BME PhD Dissertation Defense: Leo Steiner

Title: "The Cellular and Network Mechanisms of Subthalamic Nucleus Deep Brain Stimulation"

Advisory Committee: Xue Han, PhD – BME (Research Advisor) Brian DePasquale, PhD – BME (Chair) Mark Howe, PhD – Psychological & Brain Sciences Robert Reinhart, MD – Psychological & Brain Sciences Ludy Shih, MD – Department of Neurology, Beth Israel Deaconess Milton

Abstract: Deep brain stimulation (DBS) is an effective therapy for Parkinson's Disease (PD), yet its mechanisms remain poorly understood. Using state-of-the-art electrophysiology and voltage imaging in mice, we investigated how dopamine loss and subthalamic nucleus DBS (STN-DBS) shape neural dynamics locally in the STN and across connected basal ganglia circuits. In the STN, simultaneous multi-unit electrophysiological recordings during voluntary locomotion revealed that dopamine loss exaggerates movement-related activation and selectively elevates beta-rhythmic firing at rest, while leaving individual neuron gait encoding largely intact. While DBS suppressed firing in both healthy and dopamine depleted PD mice, it selectively reduced STN beta-rhythmic spiking, desynchronized STN networks, and rescued gait deficits associated with the loss of dopamine. These results identify beta reduction and network desynchronization as core therapeutic mechanisms of STN-DBS for PD. In the striatum, voltage imaging of medium spiny projecting neurons expressing dopamine D2 receptors (D2-MSNs) revealed that STN-DBS at both 140 Hz and 10 Hz produced robust membrane depolarization in D2-MSNs. Low frequency stimulation at 10 Hz entrained D2-MSN membrane voltage (Vm) oscillations, while 140 Hz produced sustained Vm depolarization without entrainment. More importantly, 140 Hz DBS, but not 10Hz DBS, selectively attenuated sensory-evoked D2-MSN response. Together, these findings demonstrate that STN-DBS engage both local and connected basal ganglia circuits to shape sensorimotor processing, and providing direct cellular and network evidence underlying frequency specific DBS therapeutic effects. This work advances mechanistic understanding of DBS by providing single-cell resolution evidence of how DBS interferes with pathological dynamics across the basal ganglia circuit. These insights lay the groundwork for more effective, individualized DBS therapeutic strategies.