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

Abstract

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.