Hippocampal Structure, Metabolism, and Inflammatory Response after a 6-Week Intense Aerobic Exercise in Healthy Young Adults: A Controlled Trial

Interventional studies suggest that changes in physical fitness affect brain function and structure. We studied the influence of high intensity physical exercise on hippocampal volume and metabolism in 17 young healthy male adults during a 6-week exercise program compared with matched controls. We further aimed to relate these changes to hypothesized changes in exercised-induced brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). We show profound improvement of physical fitness in most subjects and a positive correlation between the degree of fitness improvement and increased BDNF levels. We unexpectedly observed an average volume decrease of about 2%, which was restricted to right hippocampal subfields CA2/3, subiculum, and dentate gyrus and which correlated with fitness improvement and increased BDNF levels negatively. This result indicates that mainly those subjects who did not benefit from the exercise program show decreased hippocampal volume, reduced BDNF levels, and increased TNF-α concentrations. While spectroscopy results do not indicate any neuronal loss (unchanged N-acetylaspartate levels) decreased glutamate-glutamine levels were observed in the right anterior hippocampus in the exercise group only. Responder characteristics need to be studied in more detail. Our results point to an important role of the inflammatory response after exercise on changes in hippocampal structure.

[1]  Polina Golland,et al.  Automated segmentation of hippocampal subfields from ultra‐high resolution in vivo MRI , 2009, Hippocampus.

[2]  E. McAuley,et al.  Aerobic fitness is associated with hippocampal volume in elderly humans , 2009, Hippocampus.

[3]  J. E. Cunnick,et al.  Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of β-blockers, BMI, and psychosocial factors in older adults , 2006, Brain, Behavior, and Immunity.

[4]  Ryosuke Kawakami,et al.  Asymmetrical Allocation of NMDA Receptor ε2 Subunits in Hippocampal Circuitry , 2003, Science.

[5]  P. Magistretti,et al.  Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[6]  W. Kindermann,et al.  Lactate Kinetics and Individual Anaerobic Threshold* , 1981, International journal of sports medicine.

[7]  M. Okamoto,et al.  Brain glycogen decreases during prolonged exercise , 2011 .

[8]  Shane M. O'Mara,et al.  Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males , 2011, Physiology & Behavior.

[9]  R. J. Shephard,et al.  A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children , 2011 .

[10]  A. Kramer,et al.  Be smart, exercise your heart: exercise effects on brain and cognition , 2008, Nature Reviews Neuroscience.

[11]  T. Hergueta,et al.  The mini international neuropsychiatric interview , 1998, European Psychiatry.

[12]  Carl W. Cotman,et al.  Exercise builds brain health: key roles of growth factor cascades and inflammation , 2007, Trends in Neurosciences.

[13]  Brian K. McFarlin,et al.  State of the Art Reviews: The Anti-Inflammatory Actions of Exercise Training , 2007 .

[14]  Lei Zheng,et al.  In vivo voxel based morphometry: Detection of increased hippocampal volume and decreased glutamate levels in exercising mice , 2012, NeuroImage.

[15]  E. McAuley,et al.  Exercise training increases size of hippocampus and improves memory , 2011, Proceedings of the National Academy of Sciences.

[16]  Bente Klarlund Pedersen,et al.  The anti-inflammatory effect of exercise. , 2005, Journal of applied physiology.

[17]  J. Deakin,et al.  Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains. , 2009, Journal of psychiatric research.

[18]  L. Sundstrom,et al.  Brain-derived neurotrophic factor, but not neurotrophin-3, prevents ischaemia-induced neuronal cell death in organotypic rat hippocampal slice cultures , 1996, Neuroscience Letters.

[19]  Heidi Johansen-Berg,et al.  The Effects of Aerobic Activity on Brain Structure , 2011, Front. Psychology.

[20]  Fred H. Gage,et al.  Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice , 2005, The Journal of Neuroscience.

[21]  Fred H. Gage,et al.  An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus , 2007, Proceedings of the National Academy of Sciences.

[22]  B. McFarlin,et al.  The Anti-Inflammatory Actions of Exercise Training. , 2007, American journal of lifestyle medicine.

[23]  I. Papassotiriou,et al.  Dramatic elevations of interleukin-6 and acute-phase reactants in athletes participating in the ultradistance foot race spartathlon: severe systemic inflammation and lipid and lipoprotein changes in protracted exercise. , 2005, The Journal of clinical endocrinology and metabolism.

[24]  M. Suwa,et al.  Different circulating brain-derived neurotrophic factor responses to acute exercise between physically active and sedentary subjects. , 2012, Journal of sports science & medicine.

[25]  D. Sheehan,et al.  The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. , 1998, The Journal of clinical psychiatry.

[26]  E. Cacci,et al.  Microglia‐derived tumor necrosis factor‐α exaggerates death of newborn hippocampal progenitor cells in vitro , 2005, Journal of neuroscience research.

[27]  H. Nakata,et al.  Brain‐derived neurotrophic factor regulates AMPA receptor trafficking to post‐synaptic densities via IP3R and TRPC calcium signaling , 2007, FEBS letters.

[28]  J. Zoladz,et al.  Endurance training increases plasma brain-derived neurotrophic factor concentration in young healthy men. , 2008, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[29]  B. K. Pedersen.  The diseasome of physical inactivity – and the role of myokines in muscle–fat cross talk , 2009, The Journal of physiology.

[30]  Tyrone D. Cannon,et al.  The effect of aerobic exercise on cortical architecture in patients with chronic schizophrenia: a randomized controlled MRI study , 2013, European Archives of Psychiatry and Clinical Neuroscience.

[31]  J Xiong,et al.  Amygdalar and hippocampal volumetry in control participants: differences regarding handedness. , 2001, AJNR. American journal of neuroradiology.

[32]  Bruce Fischl,et al.  Within-subject template estimation for unbiased longitudinal image analysis , 2012, NeuroImage.

[33]  Y. Omidi,et al.  Asymmetrical expression of BDNF and NTRK3 genes in frontoparietal cortex of stress‐resilient rats in an animal model of depression , 2014, Synapse.

[34]  M. Okamoto,et al.  Brain glycogen decreases during prolonged exercise. , 2011, The Journal of physiology.

[35]  Tao Huang,et al.  The effects of physical activity and exercise on brain‐derived neurotrophic factor in healthy humans: A review , 2014, Scandinavian journal of medicine & science in sports.

[36]  Anatol C. Kreitzer,et al.  Plasticity in gray and white: neuroimaging changes in brain structure during learning , 2012, Nature Neuroscience.

[37]  S. Schulte,et al.  Effects of strength and endurance training on brain-derived neurotrophic factor and insulin-like growth factor 1 in humans. , 2009, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[38]  Wendy Suzuki,et al.  Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults , 2014, Nature Neuroscience.

[39]  R. Nebes,et al.  Patterns of Hand Preference in a Student Population , 1975, Cortex.

[40]  K. Petersen,et al.  Astroglial Contribution to Brain Energy Metabolism in Humans Revealed by 13C Nuclear Magnetic Resonance Spectroscopy: Elucidation of the Dominant Pathway for Neurotransmitter Glutamate Repletion and Measurement of Astrocytic Oxidative Metabolism , 2002, The Journal of Neuroscience.

[41]  Kirk I. Erickson,et al.  Physical activity, fitness, and gray matter volume , 2014, Neurobiology of Aging.

[42]  Gabriele Ende,et al.  The hippocampus and exercise: histological correlates of MR-detected volume changes , 2014, Brain Structure and Function.

[43]  Masahiko Watanabe,et al.  Left-right asymmetry of the hippocampal synapses with differential subunit allocation of glutamate receptors , 2008, Proceedings of the National Academy of Sciences.

[44]  Ryosuke Kawakami,et al.  Asymmetrical allocation of NMDA receptor epsilon2 subunits in hippocampal circuitry. , 2003, Science.