Loss of Cdk5 function in the nucleus accumbens decreases wheel running and may mediate age‐related declines in voluntary physical activity

Abstract

Key pointsr Physical inactivity, which drastically increases with advancing age, is associated with numerous chronic diseases.r The nucleus accumbens (the pleasure and reward 'hub' in the brain) influences wheel running behaviour in rodents.r RNA-sequencing and subsequent bioinformatics analysis led us to hypothesize a potential relationship between the regulation of dendritic spine density, the molecules involved in synaptic transmission, and age-related reductions in wheel running. Upon completion of follow-up studies, we developed the working model that synaptic plasticity in the nucleus accumbens is central to age-related changes in voluntary running.r Testing this hypothesis, inhibition of Cdk5 (comprising a molecule central to the processes described above) in the nucleus accumbens reduced wheel running.r The results of the present study show that reductions in synaptic transmission and Cdk5 function are related to decreases in voluntary running behaviour and provide guidance for understanding the neural mechanisms that underlie age-dependent reductions in the motivation to be physically active.Abstract Increases in age are often associated with reduced levels of physical activity, which, in turn, associates with the development of numerous chronic diseases. We aimed to assess molecular differences in the nucleus accumbens (NAc) (a specific brain nucleus postulated to influence rewarding behaviour) with respect to wheel running and sedentary female Wistar rats at 8 and 14 weeks of age. RNA-sequencing was used to interrogate transcriptomic changes between 8-and 14-week-old wheel running rats, and select transcripts were later analysed by quantitative RT-PCR in age-matched sedentary rats. Voluntary wheel running was greatest at 8 weeks and had significantly decreased by 12 weeks. From 619 differentially expressed mRNAs, bioinformatics suggested that cAMP-mediated signalling, dopamine-and cAMP-regulated neuronal phosphoprotein of 32 kDa feedback, and synaptic plasticity were greater in 8-vs. 14-week-old rats. In depth analysis of these networks showed significant (ß20-30%; P < 0.05) decreases in cell adhesion molecule (Cadm)4 and p39 mRNAs, as well as their proteins from 8 to 14 weeks of age in running and sedentary rats. Furthermore, Cadm4, cyclin-dependent kinase 5 (Cdk5) and p39 mRNAs were significantly correlated with voluntary running distance. Analysis of dendritic spine density in the NAc showed that wheel access increased spine density (P < 0.001), whereas spine density was lower in 14-vs. 8-week-old sedentary rats (P = 0.03). Intriguingly, intra-NAc injection of the Cdk5 inhibitor roscovitine, dose-dependently decreased AbbreviationsCadm, cell adhesion molecule; Cdk5, cyclin-dependent kinase 5; Darpp-32, dopamine-and cAMP-regulated neuronal phosphoprotein of 32 kDa; Gad, glutamic acid decarboxylase; GO, Gene Ontology; IPA, ingenuity pathway analysis; MSN, medium spiny neuron; Nac, nucleus accumbens; RPKM, reads per kilobase per million mapped reads; RNA-seq, RNA-sequencing; TBST, Tris-buffered sali...

Voluntary wheel running promotes resilience to chronic social defeat stress in mice: a role for nucleus accumbens ΔFosB

“…These observations suggest that the specific increase in thin spines observed in this study could result from the time when the VWR mice were euthanized, that is, during the light phase when mice are resting (i.e., voluntary short-term withdrawal from VWR). Similar to our observations in mice, a recent study in female Wistar rats demonstrated that 3 weeks of VWR is associated with increased total spine density, and a relative increase and decrease in thin and stubby spines, respectively [61]. Collectively, these studies provide strong rationale to investigate how VWR alters synaptic maturation and function in the NAc, and to identify the functional consequences of altered VWR-associated NAc MSN spine formation on stress resilience.…”

Yearning predicts subgenual anterior cingulate activity in bereaved individuals

“…The intensity of absolute nucleus accumbens responsiveness may be lower in this age group. Recent studies in older animals have shown changes in nucleus accumbens functioning and behavior ( Ruegsegger et al., 2017 ). However, the small sample size may have limited the statistical power to detect a smaller effect size.…”

Assessed and Emerging Biomarkers in Stroke and Training-Mediated Stroke Recovery: State of the Art

“…BDNF induces local synaptic plasticity [ 82 ] and more interestingly cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase involved in the rescue of synaptic plasticity [ 83 ], is involved in the BDNF-stimulated dendritic growth in hippocampus [ 84 ]. In poststroke patients, the role of Cdk5 has been associated with the long-term postischemic neurodegeneration and Cdk5 might be a pharmacological target; its inhibition or gene silencing increases the expression of BDNF in the hippocampal neurons [ 85 ]. The loss of this serine/threonine kinase in the nucleus accumbens reduces the ability to sustain a muscular physical exercise [ 85 ].…”

“…In poststroke patients, the role of Cdk5 has been associated with the long-term postischemic neurodegeneration and Cdk5 might be a pharmacological target; its inhibition or gene silencing increases the expression of BDNF in the hippocampal neurons [ 85 ]. The loss of this serine/threonine kinase in the nucleus accumbens reduces the ability to sustain a muscular physical exercise [ 85 ]. The relationship between the different degrees of the muscular activity (training, sustained and endurance physical exercise, moderate aerobic exercise, etc.)…”