Repeated labilization-reconsolidation processes strengthen declarative memory in humans

The idea that memories are immutable after consolidation has been challenged. Several reports have shown that after the presentation of a specific reminder, reactivated old memories become labile and again susceptible to amnesic agents. Such vulnerability diminishes with the progress of time and implies a re-stabilization phase, usually referred to as reconsolidation. To date, the main findings describe the mechanisms associated with the labilization-reconsolidation process, but little is known about its functionality from a biological standpoint. Indeed, two functions have been proposed. One suggests that destabilization of the original memory after the reminder allows the integration of new information into the background of the original memory (memory updating), and the other suggests that the labilization-reconsolidation process strengthens the original memory (memory strengthening). We have previously reported the reconsolidation of human declarative memories, demonstrating memory updating in the framework of reconsolidation. Here we deal with the strengthening function attributed to the reconsolidation process. We triggered labilization-reconsolidation processes successively by repeated presentations of the proper reminder. Participants learned an association between five cue-syllables and their respective response-syllables. Twenty-four hours later, the paired-associate verbal memory was labilized by exposing the subjects to one, two or four reminders. The List-memory was evaluated on Day 3 showing that the memory was improved when at least a second reminder was presented in the time window of the first labilization-reconsolidation process prompted by the earlier reminder. However, the improvement effect was revealed on Day 3, only when at least two reminders were presented on Day 2 and not as a consequence of only retrieval. Therefore, we propose central concepts for the reconsolidation process, emphasizing its biological role and the parametrical constrains for this function to be operative.     

From cognitive to neural models of working memory

Working memory refers to the temporary retention of information that was just experienced or just retrieved from long-term memory but no longer exists in the external environment. These internal representations are short-lived, but can be stored for longer periods of time through active maintenance or rehearsal strategies, and can be subjected to various operations that manipulate the information in such a way that makes it useful for goal-directed behaviour. Empirical studies of working memory using neuroscientific techniques, such as neuronal recordings in monkeys or functional neuroimaging in humans, have advanced our knowledge of the underlying neural mechanisms of working memory. This rich dataset can be reconciled with behavioural findings derived from investigating the cognitive mechanisms underlying working memory. In this paper, I review the progress that has been made towards this effort by illustrating how investigations of the neural mechanisms underlying working memory can be influenced by cognitive models and, in turn, how cognitive models can be shaped and modified by neuroscientific data. One conclusion that arises from this research is that working memory can be viewed as neither a unitary nor a dedicated system. A network of brain regions, including the prefrontal cortex (PFC), is critical for the active maintenance of internal representations that are necessary for goal-directed behaviour. Thus, working memory is not localized to a single brain region but probably is an emergent property of the functional interactions between the PFC and the rest of the brain.     

Remembering: functional organization of the declarative memory system

How do brain systems support our subjective experience of recollection and our senses of familiarity and novelty? A new functional imaging study concludes that each of these functions is accomplished by a distinct component of the medial temporal lobe, shedding new light on the functional organization of this memory system.     

Hippocampus and neocortex: recognition and spatial memory

Recognition and spatial memory are typically associated with the perirhinal cortex and hippocampal formation, respectively. Solely focusing on these structures for these specific mnemonic functions may, however, be limiting progress in the field. The distinction between these subdivisions of memory is becoming less defined as, for example, hippocampal cells traditionally considered to encode locations also encode place-object associations. There is increasing evidence for the involvement of overlapping networks of brain structures for aspects of both spatial and recognition memory. Future models of spatial and recognition memory will have to extend beyond the hippocampus and perirhinal cortex to incorporate a wider network of cortical and subcortical structures.     

Pulsation and stabilization: Contractile forces that underlie morphogenesis

Embryonic development involves global changes in tissue shape and architecture that are driven by cell shape changes and rearrangements within cohesive cell sheets. Morphogenetic changes at the cell and tissue level require that cells generate forces and that these forces are transmitted between the cells of a coherent tissue. Contractile forces generated by the actin-myosin cytoskeleton are critical for morphogenesis, but the cellular and molecular mechanisms of contraction have been elusive for many cell shape changes and movements. Recent studies that have combined live imaging with computational and biophysical approaches have provided new insights into how contractile forces are generated and coordinated between cells and tissues. In this review, we discuss our current understanding of the mechanical forces that shape cells, tissues, and embryos, emphasizing the different modes of actomyosin contraction that generate various temporal and spatial patterns of force generation.     

Hippocampus: memory, habit and voluntary movement

A general method for studying monkeys' memories is to teach the animals memory-dependent performance rules: for example, to choose, out of two visual stimuli, the one that flashed last time the animal saw it. One may thus assess the animal's memory for any arbitrarily chosen event such as flashing even if the event itself has no intrinsic importance for the animal. The method also allows assessment of an animal's memory of the animal's own previous behaviour. The use of these methods has revealed a simple generalization about the function of the hippocampus in memory: hippocampal lesions impair memory of the voluntary movement that a stimulus previously elicited, but leave intact memory for relations between environmental events other than voluntary movements. The impairment in memory for voluntary movements produces deficits in exploration and in habit formation.     

Dissociating memory retrieval processes using fMRI: evidence that priming does not support recognition memory

We employed event-related fMRI to constrain cognitive accounts of memory retrieval. Studies of explicit retrieval reveal that lateral and medial parietal, dorsal middle frontal gyrus, and anterior prefrontal cortex respond more for studied than new words, reflecting a correlate of "retrieval success." Studies of implicit memory suggest left temporal cortex, ventral and dorsal inferior frontal gyrus respond less for studied than new words, reflecting a correlate of "conceptual priming." In the present study, responses for old and new items were compared during performance on explicit recognition (old/new judgement) and semantic (abstract/concrete judgement) tasks. Regions associated with priming were only modulated during the semantic task, whereas regions associated with retrieval success were modulated during both tasks. These findings constrain functional-anatomic accounts of the networks, suggesting that processes associated with priming do not support explicit recognition judgments.     

Interfering with theories of sleep and memory: sleep, declarative memory, and associative interference

Mounting behavioral evidence in humans supports the claim that sleep leads to improvements in recently acquired, nondeclarative memories. Examples include motor-sequence learning; visual-discrimination learning; and perceptual learning of a synthetic language. In contrast, there are limited human data supporting a benefit of sleep for declarative (hippocampus-mediated) memory in humans (for review, see). This is particularly surprising given that animal models (e.g.,) and neuroimaging studies (e.g.,) predict that sleep facilitates hippocampus-based memory consolidation. We hypothesized that we could unmask the benefits of sleep by challenging the declarative memory system with competing information (interference). This is the first study to demonstrate that sleep protects declarative memories from subsequent associative interference, and it has important implications for understanding the neurobiology of memory consolidation.     

Disentangling cognitive processes from neural activation and psychic mechanisms: The example of empathy

Empathy processes can be explored within a three-level model distinguishing neuronal, cognitive and intra-psychic operating levels. Cognitive and intra-psychic processes need not to be collapsed. Neural systems involved in empathy are described through neuroimaging and event-related potential (ERP) studies. On the cognitive level, empathy is threefold: procedural, semantic and biographical. Automatically activated since birth, procedural empathy processes are deeply enrooted in visuo-motor response capacities and responsible for automatic mimicry. These processes might rely on a prior sensori-motor contagion system. Semantic empathy parallels language development and expresses connexion between words, meaning and emotion. Biographical emerges later in life and corresponds to the interweaving of personal experience with feelings and words, together with a capacity to bridge with the others’ experiences. On the intra-psychic level, defence mechanisms as well as identification processes, depicted from a subjective and interpersonal standpoint, are corresponding, without being similar, to empathetic processes described in cognitive neuroscience studies. Studies on semantic empathy need to control for the participants biographical information and concomitant memory activation. The interface between cognitive and intra-psychic processes needs to be further investigated.     

An associative memory that can form hypotheses: a phase-coded neural network

 Nonlinear associative memories as realized, e.g., by Hopfield nets are characterized by attractor-type dynamics. When fed with a starting pattern, they converge to exactly one of the stored patterns which is supposed to be most similar. These systems cannot render hypotheses of classification, i.e., render several possible answers to a given classification problem. Inspired by von der Malsburg’s correlation theory of brain function, we extend conventional neural network architectures by introducing additional dynamical variables. Assuming an oscillatory time structure of neural firing, i.e., the existence of neural clocks, we assign a so-called phase to each formal neuron. The phases explicitly describe detailed correlations of neural activities neglected in conventional neural network architectures. Implementing this extension into a simple self-organizing network based on a feature map, we present an associative memory that actually is capable of forming hypotheses of classification. Received: 6 December 1993/Accepted in revised form: 14 July 1994     

Cellular mechanisms that underlie bleaching and background adaptation.

Experiments were performed on rod photoreceptors isolated from the eye of the larval tiger salamander to determine if the same or different mechanisms underlie the desensitization produced by dim background light (background adaptation) and that which persists in the steady state in darkness after a significant fraction of the photopigment is bleached (bleaching adaptation). We have examined adaptational effects after light that bleached between approximately 50% and 95% of the photopigment under conditions which preclude pigment regeneration. The steady-state desensitization, far greater than that predicted by quantum-catch loss, is relieved upon regeneration of the visual pigment with 11-cis retinal. We measured the spread of desensitization along the long axis of the rod after a local bright bleach at one end by comparing responses to dim local test flashes elicited in different regions of the outer segment, before and after bleaching. The space constant for this spread was less than 2.5 microns. We have previously measured the space constant for the longitudinal spread of desensitization during a local dim background in Ambystoma rods to be 7 microns. This is similar to a space constant of 6 microns measured under similar conditions in Bufo rods by Lamb et al. (1981. J. Physiol. 319:463-496). If calcium carries the signal for background desensitization, this difference in space constant for background and bleaching adaptation precludes it as the messenger for the steady component of bleaching adaptation. Experiments with isobutylmethyl xanthine (IBMX) also indicate that Ca2+ as well as c-GMP are unlikely regulators of bleaching desensitization, since elevation of cytosolic levels of both of these internal messengers by IBMX has little effect on sensitivity in bleach-adapted cells. All of our findings are consistent with the notion that bleaching adaptation is not mediated by a freely diffusible cytoplasmic messenger.     

Mechanisms that underlie co-variation of the brain and face

The effect of the brain on the morphology of the face has long been recognized in both evolutionary biology and clinical medicine. In this work, we describe factors that are active between the development of the brain and face and how these might impact craniofacial variation. First, there is the physical influence of the brain, which contributes to overall growth and morphology of the face through direct structural interactions. Second, there is the molecular influence of the brain, which signals to facial tissues to establish signaling centers that regulate patterned growth. Importantly, subtle alterations to these physical or molecular interactions may contribute to both normal and abnormal variation. These interactions are therefore critical to our understanding of how a diversity of facial morphologies can be generated both within species and across evolutionary time.     

Distinct axonemal processes underlie spontaneous and stimulated airway ciliary activity

Cilia are small organelles protruding from the cell surface that beat synchronously, producing biological transport. Despite intense research for over a century, the mechanisms underlying ciliary beating are still not well understood. Even the nature of the cytosolic molecules required for spontaneous and stimulated beating is debatable. In an effort to resolve fundamental questions related to cilia beating, we developed a method that integrates the whole-cell mode of the patch-clamp technique with ciliary beat frequency measurements on a single cell. This method enables to control the composition of the intracellular solution while the cilia remain intact, thus providing a unique tool to simultaneously investigate the biochemical and physiological mechanism of ciliary beating. Thus far, we investigated whether the spontaneous and stimulated states of cilia beating are controlled by the same intracellular molecular mechanisms. It was found that: (a) MgATP was sufficient to support spontaneous beating. (b) Ca(2+) alone or Ca(2+)-calmodulin at concentrations as high as 1 microM could not alter ciliary beating. (c) In the absence of Ca(2+), cyclic nucleotides produced a moderate rise in ciliary beating while in the presence of Ca(2+) robust enhancement was observed. These results suggest that the axonemal machinery can function in at least two different modes.     

Impact of load-related neural processes on feature binding in visuospatial working memory

Background

The capacity of visual working memory (WM) is substantially limited and only a fraction of what we see is maintained as a temporary trace. The process of binding visual features has been proposed as an adaptive means of minimising information demands on WM. However the neural mechanisms underlying this process, and its modulation by task and load effects, are not well understood.

Objective

To investigate the neural correlates of feature binding and its modulation by WM load during the sequential phases of encoding, maintenance and retrieval.

Methods and Findings

18 young healthy participants performed a visuospatial WM task with independent factors of load and feature conjunction (object identity and position) in an event-related functional MRI study. During stimulus encoding, load-invariant conjunction-related activity was observed in left prefrontal cortex and left hippocampus. During maintenance, greater activity for task demands of feature conjunction versus single features, and for increased load was observed in left-sided regions of the superior occipital cortex, precuneus and superior frontal cortex. Where these effects were expressed in overlapping cortical regions, their combined effect was additive. During retrieval, however, an interaction of load and feature conjunction was observed. This modulation of feature conjunction activity under increased load was expressed through greater deactivation in medial structures identified as part of the default mode network.

Conclusions and Significance

The relationship between memory load and feature binding qualitatively differed through each phase of the WM task. Of particular interest was the interaction of these factors observed within regions of the default mode network during retrieval which we interpret as suggesting that at low loads, binding processes may be ‘automatic’ but at higher loads it becomes a resource-intensive process leading to disengagement of activity in this network. These findings provide new insights into how feature binding operates within the capacity-limited WM system.     

Annual rhythms that underlie phenology: biological time-keeping meets environmental change

Seasonal recurrence of biological processes (phenology) and its relationship to environmental change is recognized as being of key scientific and public concern, but its current study largely overlooks the extent to which phenology is based on biological time-keeping mechanisms. We highlight the relevance of physiological and neurobiological regulation for organisms’ responsiveness to environmental conditions. Focusing on avian and mammalian examples, we describe circannual rhythmicity of reproduction, migration and hibernation, and address responses of animals to photic and thermal conditions. Climate change and urbanization are used as urgent examples of anthropogenic influences that put biological timing systems under pressure. We furthermore propose that consideration of Homo sapiens as principally a ‘seasonal animal’ can inspire new perspectives for understanding medical and psychological problems.     

Cellular and molecular mechanisms that underlie Entamoeba histolytica pathogenesis: prospects for intervention

The protozoan parasite Entamoeba histolytica is the causative agent of amoebic dysentery. It is prevalent in developing countries that cannot prevent its fecal-oral spread and ranks second in worldwide causes of morbidity by parasitic infection. Improvements in sanitation would help curb disease spread. However, a lack of significant progress in this area has resulted in the need for a better understanding of the molecular and cellular biology of pathogenesis in order to design novel methods of disease treatment and prevention. Recent insight into the cellular mechanisms regulating virulence of E. histolytica has indicated that processes such as endocytosis, secretion, host cell adhesion and encystation play major roles in the infectious process. This review focuses on components of the molecular machinery that govern these cellular processes and their role in virulence, and discusses how an understanding of this might reveal opportunities to interfere with E. histolytica infection.     

A cognitive and associative memory

By introducing a physiological constraint in the auto-correlation matrix memory, the system is found to acquire an ability in cognition i.e. the ability to identify and input pattern by its proximity to any one of the stored memories. The physiological constraint here is that the attribute of a given synapse (i.e. excitatory or inhibitory) is uniquely determined by the neuron it belongs. Thus the synaptic coupling is generally not symmetric. Analytical and numerical analyses revealed that the present model retrieves a memory if an input pattern is close to the pattern of the stored memories; if not, it gives a clear response by going into a special mode where almost all neurons are in the same state in each time step. This uniform mode may be stationary or periodic, depending on whether or not the number of the excitatory neurons exceeds the number of inhibitory neurons.