Motor cortical circuit adaptations in parkinsonism

We employed the mice with 6-hydroxydopamine lesions of the medial forebrain bundle as a model of parkinsonism (Chen et al., 2023). This model recapitulates key features of neural network activity and behavior phenotypes of parkinsonism, as seen in people with Parkinson’s disease, making it suitable for mechanistic studies of cellular and synaptic adaptation after the loss of dopamine. Combining viral-mediated optogenetics and ex vivo electrophysiology, we found that following the loss of dopamine, there is a significant reduction of thalamic excitation to pyramidal tract (PT) neurons, but not the intratelencephalic (IT) neurons, in the layer 5 of the primary motor cortex (M1). Further anatomical studies also found that PT, but not IT, neurons exhibit a cortical layer-specific loss of dendritic spines in dopamine-depleted mice, supporting a cell subtype-specific decrease of thalamic excitation to M1 pyramidal neurons. Moreover, the connection strength of the corticocortical projections was not affected by dopamine depletion. Altogether, these results suggest that loss of dopamine triggers circuit-specific changes in M1.