Intrinsic Disruption of the M1 Cortical Network in a Mouse Model of Parkinson's Disease

Abstract

Background: Parkinson's disease (PD) disrupts motor performance by affecting the basal ganglia system. Yet, despite the critical position of the primary motor cortex in linking basal ganglia computations with motor performance, its contribution to motor disability in PD is largely unknown. The objective of this study was to characterize the role of the primary motor cortex in PD-related motor disability. Methods: Two-photon calcium imaging and optogenetic stimulation of primary motor cortex neurons was done during performance of a dexterous reach-to-grasp motor task in control and 6-hydroxydopamine-induced PD mice. Results: Experimental PD disrupted performance of the reach-to-grasp motor task and especially initiation of the task, which was partially restored by optogenetic activation of the primary motor cortex. Two-photon calcium imaging during task performance revealed experimental-PD affected the primary motor cortex in a cell-typespecific manner. It suppressed activation of output layer 5 pyramidal tract neurons, with greater effects on freeze versus nonfreeze trials. In contrast, it did not attenuate the initial movement-related activation response of layer 2/3 pyramidal neurons while diminishing the late inhibitory phase of their response. At the network level, experimental PD disrupted movement-related population dynamics of the layer 5 pyramidal tract network while almost not affecting the dynamics of the layer 2/3 neuronal population. It also disrupted short-and long-term robustness and stability of the pyramidal tract subnetwork, with reduced intertrial temporal accuracy and diminished reproducibility of motor parameter encoding and temporal recruitment of the output pyramidal tract neurons over repeated daily sessions. Conclusions: Experimental PD disrupts both external driving and intrinsic properties of the primary motor cortex. Motor disability in experimental PD results primarily from the inability to generate robust and stable output motor sequences in the parkinsonian primary motor cortex output layer 5 pyramidal tract subnetwork.

Motor Cortical Network Excitability in Parkinson's Disease

“…However, somatosensory co‐stimulation does not contribute significantly to the early TEPs considered in the present study 48,71 . Because we did not use individual MRI neuronavigation, variability in pre‐SMA and SMA‐proper locations may have confounded TEP results due to distinctive functional changes occurring in the pre‐SMA and SMA‐proper in PD 64 . However, because we centered our coil over pre‐SMA coordinates that did not overlap with the SMA‐proper, 46,72 and because our estimated electric field maximal values (Figure S1) were within the boundaries of the pre‐SMA maximal probability area, 72 we believe that our methods resulted in high spatial selectivity for pre‐SMA activation with limited confounding due to SMA coactivation.…”

“…48,71 Because we did not use individual MRI neuronavigation, variability in pre-SMA and SMA-proper locations may have confounded TEP results due to distinctive functional changes occurring in the pre-SMA and SMA-proper in PD. 64 However, because we centered our coil over pre-SMA coordinates that did not overlap with the SMAproper, 46,72 and because our estimated electric field maximal values (Figure S1) were within the boundaries of the pre-SMA maximal probability area, 72 we believe that our methods resulted in high spatial selectivity for pre-SMA activation with limited confounding due to SMA coactivation. Also, the increase in pre-SMA TEPs is in line with the pre-SMA hyperactivation previously reported, 66 supporting the conclusion that our results likely reflect pre-SMA excitability.…”

“…TEPs are generated by a summation of excitatory and inhibitory postsynaptic potentials generated by the activity of cortical pyramidal neurons and interneurons and reflect cortical excitability 16‐22 . Animal intracortical recordings from layer 5 showed a significant increase in the firing rate of pyramidal neurons in the P30 time range 33 and reduced pyramidal neuron activity in animal models of PD 4,5,64 . Therefore, the decreased P30 amplitude after stimulation of M1 on both sides likely reflects reduced excitability of M1 pyramidal neurons in OFF PD patients 3‐5 .…”

Acupuncture Regulates Symptoms of Parkinson’s Disease via Brain Neural Activity and Functional Connectivity in Mice

“…There have been several reports showing the importance of M1 in PD (Alexander et al, 1986 ; Lang and Lozano, 1998 ; Murer et al, 2002 ; Dejean et al, 2012 ; Vitrac et al, 2014 ). M1, which controls skilled movement, receives inputs from the other cortex and thalamus, and the thalamus integrates data from the basal ganglia and cerebellum to generate output motor commands from layer 5 pyramidal tract neurons, sending convergent signals to connect directly to descending motor pathways (Aeed et al, 2021 ). Thus, M1 strongly controls movement execution through a central location in the motor circuitry and is critically involved in mediating basal ganglia abnormalities and motor disabilities (Lanciego et al, 2012 ).…”

Current approaches to characterize micro- and macroscale circuit mechanisms of Parkinson’s disease in rodent models

“…Thus, activity sequences time-correlated to specific behavioral patterns were identified within the striatal direct and indirect pathways ( Sheng et al, 2019 ). In PD models, it was possible to show the reduced activity of M1 layer 5 pyramidal neurons in comparison to healthy conditions ( Aeed et al, 2021 ).…”