Behavior- and Cell Type-Specific Cortico-Striatal Decoupling in a Parkinson's Disease-Like Mouse Model

Area of Science:

• Neuroscience
• Motor Control
• Neurodegenerative Diseases

Background:

• Inter-brain region activity coupling is crucial for coordinated neural communication and complex processes like motor behaviors.
• Parkinson's Disease (PD) is characterized by cortico-striatal decoupling, but its onset and cellular mechanisms are not well understood.

Purpose of the Study:

• To investigate the cell-type-specific activity coordination between the primary motor cortex and dorsal striatum in a Parkinson's Disease mouse model.
• To determine the onset and cellular mechanisms underlying cortico-striatal decoupling in early PD.

Main Methods:

• Utilized dual-site fiber photometry and Cre transgenic mouse lines for cell-type-specific analysis of cortico-striatal coupling.
• Employed an alpha-synuclein preformed fibrils (PFF) model to induce PD-like symptoms in mice.
• Used optogenetics to manipulate cortico-striatal coupling and assess its impact on motor behavior.

Main Results:

• Identified motor behavior-specific coupling patterns involving D1R- and D2R-expressing medium spiny neurons (MSNs).
• Observed selective disruption of cortico-striatal coupling associated with digging behavior two months post-PFF induction, preceding later behavioral deficits.
• Demonstrated that impaired D1R MSNs primarily mediate the observed decoupling, which is responsive to D1 receptor activation and L-DOPA.

Conclusions:

• Early-onset, behavior- and cell type-specific cortico-striatal decoupling is an early feature in PD development.
• Cortico-striatal decoupling, particularly involving D1R MSNs, contributes to motor deficits in PD.
• Targeting D1R MSNs or D1 receptor pathways may offer therapeutic strategies for PD-related motor symptoms.