Newly acquired and reactivated contextual fear memories are more intense and prone to generalize after activation of prelimbic cortex NMDA receptors.

Activity in the rodent prelimbic (PL) cortex contributes to consolidation, retrieval and reconsolidation of learned fear. The PL cortex is considered homologous to the primate dorsal anterior cingulate cortex (dACC). In patients with post-traumatic stress disorder (PTSD), the dACC is often reported to be hyperactive after acquisition and/or around the retrieval of the traumatic memory. It is still unknown, however, whether there is a relationship between altered dACC functioning at these time points and PTSD-associated behavioral outcomes, such as fear overgeneralization. The present study sought to investigate this matter by associating contextual fear conditioning with bilateral and selective activation of PL cortex N-methyl-D-aspartate (NMDA) glutamate receptors with NMDA (0.03-0.3nmol) while the learned fear was being consolidated, retrieved or reconsolidated. We report that this pharmacological intervention induced generalized fear expression and/or extinction deficits in animals subjected to a strong contextual fear conditioning protocol when conducted post-acquisition, pre-retrieval or post-retrieval. These results suggest that newly acquired and reactivated fear memories undergo abnormal consolidation or reconsolidation after PL cortex NMDA receptor activation. The consolidation or reconsolidation of a contextual fear memory trace induced by a weak fear training protocol was also potentiated by PL cortex NMDA receptor activation. Altogether, the present findings connect altered PL cortex activity with changes in specificity and/or intensity of a contextual fear memory, which might shed light on the PTSD neurobiology and related behavioral outcomes.

Δ9-Tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption.

Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology. It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level. We report that THC (0.3-10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation. Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples. Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation. Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients.

Activity in prelimbic cortex subserves fear memory reconsolidation over time.

The prelimbic cortex has been implicated in the consolidation of previously learned fear. Herein, we report that temporarily inactivating this medial prefrontal cortex subregion with the GABAA agonist muscimol (4.0 nmol in 0.2 µL per hemisphere) was able to equally disrupt 1-, 7-, and 21-d-old contextual fear memories after their brief retrieval in rats. In all cases, this effect was prevented when memory reactivation was omitted. These results indicate that recent and remote fear memories are susceptible to reconsolidation blockade induced by prelimbic cortex inactivation. It was also demonstrated that the disrupting effect of prelimbic cortex inactivation on fear memory persisted over 11 d, and did not show extinction-related features, such as reinstatement. Infusing the same dose and volume of muscimol bilaterally into the infralimbic cortex after brief retrieval/reactivation of the fear memory did not disrupt it, as seen in prelimbic cortex-inactivated animals. The expression of Zif268/Egr1, the product of an immediate early gene related to memory reconsolidation, was also less pronounced in the infralimbic cortex than in prelimbic cortex following memory retrieval/reactivation. Altogether, the present findings highlight that activity in the prelimbic cortex may reestablish reactivated aversive memories and, therefore, contribute to their maintenance over time.