A working memory model for serial order that stores information in the intrinsic excitability properties of neurons

Models for temporary information storage in neuronal populations are dominated by mechanisms directly dependent on synaptic plasticity. There are nevertheless other mechanisms available that are well suited for creating short-term memories. Here we present a model for working memory which relies on the modulation of the intrinsic excitability properties of neurons, instead of synaptic plasticity, to retain novel information for periods of seconds to minutes. We show that it is possible to effectively use this mechanism to store the serial order in a sequence of patterns of activity. For this we introduce a functional class of neurons, named gate interneurons, which can store information in their membrane dynamics and can literally act as gates routing the flow of activations in the principal neurons population. The presented model exhibits properties which are in close agreement with experimental results in working memory. Namely, the recall process plays an important role in stabilizing and prolonging the memory trace. This means that the stored information is correctly maintained as long as it is being used. Moreover, the working memory model is adequate for storing completely new information, in time windows compatible with the notion of “one-shot” learning (hundreds of milliseconds).     

Working Memory Cells' Behavior May Be Explained by Cross-Regional Networks with Synaptic Facilitation

Neurons in the cortex exhibit a number of patterns that correlate with working memory. Specifically, averaged across trials of working memory tasks, neurons exhibit different firing rate patterns during the delay of those tasks. These patterns include: 1) persistent fixed-frequency elevated rates above baseline, 2) elevated rates that decay throughout the tasks memory period, 3) rates that accelerate throughout the delay, and 4) patterns of inhibited firing (below baseline) analogous to each of the preceding excitatory patterns. Persistent elevated rate patterns are believed to be the neural correlate of working memory retention and preparation for execution of behavioral/motor responses as required in working memory tasks. Models have proposed that such activity corresponds to stable attractors in cortical neural networks with fixed synaptic weights. However, the variability in patterned behavior and the firing statistics of real neurons across the entire range of those behaviors across and within trials of working memory tasks are typical not reproduced. Here we examine the effect of dynamic synapses and network architectures with multiple cortical areas on the states and dynamics of working memory networks. The analysis indicates that the multiple pattern types exhibited by cells in working memory networks are inherent in networks with dynamic synapses, and that the variability and firing statistics in such networks with distributed architectures agree with that observed in the cortex.     

Content-Specificity in Verbal Recall: A Randomized Controlled Study

In this controlled experiment we examined whether there are content effects in verbal short-term memory and working memory for verbal stimuli. Thirty-seven participants completed forward and backward digit and letter recall tasks, which were constructed to control for distance effects between stimuli. A maximum-likelihood mixed-effects logistic regression revealed main effects of direction of recall (forward vs backward) and content (digits vs letters). There was an interaction between type of recall and content, in which the recall of digits was superior to the recall of letters in verbal short-term memory but not in verbal working memory. These results demonstrate that the recall of information from verbal short-term memory is content-specific, whilst the recall of information from verbal working memory is content-general.     

Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory.

Calcineurin is a calcium-dependent protein phosphatase that has been implicated in various aspects of synaptic plasticity. By using conditional gene-targeting techniques, we created mice in which calcineurin activity is disrupted specifically in the adult forebrain. At hippocampal Schaffer collateral-CA1 synapses, LTD was significantly diminished, and there was a significant shift in the LTD/LTP modification threshold in mutant mice. Strikingly, although performance was normal in hippocampus-dependent reference memory tasks, including contextual fear conditioning and the Morris water maze, the mutant mice were impaired in hippocampus-dependent working and episodic-like memory tasks, including the delayed matching-to-place task and the radial maze task. Our results define a critical role for calcineurin in bidirectional synaptic plasticity and suggest a novel mechanistic distinction between working/episodic-like memory and reference memory.     

Network, cellular and molecular mechanisms of plasticity in simple nervous systems

In the present study we will try to single out several principles of the nervous system functioning essential for describing mechanisms of learning and memory basing on our own experimental investigation of cellular mechanisms of memory in the nervous system of gastropod molluscs and literature data: main changes in functioning due to learning occur in effectivity of synaptic inputs and in the intrinsic properties of postsynaptic neurons; due to learning some synaptic inputs of neurons selectively change its effectivity due to pre- and postsynaptic changes, but the induction of plasticity always starts in postsynapse, maintaining of long-term memory in postsynapse is also shown; reinforcement is not related to activity of the neural chain receptor-sensory neuron-interneuron-motoneuron-effector; reinforcement is mediated via activity of modulatory neurons, and in some cases can be exerted by a single neuron; activity of modulatory neurons is necessary for development of plastic modifications of behavior (including associative), but is not needed for recall of conditioned responses. At the same time, the modulatory neurons (in fact they constitute a neural reinforcement system) are necessary for recall of context associative memory; changes due to learning occur at least in two independent loci in the nervous system. A possibility for erasure of memory with participation of nitroxide is experimentally and theoretically based.     

Synaptic Scaling Enables Dynamically Distinct Short- and Long-Term Memory Formation

Memory storage in the brain relies on mechanisms acting on time scales from minutes, for long-term synaptic potentiation, to days, for memory consolidation. During such processes, neural circuits distinguish synapses relevant for forming a long-term storage, which are consolidated, from synapses of short-term storage, which fade. How time scale integration and synaptic differentiation is simultaneously achieved remains unclear. Here we show that synaptic scaling – a slow process usually associated with the maintenance of activity homeostasis – combined with synaptic plasticity may simultaneously achieve both, thereby providing a natural separation of short- from long-term storage. The interaction between plasticity and scaling provides also an explanation for an established paradox where memory consolidation critically depends on the exact order of learning and recall. These results indicate that scaling may be fundamental for stabilizing memories, providing a dynamic link between early and late memory formation processes.     

Cellular mechanisms of behavioural plasticity in simple nervous systems

In the present study, we will try to single out several principles of the nervous system functioning essential for describing the mechanisms of learning and memory, basing on our own experimental investigation of cellular mechanisms of memory in the nervous system of gastropod molluscs and literature data as follows: (1) Main changes in functioning due to learning occur in the interneurons; (2) Due to learning some synaptic inputs of command neurons selectively change its effectivity; (3) Reinforcement is not related to activity of the neural chain receptor-sensory neuron-interneuron-motoneuron-effector; reinforcement is mediated via activity of modulatory neurons, and in some cases can be exerted by a single neuron; (4) Activity of modulatory neurons is necessary for development of plastic modifications of behaviour (including associative), but is not needed for recall of conditioned responses. At the same time, the modulatory neurons (in fact they constitute a neural reinforcement system) are necessary for recall of context associative memory; (5) Changes due to learning occur at least in two independent loci in the nervous system.     

Distributed neural networks of tactile working memory

Microelectrode recordings of cortical activity in primates performing working memory tasks reveal some cortical neurons exhibiting sustained or graded persistent elevations in firing rate during the period in which sensory information is actively maintained in short-term memory. These neurons are called “memory cells”. Imaging and transcranial magnetic stimulation studies indicate that memory cells may arise from distributed cortical networks. Depending on the sensory modality of the memorandum in working memory tasks, neurons exhibiting memory-correlated patterns of firing have been detected in different association cortices including prefrontal cortex, and primary sensory cortices as well.Here we elaborate on neurophysiological experiments that lead to our understanding of the neuromechanisms of working memory, and mainly discuss findings on widely distributed cortical networks involved in tactile working memory.     

Episodic-like memory in animals: psychological criteria, neural mechanisms and the value of episodic-like tasks to investigate animal models of neurodegenerative disease

The question of whether any non-human species displays episodic memory is controversial. Associative accounts of animal learning recognize that behaviour can change in response to single events but this does not imply that animals need or are later able to recall representations of unique events at a different time and place. The lack of language is also relevant, being the usual medium for communicating about the world, but whether it is critical for the capacity to represent and recall events is a separate matter. One reason for suspecting that certain animals possess an episodic-like memory system is that a variety of learning and memory tasks have been developed that, even though they do not meet the strict criteria required for episodic memory, have an 'episodic-like' character. These include certain one-trial learning tasks, scene-specific discrimination learning, multiple reversal learning, delayed matching and non-matching tasks and, most recently, tasks demanding recollection of 'what, where and when' an event happened. Another reason is that the neuronal architecture of brain areas thought to be involved in episodic memory (including the hippocampal formation) are substantially similar in mammals and, arguably, all vertebrates. Third, our developing understanding of activity-dependent synaptic plasticity (which is a candidate neuronal mechanism for encoding memory traces) suggests that its expression reflects certain physiological characteristics that are ideal components of a neuronal episodic memory system. These include the apparently digital character of synaptic change at individual terminals and the variable persistence of potentiation accounted for by the synaptic tag hypothesis. A further value of studying episodic-like memory in animals is the opportunity it affords to model certain kinds of neurodegenerative disease that, in humans, affect episodic memory. An example is recent work on a transgenic mouse that over-expresses a mutation of human amyloid precursor protein (APP) that occurs in familial Alzheimer's disease, under the control of platelet derived (PD) growth factor promoter (the PDAPP mouse). A striking age- and amyloid plaque-related deficit is seen using a task in which the mice have to keep changing their memory representation of the world rather than learn a single fact.     

Specificity in the functional architecture of primate prefrontal cortex

Multiple lines of evidence indicate that the performance of complex cognitive processes, such as those involving working memory, depend upon the functional properties of the circuitry of the prefrontal cortex (PFC). In primates, working memory has been proposed to be dependent upon the sustained activity of specific populations of PFC pyramidal cells, with this activity regulated by certain types of GABAergic interneurons. Thus, knowledge of the connectivity between PFC pyramidal cells and interneurons is crucial to the understanding the neural mechanisms that subserve working memory. This paper reviews recent findings that reveal specificity in the spatial organization, synaptic targets and postnatal development of pyramidal cells and interneurons in the primate prefrontal cortex, and considers the relevance of these findings for the neural circuitry that subserves working memory.     

A model for integrating elementary neural functions into delayed-response behavior

It is well established that various cortical regions can implement a wide array of neural processes, yet the mechanisms which integrate these processes into behavior-producing, brain-scale activity remain elusive. We propose that an important role in this respect might be played by executive structures controlling the traffic of information between the cortical regions involved. To illustrate this hypothesis, we present a neural network model comprising a set of interconnected structures harboring stimulus-related activity (visual representation, working memory, and planning), and a group of executive units with task-related activity patterns that manage the information flowing between them. The resulting dynamics allows the network to perform the dual task of either retaining an image during a delay (delayed-matching to sample task), or recalling from this image another one that has been associated with it during training (delayed-pair association task). The model reproduces behavioral and electrophysiological data gathered on the inferior temporal and prefrontal cortices of primates performing these same tasks. It also makes predictions on how neural activity coding for the recall of the image associated with the sample emerges and becomes prospective during the training phase. The network dynamics proves to be very stable against perturbations, and it exhibits signs of scale-invariant organization and cooperativity. The present network represents a possible neural implementation for active, top-down, prospective memory retrieval in primates. The model suggests that brain activity leading to performance of cognitive tasks might be organized in modular fashion, simple neural functions becoming integrated into more complex behavior by executive structures harbored in prefrontal cortex and/or basal ganglia.     

突触上与突触外的NMDA受体及其与阿尔茨海默病关系的研究进展

突触上的N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受体与学习记忆以及细胞的存活有着密切关系,而定位于突触外的NMDA受体则参与了细胞死亡通路的激活.本文主要从突触NMDA受体的结构和功能出发,阐述突触上与突触外NMDA受体分布的原因,阐明其介导不同信号通路的具体分子机制及其在阿尔茨海默病(Alzheimer's disease,AD)中扮演的角色.最后,以突触外的NMDA受体为靶点,对AD疾病的治疗提出合理的展望,以期推动对该疾病的研究和治疗.     

A Model of Visuospatial Working Memory in Prefrontal Cortex: Recurrent Network and Cellular Bistability

We report a computer simulation of the visuospatial delayed-response experiments of Funahashi et al. (1989), using a firing-rate model that combines intrinsic cellular bistability with the recurrent local network architecture of the neocortex. In our model, the visuospatial working memory is stored in the form of a continuum of network activity profiles that coexist with a spontaneous activity state. These neuronal firing patterns provide a population code for the cue position in a graded manner. We show that neuronal persistent activity and tuning curves of delay-period activity (memory fields) can be generated by an excitatory feedback circuit and recurrent synaptic inhibition. However, if the memory fields are constructed solely by network mechanisms, noise may induce a random drift over time in the encoded cue position, so that the working memory storage becomes unreliable. Furthermore, a distraction stimulus presented during the delay period produces a systematic shift in the encoded cue position. We found that the working memory performance can be rendered robust against noise and distraction stimuli if single neurons are endowed with cellular bistability (presumably due to intrinsic ion channel mechanisms) that is conditional and realized only with sustained synaptic inputs from the recurrent network. We discuss how cellular bistability at the single cell level may be detected by analysis of spike trains recorded during delay-period activity and how local modulation of intrinsic cell properties and/or synaptic transmission can alter the memory fields of individual neurons in the prefrontal cortex.     

Inducible and reversible NR1 knockout reveals crucial role of the NMDA receptor in preserving remote memories in the brain

Long-term storage of information is a hallmark feature of the brain, yet routine turnover of synaptic receptors appears to be intrinsically paradoxical to this capability. To investigate how the brain preserves its delicate synaptic efficacies, we generated inducible and reversible knockout mice in which the NMDA receptor can be temporarily switched off in the forebrain specifically during the storage stage. Retention of 9-month contextual and cued fear memories is severely disrupted by prolonged, but not transient, loss of the NMDA receptor that occurs 6 months after initial training and at least 2 months prior to memory retrieval. Normal learning and memory function in subsequent tasks following the 9-month retention tests suggest that the observed retention deficits did not result from recall or performance impairment. Thus, our study reveals a hitherto unrecognized role of the NMDA receptor in dynamically maintaining the long-term synaptic stability of memory storage circuits in the brain.     

The impact of flavonoids on spatial memory in rodents: from behaviour to underlying hippocampal mechanisms

Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory, learning and cognition. Flavonoids have been shown to modulate critical neuronal signalling pathways involved in processes of memory, and therefore are likely to affect synaptic plasticity and long-term potentiation mechanisms, widely considered to provide a basis for memory. Animal dietary supplementation studies have further shown that flavonoid-rich foods are able to reverse age-related spatial memory and spatial learning impairments. A more accurate understanding of how a particular spatial memory task works and of which aspects of memory and learning can be assessed in each case, are necessary for a correct interpretation of data relating to diet-cognition experiments. Further understanding of how specific behavioural tasks relate to the functioning of hippocampal circuitry during learning processes might be also elucidative of the specific observed memory improvements. The overall goal of this review is to give an overview of how the hippocampal circuitry operates as a memory system during behavioural tasks, which we believe will provide a new insight into the underlying mechanisms of the action of flavonoids on cognition.     

Turning On and Off with Excitation: The Role of Spike-Timing Asynchrony and Synchrony in Sustained Neural Activity

Delay-related sustained activity in the prefrontal cortex of primates, a neurological analogue of working memory, has been proposed to arise from synaptic interactions in local cortical circuits. The implication is that memories are coded by spatially localized foci of sustained activity. We investigate the mechanisms by which sustained foci are initiated, maintained, and extinguished by excitation in networks of Hodgkin-Huxley neurons coupled with biophysical spatially structured synaptic connections. For networks with a balance between excitation and inhibition, a localized transient stimulus robustly initiates a localized focus of activity. The activity is then maintained by recurrent excitatory AMPA-like synapses. We find that to maintain the focus, the firing must be asynchronous. Consequently, inducing transient synchrony through an excitatory stimulus extinguishes the sustained activity. Such a monosynaptic excitatory turn-off mechanism is compatible with the working memory being wiped clean by an efferent copy of the motor command. The activity that codes working memories may be structured so that the motor command is both the read-out and a direct clearing signal. We show examples of data that is compatible with our theory.     

具有竞争指针的短时记忆神经网络模型

在我们以前提出的短时记忆神经网络模型基础上［３］,我们在新模型中引入突触竞争机制,提出了一个新的短时记忆神经网络模型。模型仍由两个神经网络所组成;其一为与长时记忆共有的信息内容表达网络,另一个为指针神经元环路。由于表达区神经元与指针神经元间的突触权重的竞争,使得模型可以表现出由干扰引起的短时记忆的遗忘。相应于自由回忆序列位置效应和汉字组块两个心理学实验,对模型做了计算机仿真。仿真结果显示模型的行为与两个心理实验定量地符合得很好。由此表明现在的模型更合适于作为短时记忆的模型。     

A role for Melanin-Concentrating Hormone in learning and memory

The neurobiological substrate of learning process and persistent memory storage involves multiple brain areas. The neocortex and hippocampal formation are known as processing and storage sites for explicit memory, whereas the striatum, amygdala, neocortex and cerebellum support implicit memory. Synaptic plasticity, long-term changes in synaptic transmission efficacy and transient recruitment of intracellular signaling pathways in these brain areas have been proposed as possible mechanisms underlying short- and long-term memory retention. In addition to the classical neurotransmitters (glutamate, GABA), experimental evidence supports a role for neuropeptides in modulating memory processes. This review focuses on the role of the Melanin-Concentrating Hormone (MCH) and receptors on memory formation in animal studies. Possible mechanisms may involve direct MCH modulation of neural circuit activity that support memory storage and cognitive functions, as well as indirect effect on arousal.     

Protein kinase signaling in synaptic plasticity and memory

The relay of extracellular signals into changes in cellular physiology involves a Byzantine array of intracellular signaling pathways, of which cytoplasmic protein kinases are a crucial component. In the nervous system, a great deal of effort has focused on understanding the conversion of patterns of synaptic activity into long-lasting changes in synaptic efficacy that are thought to underlie memory. The goal is both to understand synaptic plasticity mechanisms, such as long-term potentiation, at a molecular level and to understand the relationship of these synaptic mechanisms to behavioral memory. Although both involve the activation of multiple signaling pathways, recent studies are beginning to define discrete roles and mechanisms for individual kinases in the different temporal phases of both synaptic and behavioral plasticity.     

"Good Is Up” Is Not Always Better: A Memory Advantage for Words in Metaphor-Incompatible Locations

Four experiments examined whether memory for positive and negative words depended on word location and vertical hand movements. Cognitive processing is known to be facilitated when valenced stimuli are presented in locations that are congruent with the GOOD is UP conceptual metaphor, relative to when they are presented in incongruent locations. In both free recall and recognition tasks, we find a memory advantage for words that had been studied in metaphor incongruent locations (positive down, negative up). This incongruity advantage depends on the location of words during encoding, but no evidence was found to suggest that other spatial associations, such as the vertical position of the hand at encoding or word location during retrieval, affect memory. The results indicate that metaphors, like schemas, categories, and stereotypes, can influence cognition in complex ways, producing variable outcomes across different tasks.