Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F2Cross of Selectively-Bred Rats

Selectively-bred High Responder (bHR) and Low Responder (bLR) rats model the extreme externalizing and internalizing behavior accompanying many psychiatric disorders. To elucidate gene expression underlying these heritable behavioral differences, bHRs and bLRs (generation 37) were used to produce a F 0 -F 1 -F 2 cross. We measured exploratory locomotion, anxiety-like behavior, and reward cue sensitivity (Pavlovian Conditioned Approach), and performed hippocampal RNA-Seq in male and female F 0 s (n=24) and F 2 s (n=250). Behaviors that diverged during selective breeding remained correlated in F 2 s, implying a shared genetic basis. F 0 bHR/bLR differential expression was robust, surpassing differences associated with sex, and predicted expression patterns associated with F2 behavior. With bHR-like behavior, gene sets related to growth/proliferation were upregulated, whereas with bLR-like behavior, gene sets related to mitochondrial function, oxidative stress, and microglial activation were upregulated. This differential expression could be successfully predicted based on F0 genotype using cis-expression quantitative trait loci (cis-eQTLs) identified in the F2s. Colocalization of these cis-eQTLs with behavioral Quantitative Trait Loci pinpointed 16 differentially expressed genes that were strong candidates for mediating the influence of genetic variation on behavioral temperament. Our findings implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, modulating vulnerability to psychiatric disorders.