Harnessing Pallidal Cell-Type Diversity to Treat Neurological Disorders

The identification of distinct cell-types within the basal ganglia has played a critical role in our understanding of basal ganglia function and the treatment of neurological disorders. As discussed in the introduction, the use of transgenic animals and bevy of emerging tools available to isolate, manipulate and control distinct populations of neurons have revolutionized neuroscience. We are gaining insight into the underlying structure of neural circuits that previously was inaccessible. Here, we defined cellular diversity within the globus pallidus externa (GPe), a nucleus within the motor-suppressing pathway of the basal ganglia, and investigated its contributions to circuit function in health and disease. First, we defined two genetically distinct populations of GPe neurons using transgenic mouse lines. Utilizing a combination of anatomy and physiology, we found significant difference between the two populations of GPe neurons. Briefly, viral expression of EYFP revealed that Limhomeobox6 (Lhx6-) and Parvalbumin (PV-) GPe neurons differed in their axonal projection patterns as well as electrophysiological properties measured in slice recordings. These results provide a new set of tools to target molecularly, anatomically, and electrophysiologically distinct cell-types in the GPe which will enables studies of the organization and function of GPe circuits in health and disease. Next, we demonstrate that optogenetic interventions that dissociate the activity of these two neuronal populations in the GPe – elevating the activity of PV-GPe neurons over that of Lhx6-GPe neurons – restores movement in dopamine depleted mice and attenuates pathological activity of basal ganglia output neurons for hours beyond stimulation. These results establish the utility of cell-specific interventions in the GPe to target functionally distinct pathways, with the potential to induce long-lasting recovery of movement despite the continued absence of dopamine. In the final chapter, we will discuss the evolving and often-controversial field of GPe cellular heterogeneity and the future of these neural cell-types. Secondly, we will provide potential mechanisms for which GPe cell-types exert profound therapeutic benefit during the disease state that could build on current treatments. Taken together, these results demonstrate the anatomic, physiological and functional differences that exist within the GPe cell-types and its potential to disrupt pathological activity and restore behavior during disease