Hypoxia and the HIF-1 transcriptional pathway reorganize a neuronal circuit for oxygen-dependent behavior in Caenorhabditis elegans.

Rapid behavioral responses to oxygen are generated by specialized sensory neurons that sense hypoxia and hyperoxia. On a slower time scale, many cells respond to oxygen through the activity of the hypoxia-inducible transcription factor HIF-1. Here, we show that in the nematode Caenorhabditis elegans, prolonged growth in hypoxia alters the neuronal circuit for oxygen preference by activating the hif-1 pathway. Activation of hif-1 by hypoxia or by mutations in its negative regulator egl-9/prolyl hydroxylase shifts behavioral oxygen preferences to lower concentrations and eliminates a regulatory input from food. At a neuronal level, hif-1 activation transforms a distributed, regulated neuronal network for oxygen preference into a smaller, fixed network that is constitutively active. The hif-1 pathway acts both in neurons and in gonadal endocrine cells to regulate oxygen preference. These results suggest that physiological detection of hypoxia by multiple tissues provides adaptive information to neuronal circuits to modify behavior.