1. Volume 98, Issue 2, Pages 380-393.e4 (April 2018)
Dynamic ErbB4 Activity in Hippocampal-Prefrontal Synchrony and Top-Down Attention in Rodents 
Zhibing Tan, Heath L. Robinson, Dong-Min Yin, Yu Liu, Fang Liu, Hongsheng Wang, Thiri W. Lin, Guanglin Xing, Lin Gan, Wen-Cheng Xiong, Lin Mei 
Neuron 
Volume 98, Issue 2, Pages e4 (April 2018)
DOI: /j.neuron
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2. Figure 1
Positive Correlation between Correct Trials and Hippocampal-Prefrontal Synchrony
(A) Schematic diagram of the 5-CSRTT and in vivo recording.
(B) Diagram of a mouse brain with electrode positions.
(C) Coherence between PFC and hippocampal LFPs in correct (blue) and error trials (orange). The area in the rectangle is enlarged in (C’).
(D) Statistical analysis of the data in (C) (n = 14 tests, 7 mice; paired t test; delta, ∗∗∗p < 0.001; theta, ∗∗∗p < 0.001, beta, p = ; gamma, p = 0.4842; ns, not significant).
(E) Examples of in vivo recording traces showing spikes recorded from a prefrontal neuron (vertical lines) in relation to raw hippocampal LFPs (red) and filtered theta oscillation (black).
(F and H) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal delta (F) or theta (H) oscillations in correct (top) and error trials (bottom).
(G and I) Decreased PPC values at delta (G) or theta (I) bands in error trials (n = 93 units, 7 mice; paired t test; ∗∗p = in G; ∗∗∗p < in I).
Pooled data are shown as mean ± SEM. See also Figure S1.
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3. Figure 2
vHPC-PFC Synchrony Reduction and Attention Deficits in ErbB4−/− mice
(A) Accuracy rates of the indicated mice in 5-CSRTT training (control [Ctrl], n = 13 mice; ErbB4−/−, n = 13 mice; two-way ANOVA, p < 0.001).
(B) Lower correct ratios of ErbB4−/− mice compared with Ctrl during 5-CSRTT training (Ctrl, n = 13 mice; ErbB4−/−, n = 13 mice; two-way ANOVA, p = ).
(C) Increased omission ratios, but not incorrect or premature ratios, of ErbB4−/− mice (Ctrl, n = 13 mice; ErbB4−/−, n = 13 mice; t test, incorrect, p = ; omission, ∗∗∗p < 0.001; premature, p = 0.964).
(D) Coherence between PFC and vHPC LFPs in Ctrl (purple) and ErbB4−/− (green) mice (n = 11 tests, 7 mice; two-way ANOVA, p < 0.001; post hoc, Bonferroni; delta, ∗∗∗p < 0.001; theta, ∗∗∗p < 0.001; beta, ns, p = 0.992; gamma, ns, p = ).
(E and G) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal delta (E) or theta (G) oscillations in Ctrl (top) or ErbB4−/− (bottom) mice.
(F and H) Reduced delta (F) or theta (H) PPC in ErbB4−/− mice (Ctrl, n = 96 units, 7 mice; ErbB4−/−, n = 90 units, 7 mice; t test, ∗p = for F and ∗p = for H).
Pooled data are shown as mean ± SEM. See also Figure S2.
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4. Figure 3
Diminished Attention-Associated vHPC-PFC Synchrony in ErbB4−/− Mice
(A) Coherence between PFC and vHPC LFPs of correct and error trials of the two genotypes.
(B and C) Reduced delta (B) or theta (C) coherence in error trials in both genotypes (n = 15 tests, 7 mice; paired t test; for B, Ctrl, ∗∗∗p < 0.001; ErbB4−/−, ∗∗p = 0.0089; for C, ∗∗∗p < 0.001; ErbB4−/−, ∗∗p = ).
(D and E) Diminished difference (diff.) in delta (D) or theta (E) coherence between correct and error trials in ErbB4−/− mice compared with Ctrl mice (t test, ∗∗∗p < 0.001).
(F and I) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal delta (F) or theta (I) oscillations in correct (top) and error (bottom) trials in Ctrl mice (left) or ErbB4−/− mice (right).
(G and J) Reduced delta (G) or theta (J) PPC values in error trials in both genotypes (Ctrl, n = 96 units, 7 mice; ErbB4−/−, n = 90 units, 7 mice; for G, paired t test, Ctrl, ∗∗p = ; ErbB4−/−, ∗p = ; for J, Ctrl, ∗∗∗p < 0.001; ErbB4, ns, p = ).
(H and K) Diminished diff. in delta (H) or theta (K) PPC values between correct and error trials in ErbB4−/− mice (t test; for H, ∗p = ; for K, ∗p = ).
(L and M) Top: heatmaps showing normalized phase-locking values (PPC) for each PFC neuron in Ctrl mice (L) or ErbB4−/− mice (M) during correct trials (left) or error trials (right). Bottom: histograms showing the distribution of the maximal PPC value for each neuron in Ctrl mice during correct trials (left) or error trials (right). Triangles indicate mean lag value across the population. In (L), for correct trials, mean = −15.09, two-tailed signed-rank test, ∗p = ; for error trials, mean = −4.18, two-tailed signed-rank test, ns, p = ; in (M), for correct trials, mean = −8.32, two-tailed signed-rank test, ns, p = 0.225; for error trials, mean = −6.489, two-tailed signed-rank test, ns, p =
Pooled data are shown as mean ± SEM.
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5. Figure 4
Acute Inhibition of ErbB4 Impairs Attention and vHPC-PFC Synchrony
(A) Similar accuracy rates between T796G and Ctrl mice during 5-CSRTT training (Ctrl, n = 11 mice; T796G, n = 11 mice; two-way ANOVA, p = ).
(B) Time course of 1NM-PP1 inhibition of ErbB4 phosphorylation after intraperitoneal (i.p.) injection (repeated 3 times, t test; 5 min, ∗p = ; 15 min, ∗∗p = 0.0042; 30 min, ∗∗∗p < 0.001; 45 min, ∗∗p = ; 60 min, ∗p = ; 75 min, ns, p = 0.082).
(C) Increased omission ratios, but not incorrect or premature ratios, of T796G mice, but not Ctrl mice, after 1NM-PP1 treatment (i.p.; Ctrl, n = 11 mice, two-way ANOVA; incorrect, ns, p = ; omission, ns, p = ; premature, ns, p = ; T796G, n = 11 mice, two-way ANOVA; incorrect, ns, p = ; omission, ∗∗∗p < 0.001; premature, ns, p = ).
(D and I) Coherence between prefrontal and hippocampal LFPs after i.p. injection of vehicle (gray) and 1NM-PP1 (red) in T796G mice (D) or Ctrl mice (I). For (D), n = 11 tests, 6 mice; two-way ANOVA, ∗∗∗p < 0.001; post hoc, Bonferroni; delta, ∗∗∗p < 0.001; theta, ∗∗∗p < 0.001; beta, ns, p = ; gamma, ns, p = For (I), n = 11 tests; 6 mice; two way ANOVA, ns, p = ).
(E and J) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal delta oscillation in vehicle (top) or 1NM-PP1 (bottom) injection in T796G mice (E) or Ctrl mice (J).
(F and K) Reduced delta PPC in 1NM-PP1 injection in T796G mice (F), but not Ctrl mice (K). For (F), vehicle, n = 94 units, 6 mice; 1NM-PP1, n = 99 units, 6 mice; t test, ∗∗∗p < For (K), vehicle, n = 89 units, 6 mice; 1NM-PP1, n = 95 units, 6 mice; t test, ns, p = 0.89.
(G and L) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal theta oscillation in vehicle (top) or 1NM-PP1 (bottom) injection in T796G mice (G) and Ctrl mice (L).
(H and M) Reduced theta PPC in 1NM-PP1 injection in T796G mice (H), but not Ctrl mice (M). For (H), vehicle, n = 94 units, 6 mice; 1NM-PP1, n = 99 units, 6 mice; t test, ∗∗p = For (M), vehicle, n = 89 units, 6 mice; 1NM-PP1, n = 95 units, 6 mice; t test, ns, p =
Pooled data are shown as mean ± SEM. See also Figures S3–S5.
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6. Figure 5
Diminished Attention-Associated Hippocampal-Prefrontal Synchrony by 1NM-PP1
(A) Coherence between prefrontal and hippocampal LFPs of correct and error trials in vehicle- and 1NM-PP1-treated T796G mice.
(B and C) Reduced delta (B) and theta (C) coherence in error trials in vehicle- and 1NM-PP1-treated T796G mice. Vehicle, n = 13 tests (7 mice), paired t test; delta, ∗∗∗p < 0.001; theta, ∗∗∗p < NM-PP1, n = 12 tests (7 mice), paired t test; delta, ∗p = ; theta, ∗∗∗p <
(D and E) Diminished diff. between correct and error trials in delta (D) or theta (E) coherence in 1NM-PP1-treated T796G mice compared with vehicle-treated T796G mice (t test; D, ∗p = ; E, ∗p = ).
(F and I) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal delta (F) or theta (I) oscillations in correct (top) and error (bottom) trials in T796G mice injected with vehicle (left) or 1NM-PP1 (right).
(G and J) Reduced delta (G) or theta (J) PPC values in error trials, compared with correct trials, in vehicle- and 1NM-PP1-injected T796G mice (vehicle, n = 94 units, 7 mice, paired t test; delta, ∗∗∗p < 0.001; theta, ∗∗∗p < 0.001; 1NM-PP1, n = 99 units, 7 mice, paired t test; delta, ∗∗∗p < 0.001; theta, ∗p = ).
(H and K) Diminished diff. in delta (H) or theta (K) PPC values between correct and error trials in 1NM-PP1-treated T796G mice compared with vehicle-injected T796G mice (t test; delta, ∗∗p = ; theta, ∗p = ).
Pooled data are shown as mean ± SEM.
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7. Figure 6
Hippocampal ErbB4 Activity Is Required for Attention and vHPC-PFC Synchrony
(A) Reduced hippocampal-prefrontal synchrony in T796G mice by vHPC injection of 1NM-PP1 (n = 12 tests, 6 mice; two way ANOVA, ∗∗∗p < 0.001; post hoc, Bonferroni; delta, ∗∗∗p < 0.001; theta, ∗∗∗p < 0.001; beta, ns, p = 0.941; gamma, ns, p = 0.9514). Inset: schematic diagram of a mouse brain showing positions of recording electrodes and drug infusion cannula.
(B) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal delta oscillation in T796G mice after vHPC vehicle (top) or 1NM-PP1 (bottom) injection.
(C) Reduced delta PPC by vHPC 1NM-PP1 injection compared with vehicle injection (vehicle, n = 102 units, 6 mice; 1NM-PP1, n = 95 units, 6 mice; t test, ∗∗∗p < 0.001).
(D) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal theta oscillation in T796G mice after vHPC injection with vehicle (top) or 1NM-PP1 (bottom).
(E) Reduced theta PPC by vHPC 1NM-PP1 injection compared with vehicle injection (vehicle, n = 102 units, 6 mice; 1NM-PP1, n = 95 units, 6 mice; ∗∗p = ).
(F) Little effect of local PFC injection of 1NM-PP1 on hippocampal-prefrontal synchrony (n = 12 tests, 6 mice; two-way ANOVA, ns, p = ). Inset: schematic diagram of a mouse brain showing positions of recording electrodes and drug infusion cannula.
(G) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal delta oscillation in T796G mice after PFC injection with vehicle (top) or 1NM-PP1 (bottom).
(H) No effect on delta PPC by PFC 1NM-PP1 injection compared with vehicle injection (vehicle, n = 99 units, 6 mice; 1NM-PP1, n = 94 units, 6 mice; t test, ns, p = ).
(I) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal theta oscillation in T796G mice after PFC injection with vehicle (top) or 1NM-PP1 (bottom).
(J) No effect on theta PPC by PFC 1NM-PP1 injection compared with vehicle injection (vehicle, n = 99 units, 6 mice; 1NM-PP1, n = 94 units, 6 mice; t test; ns, not significant; p = ).
(K) Increased omission ratio, but not incorrect or premature ratios, in T796G mice by local vHPC injection of 1NM-PP1 or bicuculline (n = 11 mice, two-way ANOVA; incorrect, ns, p = /0.91/0.9501, respectively; omission, ∗∗∗p < 0.001; premature, ns, p = /0.7328/0.9531, respectively).
(L) Increased omission ratio, but not incorrect or premature ratios, in T796G mice by local PFC injection of 1NM-PP1 or bicuculline (n = 11 mice, two-way ANOVA; incorrect, ns, p = /0.8652/0.9196, respectively; omission, ∗∗∗p < 0.001; premature, ns, p = 0.865/0.987/0.9347, respectively).
Pooled data are shown as mean ± SEM. See also Figure S6.
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8. Figure 7
1NM-PP1 Inhibits Hippocampal GABAergic Transmission in T796G Mice
(A) Diagram of recording a pyramidal neuron (gray) that was innervated by an interneuron (yellow).
(B) Representative traces of mIPSCs before, during, and after 1NM-PP1 application.
(C) Time course of 1NM-PP1 inhibition of mIPSC frequency on hippocampal slices from T796G mice, but not Ctrl mice (Ctrl, n = 6 neurons, 3 mice; T796G, n = 9 neurons, 4 mice; one-way ANOVA, ∗∗∗p < 0.001).
(D) No effect of 1NM-PP1 on mIPSC amplitude on hippocampal slices of either genotype (Ctrl, n = 6 neurons, 3 mice; T796G, n = 9 neurons, 4 mice; one-way ANOVA; ns, p = ).
(E) Representative traces of eIPSCs before, during, and after 1NM-PP1 application in Ctrl and T796G mice.
(F) 1NM-PP1 inhibition of eIPSC amplitude in hippocampal slices from T796G (n = 6 neurons, 3 mice, t test, ∗∗p = ; ∗p = ), but not Ctrl mice (n = 7 neurons, 3 mice, t test; ns, p = ; ns, p = ).
(G) Representative traces of paired-pulse (interval, 0.25 s) stimuli.
(H) Increased eIPSC paired-pulse ratio by 1NM-PP1 (n = 6 neurons, 3 mice; one-way ANOVA, ∗∗p = ).
Pooled data are shown as mean ± SEM. See also Figures S7 and S8.
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9. Figure 8
Distinct Regulations by vHPC and PFC ErbB4+ Neurons on Hippocampal-Prefrontal Synchrony and Attention
(A and B) Representative in vivo multi-unit rasters of ErbB4+ interneuron (A) and their target neurons (B) in ErbB4-CreERT2;ArchT mice in response to yellow light emitting diode (LED) illumination.
(C) No effect on hippocampal-prefrontal synchrony by yellow LED illumination at the PFC (n = 12 tests, 6 mice; two way ANOVA; ns, p = ). Inset: schematic diagram of a mouse brain showing positions of optoelectrodes and tetrodes.
(D) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal delta oscillation without (top) or with (bottom) LED stimulation at the PFC.
(E) No effect on delta PPC by PFC LED illumination compared with no LED illumination (n = 83 units, 6 mice; t test, ns, p = ).
(F) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal theta oscillation without (top) or with (bottom) LED stimulation at the PFC.
(G) No effect on theta PPC by PFC LED illumination compared with no LED illumination (n = 83 units, 6 mice; t test, ns, p = ).
(H) Increased omission (Omis.) ratio, but not incorrect (Incor.) or premature (Prem.) ratio, by LED illumination in the PFC (n = 12 mice, two-way ANOVA; Incor., ns, p = ; Omis., ∗∗∗p < 0.001; Prem., ns, p = ).
(I) Reduced hippocampal-prefrontal synchrony by yellow LED illumination at the vHPC (n = 86 units, 6 mice; two-way ANOVA, ∗∗∗p < 0.001; post hoc, Bonferroni; delta, ∗∗∗p < 0.001; theta, ∗∗∗p < 0.001; beta, ns, p = 0.933; gamma, ns, p = ). Inset: schematic diagram of a mouse brain showing positions of optoelectrodes and tetrodes.
(J) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal delta oscillation without (top) or with (bottom) LED stimulation at the vHPC.
(K) Reduced delta PPC by vHPC LED illumination compared with no LED illumination (n = 86 units, 6 mice; t test, ∗∗∗p < 0.001).
(L) Representative distributions of preferred phases of a prefrontal unit in relation to hippocampal theta oscillation without (top) or with (bottom) LED stimulation at the vHPC.
(M) Reduced theta PPC by vHPC LED illumination compared with no LED illumination (n = 86 units, 6 mice; t test, ∗∗∗p < 0.001).
(N) Increased Omis. Ratio, but not Incor. or Prem. ratio, by LED illumination in the vHPC (n = 12 mice, two-way ANOVA; Incor., ns, p = ; Omis., ∗∗∗p < 0.001; Prem., ns, p = ).
Pooled data are shown as mean ± SEM. See also Figure S9.
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