Emergence of Task-Related Motor Cortical Dysfunction in Mice with Progressive Parkinsonism

Area of Science:

• Neuroscience
• Motor Control
• Neurodegenerative Diseases

Background:

• Parkinson's disease (PD) involves primary motor cortex (M1) dysfunction, but its link to dopaminergic (DA) neurodegeneration and motor symptoms is unclear.
• Understanding the timeline of M1 circuit changes during PD progression is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the temporal relationship between midbrain DA neurodegeneration, M1 circuit dysfunction, and motor impairments in a mouse model of PD.
• To characterize cellular and population-level changes in M1 during progressive DA loss.

Main Methods:

• Utilized MitoPark mice, a genetic model of progressive nigrostriatal DA degeneration.
• Employed AAV-mediated retrograde labeling to identify M1 pyramidal neuronal subtypes.
• Performed *in vivo* GCaMP6f imaging to assess neuronal activity and movement responsiveness during a skilled reaching task.

Main Results:

• MitoPark mice exhibited progressive impairment in skilled reaching, detectable at moderate motor stages.
• Reduced M1 pyramidal neuron activity and movement responsiveness correlated with impaired skilled movement.
• Corticospinal (CSp) neurons showed selective deficits in activity and responsiveness during reaches, unlike intratelencephalic (IT) neurons.
• M1 neuronal population activity encoding skilled movement degraded longitudinally in MitoPark mice, indicating impaired circuit stability.

Conclusions:

• Progressive DA neurodegeneration in PD leads to functional deficits in M1 circuits, impacting skilled motor control.
• M1 circuit pathophysiology emerges at both cellular and population levels during PD progression.
• Specific M1 neuronal subtypes, particularly CSp neurons, are differentially affected, contributing to motor symptoms.