A Novel Role for the Histone Demethylase JMJD3 in Mediating Heroin-Induced Relapse-Like Behaviors.

BACKGROUND: Epigenetic changes that lead to long-term neuroadaptations following opioid exposure are not well understood. We examined how histone demethylase JMJD3 in the nucleus accumbens (NAc) influences heroin seeking after abstinence from self-administration. METHODS: Male Sprague Dawley rats were trained to self-administer heroin. Western blotting and quantitative polymerase chain reaction were performed to quantify JMJD3 and bone morphogenetic protein (BMP) pathway expression in the NAc (n = 7-11/group). Pharmacological inhibitors or viral expression vectors were microinfused into the NAc to manipulate JMJD3 or the BMP pathway member SMAD1 (n = 9-11/group). The RiboTag capture method (n = 3-5/group) and viral vectors (n = 7-8/group) were used in male transgenic rats to identify the contributions of D1- and D2-expressing medium spiny neurons in the NAc. Drug seeking was tested by cue-induced response previously paired with drug infusion. RESULTS: Levels of JMJD3 and phosphorylated SMAD1/5 in the NAc were increased after 14 days of abstinence from heroin self-administration. Pharmacological and virus-mediated inhibition of JMJD3 or the BMP pathway attenuated cue-induced seeking. Pharmacological inhibition of BMP signaling reduced JMJD3 expression and H3K27me3 levels. JMJD3 bidirectionally affected seeking: expression of the wild-type increased cue-induced seeking whereas expression of a catalytic dead mutant decreased it. JMJD3 expression was increased in D2+ but not D1+ medium spiny neurons. Expression of the mutant JMJD3 in D2+ neurons was sufficient to decrease cue-induced heroin seeking. CONCLUSIONS: JMJD3 mediates persistent cellular and behavioral adaptations that underlie heroin relapse, and this activity is regulated by the BMP pathway.

Distinctiveness, not dual coding, explains the picture-superiority effect.

The picture-superiority effect is the finding that memory for pictures exceeds memory for words on many tasks. According to dual-coding theory, the pictures' mnemonic advantage stems from their greater likelihood to be labelled relative to words being imaged. In contrast, distinctiveness accounts hold that the greater variability of pictures compared to words leads to their mnemonic advantage. Ensor, Surprenant, et al. tested these accounts in old/new and forced-choice recognition by increasing the physical distinctiveness of words and decreasing the physical distinctiveness of pictures. Half of the words were presented in standard black font, and half were presented in varying font styles, font sizes, font colours, and capitalisation patterns. Half of the pictures were presented in black and white and half in colour. Consistent with the physical-distinctiveness account but contrary to the dual-coding account, the picture-superiority effect was eliminated when comparing the black-and-white pictures to distinctive words. In the present study, we extend Ensor, Surprenant, et al.'s results to associative recognition and free recall. Results were consistent with physical distinctiveness. We argue that dual-coding theory is no longer a viable explanation of the picture-superiority effect.