New Insights into the Cerebellothalamocortical Pathway: Anatomical Basis for the Integration of Basal Ganglia and Cerebellar Pathways in the Motor Thalamus

Abstract

The basal ganglia and cerebellar motor pathways project information to the motor cortex via the motor thalamus. The precise role of the thalamus in motor functioning is largely unknown. Anatomically, data suggest that basal ganglia and cerebellar terminals do not overlap, however, the two regions have very similar movement related activity, suggesting a common input. To investigate cerebellar inputs in the motor thalamus and its relation to thalamocortical neurons projecting to layer I of the motor cortex, this study anterogradely traced cerebellar inputs from interpositus using an AAV-DJ vector expressing YFP under the control of the CaMKII promoter to label glutamatergic neurons. In addition, thalamocortical neurons were retrogradely labelled using the beta-subunit cholera toxin placed on the epipial surface above the motor cortex. This is the first time cerebellothalamic and thalamocortical pathways have been traced in the same animal.

Two cerebellar pathways were observed throughout the thalamus, a major and a minor pathway, with large VGluT2 terminals colocalised with axon tracing seen in VL of the motor thalamus and VPL. The minor cerebellar axon pathway that innervates the intralaminar nuclei extended more anteriorly than previously described, and appeared to overlap with the major ventral pathway. Small cerebellar terminals were seen throughout VA and VM, apposed on thalamocortical cell bodies projecting to layer I, which is currently described as the basal ganglia input layer of the cortex. Motor thalamus cells projecting to layer I were shown to be associated with both large GAD67 and large VGluT2 terminals, known to be from the basal ganglia and cerebellum respectively, which further suggests overlap of these motor pathways at a cellular level in the motor thalamus. To examine if the cerebellothalamic pathway was affected in chronic Parkinsonian animals, induced by 6-OHDA injection into the median forebrain bundle, cerebellar terminals with colocalised YFP and VGluT2 in the cerebellar-receiving territory of the motor thalamus were counted using stereological techniques. No significant difference in the total terminal count was observed between control and lesioned animals 7 weeks post-lesion. However the minor axon pathway was more prominent and there appeared to be cerebellar axon proliferation in the border region between VL and VPL.

This study provides an anatomical basis for the similarities in movement related activity across VA, VL and VM. Basal ganglia and cerebellar pathways converge on individual motor thalamus regions enabling integration of information in the motor thalamus. Additionally, a pathological change of the cerebellar axons was shown in the thalami of animals with a 6-OHDA lesion, showing cerebellar involvement in pathology of Parkinson’s disease.