Maria Carolina Gonzalez

Ras-related C3 botulinum toxin substrate 1 (Rac1) is a small GTPase that regulates actin cytoskeleton dynamics and synaptic plasticity. Rac1 has been implicated in active forgetting, but whether it also constrains the consolidation of new memories remains unclear. Here we show that systemic administration of the Rac1 inhibitor 1A-116 after training in the novel object recognition task markedly extends memory persistence in rats. A single post-training injection of 1A-116 enhanced recognition memory for at least 28 d without altering locomotor- or anxiety-related behaviors. When given after a brief, subthreshold training session that normally supports only short-term memory, 1A-116 enabled long-term retention that required hippocampal protein synthesis. This promnesic effect was time-dependent, independent of sex, and consistent with Rac1 acting as a negative regulator of memory consolidation rather than merely promoting forgetting. These findings indicate that Rac1 activity after learning limits the consolidation process itself, functioning as a molecular brake on recognition memory stabilization, and suggest that its inhibition may represent a therapeutic avenue to enhance cognitive durability in both healthy and pathological conditions.

Theta is one of the most prominent extracellular synchronous oscillations in the mammalian brain. Hippocampal theta relies on an intact medial septum (MS) and has been consistently recorded during the training phase of some learning paradigms, suggesting that it may be implicated in hippocampus-dependent long-term memory processing. Object recognition memory (ORM) allows animals to identify familiar items and is essential for remembering facts and events. In rodents, long-term ORM formation requires a functional hippocampus but the involvement of the MS in this process remains controversial. We found that training adult male Wistar rats in a long-term ORM-inducing learning task involving exposure to two different, but behaviorally equivalent novel stimuli objects increased hippocampal theta power, and that suppressing theta via optogenetic MS inactivation caused amnesia. Importantly, the amnesia was specific to the object the animals were exploring when the MS was inactivated. Taken together, our results indicate that the MS is necessary for long-term ORM formation and suggest that hippocampal theta activity is causally linked to this process.

Avoidance memory is destabilized when recalled concurrently with conflicting information, and must undergo a hippocampus-dependent restabilization process called reconsolidation to persist. CaMKII is a serine/threonine protein kinase essential for memory processing; however, its possible involvement in avoidance memory reconsolidation has not yet been studied. Using pharmacological, electrophysiological and optogenetic tools, we found that in adult male Wistar rats hippocampal CaMKII is necessary to reconsolidate avoidance memory, but not to keep it stored while inactive, and that blocking reconsolidation via CaMKII inhibition erases learned avoidance responses.

Consolidation and reconsolidation are independent memory processes. Consolidation stabilizes new memories, whereas reconsolidation restabilizes memories destabilized when reactivated during recall. However, the biological role of the destabilization/reconsolidation cycle is still unknown. It has been hypothesized that reconsolidation links new information with reactivated memories, but some reports suggest that new and old memories are associated through consolidation mechanisms instead. Object-recognition memory (ORM) serves to judge the familiarity of items and is essential for remembering previous events. We took advantage of the fact that ORM consolidation, destabilization, and reconsolidation can be pharmacologically dissociated to demonstrate that, depending on the activation state of hippocampal dopamine D1/D5 receptors, the memory of a novel object presented during recall of the memory of a familiar one can be formed via reconsolidation or consolidation, but only reconsolidation can link them. We also found that recognition memories formed through reconsolidation can be destabilized even if indirectly reactivated. Our results indicate that dopamine couples novelty detection with memory destabilization to determine whether a new recognition trace is associated with an active network and suggest that declarative reminders should be used with caution during reconsolidation-based psychotherapeutic interventions.

Object recognition memory (ORM) serves to distinguish familiar items from novel ones. Reconsolidation is the process by which active memories are updated. The hippocampus is engaged in ORM reconsolidation through a mechanism involving induction of long-term potentiation (LTP). The transcription factor Zif268 is essential for hippocampal LTP maintenance and has been frequently associated with memory processes. However, its possible involvement in ORM reconsolidation has not been determined conclusively. Using Zif268 antisense oligonucleotides in combination with behavioural, biochemical and electrophysiological tools in rats, we found that hippocampal Zif268 is necessary to update ORM through reconsolidation but not to retrieve it or keep it stored. Our results also suggest that knocking down hippocampal Zif268 during ORM reconsolidation deletes the active recognition memory trace.

When retrieval occurs concomitantly with novelty detection, mismatch perception or reactivation of conflicting information, consolidated memories can enter into a labile state, and to persist, must be restabilized through a protein synthesis-dependent reconsolidation process during which their strength and content can be modified. Extensive literature implicates brain-derived neurotrophic factor (BDNF), a key regulator of synaptogenesis and synaptic plasticity, in the acquisition, consolidation and extinction of several memory types. However, the participation of BDNF in memory reconsolidation has been less studied. In this review, we discuss recent reports supporting the involvement of BDNF signaling in reactivation-induced memory updating.

Object recognition memory (ORM) confers the ability to discriminate the familiarity of previously encountered items. Reconsolidation is the process by which reactivated memories become labile and susceptible to modifications. The hippocampus is specifically engaged in reconsolidation to integrate new information into the original ORM through a mechanism involving activation of brain-derived neurotrophic factor (BDNF) signaling and induction of LTP. It is known that BDNF can control LTP maintenance through protein kinase Mζ (PKMζ), an atypical protein kinase C isoform that is thought to sustain memory storage by modulating glutamatergic neurotransmission. However, the potential involvement of PKMζ in ORM reconsolidation has never been studied. Using a novel ORM task combined with pharmacological, biochemical, and electrophysiological tools, we found that hippocampal PKMζ is essential to update ORM through reconsolidation, but not to maintain the inactive recognition memory trace stored over time, in adult male Wistar rats. Our results also indicate that hippocampal PKMζ acts downstream of BDNF and controls AMPAR synaptic insertion to elicit reconsolidation and suggest that blocking PKMζ activity during this process deletes active ORM.SIGNIFICANCE STATEMENTObject recognition memory (ORM) is essential to remember facts and events. Reconsolidation integrates new information into ORM through changes in hippocampal plasticity and brain-derived neurotrophic factor (BDNF) signaling. In turn, BDNF enhances synaptic efficacy through protein kinase Mζ (PKMζ), which might preserve memory. Here, we present evidence that hippocampal PKMζ acts downstream of BDNF to regulate AMPAR recycling during ORM reconsolidation and show that this kinase is essential to update the reactivated recognition memory trace, but not to consolidate or maintain an inactive ORM. We also demonstrate that the amnesia provoked by disrupting ORM reconsolidation through PKMζ inhibition is due to memory erasure and not to retrieval failure.

Reactivated memories can be modified during reconsolidation, making this process a potential therapeutic target for posttraumatic stress disorder (PTSD), a mental illness characterized by the recurring avoidance of situations that evoke trauma-related fears. However, avoidance memory reconsolidation depends on a set of still loosely defined boundary conditions, limiting the translational value of basic research. In particular, the involvement of the hippocampus in fear-motivated avoidance memory reconsolidation remains controversial. Combining behavioral and electrophysiological analyses in male Wistar rats, we found that previous learning of relevant nonaversive information is essential to elicit the participation of the hippocampus in avoidance memory reconsolidation, which is associated with an increase in theta- and gamma-oscillation power and cross-frequency coupling in dorsal CA1 during reactivation of the avoidance response. Our results indicate that the hippocampus is involved in memory reconsolidation only when reactivation results in contradictory representations regarding the consequences of avoidance and suggest that robust nesting of hippocampal theta–gamma rhythms at the time of retrieval is a specific reconsolidation marker.SIGNIFICANCE STATEMENTPosttraumatic stress disorder (PTSD) is characterized by maladaptive avoidance responses to stimuli or behaviors that represent or bear resemblance to some aspect of a traumatic experience. Disruption of reconsolidation, the process by which reactivated memories become susceptible to modifications, is a promising approach for treating PTSD patients. However, much of what is known about fear-motivated avoidance memory reconsolidation derives from studies based on fear conditioning instead of avoidance-learning paradigms. Using a step-down inhibitory avoidance task in rats, we found that the hippocampus is involved in memory reconsolidation only when the animals acquired the avoidance response in an environment that they had previously learned as safe and showed that increased theta- and gamma-oscillation coupling during reactivation is an electrophysiological signature of this process.