Behavior- and circuit-specific cortico-striatal decoupling during the early development of Parkinson’s disease-like syndrome

ABSTRACT Despite that cortico-striatal decoupling has been widely reported in individuals diagnosed with Parkinson’s Disease (PD), its onset, circuit specificity and underlying mechanism remain largely unclear. To investigate these questions, dual fiber photometry is established for the first time to evaluate cortico-striatal coupling during varied motor behaviors, whose cell-type resolution was provided by the usage of Cre transgenic mouse lines. Contralateral turning, digging and licking show distinct coupling patterns, among which digging induces the strongest coupling. Striatal D1R-expressed medium spiny neurons (dMSNs) and D2R-expressed MSNs (iMSNs) similarly contribute to the cortical-striatal coupling during turning and licking but not digging, with much tighter coupling between the dMSNs and the M1 cortex. In PD-like mouse model induced via intra-striatal injection of synthetic mouse wildtype α-synuclein preformed fibril (PFF), digging-associated cortical-striatal decoupling emerges as early as 1-month post induction (Mpi), which becomes significant since 2 Mpi and correlates with later-onset behavioral deficit. Notably, impaired dMSNs but not iMSNs mediate this decoupling, which can be rescued by activation of D1 but not D2 receptor. Mechanistically, we found an inverted U-shape decline in striatal dopamine level along the disease development in PFF-injected mice. Supplement with L-DOPA alleviates the decoupling and motor deficit, suggesting that early dopamine deficiency directly contributes to the cortical-striatal decoupling and the associated motor deficit. These findings provide new insights into the temporal profile and mechanisms underlying the PD-associated cortico-striatal decoupling, which has been implicated as functional biomarker for early diagnosis of PD.