Molecular Mechanisms Of Memory Research Articles

Hippocampal dipeptidyl peptidase 9 bidirectionally regulates memory associated with synaptic plasticity

IntroductionSubtypes of the dipeptidyl peptidase (DPP) family, such as DPP4, are reportedly associated with memory impairment. DPP9 is widely distributed in cells throughout the body, including the brain. However, whether DPP9 regulates memory has not yet been elucidated. ObjectivesThis study aimed to elucidate the role of DPP9 in memory, as well as the underlying molecular mechanism. MethodsWe performed immunofluorescence on mouse brains to explore the distribution of DPP9 in different brain regions and used AAV vectors to construct knockdown and overexpression models. The effects of changing DPP9 expression on memory were demonstrated through behavioral experiments. Finally, we used electrophysiology, proteomics and affinity purification mass spectrometry (AP-MS) to study the molecular mechanism by which DPP9 affects memory. ResultsHere, we report that DPP9, which is found almost exclusively in neurons, is expressed and has enzyme activity in many brain regions, especially in the hippocampus. Hippocampal DPP9 expression increases after fear memory formation. Fear memory was impaired by DPP9 knockdown and enhanced by DPP9 protein overexpression in the hippocampus. According to subsequent hippocampal proteomics, multiple pathways, including the peptidase pathway, which can be bidirectionally regulated by DPP9. DPP9 directly interacts with its enzymatic substrate neuropeptide Y (NPY) in neurons. Hippocampal long-term potentiation (LTP) is also bidirectionally regulated by DPP9. Moreover, inhibiting DPP enzyme activity impaired both LTP and memory. In addition, AP-MS revealed that DPP9-interacting proteins are involved in the functions of dendritic spines and axons. By combining AP-MS and proteomics, DPP9 was shown to play a role in regulating actin functions. ConclusionTaken together, our findings reveal that DPP9 affects the CNS not only through enzymatic activity but also through protein–protein interactions. This study provides new insights into the molecular mechanisms of memory and DPP family functions.

Decoding brain memory formation by single-cell RNA sequencing.

To understand how distinct memories are formed and stored in the brain is an important and fundamental question in neuroscience and computational biology. A population of neurons, termed engram cells, represents the physiological manifestation of a specific memory trace and is characterized by dynamic changes in gene expression, which in turn alters the synaptic connectivity and excitability of these cells. Recent applications of single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) are promising approaches for delineating the dynamic expression profiles in these subsets of neurons, and thus understanding memory-specific genes, their combinatorial patterns and regulatory networks. The aim of this article is to review and discuss the experimental and computational procedures of sc/snRNA-seq, new studies of molecular mechanisms of memory aided by sc/snRNA-seq in human brain diseases and related mouse models, and computational challenges in understanding the regulatory mechanisms underlying long-term memory formation.

Le rôle des états somatiques dans l’inscription de l’expérience : une rencontre entre psychanalyse et neurosciences

ObjectivesBeyond their radically heterogeneous epistemologies, the aim of this article is to describe a meeting point for an interdisciplinary dialogue between psychoanalysis and neuroscience, starting from the importance they both give to the role of perception of somatic states in the inscription of experience. Kandel's research on the molecular mechanisms of memory and brain plasticity has demonstrated that experience leaves synaptic traces in the nervous system. At the same time, we have to consider that interoceptive perception, and mainly somatic states, play a key role for the inscription of perceptions coming from the environment. This article thus examines the possibility of a meeting between Freudian theory and recent discoveries by neurobiologists, especially Damasio's theories of “somatic markers.” MethodMy methodology consists in a comparative study of the importance of the role of somatic states for memory and learning, as considered in neuroscientific research, and the influence of the pleasure principle during the inscription of the first memory traces, in Freudian theory. First, I review the significance of interoceptive perceptions in the research protocols for molecular mechanisms of synaptic plasticity. Next, I study the role of the pleasure principle in the inscription of memory traces, according to the Freudian theory of the psychic apparatus. I then emphasize Damasio's theory of “somatic markers” as a crucial meeting point between neuroscience and Freudian psychoanalysis. Finally, I propose a dialogue between neuroscience and psychoanalysis about the significance of simultaneity, a time factor, in the link between representations and somatic states during the inscription of experience. ResultsThe role of the body states, in Freudian theory, appears to be fundamental for psychic regulation, especially in the qualitative senses of pleasure and displeasure; considering that the pleasure principle is the main principle for the psychic apparatus. Taking the somatic states into account in the inscription of experience is at the heart of the Freudian theory of the psychic trace. Recent neurobiological research on molecular and cellular mechanisms leading to the inscription of experience also demonstrate the significance of somatic states in the learning and memorizing processes. Specifically, according to Damasio's theory of “somatic markers”, the processes of thinking and decision-making are based on the memory of past events and have appeared to be at the service of homeostasis and of the survival of the organism throughout evolution. Understanding our cognitive activity would require taking the brain processes involved in the representation of our body states into account. DiscussionThe latest neurobiological research on the role of the interoceptive perception in cognitive activity, especially Damasio's theory of “somatic markers”, has stunning resonances with some Freudian formulations. Furthermore, simultaneity, a time factor, appears to be decisive in memory processes. The simultaneous perception of a body state and of its representation conditions the possibility of an inscription of traces from experience: we can either consider these to be synaptic traces, from a neuroscientific point of view, or as memory traces, in the Freudian framework. Psychoanalysis and neuroscience both emphasize the role of simultaneity for the inscription of experience. Thus, we can underscore the significance of contingency in “subjective becoming” and in the unique characteristic of the inscription of memory traces. ConclusionPsychoanalysis and neuroscience, beyond their heterogeneous epistemologies, can find a meeting point around the importance they both give to the role of the perception of body states in the mechanisms of inscription of experience, through a link called R-S, between an exteroceptive perception and a somatic state. Indeed, the perception of a somatic state S, occurring simultaneously with an exteroceptive perception, conditions the possibility of the inscription of traces, synaptic as well as psychic. Psychoanalysis and neuroscience agree upon the significance of somatic states in the inscription of traces. They both emphasize the influence of simultaneity in the association of perceptive traces. The R-S link is, from both outlooks, a peculiar association, specific to one's experience. Therefore, universal and genetically determined mechanisms such as synaptic plasticity lead to the advent of subjectivity, in the story of each individual.

The Key Role of “Somatic States” in the Inscription of Experience: For a Dialogue Between Psychoanalysis and Neuroscience

ObjectivesBeyond their radically heterogeneous epistemologies, the aim of this article is to describe a meeting point for an interdisciplinary dialogue between psychoanalysis and neuroscience, starting from the importance they both give to the role of perception of somatic states in the inscription of experience. Kandel's research on the molecular mechanisms of memory and brain plasticity has demonstrated that experience leaves synaptic traces in the nervous system. At the same time, we have to consider that interoceptive perception, and mainly somatic states, play a key role for the inscription of perceptions coming from the environment. This article thus examines the possibility of a meeting between Freudian theory and recent discoveries by neurobiologists, especially Damasio's theories of “somatic markers.” MethodMy methodology consists in a comparative study of the importance of the role of somatic states for memory and learning, as considered in neuroscientific research, and the influence of the pleasure principle during the inscription of the first memory traces, in Freudian theory. First, I review the significance of interoceptive perceptions in the research protocols for molecular mechanisms of synaptic plasticity. Next, I study the role of the pleasure principle in the inscription of memory traces, according to the Freudian theory of the psychic apparatus. I then emphasize Damasio's theory of “somatic markers” as a crucial meeting point between neuroscience and Freudian psychoanalysis. Finally, I propose a dialogue between neuroscience and psychoanalysis about the significance of simultaneity, a time factor, in the link between representations and somatic states during the inscription of experience. ResultsThe role of the body states, in Freudian theory, appears to be fundamental for psychic regulation, especially in the qualitative senses of pleasure and displeasure; considering that the pleasure principle is the main principle for the psychic apparatus. Taking the somatic states into account in the inscription of experience is at the heart of the Freudian theory of the psychic trace. Recent neurobiological research on molecular and cellular mechanisms leading to the inscription of experience also demonstrate the significance of somatic states in learning and memorizing processes. Specifically, according to Damasio's theory of “somatic markers,” the processes of thinking and decision-making are based on the memory of past events and have appeared to be at the service of homeostasis and of the survival of the organism throughout evolution. Understanding our cognitive activity would require taking the brain processes involved in the representation of our body states into account. DiscussionThe latest neurobiological research on the role of the interoceptive perception in cognitive activity, especially Damasio's theory of “somatic markers,” has stunning resonances with some Freudian formulations. Furthermore, simultaneity, a time factor, appears to be decisive in memory processes. The simultaneous perception of a body state and of its representation conditions the possibility of an inscription of traces from experience: we can either consider these to be synaptic traces, from a neuroscientific point of view, or as memory traces, in the Freudian framework. Psychoanalysis and neuroscience both emphasize the role of simultaneity for the inscription of experience. Thus, we can underscore the significance of contingency in “subjective becoming” and in the unique characteristic of the inscription of memory traces. ConclusionPsychoanalysis and neuroscience, beyond their heterogeneous epistemologies, can find a meeting point around the importance they both give to the role of the perception of body states in the mechanisms of inscription of experience, through a link called R-S, between an exteroceptive perception and a somatic state. Indeed, the perception of a somatic state S, occurring simultaneously with an exteroceptive perception, conditions the possibility of the inscription of traces, synaptic as well as psychic. Psychoanalysis and neuroscience agree upon the significance of somatic states in the inscription of traces. They both emphasize the influence of simultaneity in the association of perceptive traces. The R-S link is, from both outlooks, a peculiar association, specific to one's experience. Therefore, universal and genetically determined mechanisms such as synaptic plasticity lead to the advent of subjectivity, in the story of each individual.

A Low-Cost, Odor-Reward Association Task for Tests of Learning and Memory.

Robust and simple behavioral paradigms of appetitive, associative memory are crucial for researchers interested in cellular and molecular mechanisms of memory. In this paper, an effective and low-cost mouse behavioral protocol is described for examining the effects of physiological manipulation (such as the infusion of pharmacological agents) on the learning rate and duration of odor-reward memory. Representative results are provided from a study examining the differential role of tyrosine kinase receptor activity in short-term (STM) and long-term memory (LTM). Male mice were conditioned to associate a reward (sugar pellet) with one of the two odors, and their memory for the association was tested 2 or 48 h later. Immediately prior to the training, a tyrosine kinase (Trk) receptor inhibitor or vehicle infusions were delivered into the olfactory bulb (OB). Although there was no effect of the infusion on the learning rate, blockade of the Trk receptors in the OB selectively impaired LTM (48 h), and not short-term memory (STM; 2 h). The LTM impairment was attributed to the diminished odor selectivity as measured by the length of the digging time. The culmination of the results of this experiment showed that Trk receptor activation in the OB is the key in olfactory memory consolidation.

The Tripeptide RER Mimics Secreted Amyloid Precursor Protein-Alpha in Upregulating LTP.

Secreted amyloid precursor protein-alpha (sAPPα), generated by enzymatic processing of the APP, possesses a range of neurotrophic and neuroprotective properties and plays a critical role in the molecular mechanisms of memory and learning. One of the key active regions of sAPPα is the central APP domain (E2) that contains within it the tripeptide sequence, RER. This sequence is exposed on the surface of a coiled coil substructure of E2. RER has by itself displayed memory-enhancing properties, and can protect newly formed engrams from interference in a manner similar to that displayed by sAPPα itself. In order to determine whether RER mimics other properties of sAPPα, we investigated the electrophysiological effects of the N-terminal protected acetylated RER (Ac-RER) and an isoform containing a chiral switch in the first amino acid from an l- to a d-orientation (Ac-rER), on synaptic plasticity. We found that, like sAPPα, exogenous perfusion with nanomolar concentrations of Ac-RER or Ac-rER enhanced the induction and stability of long-term potentiation (LTP) in area CA1 of rat and mouse hippocampal slices, in a protein synthesis- and trafficking-dependent manner. This effect did not occur with a control Ac-AAA or Ac-IFR tripeptide, nor with a full-length sAPPα protein where RER was substituted with AAA. Ac-rER also protected LTP against amyloid-beta (Aβ25–35)-induced LTP impairment. Our findings provide further evidence that the RER-containing region of sAPPα is functionally significant and by itself can produce effects similar to those displayed by full length sAPPα, suggesting that this tripeptide, like sAPPα, may have therapeutic potential.

Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory.

The role of insulin-regulated glucose transporter-4 (GluT4) in the brain is unclear. In the current study, we demonstrate that GluT4 is a critical component of hippocampal memory processes. Memory training increased hippocampal GluT4 translocation and memory acquisition was impaired by GluT4 blockade. Unexpectedly, whereas long-term inhibition of GluT4 impaired long-term memory, short-term memory was enhanced. These data further our understanding of the molecular mechanisms of memory and have particular significance for type 2 diabetes (in which GluT4 activity in the periphery is impaired) and Alzheimer's disease (which is linked to impaired brain insulin signaling and for which type 2 diabetes is a key risk factor). Both diseases cause marked impairment of hippocampal memory linked to hippocampal hypometabolism, suggesting the possibility that brain GluT4 dysregulation may be one cause of cognitive impairment in these disease states.

The Role of Actin Cytoskeleton in Memory Formation in Amygdala.

The central, lateral and basolateral amygdala (BLA) nuclei are essential for the formation of long-term memories including emotional and drug-related memories. Studying cellular and molecular mechanisms of memory in amygdala may lead to better understanding of how memory is formed and of fear and addiction-related disorders. A challenge is to identify molecules activated by learning that subserve cellular changes needed for memory formation and maintenance in amygdala. Recent studies show that activation of synaptic receptors during fear and drug-related learning leads to alteration in actin cytoskeleton dynamics and structure in amygdala. Such changes in actin cytoskeleton in amygdala are essential for fear and drug-related memories formation. Moreover, the actin cytoskeleton subserves, after learning, changes in neuronal morphogenesis and glutamate receptors trafficking in amygdala. These cellular events are involved in fear and drug-related memories formation. Actin polymerization is also needed for the maintenance of drug-associated memories in amygdala. Thus, the actin cytoskeleton is a key mediator between receptor activation during learning and cellular changes subserving long-term memory (LTM) in amygdala. The actin cytoskeleton may serve as a target for pharmacological treatment of fear memory associated with fear and anxiety disorders and drug addiction to prevent the debilitating consequences of these diseases.

Distribution of the SynDIG4/proline-rich transmembrane protein 1 in rat brain.

The modulation of AMPA receptor (AMPAR) content at synapses is thought to be an underlying molecular mechanism of memory and learning. AMPAR content at synapses is highly plastic and is regulated by numerous AMPAR accessory transmembrane proteins such as TARPs, cornichons, and CKAMPs. SynDIG (synapse differentiation-induced gene) defines a family of four genes (SynDIG1-4) expressed in distinct and overlapping patterns in the brain. SynDIG1 was previously identified as a novel transmembrane AMPAR-associated protein that regulates synaptic strength. The related protein SynDIG4 [also known as Prrt1 (proline-rich transmembrane protein 1)] has recently been identified as a component of AMPAR complexes. In this study, we show that SynDIG1 and SynDIG4 have distinct yet overlapping patterns of expression in the central nervous system, with SynDIG4 having especially prominent expression in the hippocampus and particularly within CA1. In contrast to SynDIG1 and other traditional AMPAR auxiliary subunits, SynDIG4 is de-enriched at the postsynaptic density and colocalizes with extrasynaptic GluA1 puncta in primary dissociated neuron culture. These results indicate that, although SynDIG4 shares sequence similarity with SynDIG1, it might act through a unique mechanism as an auxiliary factor for extrasynaptic GluA1-containing AMPARs. J. Comp. Neurol. 524:2266-2280, 2016. © 2015 Wiley Periodicals, Inc.

Neural plasticity and memory: molecular mechanism.

Deciphering the cellular and molecular mechanisms of memory has been an important topic encompassing the learning and memory domain besides the neurodegenerative disorders. Synapses accumulate cognitive information from life-lasting alterations of their molecular and structural composition. Current memory storage models identify posttranslational modification imperative for short-term information storage and mRNA translation for long-term information storage. However, the precise account of these modifications has not been summarized at the individual synapse level. Therefore, herein we describe the spatiotemporal reorganization of synaptic plasticity at the dendritic spine level to elucidate the mechanism through which synaptic substructures are remodeled; though at the molecular level, such mechanisms are still quite unclear. It has thus been concluded that the existing mechanisms do not entirely elaborate memory storage processes. Further efforts are therefore encouraged to delineate the mechanism of neuronal connectivity at the chemical level as well, including inter- or intramolecular bonding patterns at the synaptic level, which may be a permissive and vital step of memory storage.

An Interview with Eric Kandel

An Interview with Eric Kandel

Elements of episodic-like memory in animal models

Representations of unique events from one's past constitute the content of episodic memories. A number of studies with non-human animals have revealed that animals remember specific episodes from their past (referred to as episodic-like memory). The development of animal models of memory holds enormous potential for gaining insight into the biological bases of human memory. Specifically, given the extensive knowledge of the rodent brain, the development of rodent models of episodic memory would open new opportunities to explore the neuroanatomical, neurochemical, neurophysiological, and molecular mechanisms of memory. Development of such animal models holds enormous potential for studying functional changes in episodic memory in animal models of Alzheimer's disease, amnesia, and other human memory pathologies. This article reviews several approaches that have been used to assess episodic-like memory in animals. The approaches reviewed include the discrimination of what, where, and when in a radial arm maze, dissociation of recollection and familiarity, object recognition, binding, unexpected questions, and anticipation of a reproductive state. The diversity of approaches may promote the development of converging lines of evidence on the difficult problem of assessing episodic-like memory in animals.

Localization of a Stable Neural Correlate of Associative Memory

Do learning and retrieval of a memory activate the same neurons? Does the number of reactivated neurons correlate with memory strength? We developed a transgenic mouse that enables the long-lasting genetic tagging of c-fos-active neurons. We found neurons in the basolateral amygdala that are activated during Pavlovian fear conditioning and are reactivated during memory retrieval. The number of reactivated neurons correlated positively with the behavioral expression of the fear memory, indicating a stable neural correlate of associative memory. The ability to manipulate these neurons genetically should allow a more precise dissection of the molecular mechanisms of memory encoding within a distributed neuronal network.

Cellular learning theory: Theoretical comment on Cole and McNally (2007).

The idea that learning proceeds as a function of the discrepancy (or error) between expected and obtained outcomes is central to many theories of associative learning. However, remarkably little is known about the neurobiological mechanisms that underlie this learning of predictive errors in fear conditioning, a widely used preparation in studies of cellular and molecular mechanisms of memory. In this issue of Behavioral Neuroscience, S. Cole and G. P. McNally demonstrate an important dissociation between the establishment and regulation of predictive error at the cellular level. Their findings have added a level of complexity to currently established views of the function of NMDA and opioid receptors in learning and memory. This commentary discusses some of the implications of these findings for theoretical and neurobiological approaches to memory, as well as current thinking about the cellular circuitry involved in reward learning and drug abuse.

CaMKII Activation in the Entorhinal Cortex Disrupts Previously Encoded Spatial Memory

To investigate the role of the entorhinal cortex in memory at a molecular level, we developed transgenic mice in which transgene expression was inducible and limited to the superficial layers of the medial entorhinal cortex, pre- and parasubiculum. We found that expression of a constitutively active mutant form of CaMKII in these structures disrupted spatial memory formation. Immediate post-training activation of the transgene disrupted previously established memory while transgene activation 3 weeks following the training was ineffective. These results demonstrate that, similar to the hippocampus, the entorhinal cortex plays a time-limited role in spatial memory formation but is not a final cortical repository of long-term memory. Moreover, these results suggest that the indiscriminate activation of CaMKII is able to disrupt preexisting memories, possibly by altering the pattern of synaptic weight changes that are thought to form the basis of the memory trace.

Drugs and human memory (part 1): Clinical, theoretical, and methodologic issues.

Drugs and human memory (part 1): Clinical, theoretical, and methodologic issues.

Addiction, dopamine, and the molecular mechanisms of memory.

We thank Pier Piazza, Eric Nestler, Charles O'Brien, Howard Eichenbaum, and Eric Kandel for their helpful comments and criticisms of earlier versions of the manuscript.

Cellular and molecular mechanisms of memory: the LTP connection

Studies of the cellular and molecular mechanisms of memory formation have focused on the role of long-lasting forms of synaptic plasticity such as long-term potentiation (LTP). A combination of genetic, electrophysiological and behavioral techniques have been used to examine the possibility that LTP is a cellular mechanism of memory storage in the mammalian brain. Although a definitive answer remains elusive, it is clear that in many cases manipulations that alter LTP alter memory, and training regimens that produce memory can produce LTP-like potentiation of synaptic transmission.

Developmental neurobiology: New concepts in learning, memory, and neuronal development

Increasing research efforts and rapidly expanding knowledge in the neuroscientific foundations of learning, memory, and developmental disabilities have provided insights into the normal development and plasticity of neuronal circuits. Likewise, the neurobiologic and molecular genetic substrates of developmental disabilities and mental retardation syndromes are unfolding and leading to potential manipulations of these disorders in children with developmental disabilities. This review highlights the mechanisms of synaptic plasticity, long-term potentiation, and molecular mechanisms of memory. Some mental retardation syndromes due to abnormal genetic regulation are mentioned. MRDD Research Reviews 1998;4:20–25. © 1998 Wiley-Liss, Inc.

Learning from LTP: a comment on recent attempts to identify cellular and molecular mechanisms of memory.

In recent years disappointing evidence has emerged regarding all main lines of evidence supporting connections between long-term potentiation (LTP) and memory. The history of this research, including studies focusing on synaptic alterations following learning experience, on saturation of LTP, and on pharmacological and genetic manipulations of LTP, are discussed briefly and interpreted in light of their observed and inherent limitations. Other approaches, aimed at showing a continuity of plasticity from molecular to synaptic to circuit and systems levels of analysis, are highlighted as potentially more compelling future directions for this research.