H3 methylation Histone methylation can cause transcription repression. Lysine can undergo mono-, di- and tri-methylation. Di- and tri-methylation of histone H3 at lysine 9 (H3K9) is related to transcription repression. Mice deficient in a particular histone-methyltransferase gene, KMT2A (also known as MLL1), in adult excitatory neurons show impairments in hippocampus-dependent memory tasks. Aging induces decreases in the global methylation of H3K9 in the hippocampus. However, physical exercise counteracts the aging induced decreases in the global methylation of H3K9. microRNA MicroRNAs (miRNAs) have been discovered to be potential regulators of numerous biological processes within the brain, ranging from cell proliferation, differentiation, apoptosis, synaptic plasticity and memory formation, all very important processes involved in cognition. These miRNAs have also been found within the hippocampus, amygdala, and cortex, further linking its effects to memory formation and cognition. During their biogenesis, premature-miRNAs are exported from the nucleus to the cytoplasm. Subsequent processing of the pre-miRNA generates mature-miRNA, which binds to 3’UTR “seed sequence” of target mRNAs, a process that is catalyzed by the RNA-induced silencing complex (RISC). The binding of miRNA to the target mRNA can result in degradation of the target mRNA or inhibition of its translation into protein, with the degree of sequence complementarity between the miRNA and mRNA determining which mechanism is employed. Interestingly, each miRNA has the ability to interact with a large number of mRNAs (approximately 200–500 mRNA for each miRNA), suggesting that the majority of the protein-coding genes may be regulated by miRNAs. Therefore, it is not surprising that miRNAs are widely expressed in the brain, and that they can participate in epigenetic mechanisms. Eukaryotic cells can communicate directly with each other through cell–cell contact or at distance by secreting soluble factors such as hormones, growth factors, cytokines and chemokines. Both RNA and mRNAs can be functionally transferred from a donor to a recipient cell via membrane-derived vesicles called exosomes. Similarly to hormones, miRNAs are released into the circulation (called circulating miRNAs or c-miRNAs), to affect cells throughout the organism. The c-miRNAs are transported by exosomes, high-/low-density lipoproteins, apoptotic bodies, and RNA-binding proteins. A bout of exercise increases c-miR-223 levels in the circulation in young healthy men, while lack of miR-223 leads to hippocampal-dependent memory deficits and neuronal cell death. Likely arising from different mechanisms, both acute exercise and chronic endurance training have been shown to robustly modify the miRNA signature of human plasma. One pathway that involves