In Search of the Cultural Engram.

Human cultures store memories in large distributed assemblies composed of individual brains, intragenerational and intergenerational interacting brains, social constructs, and artifacts. Neuroscience, social sciences, and the humanities can benefit mutually from combining their distinctive methodologies in investigating the cultural engram.

Local Targeted Memory Reactivation in Human Sleep.

Memory consolidation can be promoted via targeted memory reactivation (TMR) that re-presents training cues or context during sleep. Whether TMR acts locally or globally on cortical sleep oscillations remains unknown. Here, we exploit the unique functional neuroanatomy of olfaction with its ipsilateral stimulus processing to perform local TMR in one brain hemisphere. Participants learned associations between words and locations in left or right visual fields with contextual odor throughout. We found lateralized event-related potentials during task training that indicate unihemispheric memory processes. During post-learning naps, odors were presented to one nostril in non-rapid eye movement (NREM) sleep. Memory for specific words processed in the cued hemisphere (ipsilateral to stimulated nostril) was improved after local TMR during sleep. Unilateral odor cues locally modulated slow-wave (SW) power such that regional SW power increase was lower in the cued hemisphere relative to the uncued hemisphere and negatively correlated with select memories for cued words. Moreover, local TMR improved phase-amplitude coupling (PAC) between slow oscillations and sleep spindles specifically in the cued hemisphere. The effects on memory performance and cortical sleep oscillations were not observed when unilateral olfactory stimulation during sleep followed learning without contextual odor. Thus, TMR in human sleep transcends global action by selectively promoting specific memories associated with local sleep oscillations.

Prestimulus Activity in the Cingulo-Opercular Network Predicts Memory for Naturalistic Episodic Experience.

Human memory is strongly influenced by brain states occurring before an event, yet we know little about the underlying mechanisms. We found that activity in the cingulo-opercular network (including bilateral anterior insula [aI] and anterior prefrontal cortex [aPFC]) seconds before an event begins can predict whether this event will subsequently be remembered. We then tested how activity in the cingulo-opercular network shapes memory performance. Our findings indicate that prestimulus cingulo-opercular activity affects memory performance by opposingly modulating subsequent activity in two sets of regions previously linked to encoding and retrieval of episodic information. Specifically, higher prestimulus cingulo-opercular activity was associated with a subsequent increase in activity in temporal regions previously linked to encoding and with a subsequent reduction in activity within a set of regions thought to play a role in retrieval and self-referential processing. Together, these findings suggest that prestimulus attentional states modulate memory for real-life events by enhancing encoding and possibly by dampening interference from competing memory substrates.

Knowledge acquisition is governed by striatal prediction errors.

Discrepancies between expectations and outcomes, or prediction errors, are central to trial-and-error learning based on reward and punishment, and their neurobiological basis is well characterized. It is not known, however, whether the same principles apply to declarative memory systems, such as those supporting semantic learning. Here, we demonstrate with fMRI that the brain parametrically encodes the degree to which new factual information violates expectations based on prior knowledge and beliefs-most prominently in the ventral striatum, and cortical regions supporting declarative memory encoding. These semantic prediction errors determine the extent to which information is incorporated into long-term memory, such that learning is superior when incoming information counters strong incorrect recollections, thereby eliciting large prediction errors. Paradoxically, by the same account, strong accurate recollections are more amenable to being supplanted by misinformation, engendering false memories. These findings highlight a commonality in brain mechanisms and computational rules that govern declarative and nondeclarative learning, traditionally deemed dissociable.

Simulation of Mental Disorders: I. Concepts, Challenges and Animal Models.

The complexity of the human brain and the difficulties in identifying and dissecting the biological, social and contextual underpinnings of mental functions confound the study of the etiology and pathophysiology of mental disorders. Large-scale computer simulation of the human brain was recently proposed as a method to circumvent some of these difficulties. In this two-partpaper, we discuss selected conceptual and pragmatic issues pertaining to the mental illness simulation in general and computer simulation in particular. We address the merits and limitations of two generic types of simulation vehicles, biological simulation in animal models (Part I) and virtual simulation in computer models (Part II), in the study of mental disorders in humans. We point to the need to tailor the vehicle and method of simulation to the goal of the simulation, and suggest future directions for maximizing the utility of mental illness simulation. We argue that at the current state of knowledge, the biological-phenomenological gap in understanding mental disorders markedly limits the ability to generate high-fidelity biological and computational models of mental illness. Simulation focusing on limited realistic objectives, such as mimicking selected distinct biological and phenomenological attributes of specific mental symptoms, may however serve as a useful tool in exploring mental disorders.

Simulation of Mental Disorders: II. Computer Models, Purposes and Future Directions.

The complexity of the human brain and the difficulties in identifying and dissecting the biological, social and contextual underpinnings of mental functions confound the study of the etiology and pathophysiology of mental disorders. Simulating mental disorders in animal models or in computer programs may contribute to the understanding of such disorders. In the companion paper (30), we discussed selected concepts and pragmatics pertaining to mental illness simulation in general, and then focused on issues pertaining to animal models of mental disease. In this paper, we focus on selected aspects of the merits and limitations of the use of large scale computer simulation in investigating mental disorders. We argue that at the current state of knowledge, the biological-phenomenological gap in understanding mental disorders markedly limits the ability to generate high-fidelity computational models of mental illness. We conclude that similarly to the animal model approach, brain simulation focusing on limited realistic objectives, such as mimicking the emergence of selected distinct attributes of specific mental symptoms in a virtual brain or parts thereof, may serve as a useful tool in exploring mental disorders.

The Consolidation and Transformation of Memory.

Memory consolidation refers to the transformation over time of experience-dependent internal representations and their neurobiological underpinnings. The process is assumed to be embodied in synaptic and cellular modifications at brain circuits in which the memory is initially encoded and to proceed by recurrent reactivations, both during wakefulness and during sleep, culminating in the distribution of information to additional locales and integration of new information into existing knowledge. We present snapshots of our current knowledge and gaps in knowledge concerning the progress of consolidation over time and the cognitive architecture that supports it and shapes our long-term memories.

Memory Retrieval in Mice and Men.

Retrieval, the use of learned information, was until recently mostly terra incognita in the neurobiology of memory, owing to shortage of research methods with the spatiotemporal resolution required to identify and dissect fast reactivation or reconstruction of complex memories in the mammalian brain. The development of novel paradigms, model systems, and new tools in molecular genetics, electrophysiology, optogenetics, in situ microscopy, and functional imaging, have contributed markedly in recent years to our ability to investigate brain mechanisms of retrieval. We review selected developments in the study of explicit retrieval in the rodent and human brain. The picture that emerges is that retrieval involves coordinated fast interplay of sparse and distributed corticohippocampal and neocortical networks that may permit permutational binding of representational elements to yield specific representations. These representations are driven largely by the activity patterns shaped during encoding, but are malleable, subject to the influence of time and interaction of the existing memory with novel information.

Zeta Inhibitory Peptide, a Candidate Inhibitor of Protein Kinase Mζ, Is Excitotoxic to Cultured Hippocampal Neurons.

The ζ-inhibitory peptide (ZIP) is considered a candidate inhibitor of the atypical protein kinase Mζ (PKMζ). ZIP has been shown to reverse established LTP and disrupt several forms of long-term memory. However, recent studies have challenged the specificity of ZIP, as it was reported to exert its effect also in PKMζ knock-out mice. These results raise the question of what are the targets of ZIP that may underlie its effect on LTP and memory. Here we report that ZIP as well as its inactive analog, scrambled ZIP, induced a dose-dependent increase in spontaneous activity of neurons in dissociated cultures of rat hippocampus. This was followed by a sustained elevation of intracellular calcium concentration ([Ca(2+)]i) which could not be blocked by conventional channel blockers. Furthermore, ZIP caused an increase in frequency of mEPSCs followed by an increase in membrane noise in patch-clamped neurons both in culture and in acute brain slices. Finally, at 5-10 µM, ZIP-induced excitotoxic death of the cultured neurons. Together, our results suggest that the potential contribution of cellular toxicity should be taken into account in interpretation of ZIP's effects on neuronal and behavioral plasticity. Significance statement: The ζ-inhibitory peptide (ZIP) is considered a candidate inhibitor of the atypical protein kinase Mζ (PKMζ). ZIP has been shown to reverse established LTP and disrupt several forms of long-term memory. Here we report that ZIP as well as its inactive analog, scrambled ZIP, induced a dose-dependent increase in spontaneous activity of neurons in dissociated cultures and brain slices of rat hippocampus. Furthermore, ZIP caused a dose- and time-dependent neuronal death in the dissociated cultures. These findings impact on the assumption that ZIP erases memory due to specific inhibition of PKMz.

Metamemory ratings predict long-term changes in reactivated episodic memories.

Reactivation of long-term memory can render the memory item temporarily labile, offering an opportunity to modify it via behavioral or pharmacological intervention. Declarative memory reactivation is accompanied by a metamemory ability to subjectively assess the knowledge available concerning the target item (Feeling of knowing, FOK). We set out to examine whether FOK can predict the extent of change of long-term episodic memories by post-retrieval manipulations. To this end, participants watched a short movie and were immediately thereafter tested on their memory for it. A day later, they were reminded of that movie, and either immediately or 1 day later, were presented with a second movie. The reminder phase consisted of memory cues to which participants were asked to judge their FOK regarding the original movie. The memory performance of participants to whom new information was presented immediately after reactivating the original episode corresponded to the degree of FOK ratings upon reactivation such that the lower their FOK, the less their memory declined. In contrast, no relation was found between FOK and memory strength for those who learned new information 1 day after the reminder phase. Our findings suggest that the subjective accessibility of reactivated memories may determine the extent to which new information might modify those memories.

Peri-encoding predictors of memory encoding and consolidation.

We review reports of brain activations that occur immediately prior to the onset or following the offset of to-be-remembered information and can predict subsequent mnemonic success. Memory-predictive pre-encoding processes, occurring from fractions of a second to minutes prior to event onset, are mainly associated with activations in the medial temporal lobe (MTL), amygdala and midbrain, and with enhanced theta oscillations. These activations may be considered as the neural correlates of one or more cognitive operations, including contextual processing, attention, and the engagement of distinct computational modes associated with prior encoding or retrieval. Post-encoding activations that correlate with subsequent memory performance are mainly observed in the MTL, sensory cortices and frontal regions. These activations may reflect binding of elements of the encoded information and initiation of memory consolidation. In all, the findings reviewed here illustrate the importance of brain states in the immediate peri-encoding time windows in determining encoding success. Understanding these brain states and their specific effects on memory may lead to optimization of the encoding of desired memories and mitigation of undesired ones.

The Naïve and the Distrustful: state dependency of hippocampal computations in manipulative memory distortion.

Flexible mnemonic mechanisms that adjust to different internal mental states can provide a major adaptive advantage. However, little is known regarding how this flexibility is achieved in the human brain. We examined brain activity during retrieval of false memories of a movie, generated by exposing participants to misleading information. Half of the participants suspected the memory manipulation (Distrustful), whereas the other half did not (Naïve). Distrustful displayed more accurate memory performance and a brain signature different than that of Naïve. In Distrustful, the ability to differentiate true from false information was driven by a qualitatively distinct hippocampal activity for endorsed items, consistent with the view that hippocampal encoding allows recollection of a specific source. Conversely, in Naïve, BOLD differences between true and false memories were linearly correlated with accuracy across participants, suggesting that Naïve subjects needed to reinstate and evaluate stored information to discern true from false. We propose that our results lend support to models suggesting that hippocampal activity can exhibit different computational schemes, depending on memorandum attributes. Furthermore, we show that trust, considered as a subjective state of mind, may alter basic hippocampal strategies, influencing the ability to separate real from false memory.

Opposing effects of oxytocin on overt compliance and lasting changes to memory.

From infancy we learn to comply with societal norms. However, overt compliance is not necessarily accompanied by a change in internal beliefs. The neuromodulatory processes underlying these different phenomena are not yet understood. Here, we test the role of oxytocin in controlling overt compliance versus internalization of information delivered by a social source. After intranasal oxytocin administration, participants showed enhanced compliance to the erroneous opinion of others. However, this expression was coupled with a decrease in the influence of others on long-term memories. Our data suggest that this dissociation may result from reduced conflict in the face of social pressure, which increases immediate conforming behavior, but reduces processing required for deep encoding. These findings reveal a neurobiological control system that oppositely affects internalization and overt compliance.

To simulate or not to simulate: what are the questions?

Simulation is a powerful method in science and engineering. However, simulation is an umbrella term, and its meaning and goals differ among disciplines. Rapid advances in neuroscience and computing draw increasing attention to large-scale brain simulations. What is the meaning of simulation, and what should the method expect to achieve? We discuss the concept of simulation from an integrated scientific and philosophical vantage point and pinpoint selected issues that are specific to brain simulation.

Unconscious learning of likes and dislikes is persistent, resilient, and reconsolidates.

Preferences profoundly influence decision-making and are often acquired through experience, yet it is unclear what role conscious awareness plays in the formation and persistence of long-term preferences and to what extent they can be altered by new experiences. We paired visually masked cues with monetary gains or losses during a decision-making task. Despite being unaware of the cues, subjects were influenced by their predictive values over successive trials of the task, and also revealed a strong preference for the appetitive over the aversive cues in supraliminal choices made days after learning. Moreover, the preferences were resistant to an intervening procedure designed to abolish them by a change in reinforcement contingencies, revealing a surprising resilience once formed. Despite their power however, the preferences were abolished when this procedure took place shortly after reactivating the memories, indicating that the underlying affective associations undergo reconsolidation. These findings highlight the importance of initial experiences in the formation of long-lasting preferences even in the absence of consciousness, while suggesting a way to overcome them in spite of their resiliency.

Shifting gears in hippocampus: temporal dissociation between familiarity and novelty signatures in a single event.

The hippocampus is known to be involved in encoding and retrieval of episodes. However, real-life experiences are expected to involve both encoding and retrieval, and it is unclear how the human hippocampus subserves both functions in the course of a single event. We presented participants with brief movie clips multiple times and examined the effect of familiarity on the hippocampal response at event onset versus event offset. Increased familiarity resulted in a decreased offset response, indicating that the offset response is a novelty-related signature. The magnitude of this offset response was correlated, across hippocampal voxels, with an independent measure of successful encoding, based on nonrepeated clips. This suggests that the attenuated offset response to familiar clips reflects reduced encoding. In addition, the posterior hippocampus exhibited an increased onset response to familiar events, switching from an online familiarity signal to an offline novelty signal during a single event. Moreover, participants with stronger memory exhibited increased reactivation of online activity during familiar events, in line with a retrieval signature. Our results reveal a spatiotemporal dissociation between novelty/encoding and familiarity/retrieval signatures, assumed to reflect different computational modes, in response to the same stimulus.

Brain substrates of recovery from misleading influence.

Humans are strongly influenced by their environment, a dependence that can lead to errors in judgment. Although a rich literature describes how people are influenced by others, little is known regarding the factors that predict subsequent rectification of misleading influence. Using a mediation model in combination with brain imaging, we propose a model for the correction of misinformation. Specifically, our data suggest that amygdala modulation of hippocampal mnemonic representations, during the time of misleading social influence, is associated with reduced subsequent anterior-lateral prefrontal cortex activity that reflects correction. These findings illuminate the process by which erroneous beliefs are, or fail to be, rectified and highlight how past influence constrains subsequent correction.

The molecular and systems biology of memory.

Learning and memory are two of the most magical capabilities of our mind. Learning is the biological process of acquiring new knowledge about the world, and memory is the process of retaining and reconstructing that knowledge over time. Most of our knowledge of the world and most of our skills are not innate but learned. Thus, we are who we are in large part because of what we have learned and what we remember and forget. In this Review, we examine the molecular, cellular, and circuit mechanisms that underlie how memories are made, stored, retrieved, and lost.

Memorable trends.

The current neuroscience of memory takes on board the remarkable achievements of molecular neurobiology and merges them with findings from systems neuroscience and cognitive psychology. This results in a highly dynamic depiction of the memory trace, appreciating its restlessness and incessant assimilation into accumulating knowledge. With an armamentarium of amazing methodologies at hand, and more around the corner, we still lack dictionaries of neuronal codes, able to translate spatiotemporal patterns of brain activity into behavioral tokens. But the path to getting there continues to fascinate, to be accompanied by fresh challenges and new approaches.