Novelty Exposition Facilitates Memory Extinction By Dopaminergic Mechanisms

Memory extinction has been considered an interesting strategy for attenuating responsiveness to the original fear memory, and has been widely used on clinic to treat fear‐related disorders. However, exposure therapy tend to require a long and slow process of treatment and generally produce transient fear reduction that is often bound to the context in which the therapy was administered. Here we investigate the effects of novelty exposure on memory extinction. 50 male Wistar rats were divided in five groups: (i) control; (ii) novelty exposure; (iii) familiar context exposure; (iv) dopamine; and, (v) dopamine + familiar. All animals were trained in Inhibitory Avoidance (IA) and 24h after submitted to extinction training carried out in three sessions 90 min apart. 24 hours after the last extinction session, the animals were submitted to the retention test, which also made 3, 7, 14 and 21 days after the extinction sessions. Thirty minutes before the first extinction training session, rats from the group (ii) were exposed for 5 min to a novelty (a novel environment). Additional control groups were exposed to a familiar environment. The animals from dopamine groups received an intrahippocampal infusion of dopamine (1 μg/μL, 1 μL per side). During the IA training, all the animals presented similar step‐down latency when compared to each other (P > 0.05). In the 24h retention test the step‐down latency of the group (ii) was significantly lower than the one of control group (i) (P<0.01), indicating that novelty promoted memory extinction. On the other hand, the group (iii) (Familiar OF) present similar step‐down latency than group (i) (P>0.05) and differences from group (ii) (P<0.01), indicating that the exposure to a familiar environment does not promote memory extinction. The group (iv) presented significantly lower latencies than control (i) and familiar (iii) groups (P<0.01), indicating that dopamine promoted memory extinction. On the other hand, the group (iv) present similar step‐down latency than group (ii) (novelty) (P>0.05), indicating that the dopamine mimics novelty effects on memory extinction. Regarding the memory persistence, we observed that the group (ii) presented step‐down latencies significantly lower than control group (i) throughout the 21 days (P<0.01 in all tests). The group (iv) also presented step‐down latencies significantly lower than control group (i) throughout the 21 days (P<0.05 in all tests). Therefore, the exposure to a novelty, as well as, the infusion of dopamine on CA1 region of the hippocampus, promoted persistent memory extinction. In the present work we confirmed that novelty exposure can facilitated the aversive memory extinction and demonstrated that the novelty effects can persist along the time. Finally, we show that the novelty effects on extinction are mimicked by dopamine infusion on CA1 region of hippocampus, reinforcing the importance of hippocampal dopamine on novelty effects. Support or Funding Information This work was supported by research grants and fellowships from Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS), CAPES, Federal University of Pampa, and the National Council of Research of Brazil (CNPq). A. Training, extinctions, and 24h test step‐down latencies on IA. B. Training, extinctions, and 3, 7, 14 and 21 days test step‐down latencies on IA. In each session, different letters represent significant differences between the groups (P < 0.05; Kruskall‐Wallis followed by Dunn’s post‐hoc). * P < 0.05 in comparison to training (Wilcoxon test, training vs. test). Figure 1