THE ROLE OF DORSOMEDIAL STRIATUM IN REGULATING THE MOTIVATION FOR WHEEL RUNNING IN MICE

Abstract Background Behavioral addiction, such as a gaming disorder, is defined as an uncontrollable desire to repeat a certain behavior despite negative consequences. Effective treatments have not been established because pathological mechanisms of behavioral addiction remain unclear probably due to the lack of appropriate animal models. Since mice exhibit a strong motivation for rotating running wheels (RWs), we considered this behavior as a model of behavioral addiction characterized by “strong motivation for a certain behavior”. We have recently shown that wheel running increases c-Fos expression in the dorsomedial striatum (DM-Str), which constitutes the motivational circuitry (Zhang et al., 2020). However, the precise DM-Str neural activity during wheel running and its related behaviors and the role of DM-Str neuronal activity for regulating the motivation for wheel running remain unclear. Aims & Objectives We aimed to determine when DM-Str neurons are activated during the free access to RWs. Moreover, we investigated whether DM-Str neuronal activity and dopaminergic/glutamatergic transmissions in the DM- Str are involved in regulating the motivation for wheel running. Methods Male C57BL/6J mice (> 6 weeks old) allowed a 30-min free access to RWs for at least 10 days. After stable wheel rotation numbers, mice received intra-DM-Str infusion of muscimol (GABAA receptor agonist, 0.2 & micro;g/side), SCH23390 (dopamine D1 receptor antagonist, 0.15 & micro;g/side), raclopride (dopamine D2 receptor antagonist, 1 & micro;g/side) or NBQX (AMPA receptor antagonist, 0.05 & micro;g/side) 2 min before the free access to RWs or open field test (OFT). The number of wheel rotations and locomotor activity in the OFT were evaluated as motivation for wheel running and motor function, respectively. To monitor DM-Str neuronal activity, fiber photometry recordings using jGCaMP8m, which was expressed by injecting pAAVdj-hSyn-jGCaMP8m, were performed during the free access to RWs. Results Fiber photometry recordings revealed that DM-Str neuronal activity was transiently increased when mice turned to RWs, put their fore paw on RWs, and started running on RWs. Interestingly, DM-Str neuronal activity was significantly decreased during wheel running compared to during sedated states. Intra-DM- Str muscimol infusion reduced the number of wheel rotations, but not the locomotor activity, indicating the association of DM-Str neuronal activity with the regulation of motivation for wheel running. On the other hand, intra-DM-Str infusion of raclopride, but not SCH23390, reduced both the wheel rotation numbers and locomotor activity. Finally, intra-DM-Str NBQX infusion decreased the number of wheel rotations without affecting the locomotor activity, indicating the involvement of glutamatergic transmission in regulating the motivation for wheel running. Discussion & Conclusion These results suggest that the increase in DM-Str neural activity at the timing of behaviors related to willingness to rotate RWs, which might be mediated by glutamatergic transmission in the DM-Str, is important for regulating the motivation for wheel running. Although it is suggested that D2 receptor- mediated dopaminergic transmission in the DM-Str may also contribute to the regulation of motivation for wheel running, further studies would be needed to clarify this point. References Kim, H.S. Son, G., Roh, E.B., Ahn, W.Y., Kim, J., Shin, S.H., Chey, J., Choi, K.H. (2022) Prevalence of gaming disorder: A meta-analysis. Addictive Behaviors, 126, 107-183 Zhang, T. Nishitani, N. Niitani, K. Nishida, R. Futami, Y. Deyama, S. Kaneda K. (2020) A spatiotemporal increase of neuronal activity accompanies the motivational effect of wheel running in mice. Behav Brain Res, 8, 432, 113981