A.V. Vinogradova, P.A. Smirnova, Z.Y. Yakovchuk, O.P. Tuchina
Immanuel Kant Baltic Federal University, Educational and scientific cluster «Institute of Medicine
and Life Sciences (MEDBIO)», High School of Life Sciences, Laboratory for Synthetic biology,
Russian Federation, 236041, ul. Universitetskaya, 2, Kaliningrad

The purpose of this review was to determine the role of physical activity as an integral component of environmental enrichment in the processes of neurogenesis in the rodent hippocampus. Material and methods. The full-text search has been carried out in the Medline (Pubmed) and Scopus databases over the past 15 years. Results. Physical activity affects neuronal precursors of the dentate gyrus of the hippocampus, probably acting through several molecular mechanisms: 1) an increase in the systemic concentration of glycolysis products (primarily lactate) promotes increased blood supply to the dentate gyrus and angiogenesis; 2) muscle-released myokines stimulate the expression of neurotrophic factors such as brain-derived neurotrophic factor BDNF; 3) a decrease in the number of adipocytes and a decrease in the concentration of leptin with regular training changes leukopoiesis, inhibiting the proliferation of potentially pro-inflammatory leukocytes; 4) stimulation of the vagus nerve contributes to the regulation of systemic inflammation and depolarization of granule cells, which probably stimulates the differentiation of neuronal progenitors. Conclusion. Physical activity, regardless of other components of the enriched environment, stimulates the proliferation and survival of neuronal precursors of the dentate gyrus of the hippocampus.
physical activity, neurogenesis, neuronal plasticity, hippocampus, dentate gyrus

Список литературы: 
  1. Rosenzweig M.R., Krech D., Bennett E.L. A search for relations between brain chemistry and behavior. Psychol. Bull. 1960; 57: 476–492. DOI: 10.1037/h0044689
  2. Krech D., Rosenzweig M.R., Bennett E.L. Relations between chemistry and problem-solving among rats raised in enriched and impoverished environments. J. Comp. Physiol. Psychol. 1962; 55: 801–807. DOI: 10.1037/h0044220
  3. Krech D., Rosenzweig M.R., Bennett E.L. Dimensions of discrimination and level of cholinesterase activity in the cerebral cortex of the rat. J. Comp. Physiol. Psychol. 1956; 49: 261–268. DOI: 10.1037/h0045136
  4. Rosenzweig M.R., Bennett E.L., Diamond M.C. Chemical and Anatomical Plasticity of Brain: Replications and Extensions, 1970. Macromolecules and Behavior. 1972. p. 205–277. DOI:10.1007/978-1-4684-6042-1_12
  5. Ferchmin P.A., Bennett E.L. Direct contact with enriched environment is required to alter cerebral weights in rats. J. Comp. Physiol. Psychol. 1975; 88: 360–367. DOI: 10.1037/h0076175
  6. Rosenzweig M.R. Modification of Brain Circuits through Experience. In: Bermúdez-Rattoni F, editor. Neural Plasticity and Memory: From Genes to Brain Imaging. Boca Raton (FL): CRC Press/Taylor & Francis; 2011.
  7. Kempermann G., Kuhn H.G., Gage F.H. Genetic influence on neurogenesis in the dentate gyrus of adult mice. Proceedings of the National Academy of Sciences. 1997. p. 10409–10414. DOI:10.1073/pnas.94.19.10409
  8. Kempermann G., Georg Kuhn H., Gage F.H. More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997. p. 493–495. DOI:10.1038/386493a0
  9. Rosenzweig M.R., Bennett E.L., Hebert M., Morimoto H. Social grouping cannot account for cerebral effects of enriched environments. Brain Res. 1978; 153: 563–576. DOI: 10.1016/0006-8993(78)90340-2
  10. van Praag H., Kempermann G., Gage F.H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 1999; 2: 266–270. DOI: 10.1038/6368
  11. Acevedo-Triana C.A., Rojas M.J., P. F.C. Running wheel training does not change neurogenesis levels or alter working memory tasks in adult rats. Peer J. 2017. p. e2976. DOI:10.7717/peerj.2976
  12. Inoue K., Okamoto M., Shibato J., Lee M.C., Matsui T., Rakwal R. et al. Long-Term Mild, rather than Intense, Exercise Enhances Adult Hippocampal Neurogenesis and Greatly Changes the Transcriptomic Profile of the Hippocampus. PLoS One. 2015; 10: e0128720. DOI: 10.1371/journal.pone.0133089
  13. Oh J-Y., Nam Y-J., Jo A., Cheon H-S., Rhee S-M., Park J-K. et al. Apolipoprotein E mRNA is transported to dendrites and may have a role in synaptic structural plasticity. J Neurochem. 2010; 114: 685–696. DOI: 10.1111/j.1471-4159.2010.06773.x
  14. Kitamura T., Sugiyama H. Running wheel exercises accelerate neuronal turnover in mouse dentate gyrus. Neurosci Res. 2006; 56: 45–52. DOI: 10.1016/j.neures.2006.05.006
  15. Kronenberg G., Bick-Sander A., Bunk E., Wolf C., Ehninger D., Kempermann G. Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiol Aging. 2006; 27: 1505–1513. DOI: 10.1016/j.neurobiolaging.2005.09.016
  16. Clark P.J., Kohman R.A., Miller D.S., Bhattacharya T.K., Haferkamp E.H., Rhodes J.S. Adult hippocampal neurogenesis and c-Fos induction during escalation of voluntary wheel running in C57BL/6J mice. Behav Brain Res. 2010; 213: 246–252. DOI: 10.1016/j.bbr.2010.05.007
  17. Lewis G.D., Farrell L., Wood M.J., Martinovic M., Arany Z., Rowe G.C. et al. Metabolic signatures of exercise in human plasma. Sci. Transl. Med.2010; 2: 33ra37. DOI: 10.1126/scitranslmed.3001006
  18. Hall C.N., Reynell C., Gesslein B., Hamilton N.B., Mishra A., Sutherland B.A. et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014; 508: 55–60. DOI: 10.1038/nature13165
  19. Bergersen L.H. Lactate transport and signaling in the brain: potential therapeutic targets and roles in body-brain interaction. J. Cereb. Blood Flow Metab. 2015; 35: 176–185. DOI: 10.1038/jcbfm.2014.206
  20. Takimoto M., Hamada T. Acute exercise increases brain region-specific expression of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins. J. App. Physiol. 2014. p. 1238–1250. DOI:10.1152/japplphysiol.01288.2013
  21. Mason S. Lactate Shuttles in Neuroenergetics–Homeostasis, Allostasis and Beyond. Frontiers in Neuroscience. 2017. DOI:10.3389/fnins.2017.00043
  22. Morland C., Andersson K.A., Haugen С.P., Hadzic A., Kleppa L., Gille A. et al. Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nat Commun. 2017; 8: 15557. DOI: 10.1038/ncomms15557
  23. Kobilo T., Liu Q-R., Gandhi K., Mughal M., Shaham Y., van Praag H. Running is the neurogenic and neurotrophic stimulus in environmental enrichment. Learn Mem. 2011; 18: 605–609. DOI:10.1101/lm.2283011
  24. Kobilo T., Yuan C., van Praag H. Endurance factors improve hippocampal neurogenesis and spatial memory in mice. Learning & Memory. 2011. p. 103–107. DOI:10.1101/lm.2001611
  25. Pedersen B.K. Physical activity and muscle–brain crosstalk. Nature Reviews Endocrinology. 2019. p. 383–392. DOI:10.1038/s41574-019-0174-x
  26. Henningsen J., Rigbolt K.T.G., Blagoev B., Pedersen B.K., Kratchmarova I. Dynamics of the skeletal muscle secretome during myoblast differentiation. Mol Cell Proteomics. 2010; 9: 2482–2496. DOI: 10.1074/mcp.M110.002113
  27. Aoi W., Takagi T., Naito Y. Unraveling the Function of Skeletal Muscle as a Secretory Organ. Nutrition and Enhanced Sports Performance. 2019. p. 385–392. DOI:10.1016/b978-0-12-813922-6.00032-1
  28. Wang Q., Yuan J., Yu Z., Lin L., Jiang Y., Cao Z. et al. FGF21 Attenuates High-Fat Diet-Induced Cognitive Impairment via Metabolic Regulation and Anti-inflammation of Obese Mice. Mol Neurobiol. 2018; 55: 4702–4717. DOI: 10.1007/s12035-017-0663-7
  29. Wrann C.D. FNDC5/irisin - their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Brain Plast. 2015; 1: 55–61. DOI: 10.3233/BPL-150019
  30. Ding Q., Vaynman S., Akhavan M., Ying Z., Gomez-Pinilla F. Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function. Neuroscience. 2006; 140: 823–833. DOI: 10.1016/j.neuroscience.2006.02.084
  31. Pedersen B.K., Pedersen M., Krabbe K.S., Bruunsgaard H., Matthews V.B., Febbraio M.A. Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals. Exp Physiol. 2009; 94: 1153–1160. DOI: 10.1113/expphysiol.2009.048561
  32. Wu C-W., Chang Y-T., Yu L., Chen H-I., Jen C.J., Wu S-Y. et al. Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice. J Appl Physiol. 2008; 105: 1585–1594. DOI: 10.1152/japplphysiol.90775.2008
  33. Chen M. J., Russo-Neustadt A. A. Exercise activates the phosphatidylinositol 3-kinase pathway. Molecular Brain Research. 2005; 135: 181–193. DOI: 10.1016/j.molbrainres.2004.12.001
  34. Hu Y-S., Long N., Pigino G., Brady S.T., Lazarov O. Molecular mechanisms of environmental enrichment: impairments in Akt/GSK3β, neurotrophin-3 and CREB signaling. PLoS One. 2013; 8: e64460. DOI: 10.1371/journal.pone.0064460
  35. Dougherty K.D., Dreyfus C.F., Black I.B. Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury. Neurobiol. Dis. 2000; 7: 574–585. DOI:10.1006/nbdi.2000.0318
  36. Rasmussen P., Brassard P., Adser H., Pedersen M.V., Leick L., Hart E. et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp. Physiol. 2009; 94: 1062–1069. DOI: 10.1113/expphysiol.2009.048512
  37. Kim S., Choi J-Y., Moon S., Park D-H., Kwak H-B., Kang J-H. Roles of myokines in exercise-induced improvement of neuropsychiatric function. Pflugers Arch. 2019; 471: 491–505. DOI: 10.1007/s00424-019-02253-8
  38. Mousavi K., Jasmin B.J. BDNF is expressed in skeletal muscle satellite cells and inhibits myogenic differentiation. J. Neurosci. 2006; 26: 5739–5749. DOI: 10.1523/JNEUROSCI.5398-05.2006
  39. Matthews V.B., Aström M-B., Chan M.H.S, Bruce C.R., Krabbe K.S., Prelovsek O. et al. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia. 2009; 52: 1409–1418. DOI: 10.1007/s00125-009-1364-1
  40. Frodermann V., Rohde D., Courties G., Severe N., Schloss M.J., Amatullah H. et al. Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells. Nat. Med. 2019; 25: 1761–1771. DOI: 10.1038/s41591-019-0633-x
  41. Bird L. Exercise lowers leptin and leukocytosis. Nature reviews. Immunology. 2020. p. 2–3. DOI: 10.1038/s41577-019-0253-1
  42. Peppler W.T., Anderson Z.G., Sutton C.D., Rector R.S., Wright D.C. Voluntary wheel running attenuates lipopolysaccharide-induced liver inflammation in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2016; 310: R934–42. DOI: 10.1152/ajpregu.00497.2015
  43. Yirmiya R., Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav. Immun. 2011; 25: 181–213. DOI: 10.1016/j.bbi.2010.10.015
  44. Monje M.L., Toda H., Palmer T.D. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003; 302: 1760–1765. DOI: 10.1126/science.1088417
  45. Tuchina O. Neuro-immune interactions in cholinergic antiinflammatory pathway. G&C. 2020; XV. DOI:10.23868/202003003
  46. 46. Tracey K.J. The inflammatory reflex. Nature. 2002. p. 853–859. DOI:10.1038/nature01321
  47. Shikano Y., Nishimura Y., Okonogi T., Ikegaya Y., Sasaki T. Vagus nerve spiking activity associated with locomotion and cortical arousal states in a freely moving rat. Eur. J. Neurosci. 2019; 49: 1298–1312. DOI: 10.1111/ejn.14275
  48. Larsen L.E., Wadman W.J., van Mierlo P., Delbeke J., Grimonprez A., Van Nieuwenhuyse B. et al. Modulation of Hippocampal Activity by Vagus Nerve Stimulation in Freely Moving Rats. Brain Stimul. 2016; 9: 124–132. DOI: 10.1016/j.brs.2015.09.009
  49. Deisseroth K., Singla S., Toda H., Monje M., Palmer T.D., Malenka R.C. Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron. 2004; 42: 535–552. DOI: 10.1016/s0896-6273(04)00266-1