Amygdalar and hippocampal theta rhythm synchronization during fear memory retrieval

The amygdalohippocampal circuit plays a pivotal role in Pavlovian fear memory. We simultaneously recorded electrical activity in the lateral amygdala (LA) and the CA1 area of the hippocampus in freely behaving fear-conditioned mice. Patterns of activity were related to fear behavior evoked by conditioned and indifferent sensory stimuli and contexts. Rhythmically synchronized activity at theta frequencies increased between the LA and the CA1 after fear conditioning and became significant during confrontation with conditioned fear stimuli and expression of freezing behavior. Synchronization of theta activities in the amygdalohippocampal network represents a neuronal correlate of conditioned fear, apt to improve neuronal communication during memory retrieval.     

Fast-forward playback of recent memory sequences in prefrontal cortex during sleep

As previously shown in the hippocampus and other brain areas, patterns of firing-rate correlations between neurons in the rat medial prefrontal cortex during a repetitive sequence task were preserved during subsequent sleep, suggesting that waking patterns are reactivated. We found that, during sleep, reactivation of spatiotemporal patterns was coherent across the network and compressed in time by a factor of 6 to 7. Thus, when behavioral constraints are removed, the brain's intrinsic processing speed may be much faster than it is in real time. Given recent evidence implicating the medial prefrontal cortex in retrieval of long-term memories, the observed replay may play a role in the process of memory consolidation.     

Generation of a synthetic memory trace

We investigated the effect of activating a competing, artificially generated, neural representation on encoding of contextual fear memory in mice. We used a c-fos-based transgenic approach to introduce the hM(3)D(q) DREADD receptor (designer receptor exclusively activated by designer drug) into neurons naturally activated by sensory experience. Neural activity could then be specifically and inducibly increased in the hM(3)D(q)-expressing neurons by an exogenous ligand. When an ensemble of neurons for one context (ctxA) was artificially activated during conditioning in a distinct second context (ctxB), mice formed a hybrid memory representation. Reactivation of the artificially stimulated network within the conditioning context was required for retrieval of the memory, and the memory was specific for the spatial pattern of neurons artificially activated during learning. Similar stimulation impaired recall when not part of the initial conditioning.     

Synaptic protein degradation underlies destabilization of retrieved fear memory

Reactivated memory undergoes a rebuilding process that depends on de novo protein synthesis. This suggests that retrieval is dynamic and serves to incorporate new information into preexisting memories. However, little is known about whether or not protein degradation is involved in the reorganization of retrieved memory. We found that postsynaptic proteins were degraded in the hippocampus by polyubiquitination after retrieval of contextual fear memory. Moreover, the infusion of proteasome inhibitor into the CA1 region immediately after retrieval prevented anisomycin-induced memory impairment, as well as the extinction of fear memory. This suggests that ubiquitin- and proteasome-dependent protein degradation underlies destabilization processes after fear memory retrieval. It also provides strong evidence for the existence of reorganization processes whereby preexisting memory is disrupted by protein degradation, and updated memory is reconsolidated by protein synthesis.     

Neuronal competition and selection during memory formation

Competition between neurons is necessary for refining neural circuits during development and may be important for selecting the neurons that participate in encoding memories in the adult brain. To examine neuronal competition during memory formation, we conducted experiments with mice in which we manipulated the function of CREB (adenosine 3',5'-monophosphate response element-binding protein) in subsets of neurons. Changes in CREB function influenced the probability that individual lateral amygdala neurons were recruited into a fear memory trace. Our results suggest a competitive model underlying memory formation, in which eligible neurons are selected to participate in amemorytrace as a function of their relative CREB activity at the time of learning.     

Electroconvulsive shock effects on a reactivated memory trace: further examination

Rats showed amnesia for conditioned fear training if given an electroconvulsive shock immediately after training. Retention was unimpaired, however, when the electroconvulsive shock treatment was given 1 day after training immediately after the presentation of the stimulus used in the fear conditioning training. These results support the view that electroconvulsive shock disrupts memory trace consolidation but does not disrupt a recently reactivated memory trace.     

Cognitive memory: cellular and network machineries and their top-down control

A brain-wide distributed network orchestrates cognitive memorizing and remembering of explicit memory (i.e., memory of facts and events). The network was initially identified in humans and is being systematically investigated in molecular/genetic, single-unit, lesion, and imaging studies in animals. The types of memory identified in humans are extended into animals as episodic-like (event) memory or semantic-like (fact) memory. The unique configurational association between environmental stimuli and behavioral context, which is likely the basis of episodic-like memory, depends on neural circuits in the medial temporal lobe, whereas memory traces representing repeated associations, which is likely the basis of semantic-like memory, are consolidated in the domain-specific regions in the temporal cortex. These regions are reactivated during remembering and contribute to the contents of a memory. Two types of retrieval signal reach the cortical representations. One runs from the frontal cortex for active (or effortful) retrieval (top-down signal), and the other spreads backward from the medial temporal lobe for automatic retrieval. By sending the top-down signal to the temporal cortex, frontal regions manipulate and organize to-be-remembered information, devise strategies for retrieval, and also monitor the outcome, with dissociated frontal regions making functionally separate contributions. The challenge is to understand the hierarchical interactions between these multiple cortical areas, not only with a correlational analysis but also with an interventional study demonstrating the causal necessity and the direction of the causality.     

Memory's penumbra: episodic memory decisions induce lingering mnemonic biases

How do we decide if the people we meet and the things we see are familiar or new? If something is new, we need to encode it as a memory distinct from already stored episodes, using a process known as pattern separation. If familiar, it can be used to reactivate a previously stored memory, by a process known as pattern completion. To orchestrate these conflicting processes, current models propose that the episodic memory system uses environmental cues to establish processing biases that favor either pattern separation during encoding or pattern completion during retrieval. To assess this theory, we measured how people's memory formation and decisions are influenced by their recent engagement in episodic encoding and retrieval. We found that the recent encoding of novel objects improved subsequent identification of subtle changes, a task thought to rely on pattern separation. Conversely, recent retrieval of old objects increased the subsequent integration of stored information into new memories, a process thought to rely on pattern completion. These experiments provide behavioral evidence that episodic encoding and retrieval evoke lingering biases that influence subsequent mnemonic processing.     

Spine-type-specific recruitment of newly synthesized AMPA receptors with learning

The stabilization of long-term memories requires de novo protein synthesis. How can proteins, synthesized in the soma, act on specific synapses that participate in a given memory? We studied the dynamics of newly synthesized AMPA-type glutamate receptors (AMPARs) induced with learning using transgenic mice expressing the GluR1 subunit fused to green fluorescent protein (GFP-GluR1) under control of the c-fos promoter. We found learning-associated recruitment of newly synthesized GFP-GluR1 selectively to mushroom-type spines in adult hippocampal CA1 neurons 24 hours after fear conditioning. Our results are consistent with a "synaptic tagging" model to allow activated synapses to subsequently capture newly synthesized receptor and also demonstrate a critical functional distinction in the mushroom spines with learning.     

The role of Drosophila mushroom body signaling in olfactory memory

The mushroom bodies of the Drosophila brain are important for olfactory learning and memory. To investigate the requirement for mushroom body signaling during the different phases of memory processing, we transiently inactivated neurotransmission through this region of the brain by expressing a temperature-sensitive allele of the shibire dynamin guanosine triphosphatase, which is required for synaptic transmission. Inactivation of mushroom body signaling through alpha/beta neurons during different phases of memory processing revealed a requirement for mushroom body signaling during memory retrieval, but not during acquisition or consolidation.     

Postsynaptic receptor trafficking underlying a form of associative learning

To elucidate molecular, cellular, and circuit changes that occur in the brain during learning, we investigated the role of a glutamate receptor subtype in fear conditioning. In this form of learning, animals associate two stimuli, such as a tone and a shock. Here we report that fear conditioning drives AMPA-type glutamate receptors into the synapse of a large fraction of postsynaptic neurons in the lateral amygdala, a brain structure essential for this learning process. Furthermore, memory was reduced if AMPA receptor synaptic incorporation was blocked in as few as 10 to 20% of lateral amygdala neurons. Thus, the encoding of memories in the lateral amygdala is mediated by AMPA receptor trafficking, is widely distributed, and displays little redundancy.     

Stability of retrieved memory: inverse correlation with trace dominance

In memory consolidation, the memory trace stabilizes and becomes resistant to certain amnesic agents. The textbook account is that for any memorized item, consolidation starts and ends just once. However, evidence has accumulated that upon activation in retrieval, the trace may reconsolidate. Whereas some authors reported transient renewed susceptibility of retrieved memories to consolidation blockers, others could not detect it. Here, we report that in both conditioned taste aversion in the rat and fear conditioning in the medaka fish, the stability of retrieved memory is inversely correlated with the control of behavior by that memory. This result may explain some conflicting findings on reconsolidation of activated memories.     

Backward spreading of memory-retrieval signal in the primate temporal cortex

Bidirectional signaling between neocortex and limbic cortex has been hypothesized to contribute to the retrieval of long-term memory. We tested this hypothesis by comparing the time courses of perceptual and memory-retrieval signals in two neighboring areas in temporal cortex, area TE (TE) and perirhinal cortex (PRh), while monkeys were performing a visual pair-association task. Perceptual signal reached TE before PRh, confirming its forward propagation. In contrast, memory-retrieval signal appeared earlier in PRh, and TE neurons were then gradually recruited to represent the sought target. A reasonable interpretation of this finding is that the rich backward fiber projections from PRh to TE may underlie the activation of TE neurons that represent a visual object retrieved from long-term memory.     

Double-labeled metabolic maps of memory

The physical changes representing a memory are believed to be localized to specific neurons, widely distributed in multiple parallel pathways in the brain. 2-Fluorodeoxyglucose, labeled with two discriminable radioactive tracers, was used to construct quantitative metabolic maps in split-brain cats during a visual task. One side of the brain served to estimate the metabolic variability of nonspecific influences. The other side was used to map metabolic changes related to the presence of previously learned visual cues, as well as changes related to nonspecific influences, in the same periods of time. When the two sides were compared, between 5 million and 100 million neurons (depending upon the significance level selected) were identified in which activity increased during presentation of the familiar cues. The wide distribution of these neurons throughout the brain is compatible with prior evidence of a distributed memory system. However, the large number of neurons involved is difficult to reconcile with theories in which individual neurons are dedicated to specific memories.     

Early tagging of cortical networks is required for the formation of enduring associative memory

Although formation and stabilization of long-lasting associative memories are thought to require time-dependent coordinated hippocampal-cortical interactions, the underlying mechanisms remain unclear. Here, we present evidence that neurons in the rat cortex must undergo a "tagging process" upon encoding to ensure the progressive hippocampal-driven rewiring of cortical networks that support remote memory storage. This process was AMPA- and N-methyl-D-aspartate receptor-dependent, information-specific, and capable of modulating remote memory persistence by affecting the temporal dynamics of hippocampal-cortical interactions. Post-learning reinforcement of the tagging process via time-limited epigenetic modifications resulted in improved remote memory retrieval. Thus, early tagging of cortical networks is a crucial neurobiological process for remote memory formation whose functional properties fit the requirements imposed by the extended time scale of systems-level memory consolidation.     

Paradoxical fear-increasing effects of tranquilizers: evidence of repression of memory in the rat

Conditioned suppression of feeding, an index of fear, was increased rather than decreased by the administration of benzodiazepine tranquilizers or amobarbital. The drug-induced increase in conditioned fear varied directly with the intensity of the shock used in fear conditioning. The drugs had no fear-increasing effect in unshocked controls or in rats made amnesic by electroconvulsive shock given immediately after fear conditioning. These observations in animals are reminiscent of clinical reports that intraveneous amobarbital facilitates the recall of repressed traumatic experiences. The retrieval of painful memories may be inhibited or repressed in animals as well as in humans. In both cases, tranquilizers may counteract repression by disinhibition of the act of retrieval.     

Calcium-permeable AMPA receptor dynamics mediate fear memory erasure

Traumatic fear memories can be inhibited by behavioral therapy for humans, or by extinction training in rodent models, but are prone to recur. Under some conditions, however, these treatments generate a permanent effect on behavior, which suggests that emotional memory erasure has occurred. The neural basis for such disparate outcomes is unknown. We found that a central component of extinction-induced erasure is the synaptic removal of calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) in the lateral amygdala. A transient up-regulation of this form of plasticity, which involves phosphorylation of the glutamate receptor 1 subunit of the AMPA receptor, defines a temporal window in which fear memory can be degraded by behavioral experience. These results reveal a molecular mechanism for fear erasure and the relative instability of recent memory.     

Common Kibra alleles are associated with human memory performance

Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States. Gene expression studies showed that KIBRA was expressed in memory-related brain structures. Functional magnetic resonance imaging detected KIBRA allele-dependent differences in hippocampal activations during memory retrieval. Evidence from these experiments suggests a role for KIBRA in human memory.     

Awake hippocampal sharp-wave ripples support spatial memory

The hippocampus is critical for spatial learning and memory. Hippocampal neurons in awake animals exhibit place field activity that encodes current location, as well as sharp-wave ripple (SWR) activity during which representations based on past experiences are often replayed. The relationship between these patterns of activity and the memory functions of the hippocampus is poorly understood. We interrupted awake SWRs in animals learning a spatial alternation task. We observed a specific learning and performance deficit that persisted throughout training. This deficit was associated with awake SWR activity, as SWR interruption left place field activity and post-experience SWR reactivation intact. These results provide a link between awake SWRs and hippocampal memory processes, which suggests that awake replay of memory-related information during SWRs supports learning and memory-guided decision-making.