Reward-related memories are essential for adaptive behavior and evolutionary fitness, but they are also a core component of maladaptive brain diseases such as addiction. Reward learning requires dopamine neurons located in the ventral tegmental area (VTA), which encode relationships between predictive cues and future rewards. Recent evidence suggests that epigenetic mechanisms, including DNA methylation, are essential regulators of neuronal plasticity and experience-driven behavioral change. However, the role of epigenetic mechanisms in reward learning is poorly understood. Here we show that the formation of reward-related associative memories in rats upregulates key plasticity genes in the VTA, which are correlated with memory strength and associated with gene-specific changes in DNA methylation. Moreover, DNA methylation in the VTA is required for the formation of stimulus-reward associations. These results provide the first evidence that that activity-dependent methylation and demethylation of DNA is an essential substrate for the behavioral and neuronal plasticity driven by reward-related experiences.
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We would like to thank all members of the Sweatt laboratory, particularly G. Kaas and I. Zovkic, for comments and suggestions during the completion of these studies. We would also like to thank the Intellectual and Developmental Disabilities Research Core at the University of Alabama at Birmingham for assistance with cell culture experiments. This work is supported by the US National Institute on Drug Abuse (DA029419 to J.J.D.), the US National Institutes of Mental Health (MH091122 and MH057014 to J.D.S.) and the Evelyn F. McKnight Brain Research Foundation.
The authors declare no competing financial interests.
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Day, J., Childs, D., Guzman-Karlsson, M. et al. DNA methylation regulates associative reward learning. Nat Neurosci 16, 1445–1452 (2013) doi:10.1038/nn.3504
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