Retrieval Of Recent Memories Research Articles

The Projection From Ventral CA1, Not Prefrontal Cortex, to Nucleus Accumbens Core Mediates Recent Memory Retrieval of Cocaine-Conditioned Place Preference.

Drug-paired cues inducing memory retrieval by expressing drug-seeking behaviors present a major challenge to drug abstinence. How neural circuits coordinate for drug memory retrieval remains unclear. Here, we report that exposure of the training chamber where cocaine-conditioned place preference (CPP) was performed increased neuronal activity in the core of nucleus accumbens (AcbC), ventral CA1 (vCA1), and medial prefrontal cortex (mPFC), as shown by elevated pERK and c-Fos levels. Chemogenetic inhibition of neuronal activity in the vCA1 and AcbC, but not mPFC, reduced the time spent in the cocaine-paired compartment, suggesting that the vCA1 and AcbC are required for the retrieval of cocaine-CPP memory and are key nodes recruited for cocaine memory storage. Furthermore, chemogenetic inhibition of the AcbC-projecting vCA1 neurons, but not the AcbC-projecting mPFC neurons, decreased the expression of cocaine-CPP. Optogenetic inhibition of the vCA1–AcbC projection, but not the mPFC–AcbC projection, also reduced the preference for the cocaine-paired compartment. Taken together, the cue-induced natural recall of cocaine memory depends on vCA1–AcbC circuits. The connectivity from the vCA1 to the AcbC may store the information of the cue–cocaine reward association critically required for memory retrieval. These data thus provide insights into the neural circuit basis of retrieval of drug-related memory.

Persistence of Fear Memory Depends on a Delayed Elevation of BAF53b and FGF1 Expression in the Lateral Amygdala.

Endurance represents a highly adaptive function of fear memory and a major cause of maladaptive fear- and anxiety-related mental disorders. However, less is known about the mechanisms underlying the persistence of fear memory. The epigenetic gene regulation recently emerged as an important mechanism for memory persistence. In the previous study, we found that BAF53b, a neuron-specific subunit of BAF chromatin remodeling complex, is induced after auditory cued fear conditioning in the lateral amygdala (LA) and is crucial for recent fear memory formation. In this study using mice of both sexes, we report a delayed induction of BAF53b in the LA 48 h after auditory fear conditioning and its critical role for the persistence of established fear memory. To specifically block the delayed but not the early induced BAF53b function, we used a postlearning knock-down method based on RNAi. The transient knockdown of Baf53b using siRNA in the lateral amygdala 24 h after cued fear conditioning led to specific impairment of remote but not recent memory retrieval. RNA-sequencing analyses identified fibroblast growth factor 1 (FGF1) as a candidate downstream effector. Consistently, postlearning administration of FGF1 peptide rescued memory persistence in Baf53b knock-down mice. These results demonstrate the crucial role of BAF53b and FGF1 in persistent retention of fear memory, giving insights into how fear memory persistently stored through consolidation processes and suggest candidate target for treating mental disorders related to traumatic memory.SIGNIFICANCE STATEMENT It is still unclear how once consolidated memory persists over time. In this study, we report the delayed induction of nucleosome remodeling factor BAF53b in the lateral nucleus of amygdala after fear learning and its crucial role for persistence of established memory beyond 24 h after learning. Our data link the regulation of BAF53b and fibroblast growth factor 1 expression in the amygdala to fear memory persistence. Results from this study open a new direction to understand the time-dependent continuous consolidation processes potentially by a nucleosome-remodeling mechanism enabling long-lasting memory formation and give insights into how to treat mental disorders caused by enduring traumatic memory.

Mapping the Neural Substrates of Recent and Remote Visual Imprinting Memory in the Chick Brain.

Social attachment formed by filial imprinting in newborn chicks undergoes a process of memory consolidation that involves rearrangement of its neural storage substrates. In the first 3 h after imprinting it depends on the integrity of the intermediate medial mesopallium (IMM) and beyond that time on unidentified memory storage structures dubbed S’. To search for the S’ memory system in the chick brain, we mapped and compared patterns of activity induced by retrieval of filial attachment memory before and after this critical transition. Chicks were trained in the visual imprinting task, and their memory was reactivated by imprinting stimulus either 1 h (recent memory retrieval) or 24 h (remote memory retrieval) after the completion of training. Patterns of brain activity were mapped by in situ hybridization to mRNA of an immediate early gene c-fos. We also mapped c-fos expression induced by the first presentation of the imprinting stimulus. Memory retrieval triggered massive c-fos expression in the chick brain both 1 and 24 h after the end of training. These activity patterns mostly coincided with the c-fos expression induced by the first presentation of imprinting stimulus. However, in the hippocampus c-fos induction was observed only after the first exposure to imprinting stimulus but not after memory retrieval. In the IMM, medio-rostral nidopallium/mesopallium, and hyperpallium densocellulare c-fos activation was induced by retrieval of only the remote but not of the recent memory. These c-fos mapping data point to the candidate brain structures for systems reorganization of imprinting memory in chicks.

Temporal evolution of cortical ensembles promoting remote memory retrieval.

Memories of fearful events can last a lifetime. The prelimbic (PL) subregion of prefrontal cortex plays a critical role in fear memory retrieval over time. Most studies have focused on acquisition, consolidation, and retrieval of recent memories, but much less is known about the neural mechanisms of remote memory. Using a new knock-in mouse for activity-dependent genetic labeling (TRAP2), we demonstrate that neuronal ensembles in PL are dynamic. PL neurons TRAPed during later memory retrievals are more likely to be reactivated and make larger behavioral contributions to remote memory retrieval compared to those TRAPed during learning or early memory retrieval. PL activity during learning is required to initiate this time-dependent reorganization in PL ensembles underlying memory retrieval. Finally, while neurons TRAPed during earlier and later retrievals have similar broad projections throughout the brain, PL neurons TRAPed later have a stronger functional recruitment of cortical targets.

Hippocampus-dependent emergence of spatial sequence coding in retrosplenial cortex.

Retrosplenial cortex (RSC) is involved in visuospatial integration and spatial learning, and RSC neurons exhibit discrete, place cell-like sequential activity that resembles the population code of space in hippocampus. To investigate the origins and population dynamics of this activity, we combined longitudinal cellular calcium imaging of dysgranular RSC neurons in mice with excitotoxic hippocampal lesions. We tracked the emergence and stability of RSC spatial activity over consecutive imaging sessions. Overall, spatial activity in RSC was experience-dependent, emerging gradually over time, but, as seen in the hippocampus, the spatial code changed dynamically across days. Bilateral but not unilateral hippocampal lesions impeded the development of spatial activity in RSC. Thus, the emergence of spatial activity in RSC, a major recipient of hippocampal information, depends critically on an intact hippocampus; the indirect connections between the dysgranular RSC and the hippocampus further indicate that hippocampus may exert such influences polysynaptically within neocortex.

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.

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.

Lifelong environmental enrichment in rats: impact on emotional behavior, spatial memory vividness, and cholinergic neurons over the lifespan

We assessed lifelong environmental enrichment effects on possible age-related modifications in emotional behaviors, spatial memory acquisition, retrieval of recent and remote spatial memory, and cholinergic forebrain systems. At the age of 1 month, Long-Evans female rats were placed in standard or enriched rearing conditions and tested after 3 (young), 12 (middle-aged), or 24 (aged) months. Environmental enrichment decreased the reactivity to stressful situations regardless of age. In the water maze test, it delayed the onset of learning deficits and prevented age-dependent spatial learning and recent memory retrieval alterations. Remote memory retrieval, which was altered independently of age under standard rearing conditions, was rescued by enrichment in young and middle-aged, but unfortunately not aged rats. A protected basal forebrain cholinergic system, which could well be one out of several neuronal manifestations of lifelong environmental enrichment, might have contributed to the behavioral benefits of this enrichment.

NMDA Receptors in Retrosplenial Cortex Are Necessary for Retrieval of Recent and Remote Context Fear Memory

Over time, memory retrieval is thought to transfer from the hippocampus to a distributed network of neocortical sites. Of these sites, the retrosplenial cortex (RSC) is robustly activated during retrieval of remotely acquired, emotionally valenced memories. It is unclear, however, whether RSC is specifically involved in memory storage or retrieval, and which neurotransmitter receptor mechanisms serve its function. We addressed these questions by inhibiting NMDARs in RSC via infusions of APV before tests for context fear in mice. Anterior cingulate cortex (ACC) and dorsal hippocampus (DH), which have been implicated in the retrieval of remote and recent memory, respectively, served as neuroanatomical controls. Surprisingly, infusion of APV only into RSC, but not ACC or DH, abolished retrieval of remote memory, as revealed by lack of freezing to the conditioning context. APV infused into RSC also impaired retrieval of recent memory, but had no effect on conditioning or memory storage. Within-subject experiments confirmed that the role of RSC in memory retrieval is not time limited. RSC-dependent context fear memory retrieval was mediated by NR2A, but not NR2B, subunit-containing NMDARs. Collectively, these data are the first demonstration that NMDARs in RSC are necessary for the retrieval of remote and recent memories of fear-evoking contexts. Dysfunction of RSC may thereby contribute significantly to the reexperiencing of traumatic memories in patients with posttraumatic stress disorder.

Context‐dependent modulation of hippocampal and cortical recruitment during remote spatial memory retrieval

According to systems consolidation, as hippocampal-dependent memories mature over time, they become additionally (or exclusively) dependent on extra-hippocampal structures. We assessed the recruitment of hippocampal and cortical structures on remote memory retrieval in a performance-degradation resistant (PDR; no performance degradation with time) versus performance-degradation prone (PDP; performance degraded with time) context. Using a water-maze task in two contexts with a hidden platform and three control conditions (home cage, visible platform with or without access to distal cues), we compared neuronal activation (c-Fos imaging) patterns in the dorsal hippocampus and the medial prefrontal cortex (mPFC) after the retrieval of recent (5 days) versus remote (25 days) spatial memory. In the PDR context, the hippocampus exhibited greater c-Fos protein expression on remote than recent memory retrieval, be it in the visible or hidden platform group. In the PDP context, hippocampal activation increased at the remote time point and only in the hidden platform group. In the anterior cingulate cortex, c-Fos expression was greater for remote than for recent memory retrieval and only in the PDR context. The necessity of the mPFC for remote memory retrieval in the PDR context was confirmed using region-specific lidocaine inactivation, which had no impact on recent memory. Conversely, inactivation of the dorsal hippocampus impaired both recent and remote memory in the PDR context, and only recent memory in the PDP context, in which remote memory performance was degraded. While confirming that neuronal circuits supporting spatial memory consolidation are reorganized in a time-dependent manner, our findings further indicate that mPFC and hippocampus recruitment (i) depends on the content and perhaps the strength of the memory and (ii) may be influenced by the environmental conditions (e.g., cue saliency, complexity) in which memories are initially formed and subsequently recalled.

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.

Cognitive mapping through electrophysiology

Cognitive mapping through electrophysiology

A putative role for neurogenesis in neurocomputational terms: Inferences from a hippocampal model

New neurons are generated daily in the hippocampus during adult life. They are integrated into the existing neuronal circuits according to several factors such as age, physical exercise and hormonal status. At present, the role of these new neurons is debated. Computational simulations of hippocampal function allow the effects of neurogenesis to be explored, at least from a computational perspective. The present work implements a model of neurogenesis in the hippocampus with artificial neural networks, based on a standard theoretical model of biologically plausible hippocampal circuits. The performance of the model in retrieval of a variable number of patterns or memories was evaluated (episodic memory evaluation). The model increased, in a phase subsequent to initial learning, the number of granular cells by 30% relative to their initial number. In contrast to a model without neurogenesis, the retrieval of recent memories was very significantly improved, although remotes memories were only slightly affected by neurogenesis. This increase in the quality of retrieval of new memories represents a clear advantage that we attribute to the neurogenesis process. This advantage becomes more significant for higher storage loads. The model presented here suggests an important functional role of neurogenesis on learning and memory.

An fMRI Study on the Time-Limited Role of the Medial Temporal Lobe in Long-Term Topographical Autobiographic Memory

The time-limited role of the medial temporal lobe (MTL) in human long-term memory is well known. However, there is still no direct neuroimaging evidence to confirm it. In this fMRI study, nine subjects were scanned while asked to recall the places they visited more than seven years ago (remote memories); and the places they visited recently (recent memories). We observed robust and dominant MTL activity peaking in the left parahippocampal gyrus when recent memories were contrasted with remote memories. This result provided direct evidence for the time-limited role of the MTL in long-term topographical autobiographic memory. Further analysis revealed that this MTL activity was not due to the fact that the retrieval of recent memories was accompanied by more details. When detailed recent memories were contrasted with detailed remote memories, there was still MTL activity peaking in the left parahippocampal gyrus. The effects of details in remote memories are also discussed.

Memory consolidation and the hippocampus: further evidence from studies of autobiographical memory in semantic dementia and frontal variant frontotemporal dementia

Studies of autobiographical memory in semantic dementia have found relative preservation of memories for recent rather than remote events. As semantic dementia is associated with progressive atrophy to temporal neocortex, with early asymmetric sparing of the hippocampus, this neuropsychological pattern suggests that the hippocampal complex plays a role in the acquisition and retrieval of recent memories, but is not necessary for the recall of older episodic events. In an alternative view of memory consolidation, however, the hippocampus plays a role in the retrieval of all autobiographical memories, regardless of the age of the memory [Curr. Opin. Neurobiol. 7(1997)217]. This ‘multiple trace theory’ predicts that patients with semantic dementia should show no effects of time in their autobiographical recall. In this article, we ask whether it is possible to reconcile the data from semantic dementia with the multiple trace theory by investigating whether the time-dependent pattern of autobiographical retrieval seen in the disease is due to (i) patients showing this effect being exceptional in their presentation; and/or (ii) patients with semantic dementia exhibiting impaired strategic retrieval from concomitant frontal damage. A series of experiments in patients with semantic dementia, the frontal variant of frontotemporal dementia and Alzheimer's disease clearly demonstrates that neither of these two factors can explain the documented effect of time seen in semantic dementia. Nonetheless, we discuss how damage to semantic knowledge could result in an autobiographical memory deficit and suggest that data from semantic dementia may be consistent with both views of hippocampal involvement in long-term memory.

Neural encoding of individual words and faces by the human hippocampus and amygdala.

Patients with lesions in the medial temporal lobe (MTL) of the brain, which includes the hippocampus, amygdala and parahippocampal gyrus, are severely impaired in their ability to remember and recognize words or faces which they saw only a short time ago. These lesions also prevent the effect of word repetition on cortical event-related potentials that are associated with these tasks. We have been able to study the response of individual neurons in the human medial temporal lobe to such delayed recognition tasks in epileptic patients undergoing neurosurgery. We found that some MTL neurons preferentially fired on sight of one particular word from a set of ten words used in a memory task, and others fired in response to one particular face. This stimulus-specific firing was maximal during the time that the neocortical event potentials are most sensitive to stimulus repetition, suggesting that the MTL contributes specific information to the cortex during the retrieval of recent memories.

Human medial temporal-lobe stimulation disrupts both formation and retrieval of recent memories

Disrupting medial temporal-lobe (MTL) activity for less than a second, either during the initial presentation of a complex scene or when it is presented again 1 min later, severely impairs recognition at the second presentation. MTL disruption during both presentation and recognition periods produces further impairment. These results are not consistent with views limiting MTL function solely to encoding or solely to retrieval mechanisms.