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For example, C57BL\/6J mice (B6J) display greater voluntary ethanol consumption and locomotor response to psychostimulants and differences in nucleus accumbens synaptic physiology relative to C57BL\/6N (B6N) mice. A non\u2010synonymous serine to phenylalanine point mutation (S968F) in the cytoplasmic FMR1\u2010interacting protein 2 (<jats:italic>Cyfip2<\/jats:italic>) gene underlies both the differential locomotor response to cocaine and the accumbal physiology exhibited by these substrains. We examined whether <jats:italic>Cyfip2<\/jats:italic> allelic variation underlies B6 substrain differences in other reward\u2010related phenotypes, such as ethanol intake and wheel\u2010running activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We compared voluntary ethanol consumption, wheel\u2010running, and binge\u2010like ethanol drinking in male and female B6J and B6NJ mice. When substrain differences were observed, additional experiments were performed in two novel mouse models in which the B6N <jats:italic>Cyfip2<\/jats:italic> mutation was either introduced (S968F) into the B6J background or corrected (F968S) via CRISPR\/Cas9 technology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>B6J consumed significantly more ethanol than B6NJ and allelic variation in <jats:italic>Cyfip2<\/jats:italic> contributed substantially to this substrain difference. In contrast, B6NJ displayed significantly more daily wheel\u2010running than B6J, with <jats:italic>Cyfip2<\/jats:italic> allelic variation playing only a minor role in this substrain difference. Lastly, no substrain differences were observed in binge\u2010like ethanol drinking.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results contribute to the characterization of behavior\u2010genetic differences between B6 substrains, support previous work indicating that free\u2010choice and binge\u2010like ethanol drinking are dependent on partially distinct genetic networks, and identify a novel phenotypic difference between B6 substrains in wheel\u2010running activity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.15137","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T00:57:15Z","timestamp":1687741035000},"page":"1518-1529","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<i>Cyfip2<\/i> allelic variation in C57BL\/6J and C57BL\/6NJ mice alters free\u2010choice ethanol drinking but not binge\u2010like drinking or wheel\u2010running 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