Understanding the physical basis of memory: Molecular mechanisms of the engram

Memory, defined as the storage and use of learned information in the brain, is necessary to modulate behavior and critical for animals to adapt to their environments and survive. Despite being a cornerstone of brain function, questions surrounding the molecular and cellular mechanisms of how information is encoded, stored, and recalled remain largely unanswered. One widely held theory is that an engram is formed by a group of neurons that are active during learning, which undergoes biochemical and physical changes to store information in a stable state, and that are later reactivated during recall of the memory. In the past decade, the development of engram labeling methodologies has proven useful to investigate the biology of memory at the molecular and cellular levels. Engram technology allows the study of individual memories associated with particular experiences and their evolution over time, with enough experimental resolution to discriminate between different memory processes: learning (encoding), consolidation (the passage from short-term to long-term memories), and storage (the maintenance of memory in the brain). Here, we review the current understanding of memory formation at a molecular and cellular level by focusing on insights provided using engram technology.     

Inception of a false memory by optogenetic manipulation of a hippocampal memory engram

Memories can be easily distorted, and a lack of relevant animal models has largely hindered our understanding of false-memory formation. Here, we first identified a population of cells in the dentate gyrus (DG) of the hippocampus that bear the engrams for a specific context; these cells were naturally activated during the encoding phase of fear conditioning and their artificial reactivation using optogenetics in an unrelated context was sufficient for inducing the fear memory specific to the conditioned context. In a further study, DG or CA1 neurons activated by exposure to a particular context were labelled with channelrhodopsin-2 (ChR2). These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context in which a foot shock was never delivered. The recall of this false memory was context specific, activated similar downstream regions engaged during natural fear-memory recall, and was also capable of driving an active fear response. Together, our data demonstrate that by substituting a natural conditioned stimulus with optogenetically reactivated DG cells that bear contextual memory engrams, it is possible to incept an internally and behaviourally represented false fear memory.     

Optogenetic stimulation of serotonin nuclei retrieve the lost memory in Alzheimer's disease

How are memories stored and retrieved? It was one of the most discussed questions in the past century by neuroscientists. Leading studies of the period brought two different explanations to this question: The first statement considers memory as a physiological change in the brain and suggest that the retrieval of memory is only occurred by the same physiologic changes observed during the memory formation, while the second suggests that memory is a psychic mood stored in mind and the retrieval of memory is occurred by mystical energy fluctuations. Although the exact reason and the pathogenesis of Alzheimer's disease have not yet been fully understood, the approaches that centered the retrieval strategy of lost memory constitutes the basis of the treatment strategies in Alzheimer's disease today. The majority of treatment studies has based on the manipulation of the cholinergic system; however, although serotonin has mnemonic effects, its role in the pathogenesis of Alzheimer's disease has not been investigated as much as the cholinergic system. Here we show how serotonin affects the pathogenesis of Alzheimer's disease in a comprehensive perspective and we suggest that the optogenetics manipulation of serotonin nuclei retrieve the lost memory by closing the inward-rectifier potassium channel Kir2 on the memory engram cells. Also, we raise the possible effects of serotonin on the memory engram cells and the interactions between the amyloid-centric hypothesis of Alzheimer's disease and the memory engram hypothesis to explain the pathophysiology of memory loss in Alzheimer's disease.     

The synaptic plasticity and memory hypothesis: encoding,storage and persistence

The synaptic plasticity and memory hypothesis asserts that activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the encoding and trace storage of the type of memory mediated by the brain area in which it is observed. Criteria for establishing the necessity and sufficiency of such plasticity in mediating trace storage have been identified and are here reviewed in relation to new work using some of the diverse techniques of contemporary neuroscience. Evidence derived using optical imaging, molecular-genetic and optogenetic techniques in conjunction with appropriate behavioural analyses continues to offer support for the idea that changing the strength of connections between neurons is one of the major mechanisms by which engrams are stored in the brain.     

Molecular mechanisms of memory retrieval

Memory retrieval is a fundamental component or stage of memory processing. In fact, retrieval is the only possible measure of memory. The ability to recall past events is a major determinant of survival strategies in all species and is of paramount importance in determining our uniqueness as individuals. Most biological studies of memory using brain lesion and/or gene manipulation techniques cannot distinguish between effects on the molecular mechanisms of the encoding or consolidation of memories and those responsible for their retrieval from storage. Here we examine recent findings indicating the major molecular steps involved in memory retrieval in selected brain regions of the mammalian brain. Together the findings strongly suggest that memory formation and retrieval may share some molecular mechanisms in the hippocampus and that retrieval initiates extinction requiring activation of several signaling cascades and protein synthesis.     

On modelling of immune memory mechanisms

In human body, the acquired protection against illness is a biological property known as immunological memory. Different mechanisms for immunological memory are proposed and modeled. The first mechanism is the persisting antigen (Ag) where parts of the Ag are anticipated to persist on some Ag presenting cells. A novel application of the Hsu et al.'s model allows stable low Ag density equilibrium state. This state will correspond to the persisting Ag mechanism for the immune memory. The second is idiotypic and extremal mechanisms where mathematical models showed that a memory state could arise in this case. Finally, a simple model is given which shows that competition between effectors may contribute to the memory state.     

谷氨酸性突触在痛觉和记忆中的突触和分子机制

谷氨酸是哺乳动物脑中的兴奋性递质。中枢神经系统的谷氨酸性突触广泛参与痛觉传递,突触可塑性和递质的调节。谷氨酸的NMDA受体参与前脑相关的学习及功能。在这篇综述中,我们提出前脑的NMDA受体通过增强谷氨酸性突触传递导致长期性的炎痛。具有增强NMDA受体功能的小鼠会产生更多的慢性痛。NMDA NR2B受体抑制剂在未来可能被用来控制人类的慢性痛。     

Common molecular mechanisms in explicit and implicit memory

Cellular and molecular studies of both implicit and explicit memory suggest that experience-dependent modulation of synaptic strength and structure is a fundamental mechanism by which these memories are encoded and stored within the brain. In this review, we focus on recent advances in our understanding of two types of memory storage: (i) sensitization in Aplysia, a simple form of implicit memory, and (ii) formation of explicit spatial memories in the mouse hippocampus. These two processes share common molecular mechanisms that have been highly conserved through evolution.     

Social organization,survival, and dispersal of cape foxes (Vulpes chama) in South Africa

We monitored 20 cape foxes (Vulpes chama) to determine the social organization, survival, and dispersal of this species on two sites in South Africa from 2005 to 2008. Cape foxes were socially monogamous and territorial, with annual home ranges of mated pairs (n = 8) overlapping 80% on average, compared to a mean overlap of 3% between foxes in adjacent ranges. At least 2 pairs remained associated for >1 breeding season, and both sexes exhibited strong site fidelity, as home ranges in consecutive years overlapped 58–98%. Members of mated pairs never foraged together, however they used the same or nearby (<100 m apart) day rests 81% of the time when pups were 0–4 months of age, but only 28% of the time during other months of the year. Dispersal was male biased, as all juvenile males (n = 6) dispersed when 9–11.5 months old, whereas 3 of 4 juvenile females remained philopatric as either breeders or non-breeding associates. At least 6 foxes bred as yearlings (3 F, 3 M), indicating cape foxes have high reproductive potential. Two adult females maintained their territories after their mates died, whereas two adult males dispersed soon after their mates died, indicating cape foxes likely have a female-based social organization. Annual survival was 0.64, and predation from larger carnivores, primarily black-backed jackals (Canis mesomelas), was responsible for 71% of mortalities. Our results provided empirical support for previous hypotheses regarding the relationship between body size and life-history patterns in Canidae, as several ecological parameters of cape foxes were similar to that of other small (<6 kg) canid species, especially Vulpes species inhabiting arid and semi-arid environments.     

Metabolic memory: mechanisms and implications for diabetic vasculopathies

In the past decades, a persistent progression of diabetic vascular complications despite reversal of hyperglycemia has been observed in both experimental and clinical studies. This durable effect of prior hyperglycemia on the initiation and progression of diabetic vasculopathies was defined as “metabolic memory”. Subsequently, enhanced glycation of cellular proteins and lipids, sustained oxidative stress, and prolonged inflammation were demonstrated to mediate this phenomenon. Recently, emerging evidence strongly suggests that epigenetic modifications may account for the molecular and phenotypic changes associated with hyperglycemic memory. In this review, we presented an overview on the discovery of metabolic memory, the recent progress in its molecular mechanisms, and the future implications related to its fundamental research and clinical application.     

Food webs reveal coexistence mechanisms and community organization in carnivores

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The social structural basis of the organization of persons in memory

This paper summarizes and discusses three studies of patterns in the recall of persons in socially bounded communities. Individual sin three different communities (a graduate academic program, a religious fellowship, and a department in a formal organization) free-listed the names of persons in their respective communities. Results indicate that the individuals in each community share a common cognitive structure of community members that is based on the community’s social structure. These studies, combined with the results of other research, strongly suggest that persons are organized in memory according to social structural principles and that affiliation and dominance are the principal dimensions of social cognition. Suggestions are offered for future research to test the generality of these findings. An earlier version of this paper was presented at the 3rd European Conference on Social Network Analysis, June, 1993, in München (Munich), Germany. This research was supported by an Air Force Laboratory Graduate Fellowship awarded to the author by the U. S. Air Force Office of Scientific Research. Devon D. Brewer received his Ph.D. from the University of California, Irvine, and is currently a research consultant with the Social Development Research Group at the University of Washington. His research focuses on social networks, cognitive anthropology, and research methods.     

Investigating the molecular mechanisms of learning and memory using Caenorhabditis elegans

Learning is an essential biological process for survival since it facilitates behavioural plasticity in response to environmental changes. This process is mediated by a wide variety of genes, mostly expressed in the nervous system. Many studies have extensively explored the molecular and cellular mechanisms underlying learning and memory. This review will focus on the advances gained through the study of the nematode Caenorhabditis elegans. C. elegans provides an excellent system to study learning because of its genetic tractability, in addition to its invariant, compact nervous system (~300 neurons) that is well-characterised at the structural level. Importantly, despite its compact nature, the nematode nervous system possesses a high level of conservation with mammalian systems. These features allow the study of genes within specific sensory-, inter- and motor neurons, facilitating the interrogation of signalling pathways that mediate learning via defined neural circuits. This review will detail how learning and memory can be studied in C. elegans through behavioural paradigms that target distinct sensory modalities. We will also summarise recent studies describing mechanisms through which key molecular and cellular pathways are proposed to affect associative and non-associative forms of learning.

     

Brain organization mirrors caste differences,colony founding and nest architecture in paper wasps (Hymenoptera: Vespidae)

The cognitive challenges that social animals face depend on species differences in social organization and may affect mosaic brain evolution. We asked whether the relative size of functionally distinct brain regions corresponds to species differences in social behaviour among paper wasps (Hymenoptera: Vespidae). We measured the volumes of targeted brain regions in eight species of paper wasps. We found species variation in functionally distinct brain regions, which was especially strong in queens. Queens from species with open-comb nests had larger central processing regions dedicated to vision (mushroom body (MB) calyx collars) than those with enclosed nests. Queens from advanced eusocial species (swarm founders), who rely on pheromones in several contexts, had larger antennal lobes than primitively eusocial independent founders. Queens from species with morphologically distinct castes had augmented central processing regions dedicated to antennal input (MB lips) relative to caste monomorphic species. Intraspecific caste differences also varied with mode of colony founding. Independent-founding queens had larger MB collars than their workers. Conversely, workers in swarm-founding species with decentralized colony regulation had larger MB calyx collars and optic lobes than their queens. Our results suggest that brain organization is affected by evolutionary transitions in social interactions and is related to the environmental stimuli group members face.     

Social organization,home ranges,and extraterritorial forays of black-backed jackals

We radio-tracked 15 black-backed jackals (Canis mesomelas) from 8 adjacent family groups on Benfontein Game Farm (i.e., Benfontein) in South Africa to investigate their movement patterns and social organization. Jackal family groups consisted of mated pairs (alphas), 0–3 nonbreeding adults (betas), and pups, depending on the season. Mean (±SE) home-range size of alphas (9.4 ± 1.2 km², n = 6) did not differ (P = 0.766) from betas (9.8 ± 0.7 km², n = 8). Most beta jackals (8 of 10) remained philopatric on Benfontein, apparently because of the high density of springbok (Antidorcas marsupialis), their preferred prey. Three of 5 alphas and all 8 betas went on extraterritorial forays (i.e., forays). Generally, betas spent more of their active time on forays (2–20% of time) than alphas (0–3%; P = 0.048), and betas went farther on forays (2–8 km) than alphas (2–3 km; P = 0.003). The number of forays differed (P < 0.001) among seasons; most forays occurred during summer (64%) when jackals visited neighboring livestock farms, apparently to predate on domestic sheep. Overall, our results indicate forays by jackals are affected by social status, seasonal availability of preferred prey, and the reproductive cycle of jackals. To reduce jackal predation on livestock farms near reserves, we recommend that preventative measures (e.g., use of herders, jackal control activities) be increased during summer when jackals are most likely to travel outside reserves. © 2019 The Wildlife Society.     

Molecular epigenetic mechanisms for the memory of temperature stresses in plants

The sessile plants encounter various stresses; some are prolonged, whereas some others are recurrent. Temperature is crucial for plant growth and development, and plants often encounter adverse high temperature fluctuations (heat stresses) as well as prolonged cold exposure such as seasonal temperature drops in winter when grown in temperate regions. Many plants can remember past temperature stresses to get adapted to adverse local temperature changes to ensure survival and/or reproductive success. Here, we summarize chromatin-based mechanisms underlying acquired thermotolerance or thermomemory in plants and review recent progresses on molecular epigenetic understanding of ‘remembering of prolonged cold in winter’ or vernalization, a process critical for various over-wintering plants to acquire competence to flower in the coming spring. In addition, perspectives on future study in temperature stress memories of economically-important crops are discussed.     

Molecular pharmacological dissection of short- and long-term memory

1. It has been discussed for over 100 years whether short-term memory (STM) is separate from, or just an early phase of, long-term memory (LTM). The only way to solve this dilemma is to find out at least one treatment that blocks STM while keeping LTM intact for the same task in the same animal.2. The effect of a large number of treatments infused into the hippocampus, amygdala, and entorhinal, posterior parietal or prefrontal cortex on STM and LTM of a one-trial step-down inhibitory avoidance task was studied. The animals were tested at 1.5 h for STM, and again at 24 h for LTM. The treatments were given after training.3. Eleven different treatments blocked STM without affecting LTM. Eighteen treatments affected the two memory types differentially, either blocking or enhancing LTM alone. Thus, STM is separate from, and parallel to the first hours of processing of, LTM of that task.4. The mechanisms of STM are different from those of LTM. The former do not include gene expression or protein synthesis; the latter include a double peak of cAMP-dependent protein kinase activity, accompanied by the phosphorylation of CREB, and both gene expression and protein synthesis.5. Possible cellular and molecular events that do not require mRNA or protein synthesis should account for STM. These might include a hyperactivation of glutamate AMPA receptors, ribosome changes, or the exocytosis of glycoproteins that participate in cell addition.     

Chromatin‐based mechanisms of temperature memory in plants

For successful growth and development, plants constantly have to gauge their environment. Plants are capable to monitor their current environmental conditions, and they are also able to integrate environmental conditions over time and store the information induced by the cues. In a developmental context, such an environmental memory is used to align developmental transitions with favourable environmental conditions. One temperature‐related example of this is the transition to flowering after experiencing winter conditions, that is, vernalization. In the context of adaptation to stress, such an environmental memory is used to improve stress adaptation even when the stress cues are intermittent. A somatic stress memory has now been described for various stresses, including extreme temperatures, drought, and pathogen infection. At the molecular level, such a memory of the environment is often mediated by epigenetic and chromatin modifications. Histone modifications in particular play an important role. In this review, we will discuss and compare different types of temperature memory and the histone modifications, as well as the reader, writer, and eraser proteins involved.     

No receptor stands alone: IgG B-cell receptor intrinsic and extrinsic mechanisms contribute to antibody memory

Acquired immunological memory is a striking phenomenon. A lethal epidemic sweeps through a naïve population, many die but those who survive are never “attacked twice ― never at least fatally”, as the historian Thucydides observed in 430 BCE. Antibody memory is critical for protection against many human infectious diseases and is the basis for nearly all current human vaccines. Antibody memory is encoded, in part, in isotype-switched immunoglobulin (Ig)G-expressing memory B cells that are generated in the primary response to antigen and give rise to rapid, high-affinity and high-titered antibody responses upon challenge with the same antigen. How IgG-B-cell receptors (BCRs) and antigen-induced IgG-BCR signaling contribute to memory antibody responses are not fully understood. In this review, we summarize exciting new advances that are revealing the cellular and molecular mechanisms at play in antibody memory and discuss how studies using different experimental approaches will help elucidate the complex phenomenon of B-cell memory.