Dissecting Neural Circuit Mechanisms Underlying Pallidal Deep Brain Stimulation

Michigan Technological University, Houghton MI

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Abstract

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.