Molecular rescue of low voluntary wheel‐running behavior in rats selectively bred to run low distances
Authors: Grigsby Kolter , Kelty Taylor Jacob , Booth Frank Weaver 
Published: June 2021

Physical inactivity is associated with onset of 40 known chronic diseases and stands as the fifth leading risk factor for death in the US. Importantly, it has been determined that ~30% of human sedentary behavior is genetic, which is reflected in our unique selectively bred rat model for low (LVR) voluntary running behavior. This model highlights the genetic contributions to the low motivation to be physically active. RNA sequencing of the NAc, a brain region believed to drive motivated behaviors, from our model has revealed a target molecule which is more lowly expressed in LVR compared to WT rats and which is positively correlated with nightly running distance; Protein Kinase Inhibitor Alpha (PKIα). This molecule functions to inhibit dopamine receptor 1 (Drd1) signaling by modulating protein kinase A (PKA) activity, an action thought to modulate the “desire” or motivation to receive reward signaling from dopamine and by extension wheel‐running.ObjectiveAddress the effect of increasing PKIα rexpression in the NAc of female WT and LVR rats on 1.) Voluntary running behavior and 2.) Dopaminergic downstream signaling events specific to PKA to better evaluate the function of PKIα on the motivation to be physically active.MethodsBilateral micoinfusion of an AAV for the overexpression of PKIα was injected into the NAc core of female LVR and WT rats and wheel‐running behavior was monitored. Overexpression of PKIα overexpression was confirmed via qPCR. An ex vivo preparation of NAc punches from WT and LVR animals was used to evaluate the effect of Drd1 stimulation with agonist SKF3893 (20 μM and 100 μM for 10 min) on immediate early gene (homer1, arc, psd‐95 and zif268) induction to act as a molecular marker of reward and motivation.ResultsOverexpression of PKIα significantly increased nightly running for 5 continuous estrous cycles (~3 wks) post injection in female LVR rats, but not in female WT rats. A 4‐fold increase in PKIα mRNA expression was confirmed in NAc punches taken from LVR rats compared to pair matched empty vector injected controls. WT punches showed a near significant (p=0.058) 2.5 fold increase in PKIα mRNA expression compared to empty vector injected controls. Evoked expression of homer1, arc, psd‐95 and zif268 significantly increased in LVR punches following the 20 μM dose of SKF38393 compared to control values, whereas WT punches decreased IEG expression following both SKF38393 concentrations. Interestingly, control values of all IEG mRNAs observed were inherently lower in LVR compared to WT punches.Conclusions & SignificanceCollectively, the above suggests that differences in dopamine downstream signaling, attributed to PKIα, may underlie inherent differences in voluntary running behavior. I have shown that increasing the genetic expression of PKIα increases nightly running distance in a polygenic model of low voluntary running behavior. Additionally I have shown that the NAc of LVR animals may confer increased dopamine signaling following Drd1 stimulation, suggesting a potential link between low levels of PKIα and signaling events related to reward and motivation. However, further work is needed to better elucidate PKIα's role in the context of reward signaling and the motivation to be physically active.Support or Funding InformationPhi Zeta Research Grant and the College of Veterinary Medicine, University of Missouri Development OfficeThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.