Studies have shown that the production of brain derived neutrophic factor (BDNF) in the hippocampus increases following exercise which may be the molecular link between physical activity and the improvements reported in memory and learning. PURPOSE: To determine if moderate intensity exercise training leads to an increase in plasma [BDNF] which may be associated with improvements in cognitive function, increased brain activity and/or structure. METHODS: 11 healthy males (23 ± 7 yrs (±SD)) completed a 5 week aerobic training program (92 ± 5% compliance) at an intensity of 65% maximal heart rate, 5 days/wk on a cycle ergometer. Prior to, and following training, each subject performed a ramp exercise test to fatigue for the determination of peak VO2 (VO2pk), work rate (WRpk), and estimated lactate threshold (LT). Arterialized-venous blood samples were obtained from a dorsal hand vein at rest, exhaustion and during recovery for the determination of plasma [BDNF]. Subjects underwent magnetic resonance imaging (fMRI) and a memory task before and after the training program. All exercise was performed on a cyle ergometer; pulmonary gas exchange was measured using standard techniques. RESULTS: While there was no difference in VO2pk between pre- and post-training (pre, 43.9 ± 9.2; post, 45.4 ± 8.5 ml/kg/min), the VO2 at LT was higher (p<0.05) following training (pre, 1773 ± 262; post, 2047 ± 289 ml/kg/min). Similarly, WRpk was higher (p<0.05) following training (pre, 288 ± 50; post, 313 ±56 W). Brain volume in right hippocampus and left cerebral cortex was significantly decreased following training. Compared to pre-training, fMRI showed an increase in the activation of the left hippocampus after training. There was no difference in plasma [BDNF] at rest between pre- and post-training; plasma [BDNF] increased (p<0.05) at exhaustion and was higher following training (pre, 15.4 ± 3.7; post, 17.5 ± 4.4 ng/ml: p<0.05). CONCLUSION: A moderate intensity training program resulted in small, but significant increases in exercise tolerance, brain structural and functional activation, particularly in the hippocampal region. However, there was little evidence for a relationship between changes in plasma [BDNF], brain structure and memory function.