Epigenetic Mechanisms: Critical Contributors to Long-Term Memory Formation
ABSTRACT Recent advances in chromatin biology have identified a role for epigenetic mechanisms in the regulation of neuronal gene expression changes, a necessary process for proper synaptic plasticity and memory formation. Experimental evidence for dynamic chromatin remodeling influencing gene transcription in postmitotic neurons grew from initial reports describing posttranslational modifications of histones, including phosphorylation and acetylation occurring in various brain regions during memory consolidation. An accumulation of recent studies, however, has also highlighted the importance of other epigenetic modifications, such as DNA methylation and histone methylation, as playing a role in memory formation. This present review examines learning-induced gene transcription by chromatin remodeling underlying long-lasting changes in neurons, with direct implications for the study of epigenetic mechanisms in long-term memory formation and behavior. Furthermore, the study of epigenetic gene regulation, in conjunction with transcription factor activation, can provide complementary lines of evidence to further understanding transcriptional mechanisms subserving memory storage.
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ABSTRACT: Epigenetic mechanisms have recently been known to play fundamental roles in the regulation of synaptic plasticity, and learning and memory tasks in many brain regions, such as the hippocampus, the amygdala, the insular cortex. However, epigenetic mechanism in the medial prefrontal cortex (mPFC), also a crucial neural locus for the control of cognition and emotion, is not well known. The present study investigated the epigenetic regulation of two genes, reelin and brain-derived neurotrophic factor (bdnf), both play important roles in neural plasticity, in the mPFC. The data showed that the levels of total DNA methyltransferase (DNMTs), total histone acetyltransferases (HATs), global acetylated histone 3 (H3) and global acetylated histone 4 (H4) were all changed with the induction of long-term potentiation (LTP) in the mPFC, implying that DNA methylation and histone acetylation may involve in synaptic plasticity in the mPFC. The present results further demonstrated that the demethylation status of reelin and bdnf, and acetylated H3 and acetylated H4 at the reelin and the bdnf promoters in the mPFC were enhanced by the delivery of LTP-inducing high-frequency stimulation (HFS). Consistently, infusion of DNMT inhibitor, 5-azacytidine (5-azaC), or histone deacetylases (HDACs) inhibitor, sodium butyrate (NaB), into the mPFC could interfere with LTP-associated demethylation and acetylation of reelin and bdnf genes, and the induction of LTP as well. Long-term retention of trace fear memory, which is dependent on mPFC function, was also altered by administration of these inhibitors into the mPFC. These findings suggest that epigenetic regulation of DNA demethylation and histone acetylation of target genes, such as reelin and bdnf, might underlie the mechanisms of synaptic plasticity and memory retention in the mPFC.Neurobiology of Learning and Memory 03/2012; 97(4):425-40. DOI:10.1016/j.nlm.2012.03.007 · 4.04 Impact Factor
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ABSTRACT: To To investigate the changes of MicroRNA-134, CREB and p-CREB expression in epileptic rat brains in order to elucidate the molecular mechanisms of epilepsy, providing new ideas for clinical treatment. Sixty-four Spraque-Dawley (SD) rats were divided into groups randomly, including control group, six hours after seizure group, 24-hour group, three-day group, one-week group, two-week group, four-week group, and eight-week group. All groups were placed under a pilocarpine-induced epilepsy model except the control group, and all rats were decapitated in different points of time. Brain specimens were taken for quantitative PCR experiments, immunohistochemistry and Western blot experiments. The results of the epilepsy model groups and the control group were compared. There were no significant differences between the six hours after seizure group, the 24-hour group and the control group about the MicroRNA-134 levels. MicroRNA-134 in the hippocampus tissue of the three-day group significantly reduced compared with the control group; same result was observed with the one-week, two-week, four-week and eight-week groups. The CREB and p-CREB levels in the three-day group's rat hippocampus significantly increased compared with the control group; and the high levels of CREB and p-CREB were constantly maintained in the one-week, two-week, four-week and eight-week groups. The MicroRNA-134 level of the epileptic rat hippocampus is significantly lower than normal after three days, and continues to maintain a low level; while CREB and p-CREB levels are rsignificantly increased after three days, and continue to remain at a high level. MicroRNA-134 plays a role in inhibiting synaptic plasticity by inhibiting CREB and p-CREB expressions. Copyright © 2015 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.Asian Pacific Journal of Tropical Medicine 04/2015; 80(4). DOI:10.1016/S1995-7645(14)60333-3 · 0.93 Impact Factor
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ABSTRACT: Memory consolidation involves transcriptional control of genes in neurons to stabilize a newly formed memory. Following retrieval, a once consolidated memory destabilizes and again requires gene transcription changes in order to restabilize, a process referred to as reconsolidation. Understanding the molecular mechanisms of gene transcription during the consolidation and reconsolidation processes could provide crucial insights into normal memory formation and memory dysfunction associated with psychiatric disorders. In the past decade, modifications of epigenetic markers such as DNA methylation and posttranslational modifications of histone proteins have emerged as critical transcriptional regulators of gene expression during initial memory formation and after retrieval. In light of the rapidly growing literature in this exciting area of research, we here examine the most recent and latest evidence demonstrating how memory acquisition and retrieval trigger epigenetic changes during the consolidation and reconsolidation phases to impact behavior. In particular we focus on the reconsolidation process, where we discuss the already identified epigenetic regulators of gene transcription during memory reconsolidation, while exploring other potential epigenetic modifications that may also be involved, and expand on how these epigenetic modifications may be precisely and temporally controlled by important signaling cascades critical to the reconsolidation process. Finally, we explore the possibility that epigenetic mechanisms may serve to regulate a system or circuit level reconsolidation process and may be involved in retrieval-dependent memory updating. Hence, we propose that epigenetic mechanisms coordinate changes in neuronal gene transcription, not only during the initial memory consolidation phase, but are triggered by retrieval to regulate molecular and cellular processes during memory reconsolidation.Neurobiology of Learning and Memory 08/2014; 115. DOI:10.1016/j.nlm.2014.08.002 · 4.04 Impact Factor