Electrically-Driven Cell-Type Specific Neuromodulation in the External Globus Pallidus

Abstract

The identification of distinct cell-types throughout the basal ganglia has been essential in advancing our understanding of network function and improving neurological therapies. In the globus pallidus externa (GPe), interventions targeted to neuronal subpopulations have profound therapeutic potential, but are challenging to implement in clinical settings. We investigated whether electrical stimulation can be tuned to engage cell-type specific responses in the GPe. Although conventional stimulation was non-specific, variance in the synaptic inputs onto Parvalbumin (PV-GPe) and Lim homeobox 6 (Lhx6-GPe) subpopulations enabled us to segregate the responses of these neurons using brief, high frequency bursts of stimulation. The circuit elements responsible for this synaptic variation were found to be asymmetrical inputs from the STN and collaterals of striatonigral neurons. Using a machine-learning approach, we established stimulus parameters that maximize this cell-type specific neuromodulation. These results establish the feasibility of rapidly transforming knowledge about circuit architecture into translatable therapeutic approaches.