Boosting hyperalignment performance with age-specific templates.

Dr. Eric Nestler and his many colleagues have been at the forefront of defining the molecular effects of cocaine and other drugs of abuse for over three decades. Recently, their group used RNA sequencing (RNA-seq) to assess patterns of gene expression in limbic nuclei following cocaine self-administration by male mice. Rather than relating mRNA changes to a single factor, such as cocaine infusions, an “addiction index” was calculated for each subject reflecting a composite of (1) cocaine intake, (2) discrimination of active and inactive lever pressing, and (3) consummatory regulation. The resulting addiction index was used to identify genes that were positively or negatively related with this composite behavioral score. RNA-seq results indicated region-specific patterns of cocaine-associated changes in gene expression. Reassuringly, informatic analyses revealed that CREB1, which has long been the focus of the Nestler lab and many other groups, was identified as a potential upstream regulator of cocaine-associated genes. Pattern identification analysis detected several transcripts that were associated with the cocaine addiction index. Although none of these transcripts were validated behaviorally, convincing arguments were made for their potential involvement in cocaine-mediated behaviors. For example, expression of the gene that encodes lipocalin-2, , was positively associated with the cocaine addiction index in five brain regions including the nucleus accumbens, a key limbic regulator of motivated behaviors. LCN2 modulates the degradation and enzymatic activity of matrix metalloproteinase-9, which was previously linked to models of cocaine relapse, leading Walker, Nestler, and colleagues to suggest that LCN2 may be a potential novel therapeutic target for addiction. Motif analysis predicted that nuclear receptors were pattern regulators of transcriptional programs associated with the cocaine addiction index. Nuclear receptors form heterodimers with other proteins, and the resulting complex can bind directly to DNA to influence transcription. Interestingly, subsequent analysis identified regions in the promoter of where CREB and nuclear receptor binding motifs occur in close proximity. Specifically, in the nucleus accumbens, expression of a nuclear receptor () was positively associated with the cocaine addiction index, suggesting that cocaine self-administration may enhance the coupling of NR2B1 and CREB, thereby promoting the transcription of genes including . Further assessing the role of NR2B1 in animal models of cocaine addiction is the subject of the paper published by Godino, Nestler, and colleagues in the current issue of .