Epigenetics in learning and memory

While the cellular and molecular mechanisms of learning and memory have long been a central focus of neuroscience, it is only in recent years that attention has turned to the epigenetic mechanisms behind the dynamic changes in gene transcription responsible for memory formation and maintenance. Epigenetic gene regulation often involves the physical marking (chemical modification) of DNA or associated proteins to cause or allow long-lasting changes in gene activity. Epigenetic mechanisms such as DNA methylation and histone modifications (methylation, acetylation, and deacetylation) have been shown to play an important role in learning and memory.

DNA methylation involves the addition of a methyl group to a 5' cytosine residue. This usually occurs at cytosines that form part of a cytosine-guanine dinucleotide (CpG sites). Methylation can lead to activation or repression of gene transcription and is mediated through the activity of DNA methyltransferases (DNMTs). DNMT3A and DNMT3B regulate de novo methylation of CpG sites, while DNMT1 maintains established methylation patterns. S-adenosyl methionine acts as the methyl donor.

The current hypothesis for how DNA methylation contributes to the storage of memories is that dynamic DNA methylation changes occur temporally to activate transcription of genes that encode for proteins whose role is to stabilize memory.

Miller and Sweatt demonstrated that rats trained in a contextual fear-conditioning paradigm had elevated levels of mRNA for DNMT3a and DNMT3b in the hippocampus. Fear conditioning is an associative memory task where a context, like a room, is paired with an aversive stimulus, like a foot shock; animals who have learned the association show higher levels of freezing behavior when exposed to the context even in the absence of the aversive stimulation. However, when rats were treated with the DNMT inhibitors zebularine or 5-aza-2′-deoxycytidine immediately after fear-conditioning, they demonstrated reduced learning (freezing behavior). When treated rats were re-trained 24 hours later, they performed as well as non-treated rats. Furthermore, it was shown that when these DNMT inhibitors were given 6 hours after training, and the rats were tested 24 hours later, the rats displayed normal fear memory, indicating that DNMTs are involved specifically in memory consolidation. These findings reveal the importance of dynamic changes in methylation status in memory formation.

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