Time-dependent inhibition of Rac1 in the VTA enhances long-term aversive memory: implications in active forgetting mechanisms.

The fate of memories depends mainly on two opposing forces: the mechanisms required for the storage and maintenance of memory and the mechanisms underlying forgetting, being the latter much less understood. Here, we show the effect of inhibiting the small Rho GTPase Rac1 on the fate of inhibitory avoidance memory in male rats. The immediate post-training micro-infusion of the specific Rac1 inhibitor NSC23766 (150 ng/0.5 µl/ side) into the ventral tegmental area (VTA) enhanced long-term memory at 1, 7, and 14 days after a single training. Additionally, an opposed effect occurred when the inhibitor was infused at 12 h after training while no effect was observed immediately after testing animals at 1 day. Control experiments ruled out the possibility that post-training memory enhancement was due to facilitation of memory formation since no effect was found when animals were tested at 1 h after acquisition and no memory enhancement was observed after the formation of a weak memory. Immediate post-training micro-infusion of Rac1 inhibitor into the dorsal hippocampus, or the amygdala did not affect memory. Our findings support the idea of a Rac1-dependent time-specific active forgetting mechanism in the VTA controlling the strength of a long-term aversive memory.

α7 nicotinic acetylcholine receptors in the medial prefrontal cortex control rewarding but not aversive memory expression in a dopamine-sensitive manner.

Emotional learning involves the association between sensory cues and rewarding or aversive stimuli, and this stored information can be recalled during memory retrieval. In this process, the medial prefrontal cortex (mPFC) plays an essential role. We have previously shown that the antagonism of α7 nicotinic acetylcholine receptors (nAChRs) by methyllycaconitine (MLA) in the mPFC blocked cue-induced cocaine memory retrieval. However, little is known about the involvement of prefrontal α7 nAChRs in the retrieval of aversive memories. Here, by using pharmacology and different behavioral tasks, we found that MLA did not affect aversive memory retrieval, indicating a differential effect of cholinergic prefrontal control of appetitive and aversive memories. Despite being shown that acetylcholine modulates dopamine release in the mPFC, it remains unknown if those modulatory systems act together to control reward-based behavior. We examined that question and found that dopamine type 1 receptor (D1R) activation prevented MLA-induced blockade of cocaine CPP retrieval. Our results suggest that α7 nAChRs and D1R signaling interact in the mPFC to modulate cocaine-associated memory retrieval.

Dopamine neurotransmission in the VTA regulates aversive memory formation and persistence.

Dopamine (DA) neurons in the ventral tegmental area (VTA) innervating several limbic and neocortical regions of the mammalian brain have long been implicated in motivation, rewarding and aversive behaviors, and memory processing. Recently, we demonstrated that somatodendritic release of DA in the VTA regulates the formation and maintenance of appetitive long-term memories (LTM). However, less is known about the impact of DA neurotransmission in the VTA on aversive LTM. Here, we describe the modulation of negative-valence memories by D1/D5-type DA (D1R)-receptor-mediated neurotransmission in the VTA. As aversive stimuli elicit both active and passive behavioral responses, we used two single-trial aversive training protocols: inhibitory avoidance task and conditioned place aversion. We bilaterally microinfused SCH23390, an antagonist of D1R, into the VTA immediately after training and found that DA neurotransmission in the VTA modulates LTM consolidation and persistence of aversive experiences. Together with previous findings demonstrating that D1R-mediated DA neurotransmission in the medial prefrontal cortex and hippocampus is involved in the formation and persistence of LTM for aversive events, our present results indicate that memory processing of environmental stimuli with negative-valence depends on the integration of information mediated by D1R activation in both the VTA region and in selected downstream target areas.

Prefrontal cortex nicotinic receptor inhibition by methyllycaconitine impaired cocaine-associated memory acquisition and retrieval.

Cocaine administration has been shown to induce plastic changes in the medial prefrontal cortex (mPFC), which could represent a mechanism by which cocaine facilitates the association between cocaine rewarding effects with contextual cues. Nicotinic acetylcholine receptors (nAChRs) in the mPFC have critical roles in cognitive function including attention and memory and are key players in plasticity processes. However, whether nAChRs in the mPFC are required for the acquisition and maintenance of cocaine-associated memories is still unknown. To assess this question, we used the conditioning place preference (CPP) model to study the effect of intra-mPFC infusion of methyllycaconitine, a selective antagonist of α7 nAChRs, on the acquisition, consolidation and expression of cocaine-associated memory in adult rats. Our findings reveal that mPFC α7 nAChRs activation is necessary for the acquisition and retrieval, but not consolidation, of cocaine induced CPP. Moreover, cocaine-induced sensitization during CPP conditioning sessions was abolished by methyllycaconitine infusion in the mPFC. Together, these results identify mPFC α7 nAChRs as critical players involved in both acquiring and retrieving cocaine-associated memories. Considering that drug seeking often depends on the association between drug-paired cues and the rewarding effects of the drug, α7 nAChRs in the mPFC could be considered as potential targets for the prevention or treatment of cocaine use disorder.