Nucleus Accumbens Expression of PKIα May Modulate the Motivation to be Physically Active
Authors: Grigsby Kolter Bill , Ruegsegger Gregory N. , Booth Frank W. 
Published: November 2023

The health benefits of voluntary exercise are numerous and vast. Despite the depth of knowledge concerning the physiology of exercise, little is known about the genetic factors underlying the motivation to be physically active. Voluntary exercise is known to be driven by distinct reward circuits, specifically within the nucleus accumbens (NAc). To address this topic, our lab has created a selective breeding model for high (HVR) and low (LVR) voluntary wheel running behavior.ObjectiveWe aimed to elucidate if genetic differences in PKA signaling within the NAc, in particular the role of PKIα (protein kinase inhibitor alpha), influences the motivation to voluntarily wheel run in HVR and LVR rats.MethodsqRT‐PCR was used to assess PKIα mRNA levels in sedentary (endogenous) and wheel running HVR and LVR rats. In addition, letiviral overexpression and shRNA knockdown of PKIα at the level of the NAc was performed in male and female HVR and LVR rats, and nightly wheel running was assessed up to 3‐weeks post transfection.ResultsEndogenous levels of PKIα in the NAc were 2 fold higher in sedentary HVR rats compared to sedentary LVR rats. Wheel access had no effect on PKIα mRNA expression in HVR rats, but trended to decrease PKIα mRNA expression in LVR rats (p=.052). Additionally, PKIα mRNA expression in the NAc significantly correlated (p < 0.05) with run time in both male and female HVR rats (r = 0.51), as well as in male and female LVR rats (r = .71), with an overall correlation, regardless of selection line (r = 0.70). Ongoing lentiviral overexpression of PKIα, as well as shRNA knock‐down of PKIα in the NAc of HVR male and female experiments shows promising and distinct gender effects on voluntary wheel running behavior. In female HVR rats, PKIα overexpression tends to increase running at 3 weeks post transfection (p=0.146), whereas in males PKIα overexpression tends to decrease running compared to empty vectors (p=0.165). This is further supported by shRNA knockdown of PKIα levels, in which male HVR rats tends to increase nightly running distance at 3 weeks post transfection compared to empty vectors (p=0.177). Current studies continue to access PKIα overexpression and knock‐down influences on running behavior.ConclusionWe observed endogenous, differential expression of PKIα at the level of the NAc between HVR and LVR rats, whith increased PKIα mRNA expression in HVR rats. There was a positive relationship between average nightly running time and PKIα expression in both lines. Genetic manipulation of PKIα shows promising effects on voluntary wheel running performance, which may have an underlying gender effect.SignificanceGiven the blaring health benefits of physical activity and the epidemic rise in physical inactivity worldwide, the ability to find the motivational switch for physical activity is paramount. Understanding the molecular and genetic differences between HVR and LVR rats, for instance the role of PKIα, offers keen insight into elucidating mechanisms for the motivation to be physically active.