Emotional Value of Fear Memory and the Role of the Ventral Hippocampus in Systems Consolidation.

Recent studies have explored the circuitry involving the ventral hippocampus (vHPC), the amygdala, and the prefrontal cortex, a pathway mainly activated to store contextual information efficiently. Lesions in the vHPC impair remote memory, but not in the short term. However, how the vHPC is affected by distinct memory strength or its role in systems consolidation has not yet been elucidated. Here, we investigated how distinct training intensities, with strong or weak contextual fear conditioning, affect activation of the dorsal hippocampus (dHPC) and the vHPC. We found that the time course of memory consolidation differs in fear memories of different training intensities in both the dHPC and vHPC. Our results also indicate that memory generalization happens alongside greater activation of the vHPC, and these processes occur faster with stronger fear memories. The vHPC is required for the expression of remote fear memory and may control contextual fear generalization, a view corroborated by the fact that inactivation of the vHPC suppresses generalized fear expression, making memory more precise again. Systems consolidation occurs concomitantly with greater activation of the vHPC, which is accelerated in stronger fear memories. These findings lead us to propose that greater activation of the vHPC could be used as a marker for memory generalization.

Remote contextual fear retrieval engages activity from salience network regions in rats.

The ability to retrieve contextual fear memories depends on the coordinated activation of a brain-wide circuitry. Transition from recent to remote memories seems to involve the reorganization of this circuitry, a process called systems consolidation that has been associated with time-dependent fear generalization. However, it is unknown whether emotional memories acquired under different stress levels can undergo different systems consolidation processes. Here, we explored the activation pattern and functional connectivity of key brain regions associated with contextual fear conditioning (CFC) retrieval after recent (2 days) or remote (28 days) memory tests performed in rats submitted to strong (1.0 mA footshock) or mild (0.3 mA footshock) training. We used brain tissue from Wistar rats from a previous study, where we observed that increasing training intensity promotes fear memory generalization over time, possibly due to an increase in corticosterone (CORT) levels during memory consolidation. Analysis of Fos expression across 8 regions of interest (ROIs) allowed us to identify coactivation between them at both timepoints following memory recall. Our results showed that strong CFC elicits higher Fos activation in the anterior insular and prelimbic cortices during remote retrieval, which was positively correlated with freezing along with the basolateral amygdala. Rats trained either with mild or strong CFC showed broad functional connectivity at the recent timepoint whereas only animals submitted to the strong CFC showed a widespread loss of coactivation during remote retrieval. Post-training plasma CORT levels are positively correlated with FOS expression during recent retrieval in strong CFC, but negatively correlated with FOS expression during remote retrieval in mild CFC. Our findings suggest that increasing training intensity results in differential processes of systems consolidation, possibly associated with increased post-training CORT release, and that strong CFC engages activity from the aIC, BLA and PrL - areas associated with the Salience Network in rats - during remote retrieval.

Systems consolidation and fear memory generalisation as a potential target for trauma-related disorders.

Fear memory generalisation is a central hallmark in the broad range of anxiety and trauma-related disorders. Recent findings suggest that fear generalisation is closely related to hippocampal dependency during retrieval. In this review, we describe the current understanding about memory generalisation and its potential influence in fear attenuation through pharmacological and behavioural interventions. In light of systems consolidation framework, we propose that keeping memory precision could be a key step to enhance therapeutic outcomes.

Relationship between footshock intensity, post-training corticosterone release and contextual fear memory specificity over time.

Overgeneralized fear has long been implicated in generalized anxiety and post-traumatic stress disorder, however, time-dependent mechanisms underlying memory retrieval are still not completely understood. Previous studies have revealed that stronger fear conditioning training protocols are associated with both increased post-training corticosterone (CORT) levels and fear responses at later retrieval tests. Here we used contextual fear conditioning (CFC) to investigate the relationship between post-training CORT levels and memory specificity in different retrieval timepoints. Wistar rats were exposed to CFC training with increasing footshock intensities (0.3, 0.6 or 1.0mA) and had their blood collected 30 min afterwards to measure post-training plasma CORT. After 2, 14 or 28 days, rats were tested for memory specificity either in the training or in the novel context. Regression analysis was used to verify linear and non-linear interactions between CORT levels and freezing. Higher footshock intensities increased post-training CORT levels and freezing times during tests in all timepoints. Moreover, stronger trainings elicited faster memory generalization, which was associated with higher CORT levels during memory consolidation. The 0.3mA training maintained memory specificity up to 28 days. Additionally, linear regressions suggest that the shift from specific to generalized memories is underway at 14 days after training. These results are consistent with the hypotheses that stronger training protocols elicit a faster generalization rate, and that this process is associated with increased post-training CORT release.

Temporal Flexibility of Systems Consolidation and the Synaptic Occupancy/Reset Theory (SORT): Cues About the Nature of the Engram.

The ability to adapt to new situations involves behavioral changes expressed either from an innate repertoire, or by acquiring experience through memory consolidation mechanisms, by far a much richer and flexible source of adaptation. Memory formation consists of two interrelated processes that take place at different spatial and temporal scales, Synaptic Consolidation, local plastic changes in the recruited neurons, and Systems Consolidation, a process of gradual reorganization of the explicit/declarative memory trace between hippocampus and the neocortex. In this review, we summarize some converging experimental results from our lab that support a normal temporal framework of memory systems consolidation as measured both from the anatomical and the psychological points of view, and propose a hypothetical model that explains these findings while predicting other phenomena. Then, the same experimental design was repeated interposing additional tasks between the training and the remote test to verify for any interference: we found that (a) when the animals were subject to a succession of new learnings, systems consolidation was accelerated, with the disengagement of the hippocampus taking place before the natural time point of this functional switch, but (b) when a few reactivation sessions reexposed the animal to the training context without the shock, systems consolidation was delayed, with the hippocampus prolonging its involvement in retrieval. We hypothesize that new learning recruits from a fixed number of plastic synapses in the CA1 area to store the engram index, while reconsolidation lead to a different outcome, in which additional synapses are made available. The first situation implies the need of a reset mechanism in order to free synapses needed for further learning, and explains the acceleration observed under intense learning activity, while the delay might be explained by a different process, able to generate extra free synapses: depending on the cognitive demands, it deals either with a fixed or a variable pool of available synapses. The Synaptic Occupancy/Reset Theory (SORT) emerged as an explanation for the temporal flexibility of systems consolidation, to encompass the two different dynamics of explicit memories, as well as to bridge both synaptic and systems consolidation in one single mechanism.

Reconsolidation-induced rescue of a remote fear memory blocked by an early cortical inhibition: Involvement of the anterior cingulate cortex and the mediation by the thalamic nucleus reuniens.

Systems consolidation is a time-dependent reorganization process involving neocortical and hippocampal networks underlying memory storage and retrieval. The involvement of the hippocampus during acquisition is well described; however we know much less about the concomitant contribution of cortical activity levels to the formation of stable remote memories. Here, after a reversible pharmacological inhibition of the anterior cingulate cortex (ACC) during the acquisition of a contextual fear conditioning, retrieval of both recent and remote memories were impaired, an effect that was reverted by a single memory reactivation session 48 h after training, through a destabilization-dependent mechanism interpreted as reconsolidation, that restored the normal course of systems consolidation in order to rescue a remote memory. Next we have shown that the integrity of both the anterior cingulate cortex and the thalamic nucleus reuniens (RE) were required for this reactivation-induced memory rescue. Because lidocaine infused into the RE inhibited LTP induction in the CA1-anterior cingulate cortex pathways, it seems that RE is a necessary component of the circuit underlying systems consolidation, mediating communication between dorsal hippocampus and cortical areas. To our notice, this is the first demonstration of the rescue of remote memories disrupted by ACC inhibition during acquisition, via a reconsolidation-driven mechanism. We have also shown the importance of RE to ensure the interconnection among brain areas that collectively seem to control the natural course of systems consolidation and allow the persistence of relevant emotional engrams. © 2017 Wiley Periodicals, Inc.

Sequential learning during contextual fear conditioning guides the rate of systems consolidation: Implications for consolidation of multiple memory traces.

Systems consolidation has been described as a time-dependent reorganization process involving the neocortical and hippocampal networks underlying memory storage and retrieval. Previous studies of our lab were able to demonstrate that systems consolidation is a dynamic process, rather than a merely passive, time-dependent phenomenon. Here, we studied the influence of sequential learning in contextual fear conditioning (CFC) with different training intensities in the time-course of hippocampal dependency and contextual specificity. We found that sequential learning with high-intensity shocks during CFC induces generalization of the first learning (context A) and maintains contextual specificity of the second learning (context B) 15 days after acquisition. Moreover, subsequent experiences reorganize brain structures involved in retrieval, accelerating the involvement of cortical structures and diminishing the hippocampal participation. Exposure to original context before novelty seems to only induce context specificity in hippocampal-dependent memories. We propose that systems consolidation could be considered a potential biological mechanism for reducing possible interferences between similar memory traces. © 2017 Wiley Periodicals, Inc.

Novel learning accelerates systems consolidation of a contextual fear memory.

After initial encoding memories may undergo a time-dependent reorganization, becoming progressively independent from the hippocampus (HPC) and dependent on cortical regions such as the anterior cingulate cortex (ACC). Although the mechanisms underlying systems consolidation are somewhat known, the factors determining its temporal dynamics are still poorly understood. Here, we studied the influence of novel learning occurring between training and test sessions on the time-course of HPC- and ACC-dependency of contextual fear conditioning (CFC) memory expression. We found that muscimol was disruptive when infused into the HPC up to 35 days after training, while the ACC is vulnerable only after 45 days. However, when animals were subjected to a series of additional, distinct tasks to be learned within the first 3 weeks, muscimol became effective sooner. Muscimol had no effect in the HPC at 20 days after training, exactly when the ACC becomes responsive to this treatment. Thus, our data indicates that the encoding of new information generates a tight interplay between distinct memories, accelerating the reorganization of previously stored long term memories between the hippocampal and cortical areas. © 2016 Wiley Periodicals, Inc.