not involved in acute hypoxia response. Instead, ILC-17.1 could modulate lifespan and damage defense mechanisms against stress in C. elegans by triggering an inhibitory network to constrain the activity of the nuclear hormone receptor, NHR-49.

In summary, our research can provide molecular and neurological understanding of how O₂ is sensed by animals. Additionally, it further emphasis C. elegans as a good model to understand oxygen sensing