Relapse to drug abuse is often caused by exposure to drug-associated cues that evoke craving. Therefore, disruption of the cue-drug memory can prevent relapse. Memories destabilize and become temporarily labile upon their retrieval, and re-stabilize in a process termed reconsolidation. Pharmacological disruption of reconsolidation prevents relapse in animal models, yet may evoke side effects. Therefore, behavioral procedures capable of preventing cue-induced craving and relapse are extremely valuable. Aversion therapies, in which drugpaired cues are re-associated (counterconditioned) with aversive consequences, have limited success, because the previous cue-drug memory may recover, triggering relapse. Here, we prevented the memory recovery and relapse to cocaine seeking by applying aversive counterconditioning during memory reconsolidation. Mice were trained to seek cocaine in a conditioned place preference procedure. The cocaine-associated compartment was then counterconditioned with lithium chloride (LiCl)-induced malaise, preceded by a brief exposure to the compartment (memory retrieval). Relapse was assessed in a reinstatement test. We found that aversive counterconditioning conducted shortly after memory retrieval (during reconsolidation) induced a long-lasting prevention of relapse to cocaine seeking. However, mice relapsed when counterconditioned without, before, or long after memory retrieval, or when receiving LiCl without place counterconditioning. Our findings suggest that post-retrieval aversive counterconditioning leads to relapse prevention, possibly by replacing the cue-drug with a cue-aversion memory, thereby the cue ceases to evoke craving. Moreover, we found that a similar memory replacement procedure prevented relapse of conditioned place aversion. Hence, this novel procedure can also prevent relapse of aversive memories, providing a safe approach to alter various maladaptive behaviors.

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Sexual dimorphisms are responsible for profound metabolic differences in health and behavior. Whether males and females react differently to environmental cues, such as solar ultraviolet (UV) exposure, is unknown. Here we show that solar exposure induces food-seeking behavior, food intake, and food-seeking behavior and food intake in men, but not in women, through epidemiological evidence of approximately 3,000 individuals throughout the year. In mice, UVB exposure leads to increased food-seeking behavior, food intake and weight gain, with a sexual dimorphism towards males. In both mice and human males, increased appetite is correlated with elevated levels of circulating ghrelin. Specifically, UVB irradiation leads to p53 transcriptional activation of ghrelin in skin adipocytes, while a conditional p53-knockout in mice abolishes UVB-induced ghrelin expression and food-seeking behavior. In females, estrogen interferes with the p53–chromatin interaction on the ghrelin promoter, thus blocking ghrelin and food-seeking behavior in response to UVB exposure. These results identify the skin as a major mediator of energy homeostasis and may lead to therapeutic opportunities for sex-based treatments of endocrine-related diseases.

Relapse, a critical issue in alcohol addiction, can be attenuated by disruption of alcohol-associated memories. Memories are thought to temporarily destabilize upon retrieval during the reconsolidation process. Here, we provide evidence for unique transcriptional dynamics underpinning alcohol memory reconsolidation. Using a mouse place-conditioning procedure, we show that alcohol-memory retrieval increases the mRNA expression of immediate-early genes in the dorsal hippocampus and medial prefrontal cortex, and that alcohol seeking is abolished by post-retrieval non-specific inhibition of gene transcription, or by downregulating ARC expression using antisense-oligodeoxynucleotides. However, since retrieval of memories for a natural reward (sucrose) also increased the same immediate-early gene expression, we explored for alcohol-specific transcriptional changes using RNA-sequencing. We revealed a unique transcriptional fingerprint activated by alcohol memories, as the expression of this set of plasticity-related genes was not altered by sucrose-memory retrieval. Our results suggest that alcohol memories may activate two parallel transcription programs: one is involved in memory reconsolidation in general, and another is specifically activated during alcohol-memory processing.