Genetic Deletion of<i>gadd45b</i>, a Regulator of Active DNA Demethylation, Enhances Long-Term Memory and Synaptic Plasticity

Sultan, Faraz; Wang, J.; Tront, Jennifer S.; Liebermann, Dan A.; Sweatt, J. David

doi:10.1523/jneurosci.1747-12.2012

Cited by 117 publications

(149 citation statements)

References 25 publications

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“…Dnmts and Gadd45b are upregulated after learning in several studies (Sultan et al, 2012;Oliveira et al, 2012;Monsey et al, 2011;Morris et al, 2014), whereas Tet is downregulated (Kaas et al, 2013). Interestingly, young mice have higher levels of Dnmt1 and Dnmt3a compared to aged mice and Dnmt3a expression increases after training in young mice only.…”

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 98%

“…A Gadd45b KO, however, improves memory retention after mild and moderate but not robust training in several different training paradigms (Sultan et al, 2012). This indicates that different proteins involved in demethylation may serve distinct functions during memory formation.…”

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

“…Vertebrates Extensive research in mammals uncovered many aspects of DNA methylation mediated regulation of memory formation (for review see: (Zovkic et al, 2013)): Most research focussed on aversive conditioning in mice and rats (Miller and Sweatt, 2007;Lubin et al, 2008;Miller 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;Mizuno et al, 2012;Sultan et al, 2012;Oliveira et al, 2012;Rudenko et al, 2013;Kaas et al, 2013;Morris et al, 2014), but one study also addressed the role of DNA methylation in appetitive (i.e. reward) conditioning (Day et al, 2013).…”

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). 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).…”

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

“…Evidence presented in this thesis supports the idea that DNA demethylation is involved in the regulation of honey bee memory formation. Several studies in mammals already established a role of Tet and Gadd45b in aversive memory formation (Sultan et al, 2012;Rudenko et al, 2013;Kaas et al, 2013;Kumar et al, 2015). I investigated only Tet expression and 5-hydroxymethylcytosine after olfactory reward conditioning in this thesis and it remains unclear which aspects of memory formation are affected by Tet-mediated demethytlation.…”

Section: Limitations and Future Researchmentioning

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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Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 98%

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

Section: Dna Methylation and Demethylation In Behavioural Plasticitymentioning

confidence: 99%

Section: Limitations and Future Researchmentioning

confidence: 99%

See 3 more Smart Citations

DNA methylation and the regulation of stimulus-specific memory formation

Biergans¹

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The Epigenetics of Neural Learning

Bronfman¹,

Ginsburg²,

Jablonka³

2016

The Wiley Handbook on the Cognitive Neuroscience of Learning

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Epigenetic Mechanisms in the Development of Behavior

Hill

Roth

2016

Developmental Psychopathology

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Within the past decade we have experienced a paradigm shift in our understanding of gene–environment interactions and pathways through which experiences can become part of our biology. Advances in molecular biology have provided new insights into epigenetic factors (e.g., DNA methylation, histone acetylation) that are remarkably sensitive to environmental input and capable of registering and perpetuating altered gene activity states without affecting the underlying sequence of DNA. Groundbreaking studies have revealed that environmental adversity, social stress, and traumatic experiences can become encoded within epigenetic factors that control gene activity. As will be highlighted here, the birth of epigenetics research has provided an exciting new level of analysis for understanding tenets central to the discipline of developmental psychopathology, and a candidate biological pathway linking gene–environment interactions to long‐term and even multigenerational trajectories in the development of behavior.

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Genetic Deletion ofgadd45b, a Regulator of Active DNA Demethylation, Enhances Long-Term Memory and Synaptic Plasticity

Cited by 117 publications

References 25 publications

DNA methylation and the regulation of stimulus-specific memory formation

DNA methylation and the regulation of stimulus-specific memory formation

The Epigenetics of Neural Learning

Epigenetic Mechanisms in the Development of Behavior

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