What do the neuronal memory “engrams” represent?

Interference with Existing Memories Alters Offline Intrinsic Functional Brain Connectivity

Human memory appears to be adaptively “biased” towards remembering the locations of (fitness-relevant) high-calorie nutritional resources. It remains to be investigated whether this high-calorie bias in human spatial memory influences how individuals navigate the modern food environment, and whether it is proximally associated with attentional processes. 60 individuals completed computer-based food eye-tracking and spatial memory tasks in a lab setting, as well as a food search and covert food choice task in an unfamiliar supermarket. The high-calorie spatial memory bias was replicated, as individuals more accurately recalled locations of high-calorie relative to low-calorie foods, regardless of hedonic evaluations or familiarity with foods. Although individuals were faster at (re)locating high-calorie (versus low-calorie) items in the supermarket, the bias did not predict a lower search time for high-calorie foods, or a higher proportion of high-calorie food choice. Rather, an enhanced memory for high-calorie food locations was associated with a lower perceived difficulty (i.e. greater ease) of finding high-calorie items in the supermarket, which may potentiate later choice of a high-calorie food. The high-calorie spatial memory bias was also found to be expressed independently of the amount of visual attention individuals allocated to high-calorie versus low-calorie foods. Findings further substantiate the notion that human spatial memory shows sensitivity to the caloric content of a potential resource and automatically prioritizes those with greater energy payoffs. Such a spatial mechanism that was adaptive for energy-efficient foraging within fluctuating ancestral food environments could presently yield maladaptive “obesogenic” consequences, through altering perceptions of food search convenience.

This chapter reviews evidence for the temporal memory binding hypothesis — the suggestion that temporal coordinates play a privileged role in the maintenance and retrieval of associative binding relations in human memory. First, it briefly discusses the relation between binding problems in perception and in memory. It then describes evidence consistent with the claim that temporal coordinates form an important part of human memory records, i.e., that memory is in some sense chronologically organized. It reviews current formal models of human memory to examine the role that time plays or might play in such models and, more specifically, the role that time plays in binding together human memories and their components. Although some recent models of free recall and serial recall ascribe an important role to time as a dimension underpinning memory, models of associative memory have not generally made the same assumption. Finally, the chapter considers studies that bear directly on the role of time in binding in human long-term memory.

According to the literature, long-term memory disorders appear earliest as mild cognitive impairment progresses to Alzheimer’s disease. Other types of memory impairment are discussed sparcely in literature, most studies include general tests of memory performance. Objective: Compare memory disorders in amnestic mild cognitive impairment and Alzheimer’s disease. Subjects: 75 patients were tested twice in the period of one year, 44 of those with amnestic mild cognitive impairment and 12 with Alzheimer’s disease. Method: Memory disorders were tested using 10 Word Test, Backwards Digit Span, Associative Memory Test, and Rey- Osterrieth Complex Figure Test. Results: Estimate means of associative and visual memory corresponds the norm; disorders appear in domains of short-term memory, working memory, long-term memory, and maximal retrieval in amnestic mild cognitive impairment. All memory domains are below norm in Alzheimer’s disease. Statistically significant mean differences (p < 0,05) were obtained in such domains as short-term memory, maximal retrieval, associative and working memory when comparing the groups of amnestic mild cognitive impairment and Alzheimer’s disease. The level of disturbance is significantly lower in all memory domains in single-domain amnestic mild cognitive impairment than those of Alzheimer’s disease. In multiple-domain amnestic mild cognitive impairment, significantly lower memory disturbances appear only in maximal retrieval (p = 0,026) and working memory (p = 0,001) domains. Conclusions: Disorders in all memory domains – i.e., short-term, working, associative, long-term, visual memory, and maximal retrieval – are characteristic to Alzheimer’s disease. Disorders of short-term, working, long-term memory, and maximal retrieval are characteristic to amnestic mild cognitive impairment. Disorders of memory in multiple-domain amnestic mild cognitive impairment display similar pattern to those in Alzheimer’s disease. It can be assumed that single-domain amnestic mild cognitive impairment progresses to multiple-domain amnestic mild cognitive impairment, as mild cognitive impairment progresses to Alzheimer’s disease. Article in Lithuanian doi:10.5200/sm-hs.2012.114

OF THE DISSERTATION Application-Specific Memory Subsystems by Joseph G. Wingbermuehle Doctor of Philosophy in Computer Science Washington University in St. Louis, 2015 Professor Roger D. Chamberlain, Chair The disparity in performance between processors and main memories has led computer architects to incorporate large cache hierarchies in modern computers. These cache hierarchies are designed to be general-purpose in that they strive to provide the best possible performance across a wide range of applications. However, such a memory subsystem does not necessarily provide the best possible performance for a particular application. Although general-purpose memory subsystems are desirable when the work-load is unknown and the memory subsystem must remain fixed, when this is not the case a custom memory subsystem may be beneficial. For example, in an application-specific integrated circuit (ASIC) or a field-programmable gate array (FPGA) designed to run a particular application, a custom memory subsystem optimized for that application would be desirable. In addition, when there are tunable parameters in the memory subsystem, it may make sense to change these parameters depending on the application being run. Such a situation arises today with FPGAs and, to a lesser extent, GPUs, and it is plausible that general-purpose computers will begin to support greater flexibility in the memory subsystem in the future. In this dissertation, we first show that it is possible to create application-specific memory subsystems that provide much better performance than a general-purpose memory subsystem. In addition, we show a way to discover such memory subsystems automatically using a superoptimization technique on memory address traces gathered from applications. This allows one to generate a custom memory subsystem with little effort. xi We next show that our memory subsystem superoptimization technique can be used to optimize for objectives other than performance. As an example, we show that it is possible to reduce the number of writes to the main memory, which can be useful for main memories with limited write durability, such as flash or Phase-Change Memory (PCM). Finally, we show how to superoptimize memory subsystems for streaming applications, which are a class of parallel applications. In particular, we show that, through the use of ScalaPipe, we can author and deploy streaming applications targeting FPGAs with superoptimized memory subsystems. ScalaPipe is a domain-specific language (DSL) embedded in the Scala programming language for generating streaming applications that can be implemented on CPUs and FPGAs. Using the ScalaPipe implementation, we are able to demonstrate actual performance improvements using the superoptimized memory subsystem with applications implemented in hardware.

Non-volatile memories (NVM) including flash memories and resistive memories have attracted significant interest as data storage media. Flash memories are widely employed in mobile devices and solid-state drives (SSD). Resistive memories are promising as storage class memory and embedded memory applications. Data reliability is the fundamental requirement of NVM as data storage media. However, modern nano-scale NVM suffers from challenges of inter-cell interference (ICI), charge leakage, and write endurance, which threaten the reliability of stored data. In order to cope with these adverse effects, advanced coding techniques including soft decision decoding have been investigated actively. However, current coding techniques do not capture the physical properties of NVM well, so the improvement of data reliability is limited. Although soft decision decoding improves the data reliability by using soft decision values, it degrades read speed performance due to multiple read operations needed to obtain soft decision values. In this dissertation, we explore coding schemes that use side information corresponding to the physical phenomena to improve the data reliability significantly. The side information is obtained before writing data into memory and incorporated during the encoding stage. Hence, the proposed coding schemes maintain the read speed whereas the write speed performance would be degraded. It is a big advantage from the perspective of speed performance since the read speed is more critical than the write speed in many memory applications. First, this dissertation investigates the coding techniques for memory with stuckat defects. The idea of coding techniques for memory with stuck-at defects is employed to handle critical problems of flash memories and resistive memories. For 2D planar flash memories, we propose a coding scheme that combats the ICI, which is a primary challenge of 2D planar flash memories. Also, we propose a coding scheme that reduces the effect of fast detrapping, a degradation factor in 3D vertical flash memories. Finally, we investigate the coding techniques that improve write endurance and power consumption of resistive memories.

Throughout our entire life, memory is central to our ability to carry out everyday tasks. Therefore, diseases that affect cognition have severe consequences, that influence patients' daily lives. However, not only do deficits in forming or recalling memories impact peoples' lives but also the inability to forget traumatic events or fear towards specific stimuli, such as with post-traumatic stress disorder (PTSD), anxiety disorders and phobias. Hence, it is essential to understand the cellular and molecular mechanisms in order to help people with any of these disorders. In the first study of this thesis, I investigated if nuclear calcium, which is known to control cAMP response element binding protein (CREB)/CREB binding protein (CBP)-mediated transcription is required for the formation of memory. Indeed, I found that inhibition of hippocampal nuclear calcium impairs memory formation in two hippocampus-dependent tasks. I further investigated the possible mechanisms that contribute to these deficits and found that dysregulation of nuclear calcium leads to alterations in dendritic morphology. I was able to rescue these morphological alterations via overexpression of the vascular endothelial growth factor D (VEGFD). VEGFD is regulated by nuclear calcium under basal conditions and is known to be important for the maintenance of dendritic morphology. Additionally, I could show that overexpression of VEGFD rescued memory deficits caused by nuclear calcium inhibition, probably due to the restoration of the dendritic architecture. In the second study, we aimed to investigate whether DNA methyltransferases (DNMTs) are required for memory formation. We found that DNMT3a2 is regulated by nuclear calcium and is induced upon neuronal activity. Additionally, we were able to show that the level of DNMT3a2 determines memory performance in mice. Downregulation of DNMT3a2 caused memory deficits and, in addition, a decrease in DNMT3a2 expression was associated with age-dependent memory decline. Further, restoring the level of DNMT3a2 in aged mice rescued memory impairments. In addition, we showed that DNMT3a2 expression correlates with global methylation levels, and we were able to identify two of the target genes of DNMT3a2, namely, activity-regulated cytoskeleton-associated protein (ARC) and brain-derived neurotrophic factor (BDNF). In the third part of this thesis, I studied if nuclear calcium is also required for fear memory extinction, which is routinely used as a model of PTSD. It is widely accepted that during fear extinction a new memory is built up that inhibits the previous, acquired memory. Though it is known that memory formation and fear extinction share common mechanisms, studies investigating the role of transcription in fear extinction are partly controversial. Here, I have shown that nuclear calcium is involved in fear extinction, pointing to a requirement of gene transcription. As I have shown in the first study of this thesis, nuclear calcium, which maintains the dendritic architecture primarily via alterations in the dendritic tree, probably also contributes to fear memory extinction. In summary, I have shown in this thesis that nuclear calcium mediates two forms of cognition, memory formation and fear extinction. I provide evidence that nuclear calcium-regulated VEGFD maintains the dendritic structure, which is important for the permissiveness of the neuron to process information required for long-term adaptations. Additionally, nuclear calcium regulates DNMT3a2, and we show that the level of DNMT3a2 has an impact on memory formation. Overexpression of DNMT3a2 restored the level of DNMT3a2 in aged mice and rescued age-dependent memory deficits.

<b>Purpose: </b>The study aimed to test a combination of semantic memory and traditional episodic memory therapies on episodic memory deficits in adults with traumatic brain injury.<b>Method: </b>Twenty-five participants who had been diagnosed with traumatic brain injury and had episodic memory deficits were randomly assigned either to a combined memory treatment group (<i>n</i> = 16) or to a wait-list control group (<i>n</i> = 9). Before and after treatment, they completed standardized neuropsychological testing for episodic memory and related cognitive domains, including the California Verbal Learning Test–Second Edition, the Controlled Oral Word Association Test, the University of Southern California Repeatable Episodic Memory Test, the Wechsler Abbreviated Scale of Intelligence–Second Edition Matrices, the Test of Everyday Attention, the Memory Assessment Clinics Self-Rating Scale, the Expressive Vocabulary Test–Second Edition, and the Story Recall subtest from the Rivermead Behavioural Memory Test. In addition to a traditional episodic memory therapy, the treatment group received a novel semantic memory–focused therapy, which involved participants finding meaningful connections between diverse concepts represented by sets of two or three words.<b>Results:</b> The treatment group demonstrated statistically significant improvement in memory for list learning tasks, and there was a significant difference from pretest to posttest between the treatment group and the wait-list control group. Clinical significance was demonstrated for the treatment group using minimally important difference calculations.<b>Conclusion: </b>Combined memory therapy resulted in significant improvements in episodic memory, semantic memory, and attention, in comparison to no treatment.<b><br></b><b>Supplemental Material S1. </b>Time-ordered session treatment plan.<br>D'Angelo, E. C., Ober, B. A., &amp; Shenaut, G. K. (2021). Combined memory training: An approach for episodic memory deficits in traumatic brain injury.<i> American Journal of Speech-Language Pathology</i>. Advance online publication. https://doi.org/10.1044/2020_AJSLP-20-00075<br><b>Publisher Note: </b>This article is part of the Special Issue: Select Papers From the International Cognitive-Communication Disorders Conference.<br>

Emotional Reactivity in Posttraumatic Stress Disorder:Behavioural and Neurobiological Correlates of Underlying Mechanisms and the Role of Emotional Memory Modification

Objective To explore the memory function and the effects of sleep on memory consolidation in patients with stable paranoid schizophrenia. Method Sixty patients with stable paranoid schizophrenia were randomly assigned into research group(n=30) and control group(n=30).30 healthy people were raised as a healthy control group.The polysomnography (PSG) was used for 10 hours of sleep monitoring in the research group and the healthy control group and the multiple memory assessment scale(MMAS) was used to test the subjects memory before and after the sleep monitoring.Control group performed memory tests in equal length daytime.Pre-test and post-memory measurements were compared. Results The pre-memory test of three groups had significant statistical differences (F(2, 87)=31.40, 39.89; P 0.05) .But compared with the control group, auditory verbal memory conservation rate((62.64±9.06)% vs (43.00±9.73)%, P<0.01), recognition accuracy rate ((69.11±11.04)% vs (61.78±11.67)%, P<0.05), picture memory conservation rate((71.20±14.95)% vs (58.72±16.19)%, P<0.01), recognition accuracy rate ((86.89±8.02)% vs (78.89±12.63)%, P<0.01) of the research group showed statistical significance differences (P<0.05). Both N2 (r=0.377, P<0.05) and REM(r=0.436, P<0.05) had positive correlation with recognition accuracy rate of auditory verbal memory in research group. Conclusion Stable paranoid schizophrenic patients have poorer memory function(auditory verbal words memory recall, picture memory recall) than healthy people.Sleep promotes the consolidation of memory in patients with schizophrenia.Both N2 and REM of patients with stable paranoid schizophrenic have positive correlation with recognition accuracy rate of auditory verbal memory. Key words: Paranoid; Schizophrenia; Sleep; Memory consolidation

Memory abilities and maladaptive schemas among Moroccan students

How humans infer probable information from the limited observed data? How they are able to build on little knowledge about the context in hand? Is the human memory repeatedly constructing and reconstructing the events that are being recalled? These are a few questions that we are interested in answering with our multimodal memory game (MMG) platform that studies human memory and their behaviors while watching and remembering TV dramas for a better recall. Based on the preliminary results of human learning obtained from the MMG games, we attempt to show that the human memory recall improves steadily with the number of game sessions. As an example case, we provide a comparison for the text-to-text and text-image-to-text learning and demonstrate that the addition of image context is useful in improving the learning.Keywordshuman learningmemory recallBayesian inferencehuman cognition

Objective Temporal lobe epilepsy (TLE), frequently accompanied by working memory dysfunction, is an important form of adult epilepsy syndrome. Study on neural mechanisms of TLE with working memory dysfunction has important scientific value and clinical significance. Theta oscillations are synchronous activity of the brain in the 4-8 Hz frequency range. It is well recognized that there is a close relationship between the theta oscillations and working memory behavior. TLE patients with working memory dysfunction were taken as the research subjects, and the theta oscillations absence in TLE with working memory behavioral disorder was carried out, which provide the reference for further research into the neural mechanisms of TLE with working memory dysfunction. Methods The 34-channel electroencephalographs (EEGs) were recorded from TLE group (18 TLE patients) and control groups (18 healthy subjects) while subjects were performing visual working memory (delayed matching-to-sample) tasks. The EEGs during the 3 s delay period was analyzed as experimental data. Fourier transform was used to assess the EEGs spectrum. The channel with the strongest spectrum was selected as the feature channel. Short-time Fourier transform algosiths was employed to calculate the time-frequency representation of the feature channel for the TLE and control groups. Frequency band with the strongest spectrum was selected for control group as the feature frequency band in working memory. Then, the topographical maps of the feature frequency band spectrum were calculated for the TLE and control groups. Results Compared with the control group, the working memory behavioral performance of the TLE group was lower: accuracy of the TLE group was significantly lower than that of the control group (P<0.05), and reaction time of the TLE group was significantly longer than that of the control group (P<0.001). The feature channel in working memory was frontal midline (Fz) and the feature frequency band was theta band. The Fz spectrum of the feature frequency for TLE was lower than that for control (P<0.05). The frontal spectrum (seven channels) of the feature frequency for TLE was lower than that of control (P<0.01). Conclusions Theta oscillations for TLE with working memory behavioral disorder is absent, which maybe one of the possible neural mechanism of TLE with working memory dysfunction. Key words: Temporal lobe epilepsy; Working memory dysfunction; Multi-channel electroencephalographs; Theta oscillations

A wide body of animal and human research suggests that MDMA/ecstasy use is associated with lasting serotonergic neurotoxicity, particularly in mediotemporal and frontostriatal brain regions (Benningfield, 2013; Green, Mechan, Elliott, O'Shea, & Colado, 2003). Serotonin is important for a wide range of neurocognitive and psychobiological processes, and therefore neurotoxicity in these regions may have significant functional implications for ecstasy users. The objective of this thesis was to examine the neurocognitive and psychobiological effects of ecstasy that may be associated with serotonergic damage to mediotemporal and frontostriatal regions. Specifically, we examined this using an overnight memory consolidation paradigm. Overnight memory consolidation refers to the process of memory enhancement and increased resistance to interference that occurs across an episode of sleep, relative to a similar time-frame of wakefulness (Stickgold & Walker, 2013). The consolidation of declarative material in healthy participants is associated with prefrontal slow wave activity normally observed during deep sleep (Mander et al., 2013). The findings outlined above of serotonergic dysfunction in frontostriatal regions, coupled with evidence that ecstasy users have disrupted sleep architecture (Ogeil, Rajaratnam, & Broadbear, 2012) led us to hypothesise that ecstasy users will show impairments in the overnight consolidation of memory. We examined this hypothesis in two overnight consolidation studies. The first explored the overnight consolidation of emotional material using a visual recognition task delivered in an online environment. We found that compared to drug-naive controls (N=16), ecstasy users (N=15) tested after a period of sleep had stronger memory for negative visual images relative to neutral visual images. We suggest that this is due to a negative attribution bias, whereby material with negative content is preferentially consolidated and better recalled relative to material with neutral or positive content. The second overnight consolidation study utilised a verbal memory task to explore overnight memory consolidation in a laboratory setting. The task assessed whether sleep protects against interference from similar material, a phenomenon that has been confirmed in several studies among drug-naive controls (e.g. Ellenbogen, Hulbert, Jiang, & Stickgold, 2009). The results indicated that ecstasy users (N=12) did not show the same resistance to interference that was conferred to control participants (N=13) by overnight consolidation processes. Furthermore, our objective measurement of sleep architecture indicated that ecstasy users spent less time in deep sleep relative to controls, indicating that less time was spent in sleep stages that are known to be important for overnight memory consolidation. Together, this data suggests that ecstasy users experience dysfunctional sleep leading to impaired overnight memory consolidation. Finally, additional functional implications of disrupted mediotemporal and frontostriatal circuitry were examined using neurocognitive tasks that recruit these regions. Consistent with past research, we found reduced performance in a (same day) declarative long term memory task in ecstasy users. We also found that ecstasy users were selectively impaired on tasks of encoding, proactive interference memory, updating of working memory and complex planning, and therefore propose that executive functioning tasks engaging a higher cognitive load might reveal more subtle neurocognitive impairments experienced by ecstasy users. This thesis highlights the presence of selective neurocognitive executive dysfunction among ecstasy users. Furthermore, this thesis provides a unique contribution to the literature by demonstrating the key role of disrupted overnight consolidation processes in subsequent dysfunctional memory recall.

\tNaïve CD8+ T cells become activated if they recognize their specific antigen in the presence of co-stimulatory signals and inflammatory cytokines. This activation is followed by a rapid clonal expansion and differentiation into effector cells. These energetically demanding processes require significant changes in cellular metabolism. T cell activation induces metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis, proving both energy and metabolic intermediates. When the pathogen is cleared, the majority of antigen-specific CD8+ T cells undergo apoptosis. Only a small subset switch back to oxidative phosphorylation and survives this contraction phase to form a long-lived memory T cell pool with the ability to respond faster and stronger after reinfection. &#13;\n\tAlthough both naïve and memory CD8+ T cells use oxidative phosphorylation to generate ATP for their housekeeping functions, there are fundamental metabolic differences between these two subsets. Our group recently demonstrated that memory CD8+ T cells are able to rapidly induce glycolysis upon reactivation. This immediate-early glycolytic switch is required for memory recall response and it is regulated by the mTORC2-Akt axis. Interestingly, memory CD8+ T cells have higher mitochondrial mass and functionality than their naïve counterparts. Whether the rapid increase in glucose metabolism in memory T cells also involves oxidation in the mitochondria via TCA cycle remains to be elucidated. &#13;\n\tHow and when mitochondrial biogenesis occurs in the naïve to effector transition is still unknown. The kinetics, regulation and functional implications of mitochondrial biogenesis in naïve CD8+ T cells are the main focus of manuscript 1. Naïve CD8+ T cells were activated in vitro and mitochondrial mass and functions were assessed. We found that mitochondrial mass was increased in naïve CD8+ T cells early after activation and before the first division. In parallel to glycolysis, both mitochondrial respiration and mROS generation were increased in early-activated naïve CD8+ T cells. Inhibition of mitochondrial biogenesis diminished activation-induced mROS generation and IL-2, TNF and IFN-γ secretion. Notably, direct inhibition of mROS had a similar effect on early-effector cytokine secretion. The study presented here assigned additional roles for mitochondrial biogenesis early after activation, and that this event is mROS dependent, which results in increased IL-2 secretion and the modulation of TNF and IFN-γ production.&#13;\n\tHow mitochondrial differences contribute to early effector response in memory CD8+ T cells is still elusive. In manuscript 2, we studied the impact of glucose oxidation in mitochondria on early effector functions in both naïve and memory CD8+ T cells. Metabolomic and glucose tracing experiments assessing metabolic intermediates in both subsets revealed that glycolysis and TCA cycle intermediates were elevated in activated memory CD8+ T cells upon activation. Moreover, we demonstrated that mitochondrial respiration was increased early after activation in memory CD8+ T cells. Blocking mitochondrial respiration diminished early-recall response in memory CD8+ T cells. This suggests that both glycolysis and glucose flux into the TCA are important for rapid IFN-γ secretion. Additionally, we also demonstrated that key components of the mTORC2-Akt axis are present in the mitochondria associated membrane of the endoplasmic reticulum in CD8+ T cells, suggesting a close association between mTORC2-Akt signaling and mitochondrial function. These results further established metabolic differences between naïve and memory CD8+ T cells. Thus, the resulting metabolic plasticity in memory CD8+ T cells could be a requirement to support effector functions in competitive microenvironments. &#13;\n\tLastly, to mimic a CD8+ T cell - APC interaction in vitro we established a protocol using dual antibody coupling on polystyrene beads and assessed distinct antibody ratios loaded on the beads. This is the topic of manuscript 3 (technical notes). We found that input ratios of antibody were not always directly reflected by the final ratio loaded on the beads. Moreover, differently loaded beads showed differences in CD8+ activation, in vitro.&#13;\n\tAll together, the studies presented here contribute to a better understanding on how T cell metabolism supports immune function and could have implications for future strategies aiming to therapeutically manipulate CD8+ effector and memory functions. &#13;\n &#13;\n