Aging, Environment, & DiseaseDNA Methylation and HydroxymethylationHistone Modifications

Aerobic Exercise Increases Function of the Hippocampus, HAT and HDAC Activity

Aerobic exercise increases HAT and HDAC activityStaying physically active is an effective method of delaying age-related cognitive decline [1]. Aerobic exercise increases expression of brain derived neurotrophic factor (BDNF) in the hippocampus, maintaining cognitive function [2], [3]. This exercise induced BDNF expression is accompanied by increased acetylation of histone 3 [4]. It is unknown what molecular pathway induces exercise-related BDNF expression [5], [6] or whether changes in histone 3 acetylation are due to activity of histone acetyl transferase (HAT) or histone deacetylase (HDAC) [7].

Maejima et al used senescence accelerated mouse (SAM) model to research the role of aging and exercise on expression of neutrophins and their receptors, HAT and HDAC activity, and hippocampal performance. 13-month old SAMP1 mice served as the aged model, while SAMR1 mice were the control group. Both sets of mice were exercised on a treadmill 5 days per week for 4 weeks. Aerobic exercise increased mRNA and protein levels of the neutrophin BDNF independent of age, and mRNA of the neutrophin NT-4 only in SAMP1 mice. Gene expression of the neurotrophin receptor, TrkB, was lower in sedentary aged mice, while exercise decreased p75 neutrophin receptor gene expression independent of genotype. The expression ratio of p75 to TrkB mRNA showed a more significant decrease in the aged group than control mice. However, this decrease in p75 to TrkB ratio was not confirmed in protein levels. Aerobic exercise had epigenetic effects in SAMP1 and SAMR1 mice, increasing activity of HAT and HDAC, possibly leading to the changes in gene expression and protein levels of neurotrophins and their receptors [8]. A novel-object recognition test was used to evaluate recognition memory, a measure of hippocampal function. Exercise increased the ratio of time spent exploring the novel object to total time exploring either object in both SAMR1 and SAMP1 mice.

The above study looked into the effects of long-term exercise on function of the hippocampus and the mechanisms behind these changes. Long-term exercise can increase the activity of both HAT and HDAC activity, which is thought to induce expression of BDNF and NT-4, increasing hippocampal performance. Although the protein levels did not correspond with the decrease in transcription of p75 relative to TrkB seen with long-term exercise, this may still lead to a protection against apoptosis and neuronal death in the hippocampus if exercise is continued for longer time periods [9].

Original Article

  1. H. Maejima, N. Kanemura, T. Kokubun, K. Murata, and K. Takayanagi, “Exercise enhances cognitive function and neurotrophin expression in the hippocampus accompanied by changes in epigenetic programming in senescence-accelerated mice.,” Neurosci. Lett., vol. 665, pp. 67–73, Feb. 2018.


  1. J. E. Ahlskog, Y. E. Geda, N. R. Graff-Radford, and R. C. Petersen, “Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging.,” Mayo Clin. Proc., vol. 86, no. 9, pp. 876–884, Sep. 2011.
  2. S. A. Neeper, F. Gómez-Pinilla, J. Choi, and C. W. Cotman, “Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain.,” Brain Res., vol. 726, no. 1–2, pp. 49–56, Jul. 1996.
  3. R. M. O’Callaghan, R. Ohle, and A. M. Kelly, “The effects of forced exercise on hippocampal plasticity in the rat: A comparison of LTP, spatial- and non-spatial learning.,” Behav. brain Res., vol. 176, no. 2, pp. 362–366, Jan. 2007.
  4. A. Ieraci, A. Mallei, L. Musazzi, and M. Popoli, “Physical exercise and acute restraint stress differentially modulate hippocampal brain-derived neurotrophic factor transcripts and epigenetic mechanisms in mice.,” Hippocampus, vol. 25, no. 11, pp. 1380–1392, Nov. 2015.
  5. L. F. Reichardt, “Neurotrophin-regulated signalling pathways.,” Philos. Trans. R. Soc. London. Ser. B, Biol. Sci., vol. 361, no. 1473, pp. 1545–1564, Sep. 2006.
  6. V. K. Sandhya et al., “A network map of BDNF/TRKB and BDNF/p75NTR signaling system.,” J. cell Commun. Signal., vol. 7, no. 4, pp. 301–307, Dec. 2013.
  7. V. R. Elsner et al., “Effect of different exercise protocols on histone acetyltransferases and histone deacetylases activities in rat hippocampus.,” Neuroscience, vol. 192, pp. 580–587, Sep. 2011.
  8. J. L. Abel and E. F. Rissman, “Running-induced epigenetic and gene expression changes in the adolescent brain.,” Int. J. Dev. Neurosci. : Off. J. Int. Soc. Dev. Neurosci., vol. 31, no. 6, pp. 382–390, Oct. 2013.
  9. K. Takahashi, H. Maejima, G. Ikuta, H. Mani, and T. Asaka, “Exercise combined with low-level GABAreceptor inhibition up-regulates the expression of neurotrophins in the motor cortex.,” Neurosci. Lett., vol. 636, pp. 101–107, Jan. 2017.
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Aaron Barnett

Aaron Barnett