PT - JOURNAL ARTICLE AU - Floris van Breugel AU - Ainul Huda AU - Michael H. Dickinson TI - <em>Drosophila</em> have distinct activity-gated pathways that mediate attraction and aversion to CO<sub>2</sub> AID - 10.1101/227991 DP - 2017 Jan 01 TA - bioRxiv PG - 227991 4099 - http://biorxiv.org/content/early/2017/12/03/227991.short 4100 - http://biorxiv.org/content/early/2017/12/03/227991.full AB - Carbon dioxide is a volatile and broad signal of many organic processes, and serves as a convenient cue for insects in search of blood hosts1–6, flowers7, decaying matter8–11, communal nests12, fruit13, and wildfires14. Curiously, although Drosophila melanogaster feed on yeast that produce CO2 and ethanol during fermentation, laboratory experiments suggest that flies actively avoid CO215–25. Here, we resolve this paradox by showing that both flying and walking fruit flies do actually find CO2 attractive, but only when they are in an active state associated with foraging. Aversion at low activity levels may be an adaptation to avoid CO2-seeking-parasites, or succumbing to respiratory acidosis in the presence of high concentrations of CO2 that are occasionally found in nature26,27. In contrast to CO2, flies are attracted to ethanol in all behavioral states, and invest twice as much time searching near ethanol compared to CO2. These behavioral differences reflect the fact that whereas CO2 is a generated by many natural processes, ethanol is a unique signature of yeast fermentation. Using genetic tools, we determined that the evolutionarily ancient ionotropic co-receptor IR25a is required for both CO2 and ethanol attraction, and that the receptors previously identified for CO2 avoidance are not involved. Our study lays the foundation for future research to determine the neural circuits underlying both state- and odorant-dependent decision making in Drosophila.