The amygdala processes and directs inputs and outputs that are key to fear behavior. However, whether it directly senses fear-evoking stimuli is unknown. Because the amygdala expresses acid-sensing ion channel-1a (ASIC1a), and ASIC1a is required for normal fear responses, we hypothesized that the amygdala might detect a reduced pH. We found that inhaled CO2 reduced brain pH and evoked fear behavior in mice. Eliminating or inhibiting ASIC1a markedly impaired this activity, and localized ASIC1a expression in the amygdala rescued the CO2-induced fear deficit of ASIC1a null animals. Buffering pH attenuated fear behavior, whereas directly reducing pH with amygdala microinjections reproduced the effect of CO2. These data identify the amygdala as an important chemosensor that detects hypercarbia and acidosis and initiates behavioral responses. They also give a molecular explanation for how rising CO2 concentrations elicit intense fear and provide a foundation for dissecting the bases of anxiety and panic disorders.
Bibliographical noteFunding Information:
We thank Sam Hartman, Huiyu Gong, and Runping Wang for assistance. We also thank Dr. Mark Chapleau for use of the plethysmography and the University of Iowa Gene Vector Core. This work was supported by Young Investigator Awards from ADAA and NARSAD, VA Merit Award, and 1R01MH085724-01 (to J.A.W.) and by the University of Iowa Interdisciplinary Training Program in Pain Research NINDS T32NS045549 (to A.E.Z.). M.J.W. is an Investigator of the Howard Hughes Medical Institute.