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. Author manuscript; available in PMC: 2023 Aug 1.
Published in final edited form as: Nat Neurosci. 2022 Jul 28;25(8):1071–1081. doi: 10.1038/s41593-022-01126-1

Figure 4. Dopamine responses to pre-exposed cues are causal to future aversive learning; pre-exposed cues do not function as conditioned inhibitors.

Figure 4.

(a) Averaged fiber photometry traces showing dopamine responses to the CS−, CS+, and pre-exposed CS+ during each trial during session 1 of fear conditioning training. (b) AAV5.Ef1a.DIO.eYFP (eYFP), AAV5-Ef1a-DIO.eNpHR.3.0-eYFP (NpHR), or AAV5.Ef1a.DIO.hchR2.eYFP (ChR2) were co-injected with AAV9.rTH.PI.Cre into the VTA to achieve dopamine-specific expression of excitatory or inhibitory opsins. (c) Representative histology showing expression of ChR2 and TH in the VTA and ChR2 in the NAc core dopamine terminals (n=21 mice; 9 males, 12 females). (d) NAc core dopamine terminals were stimulated or inhibited at the time of the cue during the first cue-shock pairing of fear conditioning (n= 15 mice; 7 males, 8 females). (e) Stimulating dopamine terminals at the time of the initial cue presentation disrupted the latent inhibition effect (2-way ANOVA cue × group interaction F(2,12)=4.556 p=0.033; Bonferroni multiple comparisons: eYFP pre-exposed vs. non-pre-exposed p=0.049; ChR2 pre-exposed vs. non-pre-exposed p=0.999; NpHR pre-exposed vs. non-pre-exposed p=0.011), while inhibiting terminals had no effect. (f) In a pre-exposure session, mice (n=8 mice; 4 males, 4 females) were given repeated presentations of a cue. In a subsequent fear conditioning session, another cue (the excitor) was paired with a shock. In the conditioned inhibition testing session, three trial types were presented: excitor alone, excitor + the pre-exposed cue, and excitor + novel cue. (g) In the conditioned inhibition test session, the pre-exposed cue does not reduce freezing response to the cue that was paired with the shock outcome (RM ANOVA F(1.37,9.60)= 10.21, p=0.0069; Bonferroni post-hocs Excitor alone vs. Excitor+Pre-exposed cue, p>0.05). A novel stimulus that was not presented before reduced freezing response to the excitor (Bonferroni post-hocs Excitor alone vs. Excitor+Novel Cue, p=0.026). Data represented as mean ± S.E.M., * p<0.05, ns = not significant.