Differential olfactory bulb methylation and hydroxymethylation are linked to odor location memory bias in injured mice

Chronic pain is often linked to comorbidities such as anxiety and cognitive dysfunction, alterations that are reflected in brain plasticity in regions such as the prefrontal cortex and the limbic area. Despite the growing interest in pain-related cognitive deficits, little is known about the relationship between the emotional valence of the stimulus and the salience of its memory following painful injuries. We used the tibia fracture model of chronic pain in mice to determine whether pleasant and unpleasant odor location memories differ in their salience seven weeks following the onset of the painful injury. Our results indicate that injured mice show a bias toward recalling unpleasant memories, thereby propagating the vicious cycle of chronic pain and negative affect. Next, we linked these behavioral differences to mechanisms of molecular plasticity by measuring the levels of global methylation and hydroxymethylation in the olfactory bulb. Compared to controls, global methylation levels were shown to be increased, while hydroxymethylation levels were decreased in the olfactory bulb of injured mice, indicative of overall changes in DNA regulation machinery and the subsequent alterations in sensory systems.