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Fear conditioning (FC) may provide a useful model for some components of post-traumatic stress disorder (PTSD). We used a C57BL/6J × DBA/2J F intercross (n = 620) and a C57BL/6J × DBA/2J F advanced intercross line (n = 567) to fine-map quantitative trait loci (QTL) associated with FC. We conducted an integrated genome-wide association analysis in QTLRel and identified five highly significant QTL affecting freezing to context as well as four highly significant QTL associated with freezing to cue. The average percent decrease in QTL width between the F and the integrated analysis was 59.2%. Next, we exploited bioinformatic sequence and expression data to identify candidate genes based on the existence of non-synonymous coding polymorphisms and/or expression QTLs. We identified numerous candidate genes that have been previously implicated in either fear learning in animal models ( Bcl2, Btg2, Dbi, Gabr1b, Lypd1, Pam and Rgs14) or PTSD in humans ( Gabra2, Oprm1 and Trkb); other identified genes may represent novel findings. The integration of F and AIL data maintains the advantages of studying FC in model organisms while significantly improving resolution over previous approaches. [ABSTRACT FROM AUTHOR]

The present study measured variation in body weight using a combined analysis in an F intercross and an F advanced intercross line (AIL). Both crosses were derived from inbred LG/J and SM/J mice, which were selected for large and small body size prior to inbreeding. Body weight was measured at 62 (±5) days of age. Using an integrated GWAS and forward model selection approach, we identified 11 significant QTLs that affected body weight on ten different chromosomes. With these results we developed a full model that explained over 18% of the phenotypic variance. The median 1.5-LOD support interval was 5.55 Mb, which is a significant improvement over most prior body weight QTLs. We identified nonsynonymous coding SNPs between LG/J and SM/J mice in order to further narrow the list of candidate genes. Three of the genes with nonsynonymous coding SNPs ( Rad23b, Stk33, and Anks1b) have been associated with adiposity, waist circumference, and body mass index in human GWAS, thus providing evidence that these genes may underlie our QTLs. Our results demonstrate that a relatively small number of loci contribute significantly to the phenotypic variance in body weight, which is in marked contrast to the situation in humans. This difference is likely to be the result of strong selective pressure and the simplified genetic architecture, both of which are important advantages of our system. [ABSTRACT FROM AUTHOR]

Some BALB/c substrains exhibit different levels of aggression. We compared aggression levels between male BALB/cJ and BALB/cByJ substrains using the resident intruder paradigm. These substrains were also assessed in other tests of emotionality and information processing including the open field, forced swim, fear conditioning, and prepulse inhibition tests. We also evaluated single nucleotide polymorphisms (SNPs) previously reported between these BALB/c substrains. Finally, we compared BALB/cJ and BALB/cByJ mice for genomic deletions or duplications, collectively termed copy number variants (CNVs), to identify candidate genes that might underlie the observed behavioral differences. BALB/cJ mice showed substantially higher aggression levels than BALB/cByJ mice; however, only minor differences in other behaviors were observed. None of the previously reported SNPs were verified. Eleven CNV regions were identified between the two BALB/c substrains. Our findings identify a robust difference in aggressive behavior between BALB/cJ and BALB/cByJ substrains, which could be the result of the identified CNVs. [ABSTRACT FROM AUTHOR]

We previously colocalized a quantitative trait locus (QTL) for sensitivity to the locomotor stimulant effects of methamphetamine (MA) with a QTL for expression of casein kinase 1 epsilon (Csnk1-ɛ) in the nucleus accumbens (NAc). Subsequently, we identified a single nucleotide polymorphism in CSNK1E (rs135745) that was associated with increased sensitivity to the subjective effects of d-amphetamine in healthy human subjects. Based on these results, we hypothesized that differential expression of Csnk1-ɛ causes differential sensitivity to MA-induced locomotor activity in mice. In the present study, we used PF-670462 (PF), which is a selective inhibitor of Csnk1-ɛ, to directly evaluate the role of Csnk1-ɛ in the locomotor stimulant response to MA in male C57BL/6J mice. We administered vehicle, PF, MA, or MA + PF, either via intraperitoneal injections or bilateral intra-NAc microinjections. We also examined Darpp-32 phosphorylation in mice receiving intraperitoneal injections. Intraperitoneal PF (20–40 mg/kg) attenuated the locomotor stimulant response to MA (2 mg/kg) without affecting baseline activity. The high dose of PF also significantly inhibited MA-induced phosphorylation of Darpp-32, providing a potential mechanism by which Csnk1-ɛ contributes to MA-induced locomotor activity. Furthermore, microinjection of PF (5 μg/side) into the NAc completely blocked the locomotor stimulant response to MA (2.5 μg/side) without affecting baseline activity. These results provide direct evidence that Csnk1-ɛ is crucial for the locomotor stimulant response to a moderate dose of MA and suggest that genetic polymorphisms affecting Csnk1-ɛ expression or function could influence sensitivity to amphetamines in both mice and humans. [ABSTRACT FROM AUTHOR]