Cerebellum Transcriptome of Mice Bred for High Voluntary Activity Offers Insights into Locomotor Control and Reward-Dependent Behaviors

Abstract

The role of the cerebellum in motivation and addictive behaviors is less understood than that in control and coordination of movements. High running can be a self-rewarding behavior exhibiting addictive properties. Changes in the cerebellum transcriptional networks of mice from a line selectively bred for High voluntary running (H) were profiled relative to an unselected Control (C) line. The environmental modulation of these changes was assessed both in activity environments corresponding to 7 days of Free (F) access to running wheel and to Blocked (B) access on day 7. Overall, 457 genes exhibited a significant (FDR-adjusted P-value < 0.05) genotype-by-environment interaction effect, indicating that activity genotype differences in gene expression depend on environmental access to running. Among these genes, network analysis highlighted 6 genes (Nrgn, Drd2, Rxrg, Gda, Adora2a, and Rab40b) connected by their products that displayed opposite expression patterns in the activity genotype contrast within the B and F environments. The comparison of network expression topologies suggests that selection for high voluntary running is linked to a predominant dysregulation of hub genes in the F environment that enables running whereas a dysregulation of ancillary genes is favored in the B environment that blocks running. Genes associated with locomotor regulation, signaling pathways, reward-processing, goal-focused, and reward-dependent behaviors exhibited significant genotype-by-environment interaction (e.g. Pak6, Adora2a, Drd2, and Arhgap8). Neuropeptide genes including Adcyap1, Cck, Sst, Vgf, Npy, Nts, Penk, and Tac2 and related receptor genes also exhibited significant genotype-by-environment interaction. The majority of the 183 differentially expressed genes between activity genotypes (e.g. Drd1) were under-expressed in C relative to H genotypes and were also under-expressed in B relative to F environments. Our findings indicate that the high voluntary running mouse line studied is a helpful model for understanding the molecular mechanisms in the cerebellum that influence locomotor control and reward-dependent behaviors.

Behavioral and neuronal interactions between exercise and alcohol: Sex and genetic differences

“…In complementary studies, High Runner lines of mice have been selected for high levels of daily wheel running, and nonselected controls have been maintained for many years (reviewed in). Although these animals have not been tested in the context of addictive drugs, which is an important area for future research, transcriptional profiling revealed differential gene expression patterns in neuronal networks also implicated in addiction, including differences in Drd2 expression …”

“…In complementary studies, High Runner lines of mice have been selected for high levels of daily wheel running, and nonselected controls have been maintained for many years (reviewed in103 ). Although these animals have not been tested in the context of addictive drugs, which is an important area for future research, transcriptional profiling revealed differential gene expression patterns in neuronal networks also implicated in addiction, including differences in Drd2 expression 104. Because alcohol and exercise both activate the mesolimbic dopaminergic reward pathway,11,66,88 it can be hypothesized that greater alcohol consuming strains of mice will run farther distances than low or moderate consuming strain of mice.…”

Differential response trajectories to acute exercise in blood and muscle

“…Supplementary Table 2 ). Its function in muscle is largely unknown, but differential expression has been found in rodent cerebellum and spinal cord with exercise (Caetano-Anollés et al, 2016;Perreau et al, 2005) . ID3 is a transcriptional regulator that inhibits skeletal muscle differentiation and promotes muscle precursor cells proliferation (Baas et al, 2012;Liu et al, 2002;Wu and Lim, 2005) .…”

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

“…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 ].…”

“…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.…”