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. Author manuscript; available in PMC: 2020 Nov 25.
Published in final edited form as: Nat Neurosci. 2020 May 25;23(7):892–902. doi: 10.1038/s41593-020-0647-1

Fig. 4. Out-of-phase, but not in-phase, gamma-frequency stimulation of PV interneurons disrupts learning during rule shifts but not during initial associations or rule reversals.

Fig. 4.

a, PV-Cre, Ai14 mice had injections of AAV-DIO-eYFP or AAV-DIO-ChR2-eYFP in mPFC and fiber-optic implants bilaterally in mPFC. Experimental design: Day 1: out-of-phase 40 Hz stimulation during the rule shift (RS); Day 2: no stimulation. b–c, Out of phase 40 Hz stimulation impairs rule shift performance in ChR2-expressing mice compared to eYFP-expressing controls (n = 5 mice in each cohort; two-way ANOVA; main effect of day: F1,8 = 40.2, ***P = 0.0002; main effect of virus: F1,8 = 32.5, ***P = 0.0005; day X virus interaction: F1,8 = 47.3, ***P = 0.0001). b, Performance of eYFP-expressing controls did not change from Day 1 to 2 (n = 5 mice; post hoc t(8) = 0.38, P > 0.99). c, Out-of-phase 40 Hz stimulation of PV interneurons across hemispheres during the RS on Day 1 impaired rule shifts in ChR2-expressing mice, compared to no stimulation on Day 2 (n = 5 mice; post hoc t(8) = 9.34, ****P = 0.00003). d, PV-Cre mice had bilateral injections of AAV-DIO-ChR2-eYFP and fiber-optic implants in mPFC. Experimental design: Day 1: out-of-phase 20 Hz stimulation; Day 2: out-of-phase 40 Hz stimulation; Day 3: in-phase 40 Hz stimulation. e, Out-of-phase 40 Hz stimulation (Day 2) impairs rule shifts relative to out-of-phase 20 Hz stimulation (Day 1) or in-phase 40 Hz stimulation (Day 3) (n = 5 mice; one-way repeated measures ANOVA followed by Tukey’s multiple comparisons test, main effect of treatment: F1.294,5.175 = 25.3, **P = 0.003; Day 1 vs. Day 2: *P = 0.025, Day 2 vs. Day 3: **P = 0.006, Day 1 vs. Day 3: P = 0.47). f, PV-Cre, Ai14 mice had bilateral injections of AAV-DIO-eYFP or AAV-DIO-ChR2-eYFP and fiber-optic implants in mPFC. Experimental design: Day 1: out-of-phase 40 Hz stimulation during the initial association (IA); Day 2: no stimulation during the IA, followed by out-of-phase 40 Hz stimulation during the rule reversal (RR). g, Out-of-phase 40 Hz stimulation does not affect the ability of ChR2-expressing mice to learn an IA (n = 5 mice in each cohort; two-tailed, unpaired t-test; compared to control eYFP-expressing mice; t(8) = 0.69, P = 0.51). h, Out-of-phase 40 Hz stimulation does not affect the ability of ChR2-expressing mice to learn a RR (n = 5 mice in each cohort; two-tailed, unpaired t-test; compared to control eYFP-expressing mice; t(8) = 0.89, P = 0.40). Data are shown as means (g, h); error bars (g, h) denote s.e.m. Two-way ANOVA followed by Bonferroni post hoc comparisons, unless otherwise noted.