Environmental enrichment modulates glucocorticoid receptor expression and reduces anxiety in Indian field male mouse Mus booduga through up-regulation of microRNA-124a
“…Furthermore, we also found a strong negative correlation between miR-124a expression and GR mRNA levels in the dentate gyrus at FS30, the time point at which stress-induced miR-124a levels are beginning to rise and the decline in GR levels has just reached statistical significance. This observation supports the findings from studies of stress-related miR-124a expression in the amygdala [24] and corpus callosum [26] confirming that up-regulation of miR-124a is associated with the suppression of GR mRNA expression in vivo. Given the FSS-induced correlation between miR-124a and the decrease in GR mRNA, we investigated if an RU486-induced increase in miR-124a expression could explain the enhanced suppression of GR mRNA observed in the presence of the antagonist.…”
Section: Discussionsupporting
confidence: 90%
“…Previously, miR-124a has been shown to be associated with GR down-regulation in cultured cells [23]. Furthermore, environmental enrichment of the Indian field mouse resulted in increased miR-124a expression which was associated with reduced GR mRNA and protein expression in the amygdala [24]. We therefore investigated the effect of forced swimming on miR-124a expression in the dentate gyrus to elucidate a putative role of this microRNA in the observed stress-induced decline in GR mRNA in this hippocampal region.…”
Section: Resultsmentioning
confidence: 99%
“…Forced swimming evoked a significant time-dependent increase in miR-124a, a microRNA known to interact with the 3′ UTR region of the Nr3c1 gene to regulate GR expression [23,24]. Furthermore, we also found a strong negative correlation between miR-124a expression and GR mRNA levels in the dentate gyrus at FS30, the time point at which stress-induced miR-124a levels are beginning to rise and the decline in GR levels has just reached statistical significance.…”
Section: Discussionmentioning
confidence: 99%
“…In addition to DNA methylation changes, GR mRNA can be the target for active degradation by microRNAs including miR-18 and miR-124a [13,23,24]. miR-124a is the predominant microRNA expressed in the brain, accounting for 25-48% of all brain microRNAs [25], and expression has been confirmed in the rat hippocampus during adolescence [23] and adulthood [13].…”
Background: Although glucocorticoid receptors (GRs) in the hippocampus play a vital role in the regulation of physiological and behavioural responses to stress, the regulation of receptor expression remains unclear. This work investigates the molecular mechanisms underpinning stress-induced changes in hippocampal GR mRNA levels in vivo. Methods: Male Wistar rats were killed either under baseline conditions or after forced swim stress (FSS; 15 min in 25°C water). Rat hippocampi were micro-dissected (for mRNA, microRNA, and DNA methylation analysis) or frozen whole (for chromatin immunoprecipitation). In an additional experiment, rats were pre-treated with RU486 (a GR antagonist) or vehicle. Results: FSS evoked a dentate gyrus-specific reduction in GR mRNA levels. This was related to an increased DNMT3a protein association with a discreet region of the Nr3c1 (GR gene) promoter, shown here to undergo increased DNA methylation after FSS. FSS also caused a time-dependent increase in the expression of miR-124a, a microRNA known to reduce GR mRNA expression, which was inversely correlated with a reduction in GR mRNA levels 30 min after FSS. FSS did not affect GR binding to a putative negative glucocorticoid response element within the Nr3c1 gene. Conclusions: Acute stress results in decreased GR mRNA expression specifically in the dentate gyrus. Our results indicate that a complex interplay of multiple molecular mechanisms - including increased DNA methylation of discrete CpG residues within the Nr3c1 gene, most likely facilitated by DNMT3a, and increased expression of miR-124a - could be responsible for these changes.
“…Furthermore, we also found a strong negative correlation between miR-124a expression and GR mRNA levels in the dentate gyrus at FS30, the time point at which stress-induced miR-124a levels are beginning to rise and the decline in GR levels has just reached statistical significance. This observation supports the findings from studies of stress-related miR-124a expression in the amygdala [24] and corpus callosum [26] confirming that up-regulation of miR-124a is associated with the suppression of GR mRNA expression in vivo. Given the FSS-induced correlation between miR-124a and the decrease in GR mRNA, we investigated if an RU486-induced increase in miR-124a expression could explain the enhanced suppression of GR mRNA observed in the presence of the antagonist.…”
Section: Discussionsupporting
confidence: 90%
“…Previously, miR-124a has been shown to be associated with GR down-regulation in cultured cells [23]. Furthermore, environmental enrichment of the Indian field mouse resulted in increased miR-124a expression which was associated with reduced GR mRNA and protein expression in the amygdala [24]. We therefore investigated the effect of forced swimming on miR-124a expression in the dentate gyrus to elucidate a putative role of this microRNA in the observed stress-induced decline in GR mRNA in this hippocampal region.…”
Section: Resultsmentioning
confidence: 99%
“…Forced swimming evoked a significant time-dependent increase in miR-124a, a microRNA known to interact with the 3′ UTR region of the Nr3c1 gene to regulate GR expression [23,24]. Furthermore, we also found a strong negative correlation between miR-124a expression and GR mRNA levels in the dentate gyrus at FS30, the time point at which stress-induced miR-124a levels are beginning to rise and the decline in GR levels has just reached statistical significance.…”
Section: Discussionmentioning
confidence: 99%
“…In addition to DNA methylation changes, GR mRNA can be the target for active degradation by microRNAs including miR-18 and miR-124a [13,23,24]. miR-124a is the predominant microRNA expressed in the brain, accounting for 25-48% of all brain microRNAs [25], and expression has been confirmed in the rat hippocampus during adolescence [23] and adulthood [13].…”
Background: Although glucocorticoid receptors (GRs) in the hippocampus play a vital role in the regulation of physiological and behavioural responses to stress, the regulation of receptor expression remains unclear. This work investigates the molecular mechanisms underpinning stress-induced changes in hippocampal GR mRNA levels in vivo. Methods: Male Wistar rats were killed either under baseline conditions or after forced swim stress (FSS; 15 min in 25°C water). Rat hippocampi were micro-dissected (for mRNA, microRNA, and DNA methylation analysis) or frozen whole (for chromatin immunoprecipitation). In an additional experiment, rats were pre-treated with RU486 (a GR antagonist) or vehicle. Results: FSS evoked a dentate gyrus-specific reduction in GR mRNA levels. This was related to an increased DNMT3a protein association with a discreet region of the Nr3c1 (GR gene) promoter, shown here to undergo increased DNA methylation after FSS. FSS also caused a time-dependent increase in the expression of miR-124a, a microRNA known to reduce GR mRNA expression, which was inversely correlated with a reduction in GR mRNA levels 30 min after FSS. FSS did not affect GR binding to a putative negative glucocorticoid response element within the Nr3c1 gene. Conclusions: Acute stress results in decreased GR mRNA expression specifically in the dentate gyrus. Our results indicate that a complex interplay of multiple molecular mechanisms - including increased DNA methylation of discrete CpG residues within the Nr3c1 gene, most likely facilitated by DNMT3a, and increased expression of miR-124a - could be responsible for these changes.
“…For example, MiR-183 expression could be upregulated by EE and reduce anxiety-like behavior in mice [174]. MiR-124a showed a similar performance following enriched environment condition [175]. MiR-325 was downregulated in 3 × Tg AD mice but upregulated by EE, which may open new avenues for the studies of treating AD [176].…”
Section: What Are the Mechanisms For The Effect Of Cognitive Activity?mentioning
BackgroundCognitive decline poses a great concern to elderly people and their families. In addition to pharmacological therapies, several varieties of nonpharmacological intervention have been developed. Most training trials proved that a well-organized task is clinically effective in cognition improvement.Main bodyWe will first review clinical trials of cognitive training for healthy elders, MCI and AD patients, respectively. Besides, potential neuroprotective and compensatory mechanisms in animal models of AD are discussed. Despite controversy, cognitive training has promising effect on cognitive ability. In animal model of AD, environmental enrichment showed beneficial effect for cognitive ability, as well as neuronal plasticity. Neurotrophin, neurotransmitter and neuromodulator signaling pathway were also involved in the process. Well-designed cognitive activity could benefit cognitive function, and thus life quality of patients and their families.ConclusionThe positive effects of cognitive activity is closely related with neural plasticity, neurotrophin, neurotransmitter and neuromodulator signaling pathway changes.
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