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Relapse is a major challenge in treating drug addiction, and drug seeking progressively increases after abstinence, a phenomenon termed “incubation of drug craving”. Previous studies demonstrated both sex differences and an effect of estrous cycle in female rats in incubation of cocaine craving. In contrast, while incubation of methamphetamine craving is similar across sexes, whether estrous cycle plays a role in this incubation has yet to be fully addressed. Moreover, whether neural mechanisms underlying incubation of methamphetamine craving differ across estrous cycles is largely unknown. To address these gaps, we first compared methamphetamine self-administration, and methamphetamine seeking on both abstinence days 1 and 28 between male rats and female rats across the estrous cycle. Next, we examined neuronal activation associated with incubated methamphetamine seeking in dorsomedial striatum (DMS) and lateral portion of the anterior intralaminar nucleus of thalamus (AIT-L), two brain areas previously implicated in incubation of methamphetamine craving. We found no effect of sex or estrous cycle on methamphetamine self-administration and methamphetamine seeking on abstinence days 1 and 28. We also found no effect of sex or estrous cycle on the number of Fos-expressing cells in DMS or AIT-L following methamphetamine seeking test. Taken together, our results showed that methamphetamine self-administration and incubation of methamphetamine craving was not dependent on sex or estrous cycles under our experimental condition, and the role of DMS and AIT-L in incubation of methamphetamine craving may be similar across sexes and across estrous cycles in female rats.

Abstract CHESS 3 represents an improved human gene catalog based on nearly 10,000 RNA-seq experiments across 54 body sites. It significantly improves current genome annotation by integrating the latest reference data and algorithms, machine learning techniques for noise filtering, and new protein structure prediction methods. CHESS 3 contains 41,356 genes, including 19,839 protein-coding genes and 158,377 transcripts, with 14,863 protein-coding transcripts not in other catalogs. It includes all MANE transcripts and at least one transcript for most RefSeq and GENCODE genes. On the CHM13 human genome, the CHESS 3 catalog contains an additional 129 protein-coding genes. CHESS 3 is available at http://ccb.jhu.edu/chess .

Recently developed methods to predict three-dimensional protein structure with high accuracy have opened new avenues for genome and proteome research. We explore a new hypothesis in genome annotation, namely whether computationally predicted structures can help to identify which of multiple possible gene isoforms represents a functional protein product. Guided by protein structure predictions, we evaluated over 230,000 isoforms of human protein-coding genes assembled from over 10,000 RNA sequencing experiments across many human tissues. From this set of assembled transcripts, we identified hundreds of isoforms with more confidently predicted structure and potentially superior function in comparison to canonical isoforms in the latest human gene database. We illustrate our new method with examples where structure provides a guide to function in combination with expression and evolutionary evidence. Additionally, we provide the complete set of structures as a resource to better understand the function of human genes and their isoforms. These results demonstrate the promise of protein structure prediction as a genome annotation tool, allowing us to refine even the most highly curated catalog of human proteins. More generally we demonstrate a practical, structure-guided approach that can be used to enhance the annotation of any genome.