DNA methylation regulates associative reward learning

Day, Jeremy J.; Childs, Daniel S; Guzman-Karlsson, Mikael C.; Kibe, Mercy; Moulden, Jerome; Song, Esther Y.; Tahir, Absar; Sweatt, J. David

doi:10.1038/nn.3504

Cited by 194 publications

(203 citation statements)

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“…During the past few decades we have learned how vital epigenetic processes are for learning and memory formation (Day et al 2013). RNA modifications form an additional language, much less characterized, which is capable of overwriting and redefining the hard-wired transcriptome, extending and diversifying the function of transcripts, thus adding an unchartered layer of regulation affecting genome function.…”

Section: Discussionmentioning

confidence: 99%

The RNA modification landscape in human disease

Jonkhout

Tran

Smith

et al. 2017

RNA

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RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps.

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Section: Discussionmentioning

confidence: 99%

The RNA modification landscape in human disease

Jonkhout

Tran

Smith

et al. 2017

RNA

468

420

View full text Add to dashboard Cite

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“…bdnf and reelin) show methylation changes after contextual fear conditioning, appetitive auditory conditioning or LTP induction in hippocampal slices (Levenson et al, 2006;Lubin et al, 2008;Miller and Sweatt, 2007;Day et al, 2013). Suggesting them to be potentially regulated by DNA methylation during memory formation.…”

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

“…reward) conditioning (Day et al, 2013). These studies investigated a range of different brain areas such as the hippocampus (Levenson et al, 2006;Miller and Sweatt, 2007;Miller et al, 2008;Lubin et al, 2008;Hutnick et al, 2009;Sultan et al, 2012;Mizuno et al, 2012;Rudenko et al, 2013;Kaas et al, 2013;Morris et al, 2014), the amygdala (Maddox and Schafe, 2011;Sultan et al, 2012;Monsey et al, 2011;Morris et al, 2014;Kumar et al, 2015) and the cortex (Hutnick et al, 2009;Miller et al, 2010;Sui et al, 2012;Rudenko et al, 2013).…”

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

“…These studies investigated a range of different brain areas such as the hippocampus (Levenson et al, 2006;Miller and Sweatt, 2007;Miller et al, 2008;Lubin et al, 2008;Hutnick et al, 2009;Sultan et al, 2012;Mizuno et al, 2012;Rudenko et al, 2013;Kaas et al, 2013;Morris et al, 2014), the amygdala (Maddox and Schafe, 2011;Sultan et al, 2012;Monsey et al, 2011;Morris et al, 2014;Kumar et al, 2015) and the cortex (Hutnick et al, 2009;Miller et al, 2010;Sui et al, 2012;Rudenko et al, 2013). In most cases long-term memory formation after aversive and appetitive conditioning was impaired if Dnmts were pharmacologically inhibited or knocked out (Levenson et al, 2006;Miller and Sweatt, 2007;Miller et al, 2008;Lubin et al, 2008;Hutnick et al, 2009;Miller et al, 2010;Feng et al, 2010;Maddox and Schafe, 2011;Monsey et al, 2011;Sui et al, 2012;Oliveira et al, 2012;Day et al, 2013;Morris et al, 2014). Morris et al (2014) highlighted the different dynamics Dnmt regulation can have during memory formation depending on the learning paradigm used.…”

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

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DNA methylation and the regulation of stimulus-specific memory formation

Biergans¹

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Memory formation is a crucial task of the brain. It allows animals to dynamically respond to a changing environment by combining information about current and previous experiences. Thus, it promotes complex behaviours such as living in social groups and elaborate foraging tactics. The ability to form memories is present across the animal kingdom in a variety of forms. The honeybee -an eusocial insect -is capable of both 'simple' associative and complex rule learning. Despite decades of research into the mechanisms of memory formation, however, much remains unknown.One little-understood aspect is the regulation of molecular mechanisms during memory formation.Understanding regulation of transcription is particularly important in this context, as transcription is a requirement for any stable memory. Epigenetic mechanisms regulate transcription by directly interacting with chromatin. Importantly, epigenetic mechanisms are conserved across species as distinct as humans and honeybees. This thesis aims to investigate one particular epigenetic mechanism -DNA methylation -and its role in honey bee memory formation by using behavioural, physiological and molecular assays.First, I studied the role of DNA methyltransferases (Dnmts), which catalyse DNA methylation, after olfactory reward learning. Bees were trained to associate an odour with a sugar reward. Dnmts were then blocked after conditioning using a pharmacological inhibitor. 24 hours later, bees were tested for memory retention and generalisation. Dnmt inhibition increased the generalisation to an odour that was not present during the training, thus impairing stimulus-specific memory. This effect was learning-dependent, as bees' response to odours or sugar water alone did not change after treatment. Furthermore, this effect was robust against alterations in the training paradigm, but the directionality depended on the number of training trials. Next, I used Ca2+ -imaging of the bees' primary olfactory centre (i.e. antennal lobe, AL) to investigate whether Dnmts affect changes in AL processing established during memory formation. The AL is involved in odour discrimination and olfactory learning; both processes are also crucial for stimulus-specific memory formation. If Dnmts were inhibited after olfactory reward learning, the AL response to a new odour changed 48 hours later. This effect potentially serves as a functional explanation for the behavioural phenotype observed after Dnmt inhibition. Furthermore, this study provides the first in vivo evidence for Dnmt-mediated regulation of neuronal networks during memory formation.As DNA methylation regulates transcription, I next investigated the effect of Dnmt inhibition on gene expression. Using qPCR I studied 30 memory-associated genes. In response to Dnmt inhibition, 9 genes were upregulated after conditioning. For some of these genes I then investigated their i methylation patterns using a bisulfite conversion based Mass spectrometry approach. Memory formation changed the methylation pattern compared to both...

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“…Together, both approaches have demonstrated that DNA methylation is necessary for memory formation and consolidation (Day et al, 2013;Feng et al, 2010;Maddox & Schafe, 2011;Miller & Sweatt, 2007) with a reduction in DNA methylation leading to enhanced glutamatergic synaptic scaling (Meadows et al, 2015) and increased neuronal excitability (Meadows et al, 2016).…”

Section: Dna Methylation and The Regulation Of Neural Activitymentioning

confidence: 99%

Prefrontal Cortical Deletion of DNA Methyltransferases Dnmt1 and Dnmt3a Reduces Palatable Food Intake

Joy-Gaba¹

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DNA methylation is an epigenetic mechanism most often associated with the repression of gene expression; mediated by the DNA methyltransferases (DNMT). Expression of both DNMT1 and DNMT3a isoforms within post-mitotic neurons of the central nervous system (CNS) has been shown to be important in modulating the response to drugs of abuse and other stimuli that produce changes in neuronal plasticity. Interestingly, DNMT1 and DNMT3a expression has been shown to be dynamically regulated in the medial prefrontal cortex (mPFC), suggesting that these enzymes may also be involved in the modulation of mPFC dependent behavior. Indeed, obesity induces hypermethylation of the µ-opioid receptor, suggesting that the modulation of methylation may represent an important mechanism engaged to produce changes in PFC function and thus behaviors. Based on these suggestions, we hypothesized that the DNMT enzymes in the PFC act to coordinate palatable food consumption. In a test of this hypothesis, we generated PFC-specific deletions of both the methyltransferases expressed in the CNS, DNMT1 and DNMT3a, and characterized their requirement in feeding behaviors. We demonstrate that animals lacking PFC-specific DNMT1 and DNMT3a showed a significant reduction in palatable food consumption, and that the intake of high-fat food showed less dependence on mPFC methylation state compared to a high fat and high carbohydrate food. Furthermore, the effect on behavior was selective on food intake, with no modulation on other PFC-dependent behaviors.Furthermore, we demonstrate a method to isolate discrete population of neurons ii from tissue suitable for downstream molecular assays. Our data suggest for the first time that DNA methylation is required for appropriate regulation of palatable food intake.

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DNA methylation regulates associative reward learning

Cited by 194 publications

References 53 publications

The RNA modification landscape in human disease

The RNA modification landscape in human disease

DNA methylation and the regulation of stimulus-specific memory formation

Prefrontal Cortical Deletion of DNA Methyltransferases Dnmt1 and Dnmt3a Reduces Palatable Food Intake

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