Dopamine-dependent cerebellar dysfunction enhances beta oscillations and disrupts motor learning in a multiarea model

Abstract

AbstractParkinson’s disease (PD) is a chronic degenerative disorder of the central nervous system that affects the motor system. The discovery that PD motor symptoms result from the death of dopaminergic cells in the substantia nigra led to focus most of PD research on the basal ganglia. However, recent findings point to an active involvement of the cerebellum in PD. Here, we have developed a multiscale computational model of the rodent brain’s basal ganglia-cerebellar network. Simulations showed that a direct effect of dopamine depletion on the cerebellum must be taken into account to reproduce the alterations of PD neural activity, particularly the increased beta oscillations widely reported in PD patients. Moreover, dopamine depletion indirectly impacted spike-time-dependent plasticity at the parallel fiber-Purkinje cell synapses, degrading associative motor learning as observed in PD. Overall, these results suggest a relevant involvement of cerebellum in PD motor symptoms.Significance StatementThis study highlights the role of cerebellum in Parkinson’s disease (PD). While most studies on PD concentrate on dopaminergic mechanisms in the basal ganglia, here we show that dopamine depletion impacts also on the cerebellum, generating a complex dysfunctional interaction between the two subcortical circuits. To investigate this interaction, we developedde novoa multiarea multiscale network model that mechanistically addresses the effects of dopamine depletionon the cerebellum. Our study demonstrates that this aspect is crucial to reproduce experimental data, particularly the increased beta wave activity. Moreover, alterations in spike-time-dependent plasticity at the parallel fibre – Purkinje cell synapse of cerebellum can explain the link between dopamine depletion to motor learning impairment. These simulations indicate that the cerebellum warrants more attention in future PD research.