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

Alexander, D. C.; Corman, T.; Mendoza, M.; Glass, A.; Belity, T.; Campbell, R. R.; Han, J.; Keiser, A. A.; Winkler, J.; Wood, M. A.; Garcia, B. A.; Cohen, H.; Mews, P.; Egervari, G.; Berger, S. L.

doi:10.1101/2022.05.22.492937

bioRxiv · 10.1101/2022.05.22.492937

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

Alexander, D. C.·Corman, T.·Mendoza, M.·Glass, A.·Belity, T.·Campbell, R. R.·Han, J.·Keiser, A. A.·Winkler, J.·Wood, M. A.·Garcia, B. A.·Cohen, H.·Mews, P.·Egervari, G.·Berger, S. L.

View original source ↗Export metadata ↓

Abstract

Histone acetylation is a key component in the consolidation of long-term fear memories. Epigenetic enzymes involved in histone acetylation, including histone acetyltransferases and deacetylases, have been put forward as potential pharmacological targets in the treatment of pathological fear memories, such as those that underlie post-traumatic stress disorder (PTSD). However, these enzymes typically play a ubiquitous role in gene regulation, which precludes the clinical use of systemic manipulations. Recently, we have found that a nuclear-localized metabolic enzyme, Acetyl-coA synthetase 2 (Acss2), modulates histone acetylation during learning and memory. Loss of Acss2 is well-tolerated in mice, with no impact on general health or baseline behavior. Here, we show that an Acss2 null mouse model shows reduced acquisition of long-term fear memories in assays of contextual and cued fear conditioning. We find that loss of Acss2 leads to consolidation-specific reductions in both histone acetylation and the expression of critical learning and memory-related genes in the dorsal hippocampus. Further, we show that systemic administration of blood-brain-barrier (BBB)-permeable Acss2 inhibitors during the consolidation window reduces fear memory formation in mice and rats, and also reduces anxiety in a predator-scent-stress (PSS) paradigm. Our findings suggest that Acss2 plays a critical role in the formation of fear memories, and represents a potential pharmacological target in the treatment of PTSD.

Source connections

Published article ↗

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Alexander, D. C., Corman, T., Mendoza, M., Glass, A., Belity, T., Campbell, R. R., Han, J., Keiser, A. A., Winkler, J., Wood, M. A., Garcia, B. A., Cohen, H., Mews, P., Egervari, G., Berger, S. L.. 2022-05-22. Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation. https://doi.org/10.1101/2022.05.22.492937

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Same Movements, Different Skills: How Context Shapes Learning in Humans and Neural Networks

What determines whether experiences are integrated into shared representations or split? Motor skill learning offers a revealing test: when two tasks require an identical sequence of movements, both intuition and theory suggest that practice in one should generalize to the other. Yet we find that changing context can make identical movements different skills. In simple recurrent networks trained on the same sequence across contexts, splitting was greatest when strong contextual inputs coincided with a high initial weight scale; neither alone sufficed. Greater representational separation coincided with separate context-specific learning curves. Humans practicing the same finger sequence while alternating between two performance-irrelevant contexts likewise exhibited context-specific curves, rather than the single continuous trajectory observed when practicing in a single context. State-space modeling favored split learning states in humans and very weakly coupled states in the most context-dependent networks. These findings have broader implications for understanding how learning generalizes across contexts.

neuroscience↗

bioRxiv2026

Postpartum resource scarcity reshapes maternal care, offspring prioritization, and the steroid-sensitive medial preoptic area

Parental care requires balancing offspring needs with environmental constraints, yet how resource scarcity alters the organization of maternal responses remains poorly understood. Here, we examined maternal behavior, offspring prioritization, and steroid receptor-associated extracellular matrix organization in postpartum rats exposed to limited bedding and nesting (LBN) or control conditions with ample nesting materials. LBN increased pup-directed and reduced self-directed behaviors but also increased behavioral entropy, a measure of behavioral fragmentation, indicating less predictable caregiving sequences. LBN dams preferentially retrieved male pups first, whereas control dams preferentially retrieved females first. LBN also increased the proportion of pup-investigation time directed toward males compared with controls. In offspring on postnatal day 10, corticosterone was elevated in female but not male LBN pups, a pattern that paralleled the maternal male bias. To identify associated neurobiological changes, we assessed steroid receptors and extracellular matrix organization in the medial preoptic area (mPOA), a key region for maternal behavior. LBN increased numbers of estrogen receptor (ER)- and androgen receptor (AR)-immunoreactive cells, reduced perineuronal net (PNN) abundance, and decreased receptor-positive cell enwrapment. Because PNNs constrain structural plasticity, these findings suggest that the postpartum environment alters the organization of steroid receptor-associated extracellular matrix, potentially modulating experience-dependent plasticity in neurosteroid-sensitive circuits. In sum, LBN increases the levels of maternal engagement while reshaping its temporal organization and allocation, accompanied by selective remodeling of steroid-sensitive preoptic architecture. Therefore, maternal adaptation to adversity may be better understood as changes in caregiving allocation strategies rather than a simple gain or loss of maternal care.

neuroscience↗

bioRxiv2026

The Computational Grammar of Human Behaviour in a Biological Environment

Human behaviour unfolds as an extended stream of spontaneous actions shaped by environmental demands and the agent's goals. The organisation of these actions, situated between setting abstract goals and concrete movement execution, remains poorly characterised. Here, we introduce DynaClade, an unsupervised temporal action segmentation algorithm for human full-body motion capture data, and apply it to freely moving participants navigating ecologically realistic risky foraging environments in virtual reality. DynaClade identifies discrete actions whose kinematic characteristics and spatial distributions correspond to environmental affordances, supporting the validity of the approach. Among these actions, we discovered a hitherto undescribed movement pattern defined by increased body sway without locomotion. Action sequences were highly non-random and showed clear history dependence beyond first-order Markov structure, most of which was explained by a second-order prediction. This higher-order structure was well captured in a hidden Markov model, in which some of the observed actions were associated with more than one latent state. Each of these latent states corresponded to the same action in a distinct action context. These findings suggest that spontaneous human actions are predominantly selected based on the current action and context, rather than following pre-planned or habitually assembled sequences.

neuroscience↗