A microbiome-dependent gut–brain pathway regulates motivation for exercise
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE210906 | GEO | 2022/09/19
REPOSITORIES: GEO
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Project description:Exercise exerts a wide range of beneficial effects for healthy physiology. However, the mechanisms regulating an individual's motivation to engage in physical activity remain incompletely understood. An important factor stimulating the engagement in both competitive and recreational exercise is the motivating pleasure derived from prolonged physical activity, which is triggered by exercise induced neurochemical changes in the brain. Here, we report on the discovery of a gut brain connection in mice that enhances exercise performance by augmenting dopamine signalling during physical activity. We find that microbiome dependent production of endocannabinoid metabolites in the gut stimulates the activity of TRPV1 expressing sensory neurons and thereby elevates dopamine levels in the ventral striatum during exercise. Stimulation of this pathway improves running performance, whereas microbiome depletion, peripheral endocannabinoid receptor inhibition, ablation of spinal afferent neurons or dopamine blockade abrogate exercise capacity. These findings indicate that the rewarding properties of exercise are influenced by gut derived interoceptive circuits and provide a microbiome dependent explanation for interindividual variability in exercise performance. Our study also suggests that interoceptomimetic molecules that stimulate the transmission of gut derived signals to the brain may enhance the motivation for exercise.
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Project description: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.
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