Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 32, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2114758119
Keywords
epigenetics; histone acetylation; fear conditioning; learning and memory; mass spectrometry
Categories
Funding
- National Institute of Child Health and Human Development Grant [U54 HD086984]
- NIH [RO1AA027202, T32 GM-07229, F31 CA247348-02, AARF-19-618159, K99AA027839, K99AA028577]
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Histone acetylation is crucial for the consolidation of long-term fear memories and is regulated by ACSS2 in the mouse hippocampus. The knockout of Acss2 reduces the acquisition of long-term fear memory and leads to decreased expression of learning and memory-related genes in the dorsal hippocampus. Inhibiting ACSS2 during the consolidation window also impairs fear-memory formation and reduces anxiety in mice and rats.
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.
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