Objective: To advance a novel basal ganglia thalamocortical (BGTC) model that accounts for GPi as a tonic-burst mode regulator of the thalamus and for restricted pathology along select subcircuits in different movement disorders.

Background: The classical longstanding basal ganglia rate model has proven invaluable for conceptualizing BGTC circuitry, but does not account for GABAergic influences on burst-tonic mode regulation of thalamocortical neurons and for new observations of highly restricted subcircuitry pathophysiology in such movement conditions as PD and dystonia.

Method: Extensive multi-nuclei, multi-neuronal recordings were performed in GP (equivalent to human GPe), the entopeduncular nucleus (EP; equivalent to GPi), STN, pallidal receiving thalamus, and motor cortex in head restrained awake rats during resting and movement state under optogenetic and pharmacological manipulations. Focal lesions in GP were used to selectively induce parkinsonism or dystonia. Multi-synaptic viral tracers were focally injected in the parkinsonian and dystonia territories of GP to delineate the different movement disorder subcircuits. From these findings a novel subcircuitry model was developed to account for highly diverse movement disorders.

Results: Per our modeling of dystonia, under rest conditions, GPi neurons confined to the M1 subcircuit are pathologically slow, highly irregular, and bursty. This causes insufficient hyperpolarization of thalamic neurons, shifting the desired ‘ready’ rest burst mode to the tonic mode. With movement, pathological M1 subcircuitry inhibitory striatal neurons excessively silence ventral motor territory inhibitory GPe neurons. This causes synchronized, excessive, poorly timed activation of M1 territory GPi neurons leading to pathological activation of M1 thalamocortical signaling, producing characteristic dystonic muscle activation. In parkinsonism, with movement, similar pathological striatal silencing but of dorsal SMA circuit GPe neurons causes excessive, highly abnormal GPi-thalamo-SMA signaling. This results in erroneous SMA-M1 activation and the hypokinetic features of PD.

Conclusion: Our novel BGTC model explains the observed motor features of PD and dystonia, as well as other movement disorder conditions, by overlapping mechanisms along distinct motor subcircuits.
*Part of this study has been presented before in Society for Neuroscience 2019.

References: NA

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-phasic-and-restricted-basal-ganglia-thalamocortical-subcircuitry-model/