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U.S.A."],"published-print":{"date-parts":[[2022,8,9]]},"abstract":"<jats:p>Histone acetylation is a key component in the consolidation of long-term fear memories. Histone acetylation is fueled by acetyl-coenzyme A (acetyl-CoA), and recently, nuclear-localized metabolic enzymes that produce this metabolite have emerged as direct and local regulators of chromatin. In particular, acetyl-CoA synthetase 2 (ACSS2) mediates histone acetylation in the mouse hippocampus. However, whether ACSS2 regulates long-term fear memory remains to be determined. Here, we show that Acss2 knockout is well tolerated in mice, yet the Acss2-null mouse exhibits reduced acquisition of long-term fear memory. Loss of Acss2 leads to reductions in both histone acetylation and expression of critical learning and memory-related genes in the dorsal hippocampus, specifically following fear conditioning. Furthermore, systemic administration of blood\u2013brain barrier\u2013permeable Acss2 inhibitors during the consolidation window reduces fear-memory formation in mice and rats and reduces anxiety in a predator-scent stress paradigm. Our findings suggest that nuclear acetyl-CoA metabolism via ACSS2 plays a critical, previously unappreciated, role in the formation of fear memories.<\/jats:p>","DOI":"10.1073\/pnas.2114758119","type":"journal-article","created":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T13:56:05Z","timestamp":1659534965000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":43,"title":["Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation"],"prefix":"10.1073","volume":"119","author":[{"given":"Desi C.","family":"Alexander","sequence":"first","affiliation":[{"name":"Epigenetics Institute, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Department of Genetics, University of Pennsylvania, Philadelphia, PA 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