The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus

Datson, Nicole A.; Speksnijder, Niels; Mayer, Joseph L.; Steenbergen, Peter J.; Korobko, Oksana B.; Goeman, Jelle J.; Kloet, E. Ronald de; Joëls, Marian; Lucassen, Paul J.

doi:10.1002/hipo.20905

Cited by 86 publications

(61 citation statements)

References 102 publications

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“…Chronic Stress Effects. In the nuclear genome, acute stress and GC treatment regulate a larger number of genes than chronic stress (24)(25)(26), and this pattern holds true for our observations of mitochondrial gene expression as well. Acute stress caused a significant main effect on mitochondrial gene expression and a significant down-regulation of 4 of 13 mitochondrial genes examined, although all but one gene showed reduced expression.…”

Section: Discussionsupporting

confidence: 66%

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

Hunter

Seligsohn

Rubin

et al. 2016

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

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133

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Glucocorticoids (GCs) are involved in stress and circadian regulation, and produce many actions via the GC receptor (GR), which is classically understood to function as a nuclear transcription factor. However, the nuclear genome is not the only genome in eukaryotic cells. The mitochondria also contain a small circular genome, the mitochondrial DNA (mtDNA), that encodes 13 polypeptides. Recent work has established that, in the brain and other systems, the GR is translocated from the cytosol to the mitochondria and that stress and corticosteroids have a direct influence on mtDNA transcription and mitochondrial physiology. To determine if stress affects mitochondrially transcribed mRNA (mtRNA) expression, we exposed adult male rats to both acute and chronic immobilization stress and examined mtRNA expression using quantitative RT-PCR. We found that acute stress had a main effect on mtRNA expression and that expression of NADH dehydrogenase 1, 3, and 6 (ND-1, ND-3, ND-6) and ATP synthase 6 (ATP-6) genes was significantly down-regulated. Chronic stress induced a significant up-regulation of ND-6 expression. Adrenalectomy abolished acute stress-induced mtRNA regulation, demonstrating GC dependence. ChIP sequencing of GR showed that corticosterone treatment induced a dose-dependent association of the GR with the control region of the mitochondrial genome. These findings demonstrate GR and stress-dependent transcriptional regulation of the mitochondrial genome in vivo and are consistent with previous work linking stress and GCs with changes in the function of brain mitochondria.nuclear receptors | allostasis | mitochondrial plasticity | brain metabolism | mitochondrial transcription

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Section: Discussionsupporting

confidence: 66%

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

Hunter

Seligsohn

Rubin

et al. 2016

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

Self Cite

133

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“…Interestingly, and according to previous studies (Datson et al, 2012), little overlap was found between the AD-regulated genes and pathways in the context of this paradigm of induced depressive-like behavior (uCMS) and those regulated in naive AD-treated animals (Gaska et al, 2012;Landgrebe et al, 2002;Sillaber et al, 2008). This further emphasizes the relevance of using animal models of depression to explore the molecular mechanisms of depressive-like phenotype reversion in the brain.…”

Section: Ad-specific Transcriptional Changessupporting

confidence: 60%

“…It was interesting to observe here that fluoxetine reduced the expression of IL6-signaling and of TNF signaling-related molecules. These pathways have been implicated in the development of depressive-like behaviors (Manosso et al, 2013) and were shown to be overrepresented in this and other brain regions in response to chronic stress (Datson et al, 2012;Sukoff Rizzo et al, 2012). In addition, fluoxetine treatment in uCMS rats activated pathways related to cellular respiration and metabolism, a finding in line with the presence of long-lived transcripts (Korostynski et al, 2013;Schwanhausser et al, 2011).…”

Section: Ad-specific Transcriptional Changesmentioning

confidence: 99%

“…Such approaches have been previously used to investigate the molecular alterations induced by ADs in the hippocampus and other brain regions of naive animals (Conti et al, 2007;Gaska et al, 2012;Korostynski et al, 2013;Landgrebe et al, 2002;Lee et al, 2010;Sillaber et al, 2008;Surget et al, 2009;Takahashi et al, 2006); interpretation of these studies is, however, limited by the fact that treatment of individuals who do not display signs of depressive-like behavior is not comparable to a pathological context (Cryan and Slattery, 2007). Previous comparable studies relied on measures of a single behavioral index measurement (Drigues et al, 2003;Nakatani et al, 2004), while others using multidimensional animal models of depression focused on a single class of AD (Andrus et al, 2012;Datson et al, 2012;Lisowski et al, 2013;Surget et al, 2009) or two monoaminergic ADs (Malki et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus

Patrício

Mateus‐Pinheiro

Irmler

et al. 2014

Neuropsychopharmacol

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Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited, and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine, and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine, and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine that activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.

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“…The latter include proteins affecting prereceptor metabolism, interacting transcription factors (7), and downstream NR coregulator proteins (1). Even if the effects of steroid hormones are well-studied in specific regions (1,8), overall, the brain steroid receptor targets and mediators remain largely unknown.…”

mentioning

confidence: 99%

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

Mahfouz

Lelieveldt

Grefhorst

et al. 2016

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

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Steroid receptors are pleiotropic transcription factors that coordinate adaptation to different physiological states. An important target organ is the brain, but even though their effects are well studied in specific regions, brain-wide steroid receptor targets and mediators remain largely unknown due to the complexity of the brain. Here, we tested the idea that novel aspects of steroid action can be identified through spatial correlation of steroid receptors with genome-wide mRNA expression across different regions in the mouse brain. First, we observed significant coexpression of six nuclear receptors (NRs) [androgen receptor (Ar), estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), glucocorticoid receptor (Gr), mineralocorticoid receptor (Mr), and progesterone receptor (Pgr)] with sets of steroid target genes that were identified in single brain regions. These coexpression relationships were also present in distinct other brain regions, suggestive of as yet unidentified coordinate regulation of brain regions by, for example, glucocorticoids and estrogens. Second, coexpression of a set of 62 known NR coregulators and the six steroid receptors in 12 nonoverlapping mouse brain regions revealed selective downstream pathways, such as Pak6 as a mediator for the effects of Ar and Gr on dopaminergic transmission. Third, Magel2 and Irs4 were identified and validated as strongly responsive targets to the estrogen diethylstilbestrol in the mouse hypothalamus. The brain-and genome-wide correlations of mRNA expression levels of six steroid receptors that we provide constitute a rich resource for further predictions and understanding of brain modulation by steroid hormones. neuroendocrinology | nuclear receptors | transcription regulation | estrogens | glucocorticoids S teroid receptors are part of the superfamily of nuclear receptors (NRs) that act as transcription factors regulating expression of numerous biologically important target genes (1). Their transcriptional activity is induced by steroid hormones, which respond to changed demands in terms of reproductive status, mineral balance, or stressful physical and psychological challenges. A crucial site of action is the brain, where these hormones have strong modulatory effects on physiological regulation, cognitive function, mood, and behavior. They do so by changing cellular responsiveness to a variety of neurotransmitters and peptides, and by inducing morphological changes (2, 3).Understanding the effects of steroid hormones on the brain faces the challenge to identify in as many as 900 different brain nuclei (4) both the highly cell-specific target genes that mediate the hormone effects (5, 6) and the signaling factors that mediate or influence steroid receptor signaling. The latter include proteins affecting prereceptor metabolism, interacting transcription factors (7), and downstream NR coregulator proteins (1). Even if the effects of steroid hormones are well-studied in specific regions (1, 8), overall, the brain steroid receptor targets and mediators ...

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The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus

Cited by 86 publications

References 102 publications

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus

Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

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