Katada, S. | bioRxiv Science

bioRxiv2020

Coadaptation of the chemosensory system with voluntary exercise behavior in mice

Ethologically relevant chemical senses and behavioral habits are likely to coadapt in response to selection. As olfaction is involved in intrinsically motivated behaviors in mice, we hypothesized that selective breeding for a voluntary behavior would enable us to identify novel roles of the chemosensory system. Voluntary wheel running (VWR) is an intrinsically motivated and naturally rewarding behavior, and even wild mice run on a wheel placed in nature. We have established 4 independent, artificially evolved mouse lines by selectively breeding individuals showing high VWR activity (High Runners; HRs), together with 4 non-selected Control lines, over 88 generations. We found that several sensory receptors in specific receptor clusters were differentially expressed between the vomeronasal organ (VNO) of HRs and Controls. Moreover, one of those clusters contains multiple single-nucleotide polymorphism loci for which the allele frequencies were significantly divergent between the HR and Control lines, i.e., loci that were affected by the selective breeding protocol. These results indicate that the VNO has become genetically differentiated between HR and Control lines during the selective breeding process, strongly suggesting the chemosensory receptors as quantitative trait loci (QTL) for voluntary exercise in mice. We propose that olfaction may play an important role in motivation for voluntary exercise in mammals.

animal behavior and cognition↗

bioRxiv2019

Diabetic conditions induce intolerance to accumulation of pathogenic mitochondrial DNAs

Marked accumulation of mitochondrial DNA (mtDNA) with a particular pathogenic mutation is necessary for the mutant mtDNA to express its pathogenicity as mitochondrial respiration defects. However, the nuclear genome background, or the physiological status, or both, might also be important for the pathogenic regulation of mutant mtDNAs, because most mitochondrial function is controlled by polypeptides encoded in the nuclear genome. To test this, we generated diabetic mice carrying pathogenic mtDNA with a large-scale deletion ({Delta}mtDNA) that loses six tRNA genes and seven structural genes essential for mitochondrial respiration. Compared with non-diabetic mice carrying {Delta}mtDNA, diabetic mice carrying {Delta}mtDNA showed a decrease in mitochondrial biogenesis regulated by nuclear-encoded genes, and mitochondrial respiration defects and the resultant mitochondrial disease phenotypes were induced even in the case of low loads of {Delta}mtDNA. In addition, diabetic culture conditions intensified the pathogenicity of human mtDNA with an A3243G point mutation in the tRNALue (UUR) gene. Our results indicated that the diabetic conditions are a modifier that exacerbates mitochondrial respiration defects due to mutant mtDNAs. The finding suggests the possibility that recovery from diabetic conditions might be an effective treatment strategy for some disorders involving both mutant mtDNAs and diabetic signs.\n\nAuthor SummaryIt has been reported that accumulation of pathogenic mutant mitochondrial DNA (mtDNA) and the resultant mitochondrial metabolic dysfunction are associated with a wide variety of disorders, such as mitochondrial diseases, diabetes, neuo-degenerative disorders, and cancers. Considering that most mitochondrial function is regulated by nuclear-genome-encoded polypeptides, it is very important to focus on cooperation between mutant mtDNA, nuclear genetic background, and vital conditions for understanding precise pathogeneses of mtDNA-mediated disorders. By using model cells and mice carrying pathogenic mtDNAs, we report here that diabetic conditions are a modifier for the pathogenic regulation of mutant mtDNAs. Because the onset and progression of diabetes are often associated with aging, our finding suggests that some age-associated disorders with mutant mtDNAs and diabetic complications might be induced partly by enhancement of the pathogenicity of mutant mtDNAs by diabetic conditions.

cell biology↗