The Mechanism of Substantia Nigra Pars Reticulata Deep Brain Stimulation (SNr-DBS) in Alleviating Motor Symptoms and Pain of Parkinson's Disease
Yining Wang1, Xinyang Gu1, Jingchuan Wu1, Xin Zhang1, Zengxin Qi1, Liang Chen1
1Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai
Objective:
To confirm the efficacy of SNr-DBS on motor and pain behaviors in PD mice model, and decipher the crucial circuits originating SNr independently regulating motor and pain symptoms.
Background:
The motor and pain symptoms are frequently intractable in patients with Parkinson's disease (PD). New DBS targets are required to validate except for subthalamic nucleus (STN). As a critical output region of basal ganglia, substantia nigra pars reticulata (SNr) is an emerging DBS target.
Design/Methods:
Whole brain-wide screening revealed the activation of SNr neuron in FosTRAP2::Ai9 mice undergoing unilateral 6-OHDA-lesion in contrast to sham mice. The effect of SNr-DBS with different stimulation frequency was validated by open field test and VonFrey test. Optic fiber recording was implied to detect the effect of SNr-DBS with different stimulation frequency on the Ca2+ signals of SNr neurons and astrocytes. Chemogenetic manipulation was utilized to reverse SNr-DBS effect. The effect of combined STN-SNr DBS was testified for PD patients.
Results:
SNr neurons was overactivated in PD mice model. Compared with 10Hz and 70Hz, 130Hz (100 μA current,100 μs pulse) SNr-DBS could significantly improve moving distance, average velocity and mechanical pain threshold in PD mice. A noticeable decrease in Ca2+ signals in SNr neurons and astrocytes was observed in response to SNr-DBS. The ventromedial thalamus (VM) and dorsal part of anterior pretectal nucleus (APNd) were identified as two significant downstream nuclei of of SNr-PV+ neurons. Selective chemogenetic activation of SNr-PV+→VM and SNr-PV+→APNd could reverse the distinct effect of SNr-DBS on motor and pain symptoms, respectively. SNr-DBS or combined STN-SNr DBS could also improve motor and pain symptoms of PD patients.
Conclusions:
High frequency SNr-DBS could possibly alleviate motor and pain behaviors of 6-OHDA mice via SNr-PV+ neurons projecting to VM and APNd, respectively. Combined STN+SNr-DBS might be a potential DBS strategy for complicated motor and pain symptoms of PD patients.
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