Nucleus accumbens neuronal maturation differences in young rats bred for low versus high voluntary running behaviour

Key points Selective breeding experiments with laboratory rodents have demonstrated the heritability of voluntary exercise. We performed RNA sequencing and bioinformatics analyses of the reward and pleasure hub in the brain - the nucleus accumbens - in rats selectively bred for low voluntary running (LVR) versus high voluntary running (HVR). The discovery of unique genes and 'cell cycle'-related gene pathways between lines guided our hypothesis that neuron maturation may be lower in LVR rats. Testing of this hypothesis revealed that the LVR line inherently possessed fewer mature medium spiny neurons and fewer immature neurons than their HVR counterparts. However, minimal running in LVR rats appeared to rescue and/or reverse these effects. Neuron maturation in the nucleus accumbens is related to low running voluntary behaviour in our model; this allows researchers to understand the potential neural mechanisms that underlie the motivations for low physical activity behaviour. We compared the nucleus accumbens (NAc) transcriptomes of generation 8 (G8), 34-day-old rats selectively bred for low (LVR) versus high voluntary running (HVR) behaviours in rats that never ran (LVRnon-run and HVRnon-run), as well as in rats after 6days of voluntary wheel running (LVRrun and HVRrun). In addition, the NAc transcriptome of wild-type Wistar rats was compared. The purpose of this transcriptomics approach was to generate testable hypotheses as to possible NAc features that may be contributing to running motivation differences between lines. Ingenuity Pathway Analysis and Gene Ontology analyses suggested that 'cell cycle'-related transcripts and the running-induced plasticity of dopamine-related transcripts were lower in LVR versus HVR rats. From these data, a hypothesis was generated that LVR rats might have less NAc neuron maturation than HVR rats. Follow-up immunohistochemistry in G9-10 LVRnon-run rats suggested that the LVR line inherently possessed fewer mature medium spiny (Darpp-32-positive) neurons (P<0.001) and fewer immature (Dcx-positive) neurons (P<0.001) than their G9-10 HVR counterparts. However, voluntary running wheel access in our G9-10 LVRs uniquely increased their Darpp-32-positive and Dcx-positive neuron densities. In summary, NAc cellularity differences and/or the lack of running-induced plasticity in dopamine signalling-related transcripts may contribute to low voluntary running motivation in LVR rats.