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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 5. Optogenetically evoking/inhibiting dopamine response during pre-exposure bidirectionally alters subsequent learning.

Figure 5.

(a) 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. (b) Dopamine terminals were optogenetically stimulated (via ChR2) or inhibited (via NpHR) at the time of the neutral cue during pre-exposure. Mice received 4 sessions of stimulus pre-exposure followed by two sessions of fear conditioning. In the pre-exposure session, the pre-exposure cue (light or tone, counterbalanced) was presented in the absence of any outcome; in the conditioning sessions, both the pre-exposed (pre-exposed CS+) and non-pre-exposed (CS+) cues were followed by a footshock. (c) Freezing responses to the CS+ and pre-exposed CS+ for the eYFP, NpHR, and ChR2 groups throughout the 6 conditioning trials (2-way ANOVA cue × group interaction F(2,36)=8.77, p = 0.0008; eYFP n=11, NpHR n=4, ChR2 n=6 mice). Inhibition of dopamine response, which artificially reduced dopamine responses to the novel stimulus, during the pre-exposure reduced subsequent aversive conditioning. i.e. the NpHR group showed an enhanced latent inhibition effect compared to the eYFP controls (2-way ANOVA cue × group interaction F(1,26)=4.34, p = 0.04; Multiple comparisons: NpHR pre-exposed CS+ vs. CS+ p=0.001; eYFP pre-exposed vs. non-pre-exposed p = 0.02). Conversely, enhancing dopamine signal, which artificially blocked the dopamine reductions we observed in Figure 1 during the pre-exposure, enhanced subsequent aversive conditioning. i.e. the ChR2 group showed a reduced latent inhibition effect compared to the eYFP controls. (2-way ANOVA cue × group interaction F(1,30)=7.22 p = 0.01; Bonferroni multiple comparisons: ChR2 pre-exposed vs. non-pre-exposed p = 0.85). (d) Trial-by-trial freezing responses to the non-pre-exposed cue in the NpHR, eYFP, and ChR2 groups (Repeated Measures ANOVA trial × group interaction F(10,90)=0.62, p = 0.79; All multiple comparisons p>0.05). (e) Trial-by-trial freezing responses to the pre-exposed cue in the NpHR, eYFP, and ChR2 groups (Repeated Measures ANOVA trial × group interaction F(10,90)=2.07, p = 0.03; Multiple comparison ChR2 vs. NpHR trial 2, p=0.007). Data represented as mean ± S.E.M., * p < 0.05, **p < 0.01, ns = not significant.