Hippocampal RNA sequencing in mice selectively bred for high and low activity

Abstract

High and Low Activity strains of mice were bidirectionally selected for differences in open‐field activity (DeFries et al., 1978, Behavior Genetics, 8: 3–13) and subsequently inbred to use as a genetic model for studying anxiety‐like behaviors (Booher et al., 2021, Genes, Brain and Behavior, 20: e12730). Hippocampal RNA‐sequencing of the High and Low Activity mice identified 3901 differentially expressed protein‐coding genes, with both sex‐dependent and sex‐independent effects. Functional enrichment analysis (PANTHER) highlighted 15 gene ontology 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 process. The most striking results were in the female high anxiety, Low Activity mice, where 39/46 genes relating to oxidative phosphorylation were upregulated. In addition, comparison of our top candidate genes with two previously curated High and Low Activity gene lists highlight 24 overlapping genes, where Ndufa13, which encodes the supernumerary subunit A13 of complex I, was the only gene to be included in all three lists. Mitochondrial dysfunction has recently been implicated 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.

Large captivity effect based on gene expression comparisons between captive and wild shrew brains

“…Parallel responses include the downregulation of genes associated with ribosome production and function, as well as 22 genes encoding for mitochondrial complex I NADH:ubiquinone oxidoreductase subunit proteins. Changes in expression of mitochondrial complex I genes, which play an important role in energy production (38), have been linked to depression and anxiety-related behavior mice (39)(40)(41), suggesting a similar phenotype for shrews in captivity conditions potentially related to a dysregulation of energy metabolism. Overall, these findings indicate a significant captivity effect in the brain, highlighting the importance of research on physiological processes in wild individuals, especially when linking results to neurodegenerative diseases.…”

“…For example, mice transplanted with gut microbiota from patients with major depressive disorder (MDD) showed specific complex I subunit inhibition (40), including 5 genes ( NDUFA5, NDUFA6, NDUFB3, NDUFS4 , and NDUFV3 ) that were also downregulated in the three brain regions of captive shrews, suggesting similar underlying mechanisms related to a depressive state. Additionally, female mice bred for low activity (an anxiety-like behavior genetic model) showed upregulation of complex I subunit genes (39), including 13 genes downregulated in captive shrews ( NDUFA2, NDUFA4, NDUFA6, NDUFA7, NDUFA12, NDUFA13, NDUFB5, NDUFB6, NDUFB7, NDUFB9, NDUFC1, NDUFC2 , and NDUFS5 ). These genes exhibit opposite expression patterns between low activity mice and captive shrews.…”