ABSTRACT
Deep brain stimulation (DBS) is an effective therapy for various movement disorders including Parkinson’s
disease. To treat PD, DBS electrodes are typically placed into either the internal globus pallidus (GPi) or the
subthalamic nucleus (STN). Rational target selection for DBS is a critical step in delivering effective treatment
for PD. Both GPi-DBS and STN-DBS have been proven to produce remarkable reductions in cardinal PD
symptoms including resting tremor, rigidity, bradykinesia, and akinesia. However, increased observations of
worsening cognitive and behavioral side effects and motor symptoms refractory to STN-DBS have raised
concerns on STN-DBS and prompted growing interest in GPi-DBS. Currently, the lack of understanding of the
circuit mechanisms underlying the therapeutic DBS hampers the development and optimization of GPi-DBS to
improve therapeutic efficacy and minimize side effects. The objective of this research proposal is to identify the
necessity of neural elements and circuits for the therapeutic effect of GPi-DBS by manipulating relevant neural
circuits during the quantitative assessment of parkinsonian motor symptoms. We will combine electrical
stimulation, optogenetic inhibition, simultaneous multisite recording, and quantitative behavioral assays in a rat
model of PD to determine the functional relevance of GPi-DBS associated neural elements and circuits including
GPi, primary motor cortex, and ventral lateral motor thalamus. Our specific aims are to (1) determine the
necessity of neural elements and circuits for the effects of GPi-DBS and STN-DBS on parkinsonian motor
symptoms; (2) quantify the changes of neural activity in GPi neural circuits during GPi-DBS with selective
optogenetic inhibition. The combination of electrical stimulation and optogenetic inhibition will provide an
innovative and powerful strategy for circuit function analyses, and such an approach will identify the effective
and non-effective circuits in GPi-DBS. We hypothesize that selective suppression of therapeutically effective
DBS neural circuits will disrupt DBS symptom amelioration efficacy, reduce neural activity and attenuate DBS
effects on pathological neural oscillations and synchrony. The outcomes of the proposed research will provide
novel insight into the neural mechanisms underlying GPi-DBS and ultimately establish a framework for
developing novel therapeutic strategies to improve the efficacy and efficiency of DBS therapy in PD and other
neurological and psychiatric disorders.