Physical activity elicits sustained activation of the cyclic AMP response element-binding protein and mitogen-activated protein kinase in the rat hippocampus

To elucidate molecular mechanisms involved in physical activity-induced ben eficial effects on brain function. we studied in rats the influence of volu ntary running on the activation in the hippocampus of cyclic AMP response e lement-binding protein (CREB) and mitogen-activated protein kinase (MAPK)/e xtracellular signal-regulated protein kinase (ERK). These are signaling mol ecules that play critical roles in synaptic plasticity, including learning and memory, Exercise resulted in an increase in the level of the activated transcription factor. CREB phosphorylated at Ser-133. The amount of the act ivated transcription Factor about doubled already after I night of running and remained elevated for at least a week, although control levels were res tored after I month of exercise. In addition, binding activity in nuclear e xtracts to cyclic AMP response element (CRE) motif containing oligonucleoti des increased significantly in the hippocampus after 3 nights of exercise. although the total amount of the immunochemically identified CREB remained unaltered. Electrophoretic mobility supershift assays indicated that the in creased binding was due to the recruitment of members of this transcription Factor family. in addition to the CREB proper. Voluntary running also resu lted in an increase in the level of phosphorylated MAPK (both p42 and p44). The time-courses of the increases in the level of the phosphorylated prote in kinase and the activated transcription factor were different. In compari son with the activated CREB, the increase in the phosphorylated MAPK was de layed, but lasted longer, being detectable even after I month of exercise. These observations are consistent with the view that the relatively long-la sting activation of these signaling molecules participates in the regulatio n of genes. such as the neurotrophin genes, and contributes to the benefici al effects of physical exercise on brain function. (C), 2001 Published by E lsevier Science Ltd on behalf of IBRO.