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Epigenetics

Main article: Epigenetics in learning and memory

Cytosine and 5-methylcytosine

Early theories, in 1969 and 1999, on the molecular basis of memory proposed that addition of a methyl group to particular cytosines in DNA of neurons (epigenetic alterations) could be the basis of memory. In 2007, Miller and Sweatt first experimentally explored the role of cytosine methylation in memory formation. They found that DNA methylation levels are rapidly and dynamically regulated in the rat brain hippocampus following formation of a new strong memory due to contextual fear conditioning. By 2015 it had become clear that long-term memory requires gene transcription activation and de novo protein synthesis in neurons, and that activation and repression of genes during memory formation was controlled in large part by DNA methylation/DNA demethylation .

When a new, strong, long-term memory is created in rats through contexual fear conditioning, those rats can have reduced expression of roughly 1,000 genes and increased expression of roughly 500 genes in the hippocampus at a time-point 24 hours after training. In total, this reflects altered expression of about 9% of the rat hippocampal genome. Reduced expression of genes was associated with methylation of the genes.

As shown in 2019, the neuronal genes that had methylation-controlled increases or decreases in transcription then had their induced messenger RNAs (mRNAs) transported by neural granules (messenger RNPs) to the dendritic spines, where synapses are formed. At these locations the mRNAs can be translated into the proteins that control signaling at neuronal synapses.