@article{c1a5ce1c6c6f4521969343de3b6a29ef,
title = "Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation",
abstract = "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-brain barrier-permeable 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.",
keywords = "epigenetics, fear conditioning, histone acetylation, learning and memory, mass spectrometry",
author = "Alexander, {Desi C.} and Tanya Corman and Mariel Mendoza and Andrew Glass and Tal Belity and Ranran Wu and Campbell, {Rianne R.} and Joseph Han and Keiser, {Ashley A.} and Jeffrey Winkler and Wood, {Marcelo A.} and Thomas Kim and Garcia, {Benjamin A.} and Hagit Cohen and Philipp Mews and Gabor Egervari and Berger, {Shelley L.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank E. Korb and K. Wellen for insightful discussions on behavior and metabolism, respectively. Acss2KO were generated with the University of Pennsylvania Transgenic and Chimeric Mouse Core (Institute for Diabetes, Obesity and Metabolism, the Center for Molecular Studies in Digestive and Liver Diseases). Behavior procedures were performed with The Neurobehav-ior Testing Core at University of Pennsylvania/Institute for Translational Medicine and Therapeutics and the Intellectual and Developmental Disabilities Research Center at Children{\textquoteright}s Hospital of Pennsylvania/University of Pennsylvania (National Institute of Child Health and Human Development Grant U54 HD086984). We thank J.A. Youssefian for material and logistical support. This work was supported by NIH grants RO1AA027202 (S.L.B), T32 GM-07229 (D.C.A), F31 CA247348-02 (M.M.), AARF-19-618159 (G.E.), K99AA027839 (P.M.), and K99AA028577 (G.E.). Publisher Copyright: {\textcopyright} 2022 National Academy of Sciences. All rights reserved.",
year = "2022",
month = aug,
day = "9",
doi = "10.1073/pnas.2114758119",
language = "English",
volume = "119",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "32",
}