Deep brain stimulation (DBS) effectively treats motor symptoms of advanced Parkinson's disease (PD), with the globus pallidus interna (GPi) commonly targeted. However, its therapeutic mechanisms remain unclear. We employed optogenetic stimulation in the entopeduncular nucleus (EP), the rat homolog of GPi, in a unilateral 6-hydroxydopamine lesioned female Sprague Dawley rat model of PD. We quantified behavioral effects of optogenetic EP DBS on motor symptoms and conducted single-unit recordings in EP and ventral lateral motor thalamus (VL) to examine changes in neural activity. High-frequency optogenetic EP DBS (75, 100, 130 Hz) reduced ipsilateral turning and corrected forelimb stepping, while low-frequency stimulation (5 and 20 Hz) had no effect. EP and VL neurons exhibited mixed response during stimulation, with both increased and decreased firing. The average firing rate of all recorded neurons in the EP and VL significantly increased at 130 Hz but not at other frequencies. Beta-band oscillatory activity was reduced in most EP neurons across high frequencies (75, 100, 130 Hz), while reductions in beta-band oscillations in VL occurred only at 130 Hz. These findings suggest that the neural firing rates within EP and VL circuits were differentially modulated by EP DBS
they may not fully explain the frequency-dependent behavioral effect. Instead, high-frequency optogenetic EP DBS at 130 Hz may ameliorate parkinsonian motor symptoms by reducing abnormal oscillatory activity in the EP-VL circuits. This study underscores the therapeutic potential of circuit-specific modulation in the pallidothalamic pathway using optogenetic EP DBS to alleviate motor deficits in a PD rat model.