Recall Of Recent Memories Research Articles

Systems consolidation induces multiple memory engrams for a flexible recall strategy in observational fear memory in male mice

Observers learn to fear the context in which they witnessed a demonstrator’s aversive experience, called observational contextual fear conditioning (CFC). The neural mechanisms governing whether recall of the observational CFC memory occurs from the observer’s own or from the demonstrator’s point of view remain unclear. Here, we show in male mice that recent observational CFC memory is recalled in the observer’s context only, but remote memory is recalled in both observer and demonstrator contexts. Recall of recent memory in the observer’s context requires dorsal hippocampus activity, while recall of remote memory in both contexts requires the medial prefrontal cortex (mPFC)-basolateral amygdala pathway. Although mPFC neurons activated by observational CFC are involved in remote recall in both contexts, distinct mPFC subpopulations regulate remote recall in each context. Our data provide insights into a flexible recall strategy and the functional reorganization of circuits and memory engram cells underlying observational CFC memory.

Brain-wide screen of prelimbic cortex inputs reveals a functional shift during early fear memory consolidation.

Memory formation and storage rely on multiple interconnected brain areas, the contribution of which varies during memory consolidation. The medial prefrontal cortex, in particular the prelimbic cortex (PL), was traditionally found to be involved in remote memory storage, but recent evidence points toward its implication in early consolidation as well. Nevertheless, the inputs to the PL governing these dynamics remain unknown. Here, we first performed a brain-wide, rabies-based retrograde tracing screen of PL engram cells activated during contextual fear memory formation in male mice to identify relevant PL input regions. Next, we assessed the specific activity pattern of these inputs across different phases of memory consolidation, from fear memory encoding to recent and remote memory recall. Using projection-specific chemogenetic inhibition, we then tested their functional role in memory consolidation, which revealed a hitherto unknown contribution of claustrum to PL inputs at encoding, and of insular cortex to PL inputs at recent memory recall. Both of these inputs further impacted how PL engram cells were reactivated at memory recall, testifying to their relevance for establishing a memory trace in the PL. Collectively, these data identify a spatiotemporal shift in PL inputs important for early memory consolidation, and thereby help to refine the working model of memory formation.

Prenatal Stress Produces Persistence of Remote Memory and Disrupts Functional Connectivity in the Hippocampal-Prefrontal Cortex Axis.

Prenatal stress is a risk factor for the development of neuropsychiatric disorders, many of which are commonly characterized by an increased persistence of aversive remote memory. Here, we addressed the effect of prenatal stress on both memory consolidation and functional connectivity in the hippocampal-prefrontal cortex axis, a dynamical interplay that is critical for mnemonic processing. Pregnant mice of the C57BL6 strain were subjected to restraint stressed during the last week of pregnancy, and male offspring were behaviorally tested at adulthood for recent and remote spatial memory performance in the Barnes Maze test under an aversive context. Prenatal stress did not affect the acquisition or recall of recent memory. In contrast, it produced the persistence of remote spatial memory. Memory persistence was not associated with alterations in major network rhythms, such as hippocampal sharp-wave ripples (SWRs) or neocortical spindles. Instead, it was associated with a large decrease in the basal discharge activity of identified principal neurons in the medial prefrontal cortex (mPFC) as measured in urethane anesthetized mice. Furthermore, functional connectivity was disrupted, as the temporal coupling between neuronal discharge in the mPFC and hippocampal SWRs was decreased by prenatal stress. These results could be relevant to understand the biological basis of the persistence of aversive remote memories in stress-related disorders.

Habit acquisition in the context of neuronal genomic and epigenomic mosaicism.

A recent paper (Graff et al., 2014) shows that remote fear memories in mice can be stably attenuated with the administration of histone de-acetylase (HDAC) inhibitors during reconsolidation. This achieved persistent attenuation of remote memories, even though it is well established that the brief period of hippocampal neuroplasticity induced by recent memory recall is absent for remote memories. Apparently, such epigenetic intervention primed the expression of neuroplasticity-related genes. This work comes shortly after the finding (McConnell et al., 2013) that individual neurons show an extraordinary degree of genomic mosaicism. Sequencing the genomes of single human frontal cortex neurons, these authors found that up to 41% of neurons contain at least one de novo copy-number variant (CNV) of at least one megabase in size. Segmental duplications have greatly expanded in African great apes (Marques-Bonet et al., 2009), and it is possible that increased retrotransposon activity during human neurogenesis also contributes to this striking diversity in CNV numbers in neuronal genomes (Singer et al., 2010). Taken together, both studies support the notion that genomic and epigenomic mosaicism allows for the introduction of heritable changes at the single-cell level that promote neuronal plasticity, and thus help to explain how human actions can modify neural circuits involved in memory and learning.

Medial prefrontal cortex is a crucial node of a rapid learning system that retrieves recent and remote memories

The neocortex is thought to be a distributed learning system that gradually integrates semantic information into the initial mnemonic representation rapidly formed by the hippocampus after acquisition. Nevertheless, an emerging view suggests that some cortical regions, in particular the medial prefrontal cortex (mPFC), may also have a role during the initial steps of memory consolidation as well as in the recall of recent memories. Here, we show that mPFC plays a critical role during the first few hours of inhibitory avoidance memory consolidation and is necessary for the normal retrieval of both recent and remote memories, supporting the idea that involvement of neocortical areas in memory processing is not restricted to the late post-training consolidation phase.

Engagement of the PFC in consolidation and recall of recent spatial memory

The standard model of system consolidation proposes that memories are initially hippocampus dependent and become hippocampus independent over time. Previous studies have demonstrated the involvement of the medial prefrontal cortex (mPFC) in the retrieval of remote memories. The transformations required to make a memory undergo system's consolidation are thought to require synaptic plasticity. In this study, we investigated the participation of the mitogen-activated protein kinase (MAPK)/ERK pathway in acquisition, memory consolidation, and recent memory recall of the Morris water maze (MWM) task using a 1-d training protocol. To this end, bilateral injections of the MEK inhibitor U0126 into the rat mPFC were performed. The injection of the MEK inhibitor in the mPFC did not affect the acquisition of the MWM. However, MEK inhibitor resulted in impairments on recent memory retrieval either when applied at the end of the learning phase (memory consolidation) or prior to the retention test. The results strongly support the concept that recently acquired and consolidated spatial memories require the mPFC, and that local activation of the MAPK/ERK pathway in the mPFC is necessary for the consolidation and recall of recent memories.

Reorganization of learning-associated prefrontal synaptic plasticity between the recall of recent and remote fear extinction memory

We have previously shown that fear extinction is accompanied by an increase of synaptic efficacy in inputs from the ventral hippocampus (vHPC) and mediodorsal thalamus (MD) to the medial prefrontal cortex (mPFC) and that disrupting these changes to mPFC synaptic transmission compromises extinction processes. The aim of this study was to examine whether these extinction-related changes undergo further plasticity as the memory of extinction becomes more remote. Changes in synaptic efficacy in both vHPC-mPFC and MD-mPFC inputs were consequently analyzed when the memory was either 1 d or 7 d old. Increases of synaptic efficacy in the vHPC-mPFC pathway were observed when the memory was 1 d old, but not 7 d after initial extinction. In contrast, potentiation of synaptic efficacy in the MD-mPFC pathway increased over time. In rats that received low-frequency vHPC stimulation immediately after extinction, both vHPC-mPFC and MD-mPFC inputs failed to develop potentiation, and the recall of extinction (both recent and remote memories) was impaired. These findings suggest that post-extinction potentiation in vHPC-mPFC inputs may be necessary for both the recall of recent memory and post-extinction potentiation in the MD-mPFC inputs. This late potentiation process may be required for the recall of remote extinction memory.

'In the course of time': a PET study of the cerebral substrates of autobiographical amnesia in Alzheimer's disease.

Neuroimaging studies in healthy subjects have yielded controversial results about the neural substrates of autobiographical memory. Moreover, the neural networks responsible for autobiographical amnesia remain poorly understood. Since autobiographical memory is frequently altered in Alzheimer's disease (AD), we used this degenerative disorder as a model and applied a correlative approach between resting cerebral glucose utilization (CMRGlc) and temporally graded memory scores to identify the cerebral structures whose synaptic dysfunction subserves the impairment in autobiographical memory. To this end, we studied a group of 17 AD patients with mild to moderate dementia in whom autobiographical memory was assessed using a specially designed task from three broad time periods [the previous 5 years (period A); middle age (period B); and teenage and childhood (period C)], and measures of resting CMRGlc were obtained with PET. The patients performed less well than a control group for all three time periods and showed the expected temporal gradient, with the most remote period being best preserved (Ribot's gradient). Qualitative analysis showed that remote memories concerned generic (i.e. semantic) rather than specific (i.e. episodic) events. We found a significant positive correlation between autobiographical scores and the metabolism of the right hippocampus (extending to the lingual gyrus), restricted to period A. In addition, period A scores were significantly correlated with the right middle and inferior frontal gyri and the right middle temporal gyrus. Period B scores correlated chiefly with the prefrontal cortex bilaterally (bilateral superior, bilateral middle and right inferior gyri). Metabolic correlations with period C scores were restricted to the left middle frontal gyrus. These findings show striking differences in metabolic correlations with the autobiographical time period, in agreement with prevalent theories of normal functioning of human memory. Thus, in accordance with theories of long-term memory consolidation, we find the expected implication of the hippocampal region in the recall of recent memories, and a disengagement of this structure when the retention interval is beyond 5 years. Moreover, according to the hemispheric encoding/retrieval asymmetry model based on activation studies in healthy subjects, the fact that recent memories preferentially involved the right prefrontal cortex whereas remote memories involved the left prefrontal cortex supports the notion of semanticization of memories with time interval, such that preserved remote memories in AD have a predominantly semantic character.

Differentiating the roles of the hippocampal complex and the neocortex in long-term memory storage: evidence from the study of semantic dementia and Alzheimer's disease.

Several computational models suggest that the hippocampal complex plays a key role in the establishment of new memories, but over time the storage of such memories becomes independent of this region. In support of such models, the authors demonstrate that patients with semantic dementia, who have relative sparing of the hippocampal complex, show a pattern of preserved recent memories and impaired distant memories. In a group study that used the Autobiographical Memory Interview, amnesic patients with Alzheimer's disease showed the more typical temporally graded loss (poor recall of recent memories), whereas patients with semantic dementia showed the reverse pattern. In a single-case study, using the Galton-Crovitz test, a patient with semantic dementia was significantly better at producing autobiographical memories from the most recent 5 years. By contrast, controls provided similarly detailed memories across all time periods back to childhood.