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

Collins, Andrew M.; Hill, Louise E.; Chandramohan, Yalini; Whitcomb, Daniel J.; Droste, Susanne K.; Reul, Johannes M. H. M.

doi:10.1371/journal.pone.0004330

Cited by 132 publications

(84 citation statements)

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“…S2 A and B). The ventral blade neurons were not affected by the stressor (as shown previously) (5,19,20) or SAM treatment. The effect of SAM was unique to the DG because stress-induced c-Fos and Egr-1 expression in the CA1 and CA3 regions of the hippocampus was unaffected by the injected methyl donor (Fig.…”

Section: Sam Impairs Consolidation Of Fs-induced Behavioral Responsessupporting

confidence: 79%

Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Saunderson

Spiers

Mifsud

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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105

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Stressful events evoke long-term changes in behavioral responses; however, the underlying mechanisms in the brain are not well understood. Previous work has shown that epigenetic changes and immediate-early gene (IEG) induction in stress-activated dentate gyrus (DG) granule neurons play a crucial role in these behavioral responses. Here, we show that an acute stressful challenge [i.e., forced swimming (FS)] results in DNA demethylation at specific CpG (5′-cytosine-phosphateguanine-3′) sites close to the c-Fos (FBJ murine osteosarcoma viral oncogene homolog) transcriptional start site and within the gene promoter region of Egr-1 (early growth response protein 1) specifically in the DG. Administration of the (endogenous) methyl donor S-adenosyl methionine (SAM) did not affect CpG methylation and IEG gene expression at baseline. However, administration of SAM before the FS challenge resulted in an enhanced CpG methylation at the IEG loci and suppression of IEG induction specifically in the DG and an impaired behavioral immobility response 24 h later. The stressor also specifically increased the expression of the de novo DNA methyltransferase Dnmt3a [DNA (cytosine-5-)-methyltransferase 3 alpha] in this hippocampus region. Moreover, stress resulted in an increased association of Dnmt3a enzyme with the affected CpG loci within the IEG genes. No effects of SAM were observed on stress-evoked histone modifications, including H3S10p-K14ac (histone H3, phosphorylated serine 10 and acetylated lysine-14), H3K4me3 (histone H3, trimethylated lysine-4), H3K9me3 (histone H3, trimethylated lysine-9), and H3K27me3 (histone H3, trimethylated lysine-27). We conclude that the DNA methylation status of IEGs plays a crucial role in FS-induced IEG induction in DG granule neurons and associated behavioral responses. In addition, the concentration of available methyl donor, possibly in conjunction with Dnmt3a, is critical for the responsiveness of dentate neurons to environmental stimuli in terms of gene expression and behavior.stress | behavior | DNA methylation | immediate-early gene | hippocampus A daptation to stressful challenges is crucial for maintaining health and well-being. These events induce physiological and behavioral responses that enable the individual to cope with the challenge. In the brain, molecular mechanisms are initiated that facilitate learning of adaptive behavioral responses and the consolidation of memories of the event. Inappropriate responses to stress have been linked with psychiatric disorders, such as major depression and anxiety (1-3).Glucocorticoid hormones, secreted in response to a stressful challenge, in conjunction with activated intracellular signaling pathways in neurons of the hippocampus, play a key role in consolidating behavioral responses to stress (4, 5). The hippocampal extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) pathway, activated through N-methyl D-aspartate receptors (NMDA-Rs) and other membrane receptors, is involved in behavioral responses seen in Mo...

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Section: Sam Impairs Consolidation Of Fs-induced Behavioral Responsessupporting

confidence: 79%

Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Saunderson

Spiers

Mifsud

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

105

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“…Any abrogation in H3S10p-K14ac and c-Fos formation in these neurons due to NMDA receptor or GR antagonism, MEK (MAPK kinase) inhibition (i.e., prevention of ERK activation), or double genetic deletion of MSK1/2 resulted in an impairment of memory formation. 19,20,35 Moreover, recently we demonstrated that exercising rats show enhanced H3S10p-K14ac and c-Fos responses in their dentate gyrus to forced swimming (and novelty) as well as a better memory performance of the event than their sedentary counterparts 49 which may be due to enhanced GR function in these animals. 50,51 Preliminary data provided evidence for a role of H3S10p-K14ac and c-Fos induction in dentate neurons in Morris water maze learning ERK MAPK pathway.…”

Section: Significance Of H3s10p-k14ac-driven Gene Expression In Dentamentioning

confidence: 89%

Epigenetic mechanisms in the dentate gyrus act as a molecular switch in hippocampus-associated memory formation

Reul¹,

Hesketh²,

Collins³

et al. 2009

Epigenetics

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We make strong memories of significant events in our lives which may serve to increase our resilience and adaptation capacity to deal with future challenges. It is well established that the neurotransmitter glutamate and the ERK MAPK intracellular signaling pathway play a principal role in memory formation. In addition, stressassociated hormones like glucocorticoids released during such events are known to strengthen formation of memories. But, how do these hormones work? Do they interact with the ERK MAPK pathway or otherwise? What are the more distal, epigenomic effects? We discovered in rats and mice that confrontation with a psychological challenge (e.g., forced swimming, Morris water maze) would lead, through NMDA-ERK signaling, to MSK1 and Elk-1 activation in dentate gyrus neurons (a part of the hippocampus involved in encoding of memories) resulting in histone H3 S10-phosphorylation and K14-acetylation, H4 hyper-acetylation, gene induction and formation of memories of the event. Moreover, glucocorticoid hormones via the glucocorticoid receptor (GR) greatly facilitated the epigenomic mechanisms and cognitive performance. Therefore, we propose that formation of enduring memories of significant events requires an interaction of GRs with the NMDA/ ERK/MSK1/Elk-1 signaling pathways to allow an optimal epigenomic activation pattern in dentate gyrus neurons to accommodate their altered neurophysiological function.

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“…Previous studies have shown changes in covalent histone modification in a variety of models, including seizures (35), psychostimulant treatment (36), exercise (37), and depression (13,38). Epigenetic mechanisms are now thought to be potential contributors both to normal cognitive processes and to a variety of neuropsychiatric diseases (7,9,39).…”

Section: Discussionmentioning

confidence: 99%

Regulation of hippocampal H3 histone methylation by acute and chronic stress

Hunter

McCarthy²,

Milne³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

263

190

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The hippocampal formation is a brain region noted for its plasticity in response to stressful events and adrenal steroid hormones. Recent work has shown that chromatin remodeling in various brain regions, including the hippocampus, is associated with the effects of stress in a variety of models. We chose to examine the effects of stress, stress duration, corticosterone administration, and fluoxetine treatment on the levels of hippocampal histone H3 methylation at lysines 4, 9, and 27, marks associated, respectively, with active transcription, heterochromatin formation, and transcriptional repression. We found that acute stress increased the levels of H3K9 tri-methylation (H3K9me3) in the dentate gyrus (DG) and CA1, while it reduced levels of H3K9 mono-methylation (H3K9me1) and H3K27 tri-methylation (H3K27me3) in the same regions, and had no effect on levels of H3K4 tri-methylation (H3K4me3). Seven days of restraint stress reduced levels of H3K4me3 in the CA1 and H3K27me3 in the DG and CA1, while increasing basal levels of H3K9me3. Chronic restraint stress (CRS) for 21 days mildly increased levels of H3K4me3 and reduced H3K9me3 levels in the DG. Treatment with fluoxetine during CRS reversed the decrease in DG H3K9me3, but had no effect on the other marks. These results show a complex, surprisingly rapid, and regionally specific pattern of chromatin remodeling within hippocampus produced by stress and anti-depressant treatment that may open an avenue of understanding the interplay of stress and hippocampal gene expression, and reveal the outlines of a potential chromatin stress response that may be diminished or degraded by chronic stress.brain ͉ chromatin ͉ corticosteroids ͉ fluoxetine

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

Cited by 132 publications

References 50 publications

Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

Epigenetic mechanisms in the dentate gyrus act as a molecular switch in hippocampus-associated memory formation

Regulation of hippocampal H3 histone methylation by acute and chronic stress

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