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

Abstract

Although exercise is critical for health, 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 line. 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 γ-aminobutyric acid (GABA)-ergic signaling. System 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 and Htr1b expression. The Library of Integrated Network-Based Cellular Signatures identified the protein kinase C δ inhibitor, rottlerin, the tyrosine kinase inhibitor, Linifanib and the delta-opioid receptor antagonist 7-benzylidenenaltrexone as potential compounds for increasing the motivation to run. 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.

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

“…For example, differences between high running and control lines in the concentration of monoamines in the substantia nigra pars compacta and dorsolateral striatum, and in the expression of genes coding for chromatin regulators of monoamine receptor in the striatum have been reported [ 7 ]. 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 ].…”

“…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 ]. Significant behavioral and physiological differences can be identified between lines selected for high voluntary running and non-selected control lines [ 2 , 3 ].…”

Genomic variants in an inbred mouse model predict mania-like behaviors

“…Of preeminent interest to our work is SMARCA4, whose human ortholog is among a network of gene products predicted to play a role in the differential chromatin dynamics of BSDs based upon a meta-analysis of gene expression data from postmortem brain tissue of patients [ 10 ]. The genome region and a molecular interaction network containing Smarca4 are perturbed in our previous work [ 16 , 17 ]. Further, the human genome region containing the human SMARCA4 gene sits between D19S714 and D19S586, markers with significant linkage to BSDs in two independent studies [ 8 , 32 ].…”

“…Further, MSN animals show hippocampal gene expression perturbations similar to those seen in post-mortem limbic brain tissue from patients with BSDs including alterations in a pathway related to chromatin packaging [ 16 ], a finding that establishes provisional construct validity. Related strains to the MSN strain show additional alterations in chromatin packaging in the striatum [ 17 ], providing additional support for brain chromatin packaging as an important system dysregulated in these mice. The MSN phenotype is highly reproducible, showing mania-like behaviors at the same approximate magnitude across multiple generations [ 14 – 16 ].…”

Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling

“…Following [ 21 ], all surfaces and instruments were cleaned thoroughly with RNAse away. Brains were rapidly dissected and immediately placed on an aluminum platform on wet ice with the ventral surface exposed.…”