MeCP2 Expression in a Rat Model of Risky Decision Making.

Many neuropsychiatric disorders are associated with abnormal decision making involving risk of punishment, but the underlying molecular basis remains poorly understood. Methyl CpG-binding protein 2 (MeCP2) is an epigenetic factor that regulates transcription by directly binding to methylated DNA. Here, we evaluated MeCP2 expression in the context of risk-taking behaviors using the Risky Decision-making Task (RDT), in which rats make discrete choices between a small "safe" food reward and a large "risky" food reward accompanied by varying probabilities of punishment. In Experiment 1, expression of MeCP2 as assessed by immunoblotting in the medial prefrontal cortex (mPFC), but not the striatum, was inversely correlated with the degree of preference for the large, risky reward (risk taking) seven days after the last RDT test. In Experiment 2, MeCP2 expression 90 min after RDT testing, assessed using immunohistochemistry, was suppressed in both the dorsal mPFC (dmPFC) and nucleus accumbens compared to home cage controls, indicating that MeCP2 expression is modulated by RDT performance. Additional experiments revealed that RDT performance increased expression of MeCP2 phosphorylated at Ser421 (associated with neuronal activity and activation of gene expression) in dmPFC principal neurons. Finally, as in Experiment 1, lower expression of MeCP2 in the ventral mPFC was associated with greater risk taking under baseline conditions. Together, these findings indicate a complex regulatory role of MeCP2 in risky decision making, and suggest that epigenetic factors may be an important component of the molecular mechanisms underlying such decision-making processes.