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.
Highlights
Reward-dependent behaviors have been linked to learning, memory, and neurological disease processes [1]
Consistent with the expected association with reward-dependent pathways, we reported differential expression between the striatum of the high running and control lines of genes coding for members of the dopamine signaling pathway, including the neurotransmitters glutamate and GABA and the neuromodulator serotonin [6]
A different set of genes associated with locomotor control, reward-dependent behaviors and dopamine processes, including dopamine receptor D1 and muscarinic acetylcholine receptor M1 were differentially expressed between the cerebellum of the high running and control lines [8]
Summary
Reward-dependent behaviors have been linked to learning, memory, and neurological disease processes [1]. Mouse lines selectively bred for high voluntary wheel-running behavior have been a helpful model for uncovering the neurological basis of motor learning and adaptation, increased motivation of physical activity, and reward-dependent behaviors [2, 5, 6]. Consistent with the expected association with reward-dependent pathways, we reported differential expression between the striatum of the high running and control lines of genes coding for members of the dopamine signaling pathway, including the neurotransmitters glutamate and GABA and the neuromodulator serotonin [6]. A different set of genes associated with locomotor control, reward-dependent behaviors and dopamine processes, including dopamine receptor D1 and muscarinic acetylcholine receptor M1 were differentially expressed between the cerebellum of the high running and control lines [8]. A more complete understanding of the complementary role of the striatum and cerebellum on the motivation to exercise in particular, and for reward-dependent behaviors in general necessitates the simultaneous analysis of transcriptome between high running and control lines across brain regions
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