Pallidothalamic Circuit-Selective Manipulation Ameliorates Motor Symptoms in A Rat Model of Parkinsonian

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 homologue of GPi, in a unilateral 6-OHDA 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. Behavioral tests showed high-frequency optogenetic EP DBS (75, 100, 130Hz) reduced ipsilateral turning and corrected forelimb stepping, while low-frequency (5 and 20Hz) had no effect. EP and VL neurons exhibited mixed response during stimulation, with both increased and decreased firing. Notably, the average firing rate of all recorded neurons in the EP and VL significantly increased at 130 Hz but not at other frequencies. While beta-band oscillatory activity was reduced in most EP neurons across high frequencies (75, 100, 130 Hz), reductions in beta-band oscillations with the 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 130Hz 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.Significance Statement The contribution of EP local cells to the therapeutic effects of EP DBS in PD has been unclear. Our study addressed this by employing local cell-specific optogenetic stimulation. Directly stimulating EP local neurons using optogenetics effectively reduced parkinsonian symptoms in the 6-OHDA lesioned rat. These findings highlight the importance of precise circuit manipulation through optogenetic techniques within the pallidothalamic pathway, suggesting a promising approach for ameliorating motor deficits in PD.