Extended Data Fig. 8: Strengthening the PF→STN circuit restores motor learning in PD model mice through PV+ STN neurons, and PD model mice show depression-like phenotypes.
From: Targeting thalamic circuits rescues motor and mood deficits in PD mice
a, AMPA/NMDA ratio recordings of PF→STN circuit from WT and PD model mice in home cage and rotarod conditions (WT data from Fig. 2e, PD data from Fig. 4d). b, cFos activation of STN neurons using home cage and rotarod PD model mice (n = 4 mice per group). c, PF→STN circuit manipulation in PD model mice by injecting CaMKII-oChIEF-mCh virus in PF, optic fibers above STN, and 6-OHDA injections in SNc (left). Expression of oChIEF-mCh in PF (right). d, Optical protocols including 20 Hz- and 100 Hz-only protocols. 20 Hz blue light was delivered during trials whereas 100 Hz blue light was delivered between trials. e, Activation of the PF→STN circuit in PD model mice using the 20 Hz or 100 Hz protocol during rotarod behavior (20 Hz: n = 9, 100 Hz: n = 7 mice). f, STN cFos activation in PD model mice (n = 4 mice per group) following PF→STN circuit activation with the 20 + 100 Hz protocol during rotarod. Control PD model mice (PDmCh) was prepared similar to the PDoChIEF mice except that a mCh virus was injected in PF. g-h, PF→STN circuit strengthening with VGLUT2 or PV inhibition in STN during rotarod, using PD model mice. CaMKII-oChIEF-mCh virus was injected in PF, Cre-dependent hM4Di virus in STN, 6-OHDA in SNc, and fibers targeted STN of Vglut2-Cre or PV-Cre mice (g). Rotarod behavior (n = 8 Vglut2-Cre, n = 7 PV-Cre mice) (h). i-j, Sucrose preference (n = 8 mice per group) (i) and total immobility time in forced swim (n = 9 WT, n = 8 PD + PFCPu mCh, n = 10 PD + PFCPu hM4Di mice) and tail suspension (n = 9 WT, n = 8 PD + PFCPu mCh, n = 8 PD + PFCPu hM4Di mice) tests in PD (j). To rule out the possibility that decreased locomotion of PD model mice resulted in their performance in these assays, a retrograde RVdGL-Cre was injected in CPu and Cre-dependent hM4Di-mCh was injected in PF of PD model mice (PD + PFCPu hM4Di group). For WT and PD + PFCPu mCh groups, Cre-dependent mCh was injected in PF in place of the hM4Di virus. C21 was injected 40 min before tests to rescue locomotion deficits in PD model mice by manipulating the PF→CPu circuit. k-m, Monosynaptic retrograde RV tracing from D1+ or D2+ NAc neurons. Images show starter cells in NAc (k), FISH co-staining of GFP with D1 or D2 (l), and corresponding PF labeling (n = 3 mice per group) (m). n, Representative traces (left) and current-frequency curves (right) of ex vivo recordings from D2- (putative D1+) or D2+ MSNs in NAc using D2-eGFP mice (D1: n = 20 neurons (6, 7, 7), D2: n = 16 neurons (6, 4, 6) from 3 mice each). o, Representative images of PF sections stained with cFos from mice expressing SOUL in PF neurons, including a no light group (SOUL - light) and a 5 min light activated group (SOUL + light) in the home cage. Data are presented as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001. NS, not significant. One-way ANOVA followed by Bonferroni post-hoc test (a), two-tailed unpaired t test (b, f, m), two-tailed paired t test (e, h), and two-way ANOVA with repeated measures followed by Bonferroni post-hoc test (n). F = 5.81, P = 0.0018, Home cage WT vs. home cage PD t = 4.04, Rotarod WT vs. Home cage PD t = 1.15 (a), P = 0.84 (b), 20 Hz P = 0.87, 100 Hz P = 0.72 (e), P = 0.012 (f), Vglut2-Cre P = 0.005, PV-Cre P = 0.59 (h), F = 4.28, P = 0.028, WT vs. PD + PFCPu mCh t = 2.71, PD + PFCPu mCh vs. PD + PFCPu hM4Di t = 0.39 (i), Forced swim: F = 8.92, P = 0.0013, WT vs. PD + PFCPu mCh t = 3.95, PD + PFCPu mCh vs. PD + PFCPu hM4Di t = 0.88, Tail suspension: F = 7.18, P = 0.004, WT vs. PD + PFCPu mCh t = 3.21, PD + PFCPu mCh vs. PD + PFCPu hM4Di t = 0.07 (j), P = 0.58 (m), F = 38.34, DFn = 1, DFd = 272, P < 0.0001 (n)
