WC Booher1,2, LA Vanderlinden3,4, LA Hall1, CA Lowry6-10, LM Saba3, and MA Ehringer1,2

High and Low Activity strains of mice were bidirectionally selected for differences in open-field activity (OFA) and subsequently inbred to use as a genetic model for studying anxiety-like behaviors (DeFries et al., 1978). In addition to the extreme differences in OFA, the High and Low Activity mice demonstrate corresponding differences in other anxiety-related behaviors as assessed by light-dark box, elevated plus-maze, and novel object exploration (Booher et al., 2021). Hippocampal RNA-sequencing of the High and Low Activity mice identified 3,901 differentially expressed protein-coding genes, with both sex-dependent and sex-independent effects. Functional enrichment analysis (PANTHER) highlighted 15 GO terms, which allowed us to create a narrow list of 264 top candidate genes. Of the top candidate genes, 46 encoded four Complexes (I, II, IV, and V) and two electron carriers (cytochrome c and ubiquinone) of the mitochondrial oxidative phosphorylation (OXPHOS) process. The most striking results were in the female high anxiety, Low Activity mice, where 39/46 genes relating to OXPHOS were upregulated. In addition, comparison of our top candidate genes with two previously curated High and Low Activity gene lists and a PubMed literature review suggests Ndufa13, Ndufb7, Ndufc2, Ndufs2, Coq7, Arrb1, Crtc1, Dcc, Dlg2, Lrp8, Ntkr3 and Trim32 (the first five are involved in OXPHOS) as genes of interest for anxiety-like behaviors. In addition to the current results, mitochondrial dysfunction has recently appeared as both a cause and effect of anxiety-related disorders and thus should be further explored as a possible novel pharmaceutical treatment for anxiety disorders.