AbstractOcean acidification (OA) is known to affect the physiology, survival, behaviour, and fitness of various fish species with repercussions at the population, community, and ecosystem levels. Some fish species, however, seem to acclimate rapidly to OA conditions and even thrive in acidified environments. The molecular mechanisms that enable species to successfully inhabit high CO2environments has not been fully elucidated especially in wild fish populations. Here, we used the natural CO2seep in Vulcano Island, Italy to study the effects of elevated CO2exposure on the brain transcriptome of the anemone goby, a species with high population density in the CO2seep and investigate their potential for acclimation. When compared to fish from environments with ambient CO2, gobies living in the CO2seep showed differences in expression of transcripts involved in ion transport and pH homeostasis, cellular stress, immune response, circadian rhythm, and metabolism. We also found evidence of potential adaptive mechanisms to restore the functioning of GABAergic pathways, whose activity can be affected by exposure to elevated CO2levels. Our findings indicate that gobies living in the CO2seep may be capable of mitigating CO2induced oxidative stress and maintaining physiological pH while meeting the consequent increased energetic costs. The conspicuous difference in expression of core circadian rhythm transcripts could provide an adaptive advantage by increasing flexibility of physiological processes in elevated CO2conditions thereby facilitating acclimation. Our results show potential molecular processes of acclimation to elevated CO2in gobies enabling them to thrive in the acidified waters of Vulcano Island.