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High motivation for exercise is associated with altered chromatin regulators of monoamine receptor gene expression in the striatum of selectively bred mice

ABSTRACT: Though exercise is critical for health and wellbeing, many lack the motivation to exercise, and it is unclear how motivation might be increased. To uncover the molecular underpinnings of increased motivation for exercise, we analyzed the transcriptome of the striatum in four mouse lines selectively bred for high voluntary wheel running and four non-selected control lines. The striatum was dissected and RNA was extracted and sequenced from four individuals of each strain. We found multiple genes and gene systems with strong relationships to both selection and running history over the previous 6 days. Among these genes were Htr1b, a serotonin receptor subunit, and Slc38a2, a marker for both glutamatergic and GABAergic signaling. Systems analysis of the raw results found enrichment of transcriptional regulation and kinase genes. Further, we identified a splice variant affecting the Wnt related Golgi signaling gene Tmed5. Using coexpression network analysis, we found a cluster of interrelated coexpression modules with relationships to running behavior. From these modules, we built a network correlated with running that predicts a mechanistic relationship between transcriptional regulation by nucleosome structure, a system implicated in our previous work, and Htr1b expression, implicated in the present work. Using the Library of Integrated Cellular Signals, we found that the tyrosine kinase inhibitor Linifanib and the delta-opioid receptor antagonist 7-benzylidenenaltrexone (BNTX) produced similar patterns of gene expression in multiple cell lines as we observed in the striatum of the high-runner lines. Hence, these two drugs are predicted to increase motivation for exercise. Taken together, our findings support a neurobiological framework of exercise motivation where chromatin state leads to differences in dopamine signaling through modulation of both the primary neurotransmitters glutamate and GABA, and by neuromodulators such as serotonin.

ORGANISM(S): Mus musculus domesticus

PROVIDER: GSE86076 | GEO | 2016/10/03

SECONDARY ACCESSION(S): PRJNA340182

REPOSITORIES: GEO

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Project description:Conscious awareness of breathing requires the activation of higher brain centers. The sensation of breathing is believed to be a neural gating process. The thalamus provides the brain structure that could be responsible for the gating of respiratory sensory information to the cortex. It was reasoned that if the thalamus is the neural gate, then tracheal obstructions will modulate the gene expression profile of the thalamus. Anesthetized rats were instrumented with an inflatable cuff sutured around the trachea. The cuff was inflated to obstruct 2-4 breaths, then deflated for a minimum of 15 breaths. The obstructions were repeated for 10 min followed by immediate brain removal, and the medial thalamus was dissected and prepared for microarray analysis. Gene expression profiles were measured using Agilent Technology Oligo Microarrays. Following the occlusion protocol, 588 genes were found to be altered (p < 0.05, log2 fold change ≥ 0.4), with 327 down-regulated and 261 genes up-regulated. A significant up-regulation of the serotonin HTR2A receptor and significant down-regulation of the dopamine DRD1 receptor genes were found. A pathway analysis was performed targeting serotonin and dopamine receptor pathways. The mitogen activated protein kinase 1 (MAPK1) gene was significantly down-regulated. MAPK1 is an inhibitory regulator of the serotonin HTR2A receptor and facilitatory regulator for the dopamine DRD1 receptor. Down-regulation of MAPK1 may be related to the 2-fold up-regulation of HTR2A and 2-fold down-regulation of DRD1 suggesting an interaction in the medial thalamus serotonin-dopamine pathway elicited by airway obstruction. These results demonstrate an immediate change in gene expression in thalamic arousal-fear-anxiety-motivation related serotonin and dopamine receptors in response to airway obstruction. The results support the hypothesis that the thalamus is a component in the respiratory mechanosensory neural pathway. Four experimental animals that received tracheal occlusions and four surgical control animals were used. A reference design was used to compare all samples.

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High motivation for exercise is associated with altered chromatin regulators of monoamine receptor gene expression in the striatum of selectively bred mice

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