Figure 4. Schematic representation of mechanisms by which increased physical activity leads to improved cognitive function. The figure depicts the two compartments alongside the blood brain barrier and the bidirectional relationship of BNDF between central and peripheral compartments. For instance, muscles, liver, and immune cells in the periphery impose a significant influence on the brain, particularly on the DG of the hippocampus. Conversely, BDNF has the ability to easily cross the BBB and influence multiple mechanisms in the periphery. The fact that TrkB receptors have been found in the spinal cord, DRGs, muscles, intestines, and kidneys suggests that BDNF can exert multiple regulatory effects on both sides of the BBB. Through co-activation of PGC1α and ERRα, physical activity induces the production of FNCD5. Following cleavage by a protease, FNDC5 is cleaved into irisin, which has the ability to cross the BBB and induce BDNF gene expression in the hippocampus. Notably, it has also been shown that high concentrations of IGF-1 are released by the liver and can, in turn, improve neurogenesis in the DG and induce BDNF gene expression.