Aberrant Cerebellar-Recipient Thalamic Activity in Two Mouse Models with Prominent Tremor or Bradykinesia.

Abstract

The motor thalamus functions as a gateway between subcortical and cortical motor circuits, relaying information critical to movement initiation and execution. Inputs to motor thalamus from the basal ganglia and cerebellum form functionally distinct circuits responsible for different aspects of healthy and dysfunctional motor control. Here, we use mouse models that capture different features of Parkinson's disease pathophysiology-alpha-synuclein (α-syn) aggregation and dopamine loss-to study how thalamic subcircuits are altered under different pathophysiological conditions. Using a trans-synaptic viral approach to delineate cerebellar-recipient (CBMT) and basal ganglia-recipient (BGMT) territories of motor thalamus in mice of both sexes, we found that in the 3K α-syn model where tremor is the dominant phenotype, thalamic pathophysiology was restricted to the CBMT, whereas in the 6-OHDA depletion model where the dominant phenotype is bradykinesia, thalamic pathophysiology was present in both the CBMT and BGMT. In the CBMT of both disease models, neuronal activity was irregular and showed dampened responses to movement compared with healthy control mice. Additionally, in the 6-OHDA model, the baseline firing rates of CBMT neurons were reduced. In the BGMT, firing rates and patterns of neurons in the 3K model were indistinguishable from those of controls, but in the 6-OHDA model, firing rates and movement-related activity of BGMT neurons were reduced relative to healthy controls. These results suggest selective CBMT involvement in the 3K α-syn model whereas the 6-OHDA model involves more global thalamic pathophysiology encompassing both the CBMT and BGMT.