The role of active DNA demethylation and Tet enzyme function in memory formation and cocaine action

Abstract

Active DNA modification is a major epigenetic mechanism that regulates gene expression in an experience-dependent manner, which is thought to establish stable changes in neuronal function and behavior. Recent discoveries regarding the Ten eleven translocation (Tet1-3) family of DNA hydroxylases have provided a new avenue for the study of active DNA demethylation, and may thus help to advance our understanding of how dynamic DNA modifications lead to long-lasting changes in brain regions underlying learning and memory, as well as drug-seeking and propensity for relapse following abstinence. Drug addiction is a complex, relapsing disorder in which compulsive drug-seeking behavior can persist despite aversive consequences. Therefore, understanding the molecular mechanisms that underlie the onset and persistence of drug addiction, as well as the pronounced propensity for relapse observed in addicts, is necessary for the development of selective treatments and therapies. In this mini-review, we provide an overview of the involvement of active DNA demethylation with an emphasis on the Tet family of enzymes and 5-hydroxymethylcytosine (5-hmC) in learning and memory, as well as in drug-seeking behavior. Memory and addiction share overlapping molecular, cellular, and circuit functions allowing research in one area to inform the other. Current discrepancies and directions for future studies focusing on the dynamic interplay between DNA methylation and demethylation, and how they orchestrate gene expression required for neuronal plasticity underlying memory formation, are discussed.

Inhibition of DNA methyltransferases regulates cocaine self‐administration by rats: a genome‐wide DNA methylation study

“…So far, studies investigating the role of DNA methylation in the mode of action of drugs of abuse were focused on the ventral tegmental area and the nucleus accumbens (NAc) (Alaghband et al 2016). injection to rats of the non-selective DNMT inhibitors, dAZA and zebularine, was sufficient to dose dependently increase the reinforcing properties of cocaine measured in a self-administration paradigm.…”

Active coping of prenatally stressed rats in the forced swimming test: involvement of theNurr1gene

“…Accordingly, epigenetic mechanisms induced by prenatal stress might explain the acute stress resilience of the PS groups (even the group with decreased hippocampal Nurr1 induced by the antisense ODN) and the associated gene expression. In this regard, it has been shown that increase in the epigenetic marker 5-hydroxymethylcytocine (5hmc) facilitates the expression of immediate early genes such as Arc, c-fos, Bdnf and Nurr1 in memory formation (Alaghband et al, 2016;Kaas et al, 2013). Epigenetic changes of Nurr1 specifically induced by prenatal stress have not been elucidated.…”

Reconsolidation and extinction: Using epigenetic signatures to challenge conventional wisdom

“…During the last decade, epigenetic mechanisms have been the focus of studies examining long-term adaptations such as memory formation as they have the potential to make persistent changes at the cellular level that may ultimately lead to long-term behavioral changes (Sweatt, 2009; Fischer, 2014; Jarome and Lubin, 2014; Oliveira, 2016). The main epigenetic mechanisms that directly affect chromatin structure examined in the learning and memory field to date are histone modification (Barrett and Wood, 2008), DNA modification (Baker-Andresen et al, 2013b; Alaghband et al, 2015; Oliveira, 2016) and nucleosome remodeling (Vogel-Ciernia and Wood, 2014; López and Wood, 2015). However, the latter only recently gained attention in the fields of cognitive neuroepigenetics, learning and memory, and addiction.…”

“…In contrast, the growth arrest and DNA damage-inducible protein 45b (Gadd45b) and ten-eleven-translocation (TET) proteins are DNA demethylation enzymes that have been shown to be critical for memory formation (Ma et al, 2009; Leach et al, 2012; Sultan et al, 2012; Kaas et al, 2013; Alaghband et al, 2015). Interestingly, 5-hydroxymethylcytosine (5-hmC) has recently been shown to not only be a DNA demethylation intermediate, but also to be a stable epigenetic mark itself (Branco et al, 2012; Hahn et al, 2013).…”

“…Studies manipulating enzymes of the TET family have provided insight into the necessity of epigenetic factors in the regulation of fear memory extinction (reviewed in Alaghband et al, 2015). Tet1 KO mice were shown to have impairments in fear extinction (Rudenko et al, 2013).…”