Exercise increases SIRT1 activity and expression in the hippocampus, which deacetylates MeCP2, leading to its dissociation from BDNF promoter IV and increased BDNF expression. SIRT1 also represses miR‐134, a microRNA that blocks CREB, facilitating BDNF transcription. SIRT1 loss of function impairs BDNF and CREB expression, leading to cognitive deficits. Here, CREB1 is linked to Cognitive impairment.