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

## TL;DR

This study identifies early brain communication issues in a mouse model of Parkinson's disease, linked to specific brain cells and behaviors.

## Contribution

The study reveals behavior- and cell type-specific cortico-striatal decoupling in a PD-like mouse model and its dopamine-dependent mechanism.

## Key findings

- Cortico-striatal coupling associated with digging behavior is selectively disrupted early in the PD-like mouse model.
- Decoupling is mainly mediated by impaired D1R MSNs and can be rescued by D1 receptor activation or L-DOPA.
- Optogenetic manipulation of coupling induces or rescues digging deficits in mice.

## Abstract

Inter‐brain region activity coupling is essential for enabling coordinated neural communication, facilitating complex brain processes including motor behaviors. In Parkinson's Disease (PD) patients, cortico‐striatal decoupling is widely reported while its onset and cellular mechanism remain largely unclear. Using dual‐site fiber photometry and Cre transgenic mouse lines, we examined activity coordination between the primary motor (M1) cortex and dorsal striatum (cortico‐striatal coupling) with cell‐type resolution. This method identifies motor behavior‐specific coupling patterns with different contributions from striatal D1R‐ and D2R‐expressing medium spiny neurons (MSNs). In an α‐synuclein preformed fibrils (PFF) induced PD‐like mouse model, cortico‐striatal coupling associated with digging behavior is selectively disrupted as early as two months post‐induction, whose progressive deterioration correlates with later‐onset behavioral deficits. Optogenetic disruption or enhancement of cortico‐striatal coupling is sufficient to induce digging deficits in wild‐type mice or rescue such deficits in PFF‐injected mice, respectively. Furthermore, such decoupling is mainly mediated by impaired D1R MSNs, which can be rescued by D1 receptor activation or L‐DOPA. These findings demonstrate that early‐onset, behavior‐ and cell type‐specific cortico‐striatal decoupling emerges early during the development of PD‐like symptoms.

Utilizing dual‐site fiber photometry, this study examines cortico‐striatal coupling with cell type resolution, identifying behavior‐ and cell type‐specific cortico striatal decoupling and its dopamine‐dependent mechanism in a Parkinson's disease mouse model. The findings suggest that behavior‐specific cortico striatal decoupling may serve as a promising biomarker and therapeutic target for early‐stage Parkinson's disease.