Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation

Desi C. Alexander, Tanya Corman, Mariel Mendoza, Andrew Glass, Tal Belity, Ranran Wu, Rianne R. Campbell, Joseph Han, Ashley A. Keiser, Jeffrey Winkler, Marcelo A. Wood, Thomas Kim, Benjamin A. Garcia, Hagit Cohen, Philipp Mews, Gabor Egervari, Shelley L. Berger

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere2114758119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number32
DOIs
StatePublished - 9 Aug 2022

Keywords

  • epigenetics
  • fear conditioning
  • histone acetylation
  • learning and memory
  • mass spectrometry

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