Exercise Improves Cognitive Responses to Psychological Stress through Enhancement of Epigenetic Mechanisms and Gene Expression in the Dentate Gyrus

Background We have shown previously that exercise benefits stress resistance and stress coping capabilities. Furthermore, we reported recently that epigenetic changes related to gene transcription are involved in memory formation of stressful events. In view of the enhanced coping capabilities in exercised subjects we investigated epigenetic, gene expression and behavioral changes in 4-weeks voluntarily exercised rats. Methodology/Principal Findings Exercised and control rats coped differently when exposed to a novel environment. Whereas the control rats explored the new cage for the complete 30-min period, exercised animals only did so during the first 15 min after which they returned to sleeping or resting behavior. Both groups of animals showed similar behavioral responses in the initial forced swim session. When re-tested 24 h later however the exercised rats showed significantly more immobility behavior and less struggling and swimming. If rats were killed at 2 h after novelty or the initial swim test, i.e. at the peak of histone H3 phospho-acetylation and c-Fos induction, then the exercised rats showed a significantly higher number of dentate granule neurons expressing the histone modifications and immediate-early gene induction. Conclusions/Significance Thus, irrespective of the behavioral response in the novel cage or initial forced swim session, the impact of the event at the dentate gyrus level was greater in exercised rats than in control animals. Furthermore, in view of our concept that the neuronal response in the dentate gyrus after forced swimming is involved in memory formation of the stressful event, the observations in exercised rats of enhanced neuronal responses as well as higher immobility responses in the re-test are consistent with the reportedly improved cognitive performance in these animals. Thus, improved stress coping in exercised subjects seems to involve enhanced cognitive capabilities possibly resulting from distinct epigenetic mechanisms in dentate gyrus neurons

Epigenetic mechanisms underlying stress-related learning and memory

An organism exposed to a stressful situation will undergo a complex array of physiological and behavioural changes aimed at the preservation of the organism during the stressful event as well as at stimulating adaptive and mnemonic processes in case the event would reoccur in the future. It is well-known that the hippocampus is highly involved in these processes. It has become clear in recent years that the processing of environmental stimuli in the hippocampus could be via changes in epigenetic state that lead to changes in neural function.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Effect of forced swimming on the number of P(Ser10)-Ac(Lys14)⁺ (Left panels A, B, and C) and c-Fos⁺ neurons (right panels D, E and F) in the dentate gyrus of control, sedentary and 4-weeks exercised rats.

<p>A and D show data on total number of immuno-positive neurons in the dentate gyrus whereas in B and E and in C and F data are depicted separately for the dorsal blade and the ventral blade, respectively. Data are expressed as the number of immuno-positive neurons (mean±SEM, n = 6) in the dentate gyrus of a 10-µm section. For additional information, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004330#s2" target="_blank">Materials and Methods</a>. Statistical analyses: Two-way ANOVA: A, Effect of exercise: F(1,24) = 3.495, P = 0.077, Effect of forced swimming: F(1,24) = 32.292, P<0.0005, Interaction exercise x forced swimming: F(1,24) = 4.135, P = 0.056; B, Effect of exercise: F(1,24) = 21.144, P<0.0005, Interaction exercise x forced swimming: F(1,24) = 3.257, P = 0.087; D, Effect of exercise: F(1,24) = 5.598, P = 0.026, Effect of forced swimming: F(1,24) = 59.533, P<0.0005, Interaction exercise x forced swimming: F(1,24) = 4.993, P = 0.035; E, Effect of forced swimming: F(1,24) = 38.318, P<0.0005. *, P<0.05, compared to the respective Baseline group; ⁺, P<0.05, compared to the respective Control group, post-hoc Bonferroni test.</p

Behavior of control and exercised rats during exposure to a novel environment, i.e. a new cage in a brightly lit (500 lx) room.

<p>Changes in walking (A), rearing (B), stationary (C) and lying behavior (D) were scored every 10 sec throughout the 30-min novelty exposure. Data were binned in 5-min time bins and expressed as behavioral counts (mean±SEM, n = 6). Statistical analyses: Two-way ANOVA with repeated measures: A, Effect of time: F(5,45) = 5.387, P = 0.001, Effect of exercise: (F1,9) = 4.739, P = 0.057, Interaction time x exercise: F(5,45) = 1.331, not significant; B, Effect of time: F(5,45) = 15.545, P<0.0005, Effect of exercise: F(1,9) = 14.263, P = 0.004, Interaction time x exercise: F(5,45) = 1.305, not significant; C, Effect of time: F(5,45) = 0.153, not significant, Effect of exercise: F(1,9) = 1.878, not significant, Interaction time x exercise: F(5,45) = 7.881, P<0.0005; D, Effect of time: F(5,45) = 11.529, P<0.0005, Effect of exercise: F(1,9) = 11.332, P = 0.008, Interaction time x exercise: F(5,45) = 9.130, P<0.0005. *, P<0.05, Student's t-test.</p

Effect of novelty exposure on the number of P(Ser10)-Ac(Lys14)⁺ (Left panels A, B, and C) and c-Fos⁺ neurons (right panels D, E and F) in the dentate gyrus of control, sedentary and 4-weeks exercised rats.

<p>A and D show data on total number of immuno-positive neurons in the dentate gyrus whereas in B and E and in C and F data are depicted separately for the dorsal blade and the ventral blade, respectively. Rats were allowed to voluntarily exercise by giving them access to a running wheel in their home cage. Data are expressed as the number of immuno-positive neurons (mean±SEM, n = 6) in the dentate gyrus of a 10-µm section. For additional information, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004330#s2" target="_blank">Materials and Methods</a>. Statistical analyses: Two-way ANOVA: A, Effect of exercise: F(1,20) = 12.823, P = 0.002, Effect of novelty: F(1,20) = 93.616, P<0.0005, Interaction exercise x novelty: F(1,20) = 4.808, P = 0.043; B, Effect of Novelty: F(1,20) = 163.33, P<0.0005; C, Effect of exercise: F(1,20) = 13.346, P = 0.002; D, Effect of exercise: F(1,20) = 7.392, P = 0.013, Effect of novelty: F(1,20) = 15.921, P = 0.001, Interaction exercise x novelty: F(1,20) = 7.203, P = 0.014; E, Effect of novelty: F(1,20) = 33.302, P<0.0005; F, Effect of exercise: F(1,20) = 11.827, P = 0.003, interaction exercise x novelty: F(1,20) = 16.875, P = 0.001. *, P<0.05, compared to the respective Baseline group; ⁺, P<0.05, compared to the respective Control group, post-hoc Bonferroni test.</p

Behavior of control and exercised rats in the forced swim test.

<p>Rats were subjected to an initial test of 15 min in 25°C-water followed by a 5-min re-test 24 h later. Immobility, struggling and swimming behavior during the test (left panels) and re-test (right panels) was scored every 10 sec. Data are expressed as the accumulated behavioral scores (mean±SEM, n = 6). *, P<0.05, Student's t-test.</p

Effect of forced swimming on c-Fos expression in the nucleus accumbens of control and exercised rats.

<p>A and B show representative images of anti-c-Fos immuno-staining in an area of the nucleus accumbens dorso-lateral to the anterior commissure (AC). This area comprises parts of both the core and shell regions. Black arrows indicate positive nuclear immuno-staining. C shows the number of c-Fos⁺ neurons in this area of control and exercised rats under baseline conditions and at 2 h after forced swimming. Statistical analysis: Two-way ANOVA: Effect of forced swimming: F(1,16) = 38.157, P<0.0005. *, P<0.05, compared to the respective Baseline group, post-hoc Bonferroni test.</p