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WIREs Cogn Sci
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Epigenetic mechanisms in learning and memory

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Abstract Recent discoveries have associated epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA (miRNA) processing, with activity‐dependent changes in gene expression necessary to drive long‐term memory formation. Here, we discuss the current interpretation of epigenetic mechanisms in the context of memory and sustained behavioral change. One of the two emerging viewpoints is that epigenetic mechanisms subserve information storage in the central nervous system (CNS), a notion supported by rodent studies of fear, recognition and spatial memories, and stress. The second viewpoint is that epigenetics serves as a mechanism for passing on acquired information across generations, a provocative notion now supported by several lines of work using developing and adult rodents. Continued research on such mechanisms promises to advance our understanding of biological pathways linking experiences to long‐term and even multigenerational trajectories in neurobiology and behavior. WIREs Cogn Sci 2013, 4:105–115. doi: 10.1002/wcs.1205 This article is categorized under: Neuroscience > Behavior

Primary epigenetic modifications and pathways. (a) DNA is wrapped around histone proteins for packaging in the nucleus. Methyl groups are added to cytosines on DNA by way of DNA methyltransferases (DNMTs), and the subsequent binding of methyl‐CpG‐binding protein 2 (MeCP2) can either recruit histone deacetylases (HDACs) or other corepressors to repress transcription or transcription factors like CREB1 to promote transcription. (b) Posttranslational modifications to histone H3 include lysine (K) acetylation and methylation (for clarity, only lysines and their modifications that we have specifically discussed in this article are depicted here). Histone acetyltransferases (HATs) facilitate gene activation by adding acetyl groups (shown as green stars), which loosen chromatin packaging to allow for transcription factors to bind. HDACs remove acetyl groups, and therefore repress transcription and silence a gene. Histone methyltransferases (HMTs) and histone demethylases (HDMs) catalyze lysine methylation (shown as red circles) and demethylation, respectively, and their effects on gene transcription or suppression depend upon which basic residue is targeted and the degree of methylation. (c) The binding of microRNAs (miRNAs) to target mRNA can induce gene silencing. The molecular cascade of events that leads to gene silencing begins with the presence of a primary miRNA (pri‐miRNA) transcript, which is cleaved in the nucleus by a microprocessor complex containing the RNase III Drosha and the RNA‐binding protein DGCR8 (DiGeorge critical region 8). The binding of DGCR8 and cleaving action of Drosha in the nucleus are critical in the initiation of miRNA biogenesis, and malfunction of either of these proteins interferes with the generation of mature miRNAs. After processing in the nucleus, the immature pre‐miRNA is transported to the cytoplasm via the Exportin‐5 (Exp5) pathway, in which the Exp5, in combination with its cofactor Ran‐GTP, binds the pre‐miRNA and induces nuclear export. In the cytoplasm, the RNase III Dicer cleaves the pre‐miRNA into a mature miRNA duplex, and deletion of Dicer decreases and even eliminates mature and functional miRNAs produced in the cytoplasm. After cleavage by Dicer, the newly mature miRNA duplex is loaded into an Argonaute (Ago) protein of the RNA‐induced silencing complex (RISC). Once loaded, the RISC binds to the target mRNA, facilitating gene silencing via mRNA degradation, destabilization, or translational inhibition.

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Transgenerational epigenetic effects of early‐life adversity. In Roth et al.,65 the transgenerational effects of early‐life caregiver maltreatment were demonstrated using two generations of rats. The first generation of offspring (F0) experienced caregiver maltreatment for the first 7 days of life, which altered adult levels of Bdnf DNA methylation (increased) and gene expression (decreased) in the prefrontal cortex (PFC). *P < 0.05 versus animals that experienced nurturing care. Females in adulthood were bred to produce the second generation of infants (F1). Infants likewise showed increased Bdnf DNA methylation, an outcome shown through cross‐fostering experiments not to be directly associated with their postnatal environment/care received with the homecage. *P < 0.05 versus infants born to females with no history of maltreatment.

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Epigenetic changes in a rodent model of post‐traumatic stress disorder (PTSD). (a) In Roth et al.,57 PTSD was modeled in rats using two unpredictable and inescapable exposures to a cat, in which the rat was enclosed in a plexiglass container while the cat circled above for 1 h. Effects of trauma were enhanced by social instability in the stressed animals, which consisted of changing the animal's cagemate daily for all 31 days of the experiment while control animals had a stable cagemate throughout the experiment. (b) Bisulfite sequencing PCR demonstrated region‐specific effects of stress on Bdnf at exon IV in the hippocampus. Increases in methylation were found in the dentate gyrus and CA1 of the dorsal hippocampus, whereas decreased methylation was found in CA3 of the ventral hippocampus.

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