Fig. 3: Activation of axons from GPe PV neurons is necessary and sufficient for DBS effect. | Nature Communications

Fig. 3: Activation of axons from GPe PV neurons is necessary and sufficient for DBS effect.

From: Deep brain stimulation alleviates Parkinsonian motor deficits through desynchronizing GABA release in mice

Fig. 3

a Schematic of bilateral virus injections and bilateral implantation of optic fibers for optogenetic activation of GPe axons in DD mice. b Average velocity (bin size: 5 s) before (Pre), during (Stim, blue), and after (Post) 130 Hz HFS of GPe axons (oChIEF, n = 6 mice; tdTomato, n = 6 mice). c, Group data comparing the average velocity within 30 s before, during, and after the optogenetic HFS of GPe axons at STN. Note the increase in locomotion velocity in mice with oChlEF/tdTomato expression (n = 6 mice) but not those with tdTomato expression alone (control, n = 6 mice). oChIEF: Pre vs. Stim (P = 0.0313), Wilcoxon matched-pairs signed rank test, two-sided; tdTomato: Pre vs. Stim (P = 0.6684), paired t-test, two-sided. d–f Similar experiments as in a-c but with virus injection in PV-Cre mice to allow Cre-dependent expression of oChlEF/mCherry in GPe PV-positive neurons. Note the increase in velocity of mice with oChlEF expression (n = 12 mice) but not those with mCherry alone (n = 8 mice). For (f) oChIEF: Pre vs. Stim (P = 0.0005), mCherry: Pre vs. Stim (P = 0.5469), Wilcoxon matched-pairs signed rank test, two-sided. g–i Similar experiments as in (d–f) but with Cre-off virus injections that allow a selective expression of oChIEF in GPe non-PV neurons. Note that optogenetic activation of non-PV axons at either 130 or 20 Hz produced no change in locomotion velocity (n = 7 mice). For (i) oChIEF-130 Hz: Pre vs. Stim (P = 0.9543), oChIEF−20 Hz: Pre vs. Stim (P = 0.2290), paired t test, two-sided. j Representative images showing the expression of mCherry and PV immunosignals in PV-Cre mice with two types of viruses (Cre-on DIO and Cre-off DO). Scale bar, 100 μm. k Left, percentage of PV-positive cells in mCherry-expressing cells with the Cre-on virus injection (n = 5 mice). Right, percentage of PV-negative cells in mCherry-expressing cells with the Cre-off virus injection (n = 6 mice). l Schematic of virus injections for bilateral ablation of PV neurons and STN DBS in DD mice. m A complete loss of PV-positive cells in GPe 3–5 weeks after the virus injection (n = 5 mice). Scale bar, 500 μm. n Group data comparing the average velocity within 10 min of PV-Cre DD mice (n = 11 mice) and PV-ablated DD mice (n = 12 mice). Unpaired t-test, two-sided, P = 0.5792. o Representative traces showing the effect of 130- or 20-Hz STN DBS on the locomotion velocity of mice with PV cell ablation. p Group data comparing the average velocity within 60 s before, during, and after the DBS (n = 12 mice). 130 Hz: Pre vs. Stim (P = 0.2925), paired t-test, two-sided; 20 Hz: Pre vs. Stim (P = 0.5186), Wilcoxon matched-pairs signed rank test, two-sided. NS, not significant; *P < 0.05, ***P < 0.001. Data are represented as mean ± SEM. Source data are provided as a Source Data file. See also Supplementary Figs.  5 and 6.

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