Remote Memory Retrieval Research Articles

M1 muscarinic receptors are necessary for retrieval of remote context fear memory

Several studies have investigated the transition of consolidation of recent memory to remote memory in aversively motivated tasks, such as contextual fear conditioning (CFC) and inhibitory avoidance (IA). However, the mechanisms that serve the retrieval of remote memories, has not yet been fully understood. Some evidences suggest that the central cholinergic system appears be involved in the modulation of these processes. Therefore, the present study aimed to investigate the effects of a pre-test administration of dicyclomine, a high-affinity M1 muscarinic receptor antagonist, on the retrieval of remote memories in fear conditioning and IA tasks. Male Wistar rats were trained, and after 1 or 28days, the rats received dicyclomine (16 or 32mg/kg, intraperitoneally, i.p.) and were tested in CFC, tone fear conditioning (TFC) and IA tasks. At both time intervals, 32mg/kg dicyclomine induced impairment of CFC. In TFC task only the performance of the rats 28days after training was impaired. The IA task was not affected in any of the studied intervals. These findings suggest a differential contribution of muscarinic receptors on recent and remote memories retrieval revealing a more generalized role in remote memory.

Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval.

Forgetting of recent fear memory is promoted by treatment with memantine (MEM), which increases hippocampal neurogenesis. The approaches for treatment of post-traumatic stress disorder (PTSD) using rodent models have focused on the extinction and reconsolidation of recent, but not remote, memories. Here we show that, following prolonged re-exposure to the conditioning context, enhancers of hippocampal neurogenesis, including MEM, promote forgetting of remote contextual fear memory. However, these interventions are ineffective following shorter re-exposures. Importantly, we find that long, but not short re-exposures activate gene expression in the hippocampus and induce hippocampus-dependent reconsolidation of remote contextual fear memory. Furthermore, remote memory retrieval becomes hippocampus-dependent after the long-time recall, suggesting that remote fear memory returns to a hippocampus dependent state after the long-time recall, thereby allowing enhanced forgetting by increased hippocampal neurogenesis. Forgetting of traumatic memory may contribute to the development of PTSD treatment.

Increased task demand during spatial memory testing recruits the anterior cingulate cortex.

We examined whether increasing retrieval difficulty in a spatial memory task would promote the recruitment of the anterior cingulate cortex (ACC) similar to what is typically observed during remote memory retrieval. Rats were trained on the hidden platform version of the Morris Water Task and tested three or 30 d later. Retrieval difficulty was manipulated by removing several prominent extra-pool cues from the testing room. Immediate early gene expression (c-Fos) in the ACC was greater following the cue removal and comparable to remote memory retrieval (30-d retention interval) levels, supporting the view of increased ACC contribution during high cognitive-demand memory processes.

Retrosplenial cortex is required for the retrieval of remote memory for auditory cues.

The restrosplenial cortex (RSC) has a well-established role in contextual and spatial learning and memory, consistent with its known connectivity with visuo-spatial association areas. In contrast, RSC appears to have little involvement with delay fear conditioning to an auditory cue. However, all previous studies have examined the contribution of the RSC to recently acquired auditory fear memories. Since neocortical regions have been implicated in the permanent storage of remote memories, we examined the contribution of the RSC to remotely acquired auditory fear memories. In Experiment 1, retrieval of a remotely acquired auditory fear memory was impaired when permanent lesions (either electrolytic or neurotoxic) were made several weeks after initial conditioning. In Experiment 2, using a chemogenetic approach, we observed impairments in the retrieval of remote memory for an auditory cue when the RSC was temporarily inactivated during testing. In Experiment 3, after injection of a retrograde tracer into the RSC, we observed labeled cells in primary and secondary auditory cortices, as well as the claustrum, indicating that the RSC receives direct projections from auditory regions. Overall our results indicate the RSC has a critical role in the retrieval of remotely acquired auditory fear memories, and we suggest this is related to the quality of the memory, with less precise memories being RSC dependent.

Tracking the Time-Dependent Role of the Hippocampus in Memory Recall Using DREADDs.

The hippocampus is critical for the storage of new autobiographical experiences as memories. Following an initial encoding stage in the hippocampus, memories undergo a process of systems-level consolidation, which leads to greater stability through time and an increased reliance on neocortical areas for retrieval. The extent to which the retrieval of these consolidated memories still requires the hippocampus is unclear, as both spared and severely degraded remote memory recall have been reported following post-training hippocampal lesions. One difficulty in definitively addressing the role of the hippocampus in remote memory retrieval is the precision with which the entire volume of the hippocampal region can be inactivated. To address this issue, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), a chemical-genetic tool capable of highly specific neuronal manipulation over large volumes of brain tissue. We find that remote (>7 weeks after acquisition), but not recent (1–2 days after acquisition) contextual fear memories can be recalled after injection of the DREADD agonist (CNO) in animals expressing the inhibitory DREADD in the entire hippocampus. Our data demonstrate a time-dependent role of the hippocampus in memory retrieval, supporting the standard model of systems consolidation.

Analysis of coherent activity between retrosplenial cortex, hippocampus, thalamus, and anterior cingulate cortex during retrieval of recent and remote context fear memory

Memory for contextual fear conditioning relies upon the retrosplenial cortex (RSC) regardless of how long ago conditioning occurred, whereas areas connected to the RSC, such as the dorsal hippocampus (DH) and anterior cingulate cortex (ACC) appear to play time-limited roles. To better understand whether these brain regions functionally interact during memory processing and how the passage of time affects these interactions, we simultaneously recorded local field potentials (LFPs) from these three regions as well as anterior dorsal thalamus (ADT), which provides one of the strongest inputs to RSC, and measured coherence of oscillatory activity within the theta (4–12Hz) and gamma (30–80Hz) frequency bands. We identified changes of theta coherence related to encoding, retrieval, and extinction of context fear, whereas changes in gamma coherence were restricted to fear extinction. Specifically, exposure to a novel context and retrieval of recently acquired fear conditioning memory were associated with increased theta coherence between RSC and all three other structures. In contrast, RSC–DH and RSC–ADT theta coherence were decreased in mice that successfully retrieved, relative to mice that failed to retrieve, remote memory. Greater RSC–ADT theta and gamma coherence were observed during recent, compared to remote, extinction of freezing responses. Thus, the degree of coherence between RSC and connected brain areas may predict and contribute to context memory retrieval and retrieval-related phenomena such as fear extinction. Importantly, although theta coherence in this circuit increases during memory encoding and retrieval of recent memory, failure to decrease RSC–DH theta coherence might be linked to retrieval deficit in the long term, and possibly contribute to aberrant memory processing characteristic of neuropsychiatric disorders.

Different neural circuitry is involved in physiological and psychological stress-induced PTSD-like "nightmares" in rats.

Posttraumatic nightmares are a core component of posttraumatic stress disorder (PTSD) and mechanistically linked to the development and maintenance of this disorder, but little is known about their mechanism. We utilized a communication box to establish an animal model of physiological stress (foot-shock [FS]) and psychological stress (PS) to mimic the direct suffering and witnessing of traumatic events. Twenty-one days after traumatic stress, some of the experimental animals presented startled awakening (i.e., were startled awake by a supposed “nightmare”) with different electroencephalographic spectra features. Our neuroanatomical results showed that the secondary somatosensory cortex and primary auditory cortex may play an important role in remote traumatic memory retrieval in FS “nightmare” (FSN) rats, whereas the temporal association cortex may play an important role in PS “nightmare” (PSN) rats. The FSN and PSN groups possessed common emotion evocation circuits, including activation of the amygdala and inactivation of the infralimbic prefrontal cortex and ventral anterior cingulate cortex. The decreased activity of the granular and dysgranular insular cortex was only observed in PSN rats. The present results imply that different types of stress may cause PTSD-like “nightmares” in rodents and identified the possible neurocircuitry of memory retrieval and emotion evocation.

Dorsal medial prefrontal cortex contributes to conditioned taste aversion memory consolidation and retrieval

The medial prefrontal cortex (mPFC) is known for its role in decision making and memory processing, including the participation in the formation of extinction memories. However, little is known regarding its contribution to aversive memory consolidation. Here we demonstrate that neural activity and protein synthesis are required in the dorsal mPFC for memory formation of a conditioned taste aversion (CTA) task and that this region is involved in the retrieval of recent and remote long-term CTA memory. In addition, both NMDA receptor and CaMKII activity in dorsal mPFC are needed for CTA memory consolidation, highlighting the complexity of mPFC functions.

Transient relay function of midline thalamic nuclei during long-term memory consolidation in humans.

To test the hypothesis that thalamic midline nuclei play a transient role in memory consolidation, we reanalyzed a prospective functional MRI study, contrasting recent and progressively more remote memory retrieval. We revealed a transient thalamic connectivity increase with the hippocampus, the medial prefrontal cortex (mPFC), and a parahippocampal area, which decreased with time. In turn, mPFC-parahippocampal connectivity increased progressively. These findings support a model in which thalamic midline nuclei serve as a hub linking hippocampus, mPFC, and posterior representational areas during memory retrieval at an early (2 h) stage of consolidation, extending classical systems consolidation models by attributing a transient role to midline thalamic nuclei.

Robust hippocampal responsivity during retrieval of consolidated associative memory.

ABSTRACTA contentious point in memory research is whether or not the hippocampus plays a time‐limited role in the consolidation of declarative memories. A widely held view is that declarative memories are initially encoded in the hippocampus, then transferred to the neocortex for long‐term storage. Alternate views argue instead that the hippocampus continues to play a role in remote memory recall. These competing theories are largely based on human amnesic and animal lesion/inactivation studies. However, in vivo electrophysiological evidence supporting these views is scarce. Given that other studies examining the role of the hippocampus in remote memory retrieval using lesion and imaging techniques in human and animal models have provided mixed results, it would be particularly useful to gain insight at the in vivo electrophysiological level. Here we report hippocampal single‐neuron and theta activity recorded longitudinally during acquisition and remote retrieval of trace eyeblink conditioning. Results from conditioned rabbits were compared to those obtained from yoked pseudo‐conditioned control rabbits. Results reveal continued learning‐specific hippocampal activity one month after initial acquisition of the task. Our findings yield insight into the normal physiological responses of the hippocampus during memory processes and provide compelling in vivo electrophysiological evidence that the hippocampus is involved in both acquisition and retrieval of consolidated memories. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Grey and white matter correlates of recent and remote autobiographical memory retrieval--insights from the dementias.

The capacity to remember self-referential past events relies on the integrity of a distributed neural network. Controversy exists, however, regarding the involvement of specific brain structures for the retrieval of recently experienced versus more distant events. Here, we explored how characteristic patterns of atrophy in neurodegenerative disorders differentially disrupt remote versus recent autobiographical memory. Eleven behavioural-variant frontotemporal dementia, 10 semantic dementia, 15 Alzheimer's disease patients and 14 healthy older Controls completed the Autobiographical Interview. All patient groups displayed significant remote memory impairments relative to Controls. Similarly, recent period retrieval was significantly compromised in behavioural-variant frontotemporal dementia and Alzheimer's disease, yet semantic dementia patients scored in line with Controls. Voxel-based morphometry and diffusion tensor imaging analyses, for all participants combined, were conducted to investigate grey and white matter correlates of remote and recent autobiographical memory retrieval. Neural correlates common to both recent and remote time periods were identified, including the hippocampus, medial prefrontal, and frontopolar cortices, and the forceps minor and left hippocampal portion of the cingulum bundle. Regions exclusively implicated in each time period were also identified. The integrity of the anterior temporal cortices was related to the retrieval of remote memories, whereas the posterior cingulate cortex emerged as a structure significantly associated with recent autobiographical memory retrieval. This study represents the first investigation of the grey and white matter correlates of remote and recent autobiographical memory retrieval in neurodegenerative disorders. Our findings demonstrate the importance of core brain structures, including the medial prefrontal cortex and hippocampus, irrespective of time period, and point towards the contribution of discrete regions in mediating successful retrieval of distant versus recently experienced events.

Time course of the dependence of associative memory retrieval on the entorhinal cortex

As the gateway between the hippocampal system and the neocortex, the entorhinal cortex (EC) is hypothesized to be the hub in which the transformation of recent memory to remote memory is processed. We explored the role of the EC on the retrieval of recent and remote associative fear memory. A within-subject approach was adopted to compare the freezing rates of rats in EC intact and EC inactivated conditions following trace fear conditioning. The EC was inactivated by infusing an AMPA antagonist. The fear conditioning used a combined visual and auditory conditioned stimulus with a foot shock. On week 1 following the conditioning, the rats in the EC intact condition exhibited a freezing rate of 92.4±9.5% in response to the light stimulus compared with a 6.3±7.9% freezing rate in the EC inactivated condition. The freezing rates were 87.0±17.8% and 4.7±6.5% on week 2 in the EC intact and inactivated conditions, respectively. These results indicate that the EC participates in the retrieval of associative memory. Extinction of the fear memory was observed in the EC intact condition, as the mean freezing rate decreased to 62.7±23.0% on week 4 and 41.2±26.4% on week 5. However, the freezing rate increased to 26.8±14.2% on week 4 and 22.3±14.4% on week 5 in the EC inactivated condition. The normalized dependence of fear memory retrieval on the EC was 93.2±8.3% on week 1, and significantly decreased on weeks 4 and 5. In summary, the retrieval of associative memory depends on the EC, but this dependence decreases over time.

Inactivation of the anterior cingulate reveals enhanced reliance on cortical networks for remote spatial memory retrieval after sequential memory processing.

One system consolidation model suggests that as time passes, ensembles of cortical neurons form strong connections to represent remote memories. In this model, the anterior cingulate cortex (ACC) serves as a cortical region that represents remote memories. However, there is debate as to whether remote spatial memories go through this systems consolidation process and come to rely on the ACC. The present experiment examined whether increasing the processing demand on the hippocampus, by sequential training on two spatial tasks, would more fully engage the ACC during retrieval of a remote spatial memory. In this scenario, inactivation of the ACC at a remote time point was hypothesized to produce a severe memory deficit if rats had been trained on two, sequential spatial tasks. Rats were trained on a water maze (WM) task only or a WM task followed by a radial arm maze task. A WM probe test was given recently or remotely to all rats. Prior to the probe test, rats received an injection of saline or muscimol into the ACC. A subtle deficit in probe performance was found at the remote time point in the group trained on only one spatial task and treated with muscimol. In the group trained on two spatial tasks and treated with muscimol, a subtle deficit in probe performance was noted at the recent time point and a substantial deficit in probe performance was observed at the remote time point. c-Fos labeling in the hippocampus revealed more labeling in the CA1 region in all remotely tested groups than recently tested groups. Findings suggest that spatial remote memories come to rely more fully on the ACC when hippocampal processing requirements are increased. Results also suggest continued involvement of the hippocampus in spatial memory retrieval along with a progressive strengthening of cortical connections as time progresses.

Differential effects of dorsal hippocampal inactivation on expression of recent and remote drug and fear memory

Drugs of abuse generate strong drug-context associations, which can evoke powerful drug cravings that are linked to reinstatement in animal models and to relapse in humans. Work in learning and memory has demonstrated that contextual memories become more distributed over time, shifting from dependence on the hippocampus for retrieval to dependence on cortical structures. Implications for such changes in the structure of memory retrieval to addiction are unknown. Thus, to determine if the passage of time alters the substrates of conditioned place preference (CPP) memory retrieval, we investigated the effects of inactivation of the dorsal hippocampus (DH) with the GABA-A receptor agonist muscimol on expression of recent or remote CPP. We compared these effects with the same manipulation on expression of contextual fear conditioning. DH inactivation produced similar deficits in expression of both recent and remote CPP, but blocked expression of recent but not remote contextual fear memory. We describe the implications of these findings for mechanisms underlying long-term storage of contextual information.

New methods for understanding systems consolidation

According to the standard model of systems consolidation (SMC), neocortical circuits are reactivated during the retrieval of declarative memories. This process initially requires the hippocampus. However, with the passage of time, neocortical circuits become strengthened and can eventually retrieve memory without input from the hippocampus. Although consistent with lesion data, these assumptions have been difficult to confirm experimentally. In the current review, we discuss recent methodological advances in behavioral neuroscience that are making it possible to test the basic assumptions of SMC for the first time. For example, new transgenic mice can be used to monitor the activity of individual neurons across the entire brain while optogenetic approaches provide precise control over the activity of these cells using light stimulation. These tools can be used to examine the reactivation of neocortical neurons during recent and remote memory retrieval and determine if this process requires the hippocampus.

Autobiographical memory in semantic dementia: New insights from two patients using fMRI

Episodic autobiographical memory (EAM) consists of personal events embedded within a specific spatiotemporal context. Patients with semantic dementia (SD) generally show preserved recent EAMs, but a controversy remains concerning their ability to retrieve remote ones. Only one fMRI study examined remote autobiographical memory in SD through a longitudinal case study (Maguire, Kumaran, Hassabis, & Kopelman, 2010). Here, we propose a cross-sectional study to test the hippocampo-neocortical up-regulation hypothesis, through a multimodal approach (gray matter volume, activation, connectivity analyses), directly comparing recent and remote autobiographical memory retrieval and collecting data to asses phenomelogical re-experiencing. EAM retrieval recruits a distributed network of brain regions, notably the hippocampus which is shown to be atrophied in SD, although some studies report no hippocampal atrophy in SD. Using fMRI, we examined recent and remote EAM retrieval in two SD patients with different profiles of hippocampal atrophy, compared to 12 healthy elders (HE). JPL presented severe bilateral hippocampal atrophy, while EP showed sparing of both hippocampi. Behaviourally, JPL was impaired at retrieving EAMs from both life periods and showed poorer use of visual mental imagery than HE, while EP retrieved memories which were as episodic as those of HE for both periods and relied on greater use of visual mental imagery than HE. Neuroimaging results showed that, for JPL, hyperactivations of the residual hippocampal tissue and of frontal, lateral temporal, occipital and parietal cortices did not efficiently compensate his autobiographical memory deficit. EP however presented hyperactivations in similar neocortical regions which appeared to be more efficient in compensating for atrophy elsewhere, since EP's EAM retrieval was preserved. Functional connectivity analyses focusing on the hippocampus showed how the residual hippocampal activity was connected to other brain areas. For JPL, recent autobiographical retrieval was associated with connectivity between the posterior hippocampus and middle occipital gyrus, while for EP, connectivity was detected between the anterior hippocampus and numerous regions (medial temporal, occipital, temporal, frontal, parietal) for both recent and remote periods. These findings suggest that intensification of hippocampal atrophy in SD strongly affects both recent and remote autobiographical recollection. Up-regulation of neocortical regions and functional hippocampal–neocortical connectivity within the autobiographical network may be insufficient to compensate the lifelong episodic memory deficit for patients with extensive hippocampal atrophy.

Functional integrity of the retrosplenial cortex is essential for rapid consolidation and recall of fear memory

Memory storage is a temporally graded process involving different phases and different structures in the mammalian brain. Cortical plasticity is essential to store stable memories, but little is known regarding its involvement in memory processing. Here we show that fear memory consolidation requires early post-training macromolecular synthesis in the anterior part of the retrosplenial cortex (aRSC), and that reversible pharmacological inactivation of this cortical region impairs recall of recent as well as of remote memories. These results challenge the generally accepted idea that neocortical areas are slow encoding systems that participate in the retrieval of remote memories only.

Competitive Trace Theory: A Role for the Hippocampus in Contextual Interference during Retrieval

Much controversy exists regarding the role of the hippocampus in retrieval. The two dominant and competing accounts have been the Standard Model of Systems Consolidation (SMSC) and Multiple Trace Theory (MTT), which specifically make opposing predictions as to the necessity of the hippocampus for retrieval of remote memories. Under SMSC, memories eventually become independent of the hippocampus as they become more reliant on cortical connectivity, and thus the hippocampus is not required for retrieval of remote memories, only recent ones. MTT on the other hand claims that the hippocampus is always required no matter the age of the memory. We argue that this dissociation may be too simplistic, and a continuum model may be better suited to address the role of the hippocampus in retrieval of remote memories. Such a model is presented here with the main function of the hippocampus during retrieval being “recontextualization,” or the reconstruction of memory using overlapping traces. As memories get older, they are decontextualized due to competition among partially overlapping traces and become more semantic and reliant on neocortical storage. In this framework dubbed the Competitive Trace Theory (CTT), consolidation events that lead to the strengthening of memories enhance conceptual knowledge (semantic memory) at the expense of contextual details (episodic memory). As a result, remote memories are more likely to have a stronger semantic representation. At the same time, remote memories are also more likely to include illusory details. The CTT is a novel candidate model that may provide some resolution to the memory consolidation debate.

Reactivation of Neural Ensembles during the Retrieval of Recent and Remote Memory

Episodic memories are encoded within hippocampal and neocortical circuits. Retrieving these memories is assumed to involve reactivation of neural ensembles that were established during learning. Although it has been possible to follow the activity of individual neurons shortly after learning, it has not been possible to examine their activity weeks later during retrieval. We addressed this issue by using a stable form of GFP (H2B-GFP) to permanently tag neurons that are active during contextual fear conditioning. H2B-GFP expression in transgenic mice was increased by learning and could be regulated by doxycycline (DOX). Using this system, we found a large network of neurons in the hippocampus, amygdala, and neocortex that were active during context fear conditioning and subsequent memory retrieval 2 days later. Reactivation was contingent on memory retrieval and was not observed when animals were trained and tested in different environments. When memory was retrieved several weeks after learning, reactivation was altered in the hippocampus and amygdala but remained unchanged in the cortex. Retrieving a recently formed context fear memory reactivates neurons in the hippocampus, amygdala, and cortex. Several weeks after learning, the degree of reactivation is altered in hippocampal and amygdala networks but remains stable in the cortex.

Brain region-specific activity patterns after recent or remote memory retrieval of auditory conditioned fear

Memory is thought to be sparsely encoded throughout multiple brain regions forming unique memory trace. Although evidence has established that the amygdala is a key brain site for memory storage and retrieval of auditory conditioned fear memory, it remains elusive whether the auditory brain regions may be involved in fear memory storage or retrieval. To investigate this possibility, we systematically imaged the brain activity patterns in the lateral amygdala, MGm/PIN, and AuV/TeA using activity-dependent induction of immediate early gene zif268 after recent and remote memory retrieval of auditory conditioned fear. Consistent with the critical role of the amygdala in fear memory, the zif268 activity in the lateral amygdala was significantly increased after both recent and remote memory retrieval. Interesting, however, the density of zif268 (+) neurons in both MGm/PIN and AuV/TeA, particularly in layers IV and VI, was increased only after remote but not recent fear memory retrieval compared to control groups. Further analysis of zif268 signals in AuV/TeA revealed that conditioned tone induced stronger zif268 induction compared to familiar tone in each individual zif268 (+) neuron after recent memory retrieval. Taken together, our results support that the lateral amygdala is a key brain site for permanent fear memory storage and suggest that MGm/PIN and AuV/TeA might play a role for remote memory storage or retrieval of auditory conditioned fear, or, alternatively, that these auditory brain regions might have a different way of processing for familiar or conditioned tone information at recent and remote time phases.