Inferior olive-selective amplitude suppression and progressive dentato-cortical decoupling during haloperidol-induced parkinsonism: a longitudinal multi-unit activity study.
Inferior olive-selective amplitude suppression and progressive dentato-cortical decoupling during haloperidol-induced parkinsonism: a longitudinal multi-unit activity study.
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Original abstract
Drug-induced parkinsonism (DIP) arises from competitive D2 receptor blockade, yet its cerebellar circuit-level dynamics remain poorly characterized. We recorded multi-unit activity simultaneously from four cerebellar structures (dentate nucleus, Crus II, inferior olive, and lobulus Sim B) across three weekly sessions in male Wistar rats receiving chronic haloperidol (1.5 mg/kg/day, subcutaneous) to characterize structure-specific and longitudinally evolving cerebellar population dynamics. Resting-state discharge amplitude was suppressed only in the inferior olive after FDR correction, where all six amplitude features fell sharply (d = -6, pFDR < 0.001); reductions in the same direction in Sim B were smaller and non-significant (d = -1.24 to -1.38), as was a concurrent increase in discharge rate (Hedges' g = +1.15, 95% CI [-0.07, 2.37]). During spontaneous tremor, all four structures showed elevated population amplitude alongside reduced discharge rate and irregularity, identifying temporally concentrated synchronized discharge rather than generalized hyperactivation as the mesoscopic tremor correlate. Phase coupling diverged anatomically: dentate-Crus II synchronization declined progressively across weeks (slope = -0.024 per week, p = 0.0006, Rm2 = 0.36) while olivocerebellar coupling remained robust and static. Week-1 Crus II activity alone predicted week-3 tremor burden in this single cohort with cross-validated accuracy (rLOO = 0.993, RLOO2 = 0.901, pFDR = 9.0×10-4), and unsupervised clustering revealed progressive neural state reorganization across all structures without behavioral escalation. These findings establish DIP as a longitudinally evolving cerebellar network state driven by pharmacodynamic changes beyond acute D2 occupancy, identifying the inferior olive, the dentate-Crus II axis, and Crus II as mechanistically and anatomically distinct nodes for future pharmacological and translational investigation.