Effects on cognition Physical exercise can cause various types of epigenetic alterations, but there are four prominent types that affect cognition that will be discussed in this article. The other types of epigenetic alterations cannot be ruled out as not having an effect on cognition, but there is not much known about them yet. An extensive 2017 review describes effects of exercise on the brain due to (1) DNA methylation, (2) histone acetylation, (3) histone methylation, and (4) microRNA expression, and the consequences of these alterations on learning and memory (cognition). Generally, the reviews found that exercise had positive effects on cognition, including enhanced cognitive function and the reversal of cognitive decline that typically happens during aging. Short-term effects of exercise were found to improve several cognitive abilities, such as cognitive flexibility and working memory, as well. The epigenetic mechanisms that act as a bridge between exercise and cognition are discussed below. DNA methylation As summarized in the 2017 review, in rats, exercise enhances the expression of the gene Bdnf, which has an essential role in memory formation. Enhanced expression of Bdnf occurs through demethylation of its CpG island promoter at exon IV. Demethylation is implemented in part through the actions of thymine-DNA glycosylase and the base excision repairsystem. Exercise decreases hippocampus expression of the gene-repressive DNA methylating enzymes DNMT1, DNMT3a and DNMT3b. The hippocampus has important functions in memory, spatial navigation and is part of the reward system. Exercise also attenuates the global methylation changes induced by stress. Exercise has also been found to downregulate protein phosphatase1 (PP1) and calcineurin, both memory-suppressor genes. There is evidence that PP1 increases chromatin condensation through the action of dephosphorylating histone proteins, as well as by suppressing methylation and histone acetylation with the aid of HDACs. Additionally, Tet1, an important gene for memory formation, has been shown to be upregulated in response to two weeks of exercise. Concurrently, exercise also contributed to the demethylation of CpG islands found in the promoter region of gene VegfA, a growth factor that is known to modulate the positive effects that exercise can have towards the brain. Histone H3 acetylation Exercise causes acetylation of histone H3 in the exon IV promoter region of the Bdnf gene essential for memory formation. This acetylation contributes to upregulation of Bdnf in the brain hippocampi of rats. Two weeks of treadmill exercise improves memory performance in an inhibitory avoidance task. Histone