Medial prefrontal cortex inputs to the dorsomedial striatum regulate motivation for wheel running in male mice

Wheel running is rewarding for rodents, and thus they exhibit strong willingness to engage in it and desire for it, i.e., motivation. Although neural activity in the dorsomedial striatum (DM-Str) has been suggested to be involved in motivation for wheel running, the causal relationship between neural activity and motivation remains unknown. Here, we investigated the role of neural activity in the DM-Str and the mechanisms regulating this activity in motivation for wheel running. Fiber photometry recordings with GCaMP sensors revealed that DM-Str neural activity transiently increased at the initiation of running on running wheels (RWs), whereas it decreased during running. Intra-DM-Str injection of the GABA_A receptor agonist muscimol or the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist NBQX reduced the number of RW rotations. In the open field test, neither muscimol nor NBQX injection into the DM-Str affected locomotor activity. Additionally, selective chemogenetic inhibition of projections from the medial prefrontal cortex (mPFC) to the DM-Str reduced RW rotation numbers without altering locomotor activity. Together, our findings suggest that DM-Str neural activity, enhanced by glutamatergic projection from the mPFC, plays a critical role in regulating motivation for wheel running.