Memory accuracy predicts hippocampal mTOR pathway activation following retrieval of contextual fear memory

Prior work suggests that hippocampus‐dependent memory undergoes a systems consolidation process such that recent memories are stored in the hippocampus, while older memories are independent of the hippocampus and instead dependent on cortical areas. One problem with interpreting these studies is that memory for the contextual stimuli weakens as time passes between the training event and testing and older memories are often less detailed, making it difficult to determine if memory storage in the hippocampus is related to the age or to the accuracy of the memory. Activity of the mammalian target of rapamycin (mTOR) signaling pathway is known to be important for controlling protein translation necessary for both memory consolidation after initial learning and for the reconsolidation of memory after retrieval. We tested whether p70s6 kinase (p70s6K), a key component of the mTOR signaling pathway, is activated following retrieval of context fear memory in the dorsal hippocampus (DH) and anterior cingulate cortex (ACC) at 1, 10, or 36 days after context fear conditioning. We also tested whether strengthening memory for the contextual stimuli changed p70s6K phosphorylation in these structures 36 days after training. We show that under standard training conditions retrieval of a recently formed memory is initially precise and involves the DH. Over time it loses detail, becomes independent of the DH and depends on the ACC. In a subsequent experiment, we preserved the accuracy of older memories through pre‐exposure to the training context. We show that remote memory still involved the DH in animals given pre‐exposure. These data support the notion that detailed memories depend on the DH regardless of their age. © 2013 Wiley Periodicals, Inc.     

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.     

Hippocampal and cortical place cell plasticity: implications for episodic memory

In humans, the hippocampus is essential for storing episodic memories. These event memories require the rapid storage of novel associations, but little is known about the cellular correlates of such rapid plasticity. We studied patterns of activity and plasticity in the CA1 region of the hippocampus and in anatomically adjacent cortical regions as rats explored a novel arm of a maze to identify the neural correlates of hippocampally dependent memory formation. We found that hippocampal place fields exhibited three phenomena that may have direct relevance to the encoding of episodic memories: (1) very rapid plasticity upon exposure to the new environment, (2) instability in representations formed after short periods of exploration, and (3) a dissociation between the stability of a hippocampal representation and the apparent familiarity of a location. In contrast, cortical regions showed less dramatic changes. Taken together, these findings suggest that hippocampal activity undergoes a period of rapid reorganization during the encoding of novel information, and that even after this reorganization is complete, areas outside the hippocampus have not yet formed stable memories.     

Patterns of retrograde amnesia for recent and remote incidental spatial learning in rats

A non‐navigational test of incidental spatial learning was used to determine whether hippocampal damage causes temporally‐graded retrograde amnesia (TGRA) for allocentric‐spatial information. Rats were exposed to two identical objects in a circular open field for 7 min on seven consecutive days. In the 1–3 days after the last day of familiarization, rats received neurotoxic lesions of the hippocampal formation (HPC) or sham lesions. Another two groups received the same lesions 3 weeks after familiarization. The rats were then placed back in the open field with one object displaced, and the time spent in each of the quadrants as well as time spent exploring the objects was recorded. Rats that received HPC lesions 3 weeks but not 1–3 days after familiarization showed evidence of preserved remote spatial memory; however, their remote memory was expressed through different behavior than control rats. Rats with HPC lesions spent more time with the displaced object than with the object that remained in the same place, whereas control rats spent more time in the quadrant where the displaced object used to be. These results suggest that remote spatial memories may be preserved with a sufficiently long familiarization‐to‐surgery interval before HPC lesions, but that the nature of these memories may differ in quantity and/or quality from those of intact rats. © 2009 Wiley‐Liss, Inc.     

Hippocampal damage causes retrograde but not anterograde memory loss for context fear discrimination in rats

There is a substantial body of evidence that the hippocampus (HPC) plays and essential role in context discrimination in rodents. Studies reporting anterograde amnesia (AA) used repeated, alternating, distributed conditioning and extinction sessions to measure context fear discrimination. In addition, there is uncertainty about the extent of damage to the HPC. Here, we induced conditioned fear prior to discrimination tests and rats sustained extensive, quantified pre‐ or post‐training HPC damage. Unlike previous work, we found that extensive HPC damage spares context discrimination, we observed no AA. There must be a non‐HPC system that can acquire long‐term memories that support context fear discrimination. Post‐training HPC damage caused retrograde amnesia (RA) for context discrimination, even when rats are fear conditioned for multiple sessions. We discuss the implications of these findings for understanding the role of HPC in long‐term memory.     

Between-systems memory interference during retrieval

Context memories normally depend on the hippocampus (HPC) but, in the absence of the HPC, other memory systems are capable of acquiring and supporting these memories. This suggests that the HPC can interfere with other systems during memory acquisition. Here we ask whether the HPC can also interfere with the retrieval of a context memory that was independently acquired by a non-HPC system. Specifically, we assess whether the HPC can impair the retrieval of a contextual fear-conditioning memory that was acquired while the HPC was temporarily inactive. Rats were infused with the γ-aminobutyric acid (GABA)(A) receptor agonist muscimol in the dorsal and ventral HPC either before acquisition, retrieval, or prior to both acquisition and retrieval, consistent with the effects of permanent HPC lesions on contextual fear conditioning, if the HPC was inactive at the time of acquisition and retention memory was intact. Thus, non-HPC systems acquired and supported this memory in absence of the HPC. However, if the HPC was inactive during acquisition but active thereafter, rats displayed severe deficits during the retention test. Moreover, when the same rats received a second retention test but with the HPC inactive at this time, the memory was recovered, suggesting that removal of a form of interference allowed the memory to be expressed. Combined, these findings imply that the HPC competes and/or interferes with retrieval of a long-term memory that was established in non-HPC systems.     

A computational model of systems memory consolidation and reconsolidation

In the mammalian brain, newly acquired memories depend on the hippocampus (HPC) for maintenance and recall, but over time, the neocortex takes over these functions, rendering memories HPC‐independent. The process responsible for this transformation is called systems memory consolidation. Reactivation of a well‐consolidated memory can trigger a temporary return to a HPC‐dependent state, a phenomenon known as systems memory reconsolidation. The neural mechanisms underlying systems memory consolidation and reconsolidation are not well understood. Here, we propose a neural model based on well‐documented mechanisms of synaptic plasticity and stability and describe a computational implementation that demonstrates the model's ability to account for a range of findings from the systems consolidation and reconsolidation literature. We derive several predictions from the computational model and suggest experiments that may test its validity.     

Intact Behavioral Expression of Contextual Fear,Context Discrimination,and Object Discrimination Memories Acquired in the Absence of the Hippocampus

We test the hypothesis that the stability and precision of context and visual discrimination memories depend on interactions between the hippocampus (HPC) and other memory storage networks. In four experiments we tested the properties of memories acquired in the absence of the HPC. Long–Evans male rats were exclusively used in all experiments. Experiment 1 evaluated acquisition and retention of context fear memories in rats with prior partial or complete HPC damage. Confirming an earlier report (Zelikowsky et al., 2012) a very small but statistically reliable slowing in a single session of context fear conditioning was found after HPC damage. In contrast, retention of context fear memory was normal after HPC damage up to 30 d after learning. In experiment 2, we found that discrimination between a context paired with foot shocks and a different context never paired with foot shock was retained normally for 15 d. In experiment 3, we replicated the finding of intact context discrimination for at least 15 d in rats who display a significant impairment in acquisition of place learning in the Morris water task (MWT). In final experiment using an appetitive object discrimination task, we showed normal retention of the discrimination for at least 30 d after training in rats with complete HPC damage. These finding score against the idea that non HPC memory storage requires a period of interaction with HPC to establish a stable, precise memory.SIGNIFICANCE STATEMENT Contrary to expectations from systems memory consolidation, we find that in the absence of a functional hippocampus (HPC) context and visual memories are formed rapidly and exhibit normal persistence and precision. The findings suggest that the HPC is not obligatory for these features of long-term memories.     

Assessment of the effect of continuous theta burst stimulation of the motor cortex on manual dexterity in non‐human primates in a direct comparison with invasive intracortical pharmacological inactivation

Non‐invasive reversible perturbation techniques of brain output such as continuous theta burst stimulation (cTBS), commonly used to modulate cortical excitability in humans, allow investigation of possible roles in functional recovery played by distinct intact cortical areas following stroke. To evaluate the potential of cTBS, the behavioural effects of this non‐invasive transient perturbation of the hand representation of the primary motor cortex (M1) in non‐human primates (two adult macaques) were compared with an invasive focal transient inactivation based on intracortical microinfusion of GABA‐A agonist muscimol. The effects on the contralateral arm produced by cTBS or muscimol were directly compared based on a manual dexterity task performed by the monkeys, the “reach and grasp” drawer task, allowing quantitative assessment of the grip force produced between the thumb and index finger and exerted on the drawer's knob. cTBS only induced modest to moderate behavioural effects, with substantial variability on manual dexterity whereas the intracortical muscimol microinfusion completely impaired manual dexterity, producing a strong and clear cortical inhibition of the M1 hand area. In contrast, cTBS induced mixed inhibitory and facilitatory/excitatory perturbations of M1, though with predominant inhibition. Although cTBS impacted on manual dexterity, its effects appear too limited and variable in order to use it as a reliable proof of cortical vicariation mechanism (cortical area replacing another one) underlying functional recovery following a cortical lesion in the motor control domain, in contrast to potent pharmacological block generated by muscimol infusion, whose application is though limited to an animal model such as non‐human primate.     

c‐Fos and Arc/Arg3.1 expression in auditory and visual cortices after hearing loss: Evidence of sensory crossmodal reorganization in adult rats

Cross‐modal reorganization in the auditory and visual cortices has been reported after hearing and visual deficits mostly during the developmental period, possibly underlying sensory compensation mechanisms. However, there are very few data on the existence or nature and timeline of such reorganization events during sensory deficits in adulthood. In this study, we assessed long‐term changes in activity‐dependent immediate early genes c‐Fos and Arc/Arg3.1 in auditory and neighboring visual cortical areas after bilateral deafness in young adult rats. Specifically, we analyzed qualitatively and quantitatively c‐Fos and Arc/Arg3.1 immunoreactivity at 15 and 90 days after cochlea removal. We report extensive, global loss of c‐Fos and Arc/Arg3.1 immunoreactive neurons in the auditory cortex 15 days after permanent auditory deprivation in adult rats, which is partly reversed 90 days after deafness. Simultaneously, the number and labeling intensity of c‐Fos‐ and Arc/Arg3.1‐immunoreactive neurons progressively increase in neighboring visual cortical areas from 2 weeks after deafness and these changes stabilize three months after inducing the cochlear lesion. These findings support plastic, compensatory, long‐term changes in activity in the auditory and visual cortices after auditory deprivation in the adult rats. Further studies may clarify whether those changes result in perceptual potentiation of visual drives on auditory regions of the adult cortex.     

Involvement of the dorsal hippocampus in expression and extinction of cocaine‐induced conditioned place preference

A key aspect of substance abuse is that drug taking often occurs in a specific context. As a consequence, exposure to drug‐associated contexts can trigger cravings and relapse, even after long periods of abstinence. Although many studies have demonstrated that the hippocampus is critical for developing and retrieving contextual and spatial memories, comparatively little is known about the role of the hippocampus in acquiring and inhibiting memories involving contexts and drugs of abuse. We examined the effects of hippocampal inactivation on expression of cocaine‐induced conditioned place preference (CPP) after initial acquisition or extinction of CPP in C57BL/6 mice. During acquisition of CPP, distinct tactile cues were paired with cocaine (20 mg kg^?1, intraperitoneal, CS+) and different tactile cues were paired with saline (CS?) on alternate days. Groups differed in whether the CS+ and CS? cues were presented in the same large space (one‐compartment procedure) or distinct small spaces (two‐compartment procedure), as previous findings demonstrate that a two‐compartment configuration facilitates acquisition and attenuates extinction of a cocaine‐induced CPP. Microinjection of the GABA_A agonist, muscimol, into the dorsal hippocampus impaired (1) retrieval of a place preference after acquisition, (2) extinction of a place preference, and (3) retrieval of extinction. These effects differed depending on the spatial configuration during acquisition or extinction, suggesting that the dorsal hippocampus may differentially modulate drug seeking during retrieval and extinction of CPP.     

The effect of long‐term TENS on persistent neuroplastic changes in the human cerebral cortex

The long‐term effect of daily somatosensory stimulation with transcutaneous electrical nerve stimulation (TENS) on reorganization of the motor cortex was investigated in a group of neurologically intact humans. The scalp representation of the corticospinal projection to the finger (APB, ADM) and forearm (FCR, ECR) muscles was mapped by means of transcranial magnetic stimulation (TMS) before and after a 3‐week intervention period, using map area and volume, and topographical overlaps between the cortical motor representations of these muscles as primary dependent measures. Findings revealed a significant increase in cortical motor representation of all four muscles for the TENS group from pre to posttest (all, P ≤ 0.026). No significant changes in cortical motor representations were observed in the control group. The present observations highlight the potential benefit of sensory training by means of TENS as a useful complementary therapy in neurorehabilitation. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

Has multiple trace theory been refuted?

Multiple trace theory (Nadel & Moscovitch, Current Opinion in Neurobiology, 1997, 7, 217–227) has proven to be one of the most novel and influential recent memory theories, and played an essential role in shifting perspective on systems‐level memory consolidation. Here, we briefly review its impact and testable predictions and focus our discussion primarily on nonhuman animal experiments. Perhaps, the most often supported claim is that episodic memory tasks should exhibit comparable severity of retrograde amnesia (RA) for recent and remote memories after extensive damage to the hippocampus (HPC). By contrast, there appears to be little or no experimental support for other core predictions, such as temporally limited RA after extensive HPC damage in semantic memory tasks, temporally limited RA for episodic memories after partial HPC damage, or the existence of storage of multiple HPC traces with repeated reactivations. Despite these shortcomings, it continues to be a highly cited HPC memory theory.     

High‐resolution investigation of memory‐specific reinstatement in the hippocampus and perirhinal cortex

Episodic memory involves remembering the details that characterize a prior experience. Successful memory recovery has been associated with the reinstatement of brain activity patterns in a number of sensory regions across the cortex. However, how the hippocampus and surrounding medial temporal lobe (MTL) cortex contribute to this process is less clear. Models of episodic memory posit that hippocampal pattern reinstatement, also referred to as pattern completion, may mediate cortical reinstatement during retrieval. Empirical evidence of this process, however, remains elusive. Here, we use high‐resolution fMRI and encoding‐retrieval multi‐voxel pattern similarity analyses to demonstrate for the first time that the hippocampus, particularly right hippocampal subfield CA1, shows evidence of reinstating individual episodic memories. Furthermore, reinstatement in perirhinal cortex (PrC) is also evident. Critically, we identify distinct factors that may mediate the cortical reinstatement in PrC. First, we find that encoding activation in PrC is related to later reinstatement in this region, consistent with the theory that encoding strength in the regions that process the memoranda is important for later reinstatement. Conversely, retrieval activation in right CA1 was correlated with reinstatement in PrC, consistent with models of pattern completion. This dissociation is discussed in the context of the flow of information into and out of the hippocampus during encoding and retrieval, respectively. © 2016 Wiley Periodicals, Inc.     

Brain‐derived neurotrophic factor interacts with adult‐born immature cells in the dentate gyrus during consolidation of overlapping memories

Successful memory involves not only remembering information over time but also keeping memories distinct and less confusable. The computational process for making representations of similar input patterns more distinct from each other has been referred to as “pattern separation.” Although adult‐born immature neurons have been implicated in this memory feature, the precise role of these neurons and associated molecules in the processing of overlapping memories is unknown. Recently, we found that brain‐derived neurotrophic factor (BDNF) in the dentate gyrus is required for the encoding/consolidation of overlapping memories. In this study, we provide evidence that consolidation of these “pattern‐separated” memories requires the action of BDNF on immature neurons specifically. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Reading memory formation from the eyes

At any time, we are processing thousands of stimuli, but only few of them will be remembered hours or days later. Is there any way to predict which ones? Here, we tested whether the pupil response to ongoing stimuli, an indicator of physiological arousal known to be relevant for memory formation, is a reliable predictor of long‐term memory for these stimuli, over at least 1 day. Pupil dilation was tracked while participants performed visual and auditory encoding tasks. Memory was tested immediately after encoding and 24 hr later. Irrespective of the encoding modality, trial‐by‐trial variations in pupil dilation predicted reliably which stimuli were recalled in the immediate and 24 hr‐delayed tests, in particular for emotionally arousing stimuli. These results show that our eyes may provide a window into the formation of long‐term memories. Furthermore, our findings underline the important role of central arousal systems in the rapid formation of memories in the brain, possibly by gating synaptic plasticity mechanisms in the neocortex.     

Ventral,but not dorsal,hippocampus inactivation impairs reward memory expression and retrieval in contexts defined by proximal cues

The hippocampus (HPC) has been widely implicated in the contextual control of appetitive and aversive conditioning. However, whole hippocampal lesions do not invariably impair all forms of contextual processing, as in the case of complex biconditional context discrimination, leading to contention over the exact nature of the contribution of the HPC in contextual processing. Moreover, the increasingly well‐established functional dissociation between the dorsal (dHPC) and ventral (vHPC) subregions of the HPC has been largely overlooked in the existing literature on hippocampal‐based contextual memory processing in appetitively motivated tasks. Thus, the present study sought to investigate the individual roles of the dHPC and the vHPC in contextual biconditional discrimination (CBD) performance and memory retrieval. To this end, we examined the effects of transient post‐acquisition pharmacological inactivation (using a combination of GABA_A and GABA_B receptor agonists muscimol and baclofen) of functionally distinct subregions of the HPC (CA1/CA3 subfields of the dHPC and vHPC) on CBD memory retrieval. Additional behavioral assays including novelty preference, light‐dark box and locomotor activity test were also performed to confirm that the respective sites of inactivation were functionally silent. We observed robust deficits in CBD performance and memory retrieval following inactivation of the vHPC, but not the dHPC. Our data provides novel insight into the differential roles of the ventral and dorsal HPC in reward contextual processing, under conditions in which the context is defined by proximal cues.     

Episodic memory: Neuronal codes for what,where, and when

Episodic memory is defined as the ability to recall events in a spatiotemporal context. Formation of such memories is critically dependent on the hippocampal formation and its inputs from the entorhinal cortex. To be able to support the formation of episodic memories, entorhinal cortex and hippocampal formation should contain a neuronal code that follows several requirements. First, the code should include information about position of the agent (“where”), sequence of events (“when”), and the content of the experience itself (“what”). Second, the code should arise instantly thereby being able to support memory formation of one‐shot experiences. For successful encoding and to avoid interference between memories during recall, variations in location, time, or in content of experience should result in unique ensemble activity. Finally, the code should capture several different resolutions of experience so that the necessary details relevant for future memory‐based predictions will be stored. We review how neuronal codes in entorhinal cortex and hippocampus follow these requirements and argue that during formation of episodic memories entorhinal cortex provides hippocampus with instant information about ongoing experience. Such information originates from (a) spatially modulated neurons in medial entorhinal cortex, including grid cells, which provide a stable and universal positional metric of the environment; (b) a continuously varying signal in lateral entorhinal cortex providing a code for the temporal progression of events; and (c) entorhinal neurons coding the content of experiences exemplified by object‐coding and odor‐selective neurons. During formation of episodic memories, information from these systems are thought to be encoded as unique sequential ensemble activity in hippocampus, thereby encoding associations between the content of an event and its spatial and temporal contexts. Upon exposure to parts of the encoded stimuli, activity in these ensembles can be reinstated, leading to reactivation of the encoded activity pattern and memory recollection.