Deep brain stimulation of the substantia nigra pars reticulata improves forelimb akinesia in the 1 hemiparkinsonian rat 2 3

28 Deep brain stimulation (DBS) employing high frequency stimulation (HFS) is commonly used in the globus 29 pallidus interna (GPi) and the subthalamic nucleus (STN) for treating motor symptoms of patients with 30 Parkinson’s disease (PD). While DBS improves motor function in most PD patients, disease progression and 31 stimulation-induced non-motor complications limit DBS in these areas. In this study, we assessed whether 32 stimulation of the substantia nigra pars reticulata (SNr) improved motor function. Hemiparkinsonian rats 33 predominantly touched with their unimpaired forepaw >90% of the time in the stepping and limb-use 34 asymmetry tests. After SNr-HFS (150Hz), rats touched equally with both forepaws, similar to naïve and 35 sham-lesioned rats. In vivo, SNr-HFS decreased beta oscillations (12-30 Hz) in the SNr of freely moving 36 hemiparkinsonian rats and decreased SNr neuronal spiking activity from 28 ± 1.9 Hz before stimulation to 0.8 37 ± 1.9 Hz during DBS in anesthetized animals; also, neuronal spiking activity increased from 7 ± 1.6 Hz to 18 38 ± 1.6 Hz in the ventromedial portion of the thalamus (VM), the primary SNr efferent. In addition, HFS of the 39 SNr in brain slices from normal and reserpine-treated rat pups resulted in a depolarization block of SNr 40 neuronal activity. Taken together, we demonstrate improvement of forelimb akinesia with SNr-HFS and 41 suggest that this motor effect may have resulted from the attenuation of SNr neuronal activity, decreased 42 SNr beta oscillations and increased activity of VM thalamic neurons and suggests that the SNr may be a 43 plausible DBS target for treating motor symptoms of DBS. 44 45