Distinct epigenetic and gene expression changes in rat hippocampal neurons after Morris water maze training

Carter, Sylvia D.; Mifsud, Karen R.; Reul, Johannes M. H. M.

doi:10.3389/fnbeh.2015.00156

Cited by 34 publications

(38 citation statements)

References 51 publications

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“…Hippocampal chromatin preparation (Fig. S7), ChIP, and RNA extraction were performed using published methods (33). Analysis by qPCR was conducted using primer and probe sets listed in Dataset S1 (34).…”

Section: Methodsmentioning

confidence: 99%

Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus

Mifsud

Reul

2016

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

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153

167

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A stressful event results in secretion of glucocorticoid hormones, which bind to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the hippocampus to regulate cognitive and affective responses to the challenge. MRs are already highly occupied by low glucocorticoid levels under baseline conditions, whereas GRs only become substantially occupied by stress- or circadian-driven glucocorticoid levels. Currently, however, the binding of MRs and GRs to glucocorticoid-responsive elements (GREs) within hippocampal glucocorticoid target genes under such physiological conditions in vivo is unknown. We found that forced swim (FS) stress evoked increased hippocampal RNA expression levels of the glucocorticoid-responsive genes FK506-binding protein 5 (Fkbp5), Period 1 (Per1), and serum- and glucocorticoid-inducible kinase 1 (Sgk1). Chromatin immunoprecipitation (ChIP) analysis showed that this stressor caused substantial gene-dependent increases in GR binding and surprisingly, also MR binding to GREs within these genes. Different acute challenges, including novelty, restraint, and FS stress, produced distinct glucocorticoid responses but resulted in largely similar MR and GR binding to GREs. Sequential and tandem ChIP analyses showed that, after FS stress, MRs and GRs bind concomitantly to the same GRE sites within Fkbp5 and Per1 but not Sgk1. Thus, after stress, MRs and GRs seem to bind to GREs as homo- and/or heterodimers in a gene-dependent manner. MR binding to GREs at baseline seems to be restricted, whereas after stress, GR binding may facilitate cobinding of MR. This study reveals that the interaction of MRs and GRs with GREs within the genome constitutes an additional level of complexity in hippocampal glucocorticoid action beyond expectancies based on ligand–receptor interactions.

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Section: Methodsmentioning

confidence: 99%

Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus

Mifsud

Reul

2016

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

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153

167

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“…A complementary level of analysis involves studies of epigenetic mechanisms associated with chromatin remodeling, especially in the hippocampus (Carter et al, 2015;Mifsud et al, 2011). The hippocampus has traditionally been a brain area of intense focus because it contains high levels of glucocorticoid receptors, making it susceptible to stressors, and it contains many of the enzymes responsible for chromatin remodeling (McEwen, 2007;Trotter & Archer, 2007).…”

Section: Neural Adaptations To Stress: Role Of Transcriptional Changesmentioning

confidence: 99%

Learning about stress: neural, endocrine and behavioral adaptations

McCarty

2016

Stress

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In this review, nonassociative learning is advanced as an organizing principle to draw together findings from both sympathetic-adrenal medullary and hypothalamic-pituitary-adrenocortical (HPA) axis responses to chronic intermittent exposure to a variety of stressors. Studies of habituation, facilitation and sensitization of stress effector systems are reviewed and linked to an animal's prior experience with a given stressor, the intensity of the stressor and the appraisal by the animal of its ability to mobilize physiological systems to adapt to the stressor. Brain pathways that regulate physiological and behavioral responses to stress are discussed, especially in light of their regulation of nonassociative processes in chronic intermittent stress. These findings may have special relevance to various psychiatric diseases, including depression and post-traumatic stress disorder (PTSD).

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“…ChIP and RNA extraction were performed using published methods (7,38,39). For a complete description, see SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

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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103

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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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Distinct epigenetic and gene expression changes in rat hippocampal neurons after Morris water maze training

Cited by 34 publications

References 51 publications

Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus

Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus

Learning about stress: neural, endocrine and behavioral adaptations

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

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