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

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.