Treadmill exercise rebalances M1 response repertoires during motor state transitions in Parkinsonian mice

Movement initiation and termination rely on cortical circuits that must flexibly switch between active and quiescent states, a process markedly compromised in Parkinson's disease (PD). Although exercise has documented benefits in alleviating parkinsonian motor deficits, how it restores state-transition flexibility at the cortical population level remains insufficiently understood. Here, male C57BL/6 mice were assigned to control (CG), 6-hydroxydopamine-lesioned (PD), and PD with treadmill training (PDEX) groups. We combined free-moving behavioral tracking with in vivo single-unit and local field potential recordings from the right primary motor cortex (M1). We identified multiple transition-related firing patterns in M1, with distributions differing across groups. The proportion of biphasic neurons (start-excitation/stop-inhibition) was similar across CG (34.4%), PD (33.1%), and PDEX (36.9%) groups (p = 0.358). In contrast, the proportion of start-only neurons (start-excitation/stop-no response) was significantly increased in the PD group (23.5%) compared with CG (11.7%) and was intermediate in the PDEX group (17.9%) (p = 0.001). In parallel, CG exhibited transition-related beta power modulation during both initiation and termination, whereas this modulation was absent in PD animals. In the exercise group, transition-related modulation emerged in the gamma-band. Furthermore, waveform analysis showed that these response patterns were observed in both putative pyramidal neurons and interneurons. Together, these results show that exercise mitigates PD-related motor dysfunction, at least in part, by reinstating the diversity of M1 transition-related responses, highlighting cortical transition coding as a plastic and exercise-responsive target for functional recovery in PD.