Circadian and Ultradian Rhythms of Free Glucocorticoid Hormone Are Highly Synchronized between the Blood, the Subcutaneous Tissue, and the Brain

Total glucocorticoid hormone levels in plasma of various species, including humans, follow a circadian rhythm that is made up from an underlying series of hormone pulses. In blood most of the glucocorticoid is bound to corticosteroid-binding globulin and albumin, resulting in low levels of free hormone. Although only the free fraction is biologically active, surprisingly little is known about the rhythms of free glucocorticoid hormones. We used single-probe microdialysis to measure directly the free corticosterone levels in the blood of freely behaving rats. Free corticosterone in the blood shows a distinct circadian and ultradian rhythm with a pulse frequency of approximately one pulse per hour together with an increase in hormone levels and pulse height toward the active phase of the light/dark cycle. Similar rhythms were also evident in the subcutaneous tissue, demonstrating that free corticosterone rhythms are transferred from the blood into peripheral target tissues. Furthermore, in a dual-probe microdialysis study, we demonstrated that the circadian and ultradian rhythms of free corticosterone in the blood and the subcutaneous tissue were highly synchronized. Moreover, free corticosterone rhythms were also synchronous between the blood and the hippocampus. These data demonstrate for the first time an ultradian rhythm of free corticosterone in the blood that translates into synchronized rhythms of free glucocorticoid hormone in peripheral and central tissues. The maintenance of ultradian rhythms across tissue barriers in both the periphery and the brain has important implications for research into aberrant biological rhythms in disease and for the development of improved protocols for glucocorticoid therapy

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

Exercise improves cognitive responses to psychological stress through enhancement of epigenetic mechanisms and gene expression in the dentate gyrus. PLoS ONE 4(1): e4330

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 th

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 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