Overexpression of Protein Kinase Inhibitor Alpha Reverses Rat Low Voluntary Running Behavior

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A gene was sought that could reverse low voluntary running distances in a model of low voluntary wheel-running behavior. In order to confirm the low motivation to wheel-run in our model does not result from defects in reward valuation, we employed sucrose preference and conditioned place preference for voluntary wheel-access. We observed no differences between our model and wild-type rats regarding the aforementioned behavioral testing. Instead, low voluntary runners seemed to require less running to obtain similar rewards for low voluntary running levels compared to wild-type rats. Previous work in our lab identified protein kinase inhibitor alpha as being lower in low voluntary running than wild-type rats. Next, nucleus accumbens injections of an adenoviral-associated virus that overexpressed the protein kinase inhibitor alpha gene increased running distance in low voluntary running, but not wild-type rats. Endogenous mRNA levels for protein kinase inhibitor alpha, dopamine receptor D1, dopamine receptor D2, and Fos were all only lower in wild-type rats following overexpression compared to low voluntary runners, suggesting a potential molecular and behavioral resistance in wild-type rats. Utilizing a nucleus accumbens preparation, three intermediate early gene mRNAs increased in low voluntary running slices after dopamine receptor agonist SKF-38393 exposure, while wild-type had no response. In summary, the results suggest that protein kinase inhibitor alpha is a promising gene candidate to partially rescue physical activity in the polygenic model of low voluntary running. Importantly, there were divergent molecular responses to protein kinase inhibitor alpha overexpression in low voluntary runners compared to wild-type rats.

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  • 15 September 2018

    The original version of this article unfortunately contained mistake in Table 2 to where two directionality arrows were inverted.


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The authors would like to thank Dr. Cathleen Kovarik for the generous use of her laboratory. We are also grateful to and would like to acknowledge Dr. Tyler Jacks and Dr. Alexander Dent for their gifting of plasmids used in this study.


The study was funded by the University of Missouri.

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Correspondence to Frank W. Booth.

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Grigsby, K.B., Ruegsegger, G.N., Childs, T.E. et al. Overexpression of Protein Kinase Inhibitor Alpha Reverses Rat Low Voluntary Running Behavior. Mol Neurobiol 56, 1782–1797 (2019). https://doi.org/10.1007/s12035-018-1171-0

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  • Behavior
  • Gene
  • Brain
  • Rescue
  • Voluntary running
  • Selective breeding