How Informative Are Spatial CA3 Representations Established by the Dentate Gyrus?

In the mammalian hippocampus, the dentate gyrus (DG) is characterized by sparse and powerful unidirectional projections to CA3 pyramidal cells, the so-called mossy fibers. Mossy fiber synapses appear to duplicate, in terms of the information they convey, what CA3 cells already receive from entorhinal cortex layer II cells, which project both to the dentate gyrus and to CA3. Computational models of episodic memory have hypothesized that the function of the mossy fibers is to enforce a new, well separated pattern of activity onto CA3 cells, to represent a new memory, prevailing over the interference produced by the traces of older memories already stored on CA3 recurrent collateral connections. Can this hypothesis apply also to spatial representations, as described by recent neurophysiological recordings in rats? To address this issue quantitatively, we estimate the amount of information DG can impart on a new CA3 pattern of spatial activity, using both mathematical analysis and computer simulations of a simplified model. We confirm that, also in the spatial case, the observed sparse connectivity and level of activity are most appropriate for driving memory storage – and not to initiate retrieval. Surprisingly, the model also indicates that even when DG codes just for space, much of the information it passes on to CA3 acquires a non-spatial and episodic character, akin to that of a random number generator. It is suggested that further hippocampal processing is required to make full spatial use of DG inputs.     

Working memory training using mental calculation impacts regional gray matter of the frontal and parietal regions

Training working memory (WM) improves performance on untrained cognitive tasks and alters functional activity. However, WM training's effects on gray matter morphology and a wide range of cognitive tasks are still unknown. We investigated this issue using voxel-based morphometry (VBM), various psychological measures, such as non-trained WM tasks and a creativity task, and intensive adaptive training of WM using mental calculations (IATWMMC), all of which are typical WM tasks. IATWMMC was associated with reduced regional gray matter volume in the bilateral fronto-parietal regions and the left superior temporal gyrus. It improved verbal letter span and complex arithmetic ability, but deteriorated creativity. These results confirm the training-induced plasticity in psychological mechanisms and the plasticity of gray matter structures in regions that have been assumed to be under strong genetic control.     

How long will long-term potentiation last?

The paramount feature of long-term potentiation (LTP) as a memory mechanism is its characteristic persistence over time. Although the basic phenomenology of LTP persistence was established 30 years ago, new insights have emerged recently about the extent of LTP persistence and its regulation by activity and experience. Thus, it is now evident that LTP, at least in the dentate gyrus, can either be decremental, lasting from hours to weeks, or stable, lasting months or longer. Although mechanisms engaged during the induction of LTP regulate its subsequent persistence, the maintenance of LTP is also governed by activity patterns post-induction, whether induced experimentally or generated by experience. These new findings establish dentate gyrus LTP as a useful model system for studying the mechanisms governing the induction, maintenance and interference with long-term memory, including very long-term memory lasting months or longer. The challenge is to study LTP persistence in other brain areas, and to relate, if possible, the properties and regulation of LTP maintenance to these same properties of the information that is actually stored in those regions.     

Exact neural mass model for synaptic-based working memory

A synaptic theory of Working Memory (WM) has been developed in the last decade as a possible alternative to the persistent spiking paradigm. In this context, we have developed a neural mass model able to reproduce exactly the dynamics of heterogeneous spiking neural networks encompassing realistic cellular mechanisms for short-term synaptic plasticity. This population model reproduces the macroscopic dynamics of the network in terms of the firing rate and the mean membrane potential. The latter quantity allows us to gain insight of the Local Field Potential and electroencephalographic signals measured during WM tasks to characterize the brain activity. More specifically synaptic facilitation and depression integrate each other to efficiently mimic WM operations via either synaptic reactivation or persistent activity. Memory access and loading are related to stimulus-locked transient oscillations followed by a steady-state activity in the β-γ band, thus resembling what is observed in the cortex during vibrotactile stimuli in humans and object recognition in monkeys. Memory juggling and competition emerge already by loading only two items. However more items can be stored in WM by considering neural architectures composed of multiple excitatory populations and a common inhibitory pool. Memory capacity depends strongly on the presentation rate of the items and it maximizes for an optimal frequency range. In particular we provide an analytic expression for the maximal memory capacity. Furthermore, the mean membrane potential turns out to be a suitable proxy to measure the memory load, analogously to event driven potentials in experiments on humans. Finally we show that the γ power increases with the number of loaded items, as reported in many experiments, while θ and β power reveal non monotonic behaviours. In particular, β and γ rhythms are crucially sustained by the inhibitory activity, while the θ rhythm is controlled by excitatory synapses.     

Costs of acquiring and forgetting information affect spatial memory and its susceptibility to interference

Acquiring and storing information in memory is constrained by the limited capacity of attentional and short-term memory systems. Therefore, processes that prioritize information for storage in memory according to its survival value to the organism are likely to have evolved. Information incurring energy or time costs to acquire, or if forgotten, should be stored and retrieved more effectively than information that is less costly to acquire or forget. We manipulated the costs of acquiring and forgetting information in an eight-arm radial maze memory task for pigs, Sus scrofa, by placing ropes at the entrance to arms, which pigs had to walk over incurring an extra 2-3-s time cost for each arm entry. Each day each pig (N=16) made a sampling visit to the maze to find food in four arms, followed by a 10-min retention interval, and a recall visit in which visits to the four previously empty arms were reinforced. Baited arms were varied daily. Pigs were divided into four groups and exposed to ropes (costs) either during sampling only, recall only, both or neither. Exposure to costs during sampling visits decreased errors during recall visits. This was probably the result of enhanced attention to and encoding of information during sampling. When all groups were performing equally well, retroactive interference treatments revealed hidden differences between them. Groups experiencing costs during recall tests were least susceptible to interference effects, probably because of more considered use of retrieved information. Both memory encoding and retrieval processes may thus be modulated by even small costs of obtaining or forgetting information.     

Spike-Timing Theory of Working Memory

Working memory (WM) is the part of the brain''s memory system that provides temporary storage and manipulation of information necessary for cognition. Although WM has limited capacity at any given time, it has vast memory content in the sense that it acts on the brain''s nearly infinite repertoire of lifetime long-term memories. Using simulations, we show that large memory content and WM functionality emerge spontaneously if we take the spike-timing nature of neuronal processing into account. Here, memories are represented by extensively overlapping groups of neurons that exhibit stereotypical time-locked spatiotemporal spike-timing patterns, called polychronous patterns; and synapses forming such polychronous neuronal groups (PNGs) are subject to associative synaptic plasticity in the form of both long-term and short-term spike-timing dependent plasticity. While long-term potentiation is essential in PNG formation, we show how short-term plasticity can temporarily strengthen the synapses of selected PNGs and lead to an increase in the spontaneous reactivation rate of these PNGs. This increased reactivation rate, consistent with in vivo recordings during WM tasks, results in high interspike interval variability and irregular, yet systematically changing, elevated firing rate profiles within the neurons of the selected PNGs. Additionally, our theory explains the relationship between such slowly changing firing rates and precisely timed spikes, and it reveals a novel relationship between WM and the perception of time on the order of seconds.     

The timing of differentiation of adult hippocampal neurons is crucial for spatial memory

Adult neurogenesis in the dentate gyrus plays a critical role in hippocampus-dependent spatial learning. It remains unknown, however, how new neurons become functionally integrated into spatial circuits and contribute to hippocampus-mediated forms of learning and memory. To investigate these issues, we used a mouse model in which the differentiation of adult-generated dentate gyrus neurons can be anticipated by conditionally expressing the pro-differentiative gene PC3 (Tis21/BTG2) in nestin-positive progenitor cells. In contrast to previous studies that affected the number of newly generated neurons, this strategy selectively changes their timing of differentiation. New, adult-generated dentate gyrus progenitors, in which the PC3 transgene was expressed, showed accelerated differentiation and significantly reduced dendritic arborization and spine density. Functionally, this genetic manipulation specifically affected different hippocampus-dependent learning and memory tasks, including contextual fear conditioning, and selectively reduced synaptic plasticity in the dentate gyrus. Morphological and functional analyses of hippocampal neurons at different stages of differentiation, following transgene activation within defined time-windows, revealed that the new, adult-generated neurons up to 3–4 weeks of age are required not only to acquire new spatial information but also to use previously consolidated memories. Thus, the correct unwinding of these key memory functions, which can be an expression of the ability of adult-generated neurons to link subsequent events in memory circuits, is critically dependent on the correct timing of the initial stages of neuron maturation and connection to existing circuits.     

Directed Forgetting of Negative Self-Referential Information Is Difficult: An fMRI Study

A large body of evidence suggested that both emotion and self-referential processing can enhance memory. However, it remains unclear how these two factors influence directed forgetting. This study speculates that directed forgetting of negative self-referential memory is more difficult than forgetting of other-referential memory. To verify this speculation, we combined the directed forgetting paradigm with the self-reference task. The behavioral result suggested that although both self-referential and other-referential information can be directly forgotten, less self-referential information can be forgotten than other-referential information. At the neural level, the forget instruction strongly activated the frontal cortex, suggesting that directed forgetting is not memory decay but an active process. In addition, compared with the negative other-referential information, forgetting of the negative self-referential information were associated with a more widespread activation, including the orbital frontal gyrus (BA47), the inferior frontal gyrus (BA45, BA44), and the middle frontal gyrus. Our results suggest that forgetting of the self-referential information seems to be a more demanding and difficult process.     

Suppressing the Encoding of New Information in Memory: A Behavioral Study Derived from Principles of Hippocampal Function

Cognitive processes do not occur in isolation. Interactions between cognitive processes can be observed as a cost in performance following a switch between tasks, a cost that is greatest when the cognitive requirements of the sequential tasks compete. Interestingly, the long-term mnemonic goals associated with specific cognitive tasks can also directly compete. For example, encoding the sequential order in which stimuli are presented in the commonly-utilised 2-Back working memory (WM) tasks is counter-productive to task performance, as this task requires the continual updating of the contents of one''s current mental set. Performance of this task consistently results in reduced activity within the medial temporal lobe (MTL), and this response is believed to reflect the inhibitory mnemonic component of the task. Conversely, there are numerous cognitive paradigms in which participants are explicitly instructed to encode incoming information and performance of these tasks reliably increases MTL activity. Here, we explore the behavioural cost of sequentially performing two tasks with conflicting long-term mnemonic goals and contrasting neural profiles within the MTL. We hypothesised that performing the 2-Back WM prior to a hippocampal-dependent memory task would impair performance on the latter task. We found that participants who performed the 2-Back WM task, prior to the encoding of novel verbal/face-name stimuli, recollected significantly fewer of these stimuli, compared to those who had performed a 0-Back control task. Memory processes believed to be independent of the MTL were unaffected. Our results suggest that the inhibition of MTL-dependent mnemonic function persists beyond the cessation of the 2-Back WM task and can alter performance on entirely separate and subsequently performed memory tasks. Furthermore, they indicate that performance of such tasks may induce a temporarily-sustained, virtual lesion of the hippocampus, which could be used as a probe to explore cognitive processes in the absence of hippocampal involvement.     

From synapse to network: models of information storage and retrieval in neural circuits

The mechanisms of information storage and retrieval in brain circuits are still the subject of debate. It is widely believed that information is stored at least in part through changes in synaptic connectivity in networks that encode this information and that these changes lead in turn to modifications of network dynamics, such that the stored information can be retrieved at a later time. Here, we review recent progress in deriving synaptic plasticity rules from experimental data and in understanding how plasticity rules affect the dynamics of recurrent networks. We show that the dynamics generated by such networks exhibit a large degree of diversity, depending on parameters, similar to experimental observations in vivo during delayed response tasks.     

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.     

Prox1 Is Required for Granule Cell Maturation and Intermediate Progenitor Maintenance During Brain Neurogenesis

The dentate gyrus has an important role in learning and memory, and adult neurogenesis in the subgranular zone of the dentate gyrus may play a role in the acquisition of new memories. The homeobox gene Prox1 is expressed in the dentate gyrus during embryonic development and adult neurogenesis. Here we show that Prox1 is necessary for the maturation of granule cells in the dentate gyrus during development and for the maintenance of intermediate progenitors during adult neurogenesis. We also demonstrate that Prox1-expressing intermediate progenitors are required for adult neural stem cell self-maintenance in the subgranular zone; thus, we have identified a previously unknown non-cell autonomous regulatory feedback mechanism that controls adult neurogenesis in this region of the mammalian brain. Finally, we show that the ectopic expression of Prox1 induces premature differentiation of neural stem cells.     

Formation and Maintenance of Robust Long-Term Information Storage in the Presence of Synaptic Turnover

A long-standing problem is how memories can be stored for very long times despite the volatility of the underlying neural substrate, most notably the high turnover of dendritic spines and synapses. To address this problem, here we are using a generic and simple probabilistic model for the creation and removal of synapses. We show that information can be stored for several months when utilizing the intrinsic dynamics of multi-synapse connections. In such systems, single synapses can still show high turnover, which enables fast learning of new information, but this will not perturb prior stored information (slow forgetting), which is represented by the compound state of the connections. The model matches the time course of recent experimental spine data during learning and memory in mice supporting the assumption of multi-synapse connections as the basis for long-term storage.     

Overcoming Catastrophic Interference in Connectionist Networks Using Gram-Schmidt Orthogonalization

Connectionist models of memory storage have been studied for many years, and aim to provide insight into potential mechanisms of memory storage by the brain. A problem faced by these systems is that as the number of items to be stored increases across a finite set of neurons/synapses, the cumulative changes in synaptic weight eventually lead to a sudden and dramatic loss of the stored information (catastrophic interference, CI) as the previous changes in synaptic weight are effectively lost. This effect does not occur in the brain, where information loss is gradual. Various attempts have been made to overcome the effects of CI, but these generally use schemes that impose restrictions on the system or its inputs rather than allowing the system to intrinsically cope with increasing storage demands. We show here that catastrophic interference occurs as a result of interference among patterns that lead to catastrophic effects when the number of patterns stored exceeds a critical limit. However, when Gram-Schmidt orthogonalization is combined with the Hebb-Hopfield model, the model attains the ability to eliminate CI. This approach differs from previous orthogonalisation schemes used in connectionist networks which essentially reflect sparse coding of the input. Here CI is avoided in a network of a fixed size without setting limits on the rate or number of patterns encoded, and without separating encoding and retrieval, thus offering the advantage of allowing associations between incoming and stored patterns.PACS Nos.: 87.10.+e, 87.18.Bb, 87.18.Sn, 87.19.La     

Benefits of hierarchical generalization and storage of the representations of "object-place" associations in the hippocampal subfields (a hypothesis)

We analyzed the results of experimental research of features of processing sensory information in the hippocampus and neocortex available in literature and results of modelling the perception of information in the neocortex. It is noted that "place" fields of neurons become wider, and overlapping of receptive fields increases during upward moving in trisynaptic hippocampal pathway. These effects specify the generalization of the information processed. The results of our analysis allow us to put forward a hypothesis that a hierarchical complication of"object - place" associations occurs during upward propagation of signals through all hippocampal subfields. Complexity of neural representations of "object - place" associations that are formed and permanently stored in the hippocampal areas increases in process of propagation of signals from the entorhinal cortex to the hierarchically higher dentate gyrus, area CA3 and area CA1. Therefore, with the aim to extract information about "object - place" associations with certain details it is necessary to access that hippocampal area in which associations were processed and stored with the required degree of elaboration. By analogy with the neocortex, it is proposed that such processing of information in the hippocampus makes it possible to avoid the combinatorial explosion and provides storing (memory) the associations accumulated during the life. The proposed mechanism can serve as an addition to the known multiple trace theory, which states that the hippocampus is an integrating part of memory trace and is always involved in recall of long-delayed episodes.     

A Normative Theory of Forgetting: Lessons from the Fruit Fly

Recent experiments revealed that the fruit fly Drosophila melanogaster has a dedicated mechanism for forgetting: blocking the G-protein Rac leads to slower and activating Rac to faster forgetting. This active form of forgetting lacks a satisfactory functional explanation. We investigated optimal decision making for an agent adapting to a stochastic environment where a stimulus may switch between being indicative of reward or punishment. Like Drosophila, an optimal agent shows forgetting with a rate that is linked to the time scale of changes in the environment. Moreover, to reduce the odds of missing future reward, an optimal agent may trade the risk of immediate pain for information gain and thus forget faster after aversive conditioning. A simple neuronal network reproduces these features. Our theory shows that forgetting in Drosophila appears as an optimal adaptive behavior in a changing environment. This is in line with the view that forgetting is adaptive rather than a consequence of limitations of the memory system.     

Longitudinal Neurostimulation in Older Adults Improves Working Memory

An increasing concern affecting a growing aging population is working memory (WM) decline. Consequently, there is great interest in improving or stabilizing WM, which drives expanded use of brain training exercises. Such regimens generally result in temporary WM benefits to the trained tasks but minimal transfer of benefit to untrained tasks. Pairing training with neurostimulation may stabilize or improve WM performance by enhancing plasticity and strengthening WM-related cortical networks. We tested this possibility in healthy older adults. Participants received 10 sessions of sham (control) or active (anodal, 1.5 mA) tDCS to the right prefrontal, parietal, or prefrontal/parietal (alternating) cortices. After ten minutes of sham or active tDCS, participants performed verbal and visual WM training tasks. On the first, tenth, and follow-up sessions, participants performed transfer WM tasks including the spatial 2-back, Stroop, and digit span tasks. The results demonstrated that all groups benefited from WM training, as expected. However, at follow-up 1-month after training ended, only the participants in the active tDCS groups maintained significant improvement. Importantly, this pattern was observed for both trained and transfer tasks. These results demonstrate that tDCS-linked WM training can provide long-term benefits in maintaining cognitive training benefits and extending them to untrained tasks.     

Samuel Butler and human long term memory: Is the cupboard bare?

Memory studies in biological systems distinguish three informational processes that are generally sequential—production/acquisition, storage, and retrieval/use. Identification of DNA as a storage form for hereditary information accelerated progress in that field. Assuming the path of successful elucidation in one memory field (heredity) to be heuristic for elucidation in another (brain), then progress in neuroscience should accelerate when a storage form is identified. In the 19th century Ewald Hering and Samuel Butler held that heredity and brain memory both involved the storage of information and that the two forms of storage were the same. Hering specified storage as ‘molecular vibrations’ but, while making a fuller case, Butler was less committal. In the 20th century, the ablation studies of Karl Lashley failed to identify unique sites for storage of brain information, and Donald Hebb's ‘synaptic plasticity’ hypothesis of distributed storage over a neuronal network won favor. In the 21st century this has come under attack, and the idea that brain and hereditary information are stored as DNA is advocated. Thus, albeit without attribution, Butler's idea is reinstated. Yet, while the case is still open, the synaptic plasticity and DNA hypotheses have problems. Two broad alternatives remain on the table. Long term memory is located: (1) in the brain, either in some other macromolecular form (e.g. protein, lipid) or in some sub-molecular form (e.g. quantum computing and ‘brain as holograph’ hypotheses) or (2) outside the brain. The suggestion of the medieval physician Avicenna that the brain ‘cupboard’ is bare—i.e. the brain is a perceptual, not storage, organ—is consistent with a mysterious ‘universe as holograph’ model. Understanding how Butler came to contribute could be heuristic for future progress in a field fraught with ‘fractionation and disunity’.