Understanding the molecular mechanisms that produce and maintain long-lasting changes in brain function is critical for numerous areas of neuroscience research, and is especially relevant in the context of learning and memory. Increasing evidence now indicates that epigenetic modifications in neurons may be essential mechanisms for both the formation and storage of behavioral memory. For example, the formation and recall of contextual fear memories increases histone tagging (acetylation) in the hippocampus (Levenson et al., 2004). Blocking histone acetylation impairs both long lasting synaptic plasticity as well as behavioral performance (Korzus et al., 2004). Similarly, inhibition of histone deacetylase (HDAC) activity rescues these deficits and improves memory formation (Korzus et al., 2004; Levenson et al., 2004). Finally, normal aging-related memory impairment is associated with the lack of a specific histone acetylation mark, which can be rescued by treatment with an HDAC inhibitor to restore memory function (Peleg et al., 2010).
DNA methylation, a second form of epigenetic marking, also has a critical role in memory formation and consolidation. Contextual fear conditioning induces rapid methylation of a memory suppression gene (protein phosphatase 1, PP1) and demethylation of plasticity genes (reelin and brain-derived neurotrophic factor, BDNF) in the hippocampus (Lubin and Sweatt, 2007; Miller and Sweatt, 2007). Moreover, inhibition of DNA methyltranferases, which are required for DNA methylation, prevents memory formation (Lubin and Sweatt, 2007; Miller and Sweatt, 2007). Interestingly, both histone and DNA methylation changes that occur in the hippocampus after learning are relatively transient compared with the lifetime of a memory, indicating that other mechanisms are involved in long-term memory storage. However, a recent study found that learning can induce long-lasting DNA methylation changes in the anterior cingulate cortex, and that these changes are essential for the recall of remote memories for up to a month after conditioning (Miller et al., 2010). This finding is particularly exciting because it (1) reveals a molecular change that lasts long enough to subserve the maintenance of long-term memory, and (2) indicates region-specific regulation of DNA methylation that is largely in line with the functional roles of the hippocampus and cortex in memory consolidation and storage, respectively.
Taken together, these findings indicate that epigenetic mechanisms are key regulators of long-term memory and reveal several potential therapeutic targets for the amelioration of memory-related diseases. Nevertheless, a number of important questions remain to be answered. For example, it is unclear whether diverse histone marks and DNA methylation profiles operate in relative isolation or are integrated as part of an ‘epigenetic code’ to generate meaningful changes in gene expression and behavior. In addition, it is unclear how cell-wide changes associated with epigenetic modifications interact with synapse-specific changes long believed to underlie learning and memory processes. Finally, it is uncertain how specific epigenetic modifications are targeted within a cell and how the kinetics underlying such modifications may differ between brain regions to confer circuit-specific epigenetic patterns. Future studies will be required to address these issues and continue to elucidate the epigenetic mechanisms that generate long-term behavioral change.
Korzus E, Rosenfeld MG, Mayford M (2004). CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42: 961–972.
Levenson JM, O’Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD (2004). Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 279: 40545–40559.
Lubin FD, Sweatt JD (2007). The IkappaB kinase regulates chromatin structure during reconsolidation of conditioned fear memories. Neuron 55: 942–957.
Miller CA, Sweatt JD (2007). Covalent modification of DNA regulates memory formation. Neuron 53: 857–869.
Miller CA, Gavin CF, White JA, Parrish RR, Honasoge A, Yancey CR et al. (2010). Cortical DNA methylation maintains remote memory. Nat Neurosci 13: 664–666.
Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC et al. (2010). Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328: 753–756.
The authors declare that except for income received from primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
About this article
Cite this article
Day, J., Sweatt, J. Epigenetic Modifications in Neurons are Essential for Formation and Storage of Behavioral Memory. Neuropsychopharmacol 36, 357–358 (2011). https://doi.org/10.1038/npp.2010.125
This article is cited by
Epigenetic regulation of neuronal immediate early genes is associated with decline in their expression and memory consolidation in scopolamine-induced amnesic mice
Molecular Neurobiology (2017)
Shifting transcriptional machinery is required for long-term memory maintenance and modification in Drosophila mushroom bodies
Nature Communications (2016)