Acute or chronic stress induce cell compartment-specific phosphorylation of glucocorticoid receptor and alter its transcriptional activity in Wistar rat brain

Adžić, Miroslav; Djordjević, Jelena; Djordjević, Ana; Nićiforović, Ana; Demonacos, Constantinos; Radojčić, Marija B.; Krstic‐Demonacos, Marija

doi:10.1677/joe-08-0509

Cited by 108 publications

(78 citation statements)

References 48 publications

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“…Finally, other future experiments directed toward identifying genes occupied by distinct GR phosphoisoforms (e.g., pSer211-GR) in NPSCs could identify specific GC-regulated gene networks that are influenced by cross talk with cytoplasmic signaling pathways. In fact, alterations in GR phosphorylation in specific adult rat brain regions are generated in response to specific stresses and may impact select genes that modulate behavioral responses to stressful states (50).…”

Section: Discussionmentioning

confidence: 99%

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Peffer

Chandran

Luthra

et al. 2014

Molecular and Cellular Biology

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While glucocorticoids (GCs) are used clinically to treat many conditions, their neonatal and prenatal usage is increasingly controversial due to reports of delayed adverse outcomes, especially their effects on brain development. Such alterations may reflect the impact of GCs on neural progenitor/stem cell (NPSC) function. We previously demonstrated that the lipid raft protein caveolin-1 (Cav-1) was required for rapid GC signaling in embryonic mouse NPSCs operating through plasma membranebound glucocorticoid receptors (GRs). We show here that genomic GR signaling in NPSCs requires Cav-1. Loss of Cav-1 impacts the transcriptional response of many GR target genes (e.g., the serum-and glucocorticoid-regulated kinase 1 gene) that are likely to mediate the antiproliferative effects of GCs. Microarray analysis of wild-type C57 or Cav-1-deficient NPSCs identified approximately 100 genes that are differentially regulated by GC treatment. These changes in hormone responsiveness in Cav-1 knockout NPSCs are associated with the loss of GC-regulated phosphorylation of GR at serine 211 but not at serine 226. Chromatin recruitment of total GR to regulatory regions of target genes such as Fkbp-5, RhoJ, and Sgk-1, as well as p211-GR recruitment to Sgk-1, are compromised in Cav-1 knockout NPSCs. Cav-1 is therefore a multifunctional regulator of GR in NPSCs influencing both rapid and genomic action of the receptor to impact cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Peffer

Chandran

Luthra

et al. 2014

Molecular and Cellular Biology

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“…Although adrenal hypertrophy may be interpreted as a consequence of chronic stress conditions [38], in our experiments it was more likely to illustrate compromised HPA axis activity under isolation stress, since it was not accompanied by a respective increase in the serum CORT. Moreover, this adrenal state could be manipulated by a subsequent acute stress which caused a significant reduction of its size and a marked CORT release from the gland [8]. …”

Section: Discussionmentioning

confidence: 99%

“…Our results indicated that alterations of the glucocorticoid receptor pathway, particularly in its phosphorylation, as well as those that regulate redox balance and initiate/prevent apoptotic processes in the limbic system [8,9,10], closely resembled the alterations described in some clinical studies of depression [11,12]. Therefore, in the current study, our primary aim was to characterize animal behavior that was triggered by chronic social isolation, particularly those aspects that are similar to symptoms of depressive disorders such as anxiety, despair and helplessness symptoms.…”

Section: Introductionmentioning

confidence: 99%

Effects of Chronic Social Isolation on Wistar Rat Behavior and Brain Plasticity Markers

Djordjević¹,

Djordjević²,

Adžić³

et al. 2012

Neuropsychobiology

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Chronic stress is a contributing risk factor in the development of psychiatric illnesses, including depressive disorders. The mechanisms of their psychopathology are multifaceted and include, besides others, alterations in the brain plasticity. Previously, we investigated the effects of chronic social stress in the limbic brain structures of Wistar rats (hippocampus, HIPPO, and prefrontal cortex, PFC) and found multiple characteristics that resembled alterations described in some clinical studies of depression. We extended our investigations and followed the behavior of stressed animals by the open field test (OFT) and forced swimming test (FST), and the expression and polysialylation of synaptic plasticity markers, neural cell adhesion molecule (NCAM) and L1, in the HIPPO and PFC. We also determined the adrenal gland mass and plasma corticosterone (CORT) as a terminal part of the hypothalamic-pituitary-adrenal axis activity. Our data indicated that stressed animals avoided the central zone in the OFT and displayed decreased swimming, but prolonged immobility in the FST. The animals exhibited marked hypertrophy of the adrenal gland cortex, in spite of decreased serum CORT. Simultaneously, the stressed animals exhibited an increase in NCAM mRNA expression in the HIPPO, but not in the PFC. The synaptosomal NCAM of the HIPPO was markedly polysialylated, while cortical PSA-NCAM was significantly decreased. The results showed that chronic social isolation of Wistar rats causes both anxiety-like and depression-like behavior. These alterations are parallel with molecular changes in the limbic brain, including diminished NCAM sialylation in the PFC. Together with our previous results, the current observations suggest that a chronic social isolation model may potentially be used to study molecular mechanisms that underlie depressive symptomatology.

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“…Chronic stress and impaired GR feedback have been proposed to lead to the dysregulation of HPA axis activity. The feedback response in the extrinsic HPA structures such as the amygdala, hippocampus, and prefrontal cortex is regulated by the GR, which, in the absence of hormone, resides in the cytoplasmic compartment (Adzic et al, 2009). Upon ligand binding, GR translocates to the nucleus, and regulates neuronal target gene expression (Beato and Sanchez-Pacheco, 1996), including downregulation of the GR itself.…”

Section: Introductionmentioning

confidence: 99%

Mifepristone in the Central Nucleus of the Amygdala Reduces Yohimbine Stress-Induced Reinstatement of Ethanol-Seeking

Simms

Haass‐Koffler

Bito-Onon

et al. 2011

Neuropsychopharmacol

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Chronic ethanol exposure leads to dysregulation of the hypothalamic-pituitary-adrenal axis, leading to changes in glucocorticoid release and function that have been proposed to maintain pathological alcohol consumption and increase vulnerability to relapse during abstinence. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, plays a role in ethanol self-administration and reinstatement. Male, Long-Evans rats were trained to self-administer either ethanol or sucrose in daily 30 min operant self-administration sessions using a fixed ratio 3 schedule of reinforcement. Following establishment of stable baseline responding, we examined the effects of mifepristone on maintained responding and yohimbine-induced increases in responding for ethanol and sucrose. Lever responding was extinguished in separate groups of rats and animals were tested for yohimbine-induced reinstatement and corticosterone release. We also investigated the effects of local mifepristone infusions into the central amygdala (CeA) on yohimbine-induced reinstatement of ethanol-and sucrose-seeking. In addition, we infused mifepristone into the basolateral amygdala (BLA) in ethanol-seeking animals as an anatomical control. We show that both systemic and intra-CeA (but not BLA) mifepristone administration suppressed yohimbine-induced reinstatement of ethanol-seeking, while only systemic injections attenuated sucroseseeking. In contrast, baseline consumption, yohimbine-induced increases in responding, and circulating CORT levels were unaffected. The data indicate that the CeA plays an important role in the effects of mifepristone on yohimbine-induced reinstatement of ethanolseeking. Mifepristone may be a valuable pharmacotherapeutic strategy for preventing relapse to alcohol use disorders and, as it is FDA approved, may be a candidate for clinical trials in the near future.

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Acute or chronic stress induce cell compartment-specific phosphorylation of glucocorticoid receptor and alter its transcriptional activity in Wistar rat brain

Cited by 108 publications

References 48 publications

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Effects of Chronic Social Isolation on Wistar Rat Behavior and Brain Plasticity Markers

Mifepristone in the Central Nucleus of the Amygdala Reduces Yohimbine Stress-Induced Reinstatement of Ethanol-Seeking

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