Brain region-dependent gene networks associated with selective breeding for increased voluntary wheel-running behavior

Abstract

Mouse lines selectively bred for high voluntary wheel-running behavior are helpful models for uncovering gene networks associated with increased motivation for physical activity and other reward-dependent behaviors. The fact that multiple brain regions are hypothesized to contribute to distinct behavior components necessitates the simultaneous study of these regions. The goals of this study were to identify brain-region dependent and independent gene expression patterns, regulators, and networks associated with increased voluntary wheel-running behavior. The cerebellum and striatum from a high voluntary running line and a non-selected control line were compared. Neuropeptide genes annotated to reward-dependent processes including neuropeptide S receptor 1 (Npsr1), neuropeptide Y (Npy), and proprotein convertase subtilisin/kexin type 9 (Pcsk9), and genes implicated in motor coordination including vitamin D receptor (Vdr) and keratin, type I cytoskeletal 25 (Krt25) were among the genes exhibiting activity line-by-region interaction effects. Genes annotated to the Parkinson pathway presented consistent line patterns, albeit at different orders of magnitude between brain regions, suggesting some parallel events in response to selection for high voluntary activity. The comparison of gene networks between brain regions highlighted genes including transcription factor AP-2-delta (Tfap2d), distal-less homeobox 5 gene (Dlx5) and sine oculis homeobox homolog 3 (Six3) that exhibited line differential expression in one brain region and are associated with reward-dependent behaviors. Transcription factors including En2, Stat6 and Eomes predominated among regulators of genes that differed in expression between lines. Results from the simultaneous study of striatum and cerebellum confirm the necessity to study molecular mechanisms associated with voluntary activity and reward-dependent behaviors in consideration of brain region dependencies.

DNA Methylation Analysis of Imprinted Genes in the Cortex and Hippocampus of Cross-Fostered Mice Selectively Bred for Increased Voluntary Wheel-Running

“…While motivation and physiological ability are critical determinants of an individual’s physical activity levels (Garland et al 2017 ), long-term genetic selection experiments in laboratory mice have also illuminated genes associated with elevated levels of voluntary exercise (Kelly et al 2012 ; Kostrzewa and Kas 2014 ; Vellers et al 2018 ; Aasdahl et al 2021 ). RNA (Zhang et al 2018 ) and whole genome (Xu and Garland 2017 ; Hillis et al 2020 ) sequencing from mice selected for elevated physical activity levels have revealed differential expression of genes associated with behavior, motivation, and athletic ability, supporting a genetic basis for elevated physical activity. In addition to genetic underpinnings, non-genomic, developmental programming effects during early life can also substantially impact exercise behavior and physical activity (Li et al 2013 ; Baker et al 2015 ; Eclarinal et al 2016 ; Garland et al 2017 ).…”

Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulated in Exercise in a Mouse Model of Parkinson’s Disease

“…WGCNA analysis further conformed to the association between exercised phenotype and pathways, and further screened for critical modules and hub genes. Some of hub genes shown in Figures 4B,C have been reported in previous studies of PD: Krt25 is implicated in motor coordination ( Zhang et al, 2018 ); Aqp1, encoding astrocytic water channel proteins aquaporin 1 (AQP1) might profoundly affect α-syn deposition in the neocortex of patients with PD ( Hoshi et al, 2017 ); FolR1 is selectively expressed in the surface of midbrain DA progenitors and its level may represent the condition of TH positive neurons ( Gennet et al, 2016 ). Comprehensively considering their functions, we proposed that the hub genes manipulate behavioral susceptibility by driving synaptogenesis, neuronal network formation, and improving microenvironment in the nigrostriatal system after exercise.…”

Prefrontal Cortex Response to Prenatal Insult and Postnatal Opioid Exposure

“…The ribosome pathway profile is comparable to the under-expression of ribosomal genes in the prefrontal cortex of amphetamine-treated mice [ 37 ]. The ribosome pathway was also enriched among differentially expressed in the striatum of a mouse line selected for reward dependency for increased voluntary wheel-running behavior relative to a control line [ 38 ].…”