The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory

Lin, Qing; Wei, Wei; Coelho, Carlos M.; Li, Xiang; Baker-Andresen, Dannay; Dudley, Kevin J.; Ratnu, Vikram S.; Boskovic, Zoran; Kobor, Michæl S.; Sun, Yi; Bredy, Timothy W.

doi:10.1038/nn.2891

Cited by 181 publications

(146 citation statements)

References 16 publications

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“…These findings indicate that Tet3 is selectively activated within the adult neocortex in an experience-dependent manner. We next generated Tet1 or Tet3 knockdown lentiviral plasmids, using previously published protocols (25), and functionally validated them in N2A neuroblastoma cells (SI Appendix, Fig. S1 A and B).…”

Section: Significancementioning

confidence: 99%

“…We, and others, have recently identified epigenetic regulatory mechanisms in the ILPFC, including histone modifications and small noncoding RNAs that are selectively involved in the extinction of conditioned fear (20)(21)(22)(23)(24)(25)(26). Recent evidence indicates that Tet1 promotes active DNA demethylation in the adult hippocampus (8) and that the accumulation of 5-hmC and associated effects on gene expression are involved in adult neurogenesis, spatial learning, and the extinction of contextual fear (27)(28)(29).…”

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confidence: 99%

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Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation

Wei

Zhao

et al. 2014

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

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166

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5-hydroxymethylcytosine (5-hmC) is a novel DNA modification that is highly enriched in the adult brain and dynamically regulated by neural activity. 5-hmC accumulates across the lifespan; however, the functional relevance of this change in 5-hmC and whether it is necessary for behavioral adaptation have not been fully elucidated. Moreover, although the ten-eleven translocation (Tet) family of enzymes is known to be essential for converting methylated DNA to 5-hmC, the role of individual Tet proteins in the adult cortex remains unclear. Using 5-hmC capture together with high-throughput DNA sequencing on individual mice, we show that fear extinction, an important form of reversal learning, leads to a dramatic genome-wide redistribution of 5-hmC within the infralimbic prefrontal cortex. Moreover, extinction learning-induced Tet3-mediated accumulation of 5-hmC is associated with the establishment of epigenetic states that promote gene expression and rapid behavioral adaptation.E pigenetic mechanisms are critically involved in the regulation of gene expression underlying learning and memory (1). Dynamic variation in the accumulation of a particular epigenetic mark, 5-methycytosine (5-mC), has emerged as a key factor in experience-dependent plasticity and the formation of fearrelated memory (2). However, 5-mC is not the only covalent modification of DNA in eukaryotes, as methylated cytosine guanine (CpG) dinucleotides can be successively oxidized and converted to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine by the Tet family of DNA dioxygenases (3, 4). Although little is known about the functional relevance of 5-fC and 5-carboxylcytosine (5, 6), an understanding of 5-hmC is starting to emerge. 5-hmC is highly enriched in the adult brain (7), dynamically regulated by neural activity (8), and accumulates across the lifespan (9). This epigenetic mark is critically involved in neuronal differentiation and in the reprogramming of pluripotent stem cells (10), and rather than being an intermediate state of active DNA demethylation, 5-hmC can be either dynamic or stable (8, 10). Unlike its repressive cousin, 5-mC, which is primarily found along CpG-rich gene promoters, 5-hmC is enriched within gene bodies and at intronexon boundaries of synaptic plasticity-related genes, as well as within distal cis-regulatory elements, which together point to an important role for 5-hmC in coordinating transcriptional activity (11-13). Thus, it is evident that the relationship between this particular covalent modification of DNA and gene expression is far more complex than currently realized.The inhibition of learned fear is an evolutionarily conserved behavioral adaptation that is essential for survival. This learning process, known as extinction, involves rapid reversal of previously learned contingencies, which depend on gene expression and protein synthesis. Impairments in the neural mechanisms that promote this beneficial response to threat can lead to the development of posttraumatic stress disorder ...

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Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation

Wei

Zhao

et al. 2014

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

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166

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“…Cortactin and Rac1, regulators of actin dynamics, were identified as the critical miR-182 targets involved in the regulation of structural plasticity in the amygdala required for long-term auditory memory formation [70]. On the other hand, fear-extinction memory in the infralimbic prefrontal cortex was blocked by inhibition of miR-128b [71].…”

Section: (I) Mir-132mentioning

confidence: 99%

MicroRNAs and synaptic plasticity—a mutual relationship

Aksoy‐Aksel

Zampa

Schratt

2014

Phil. Trans. R. Soc. B

105

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MicroRNAs (miRNAs) are rapidly emerging as central regulators of gene expression in the postnatal mammalian brain. Initial studies mostly focused on the function of specific miRNAs during the development of neuronal connectivity in culture, using classical gain-and loss-of-function approaches. More recently, first examples have documented important roles of miRNAs in plastic processes in intact neural circuits in the rodent brain related to higher cognitive abilities and neuropsychiatric disease. At the same time, evidence is accumulating that miRNA function itself is subjected to sophisticated control mechanisms engaged by the activity of neural circuits. In this review, we attempt to pay tribute to this mutual relationship between miRNAs and synaptic plasticity. In particular, in the first part, we summarize how neuronal activity influences each step in the lifetime of miRNAs, including the regulation of transcription, maturation, gene regulatory function and turnover in mammals. In the second part, we discuss recent examples of miRNA function in synaptic plasticity in rodent models and their implications for higher cognitive function and neurological disorders, with a special emphasis on epilepsy as a disorder of abnormal nerve cell activity.

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“…These molecules function by repressing gene expression at the posttranscriptional level through binding, usually at the 3 0 -untranslated region (3 0 UTR) of a target mRNA, thereby providing a dynamic brake on protein synthesis 4 . Recent studies suggest that combinations of miRNAs have been preconfigured through evolution to regulate groups of molecules that function in the same process, such as cell remodelling or synaptic development processes that underpin learning and memory [5][6][7][8] . This is supported by the number of overrepresented miRNA-target sites found in the 3 0 UTRs of mRNAs that make up functional pathways of the nervous system 9 .…”

mentioning

confidence: 99%

“…Although miRNA regulation of neuronal plasticity is thought to be a conserved mechanism among higher eukaryotes, there are few vertebrate and even fewer invertebrate studies that have attempted to characterize the specific roles of miRNAs in learning and memory 7,8,10 . The use of tractable insect models such as the honeybee that offers a sophisticated behavioural repertoire, a complete genome sequence, emerging RNA interference technologies and demonstrated adult brain plasticity provides an excellent opportunity to study molecular mechanisms underlying learning and memory 11 .…”

mentioning

confidence: 99%

Neuroligin-associated microRNA-932 targets actin and regulates memory in the honeybee

et al. 2014

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Increasing evidence suggests small non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) control levels of mRNA expression during experience-related remodelling of the brain. Here we use an associative olfactory learning paradigm in the honeybee Apis mellifera to examine gene expression changes in the brain during memory formation. Brain transcriptome analysis reveals a general downregulation of protein-coding genes, including asparagine synthetase and actin, and upregulation of ncRNAs. miRNA-mRNA network predictions together with PCR validation suggest miRNAs including miR-210 and miR-932 target the downregulated protein-coding genes. Feeding cholesterol-conjugated antisense RNA to bees results in the inhibition of miR-210 and of miR-932. Loss of miR-932 impairs long-term memory formation, but not memory acquisition. Functional analyses show that miR-932 interacts with Act5C, providing evidence for direct regulation of actin expression by an miRNA. An activity-dependent increase in miR-932 expression may therefore control actin-related plasticity mechanisms and affect memory formation in the brain.

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The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory

Cited by 181 publications

References 16 publications

Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation

Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation

MicroRNAs and synaptic plasticity—a mutual relationship

Neuroligin-associated microRNA-932 targets actin and regulates memory in the honeybee

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