Long-term Memory Consolidation Research Articles

Brief disruption of activity in a subset of dopaminergic neurons during consolidation impairs long-term memory by fragmenting sleep.

Sleep disturbances are associated with poor long-term memory (LTM) formation, yet the underlying cell types and neural circuits involved have not been fully decoded. Dopamine neurons (DANs) are involved in memory processing at multiple stages. Here, using both male and female flies, Drosophila melanogaster , we show that, during the first few hours of memory consolidation, disruption of basal activity of a small subset of protocerebral anterior medial DANs (PAM-DANs), by either brief activation or inhibition of the two dorsal posterior medial (DPM) neurons, impairs 24 h LTM. Interestingly, these brief changes in activity using female flies result in sleep loss and fragmentation, especially at night. Pharmacological rescue of sleep after manipulation restores LTM. A specific subset of PAM-DANs (PAM-α1) that synapse onto DPM neurons specify the microcircuit that links sleep and memory. PAM-DANs, including PAM-α1, form functional synapses onto DPM mainly via multiple dopamine receptor subtypes. This PAM-α1 to DPM microcircuit exhibits a synchronized, transient, post-training increase in activity during the critical memory consolidation window, suggesting an effect of this microcircuit on maintaining the sleep necessary for LTM consolidation. Our results provide a new cellular and circuit basis for the complex relationship between sleep and memory.

The role of the claustrum in the acquisition, consolidation and reconsolidation of memories in mice

The claustrum is a brain structure that remains shrouded in mystery due to the limited understanding of its cellular structure, neural pathways, functionality and physiological aspects. Significant research has unveiled connections spanning from the claustrum to the entire cortex as well as subcortical areas. This widespread connectivity has led to speculations of its role in integrating information from different brain regions, possibly contributing to processes such as attention, consciousness, learning and memory. Our working hypothesis posits that claustrum neural activity contributes to the acquisition, consolidation and reconsolidation of long-term memories in mice. We found evidence in CF-1 mice of a decline in behavioral performance in an inhibitory avoidance task due to intra-claustral administration of 2% lidocaine immediately after a training session or memory recall. Nevertheless, this does not seem to be the case for the acquisition or retrieval of this type of memory, although its neural activity is significantly increased after training, evaluated through c-Fos expression. Moreover, inhibition of the claustrum’s synaptic activity appears to impair the consolidation but not acquisition or retrieval of an unconditioned memory formed in a nose-poke habituation task.

EphrinB2 in excitatory neurons and astrocytes in the basolateral amygdala controls long-term fear memory formation

EphrinB2 regulates synaptic transmission and morphology however its role in memory formation is unknown. Here we show that deleting ephrinB2 from excitatory neurons in the basolateral amygdala (BLA) of male mice impairs long-term (LTM), but not short-term (STM), fear memory formation. Deleting ephrinB2 from astrocytes in the BLA impairs fear LTM but not STM. Removing ephrinB2 from astrocytes in the BLA reduces the level of the excitatory amino acid transporter 1 (EAAT1) in these cells. Inhibiting EAAT1 activity in the BLA during fear conditioning, by its specific inhibitor UCPH-101, impairs fear LTM showing that EAAT1 in the BLA is needed for fear LTM formation. The administration of ephrinB2 into the BLA during fear conditioning training enhances fear LTM. Moreover, ephrinB2 increases the ability of fear conditioning to activate cells in the BLA as detected by c-Fos labeling. EphrinB2 therefore determines the threshold for fear memory formation. In contrast to mature neurons, we show that ephrinB2 in neural stem cells (NSCs) is not needed for fear LTM. Our study shows that ephrinB2 in the BLA determines the strength of long-term memory consolidation.

The Lysine Acetyltransferase PCAF Functionally Interacts with Estrogen Receptor Alpha in the Hippocampus of Gonadally Intact Male-But Not Female-Rats to Enhance Short-Term Memory.

Acetylation of histone proteins by histone acetyltransferases (HATs), and the resultant change in gene expression, is a well-established mechanism necessary for long-term memory (LTM) consolidation, which is not required for short-term memory (STM). However, we previously demonstrated that the HAT p300/CBP-associated factor (PCAF) also influences hippocampus (HPC)-dependent STM in male rats. In addition to their epigenetic activity, HATs acetylate nonhistone proteins involved in nongenomic cellular processes, such as estrogen receptors (ERs). Given that ERs have rapid, nongenomic effects on HPC-dependent STM, we investigated the potential interaction between ERs and PCAF for STM mediated by the dorsal hippocampus (dHPC). Using a series of pharmacological agents administered directly into the dHPC, we reveal a functional interaction between PCAF and ERα in the facilitation of short-term object-in-place memory in male but not female rats. This interaction was specific to ERα, while ERβ agonism did not enhance STM. It was further specific to dHPC STM, as the effect was not present in the dHPC for LTM or in the perirhinal cortex. Further, while STM required local (i.e., dHPC) estrogen synthesis, the facilitatory interaction effect appeared independent of estrogens. Finally, western blot analyses demonstrated that PCAF activation in the dHPC rapidly (5 min) activated downstream estrogen-related cell signaling kinases (c-Jun N-terminal kinase and extracellular signal-related kinase). Collectively, these findings indicate that PCAF, which is typically implicated in LTM through epigenetic processes, also influences STM in the dHPC, possibly via nongenomic ER activity. Critically, this novel PCAF-ER interaction might exist as a male-specific mechanism supporting STM.

Conserving a sense of self despite significantly impaired short-term memory through songwriting and formative events

This case study reflects on the use of improvisation and songwriting to support a patient with significantly impaired short-term memory and long-term memory interference as a result of acquired brain injury. Memory has long been associated with personal identity, linking the past with the present, and enabling us to project into the future. This continuity of consciousness helps us to learn from, and make sense of our experiences, strengthening our internal representation of self. Disruption to short-term memory can significantly impact decision making, planning and initiation, all of which are key components of personal identity and self-expression. Supporting patient autonomy and self-expression through improvisation, and crafting lyrical content around personal preferences and events, sessions were designed to bolster his internalised sense of self through both revisiting old memories and facilitating new memory formation within the present. While short-term memory has been considered a conduit to long-term memory consolidation, and integral to the individual’s self-expression, this case study implies short-term memory was neither the gatekeeper to formation of long-term memories, nor critical to maintaining a sense of self, and reflects on how music helped the client create and access new learning beyond procedural memories, anchoring the self in newly internalised self-expression.

The cortical amygdala consolidates a socially transmitted long-term memory

Social communication guides decision-making, which is essential for survival. Social transmission of food preference (STFP) is an ecologically relevant memory paradigm in which an animal learns a desirable food odour from another animal in a social context, creating a long-term memory1,2. How food-preference memory is acquired, consolidated and stored is unclear. Here we show that the posteromedial nucleus of the cortical amygdala (COApm) serves as a computational centre in long-term STFP memory consolidation by integrating social and sensory olfactory inputs. Blocking synaptic signalling by the COApm-based circuit selectively abolished STFP memory consolidation without impairing memory acquisition, storage or recall. COApm-mediated STFP memory consolidation depends on synaptic inputs from the accessory olfactory bulb and on synaptic outputs to the anterior olfactory nucleus. STFP memory consolidation requires protein synthesis, suggesting a gene-expression mechanism. Deep single-cell and spatially resolved transcriptomics revealed robust but distinct gene-expression signatures induced by STFP memory formation in the COApm that are consistent with synapse restructuring. Our data thus define a neural circuit for the consolidation of a socially communicated long-term memory, thereby mechanistically distinguishing protein-synthesis-dependent memory consolidation from memory acquisition, storage or retrieval.

Recognizing the opponent: The consolidation of long-term social memory in zebrafish males

Recognizing and remembering another individual in a social context could be beneficial for individual fitness. Especially in agonistic encounters, remembering an opponent and the previous fight could allow for avoiding new conflicts. Considering this, we hypothesized that this type of social interaction forms a long-term recognition memory lasting several days. It has been shown that a second encounter 24 h later between the same pair of zebrafish males is resolved with lower levels of aggression. Here, we evaluated if this behavioral change could last for longer intervals and a putative mechanism associated with memory storage: the recruitment of NMDA receptors. We found that if a pair of zebrafish males fight and fight again 48 or 72 h later, they resolve the second encounter with lower levels of aggression. However, if opponents were exposed to MK-801 (NMDA receptor antagonist) immediately after the first encounter, they solved the second one with the same levels of aggression: that is, no reduction in aggressive behaviors was observed. These amnesic effect suggest the formation of a long-term social memory related to recognizing a particular opponent and/or the outcome and features of a previous fight.

Enhanced expression of activity-regulated cytoskeleton-associated protein in the medial prefrontal cortex is involved in working memory performance.

Working memory (WM) is a cognitive function important for guiding the on-going or upcoming behavior. A memory-related protein Arc (activity-regulated cytoskeleton-associated protein) is implicated in long-term memory consolidation. Recent evidence further suggests the involvement of hippocampal Arc in spatial WM. The medial prefrontal cortex (mPFC) is a key brain region mediating WM. However, the role of mPFC Arc in WM is still uncertain. To investigate whether mPFC Arc protein is involved in WM performance, delayed non-match to sample (DNMS) T-maze task was performed in rats with or without blocking new synthesis of mPFC Arc. In DNMS task, a 10-s or 30-s delay between the sample run and the choice run was given to evaluate WM performance. To block new Arc protein synthesis during the DNMS task, Arc antisense oligodeoxynucleotides (ODNs) were injected to the bilateral mPFC. The results show that, in rats without surgery for cannula implantation and subsequent intracerebral injection of ODNs, WM was functioning well during the DNMS task with a delay of 10 s but not 30 s, which was accompanied with a significantly increased level of mPFC Arc protein, indicating a possible link between enhanced Arc protein expression and the performance of WM. After preventing the enhancement of mPFC Arc protein expression with Arc antisense ODNs, rat's WM performance was impaired. These findings support enhanced mPFC Arc protein expression playing a role during WM performance.

A coupled neural field model for the standard consolidation theory

The standard consolidation theory states that short-term memories located in the hippocampus enable the consolidation of long-term memories in the neocortex. In other words, the neocortex slowly learns long-term memories with a transient support of the hippocampus that quickly learns unstable memories. However, it is not clear yet what could be the neurobiological mechanisms underlying these differences in learning rates and memory time-scales. Here, we propose a novel modeling approach of the standard consolidation theory, that focuses on its potential neurobiological mechanisms. In addition to synaptic plasticity and spike frequency adaptation, our model incorporates adult neurogenesis in the dentate gyrus as well as the difference in size between the neocortex and the hippocampus, that we associate with distance-dependent synaptic plasticity. We also take into account the interconnected spatial structure of the involved brain areas, by incorporating the above neurobiological mechanisms in a coupled neural field framework, where each area is represented by a separate neural field with intra- and inter-area connections. To our knowledge, this is the first attempt to apply neural fields to this process. Using numerical simulations and mathematical analysis, we explore the short-term and long-term dynamics of the model upon alternance of phases of hippocampal replay and retrieval cue of an external input. This external input is encodable as a memory pattern in the form of a multiple bump attractor pattern in the individual neural fields. In the model, hippocampal memory patterns become encoded first, before neocortical ones, because of the smaller distances between the bumps of the hippocampal memory patterns. As a result, retrieval of the input pattern in the neocortex at short time-scales necessitates the additional input delivered by the memory pattern of the hippocampus. Neocortical memory patterns progressively consolidate at longer times, up to a point where their retrieval does not need the support of the hippocampus anymore. At longer times, perturbation of the hippocampal neural fields by neurogenesis erases the hippocampus pattern, leading to a final state where the memory pattern is exclusively evoked in the neocortex. Therefore, the dynamics of our model successfully reproduces the main features of the standard consolidation theory. This suggests that neurogenesis in the hippocampus and distance-dependent synaptic plasticity coupled to synaptic depression and spike frequency adaptation, are indeed critical neurobiological processes in memory consolidation.

The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity. Kdm5b Δ ARID/ Δ ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b Δ ARID/ Δ ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms.

TrkB-BDNF Signalling and Arc/Arg3.1 Immediate Early Genes in the Anterior Cingulate Cortex and Hippocampus: Insights into Novel Memory Milestones Through Behavioural Tagging.

In recent years, there has been a surge in interest in investigating the mechanisms underlying memory consolidation. However, our understanding of the behavioural tagging (BT) model and its establishment in diverse brain regions remains limited. This study elucidates the contributions of the anterior cingulate cortex (ACC) and hippocampus in the formation of long-term memory (LTM) employing behaviour tagging as a model for studying the underlying mechanism of LTM formation in rats. Existing knowledge highlights a protein synthesis-dependent phase as imperative for LTM. Brain-derived neurotrophic factor (BDNF) stands as a pivotal plasticity-related protein (PRP) in mediating molecular alterations crucial for long-term synaptic plasticity and memory consolidation. Our study offers evidence suggesting that tropomyosin receptor kinase B (TrkB), the receptor of BDNF, may act as a combined "behavioural tag/PRP". Interfering with the expression of these molecules resulted in impaired LTM after 24h. Furthermore, augmenting BDNF expression led to an elevation in Arc protein levels in both the ACC and hippocampus regions. Introducing novelty around weak inhibitory avoidance (IA) training resulted in heightened step-down latencies and expression of these molecules, respectively. We also demonstrate that the increase in Arc expression relies on BDNF synthesis, which is vital for the memory consolidation process. Additionally, inhibiting BDNF using an anti-BDNF function-blocking antibody impacted Arc expression in both the ACC and hippocampus regions, disrupting the transformations from labile to robust memory. These findings mark the initial identification of a "behavioural tag/PRP" combination and underscore the involvement of the TrkB-BDNF-Arc cascade in the behavioural tagging model of learning and memory.

Human brain activity and functional connectivity associated with verbal long-term memory consolidation across 1 month.

Declarative memories are initially dependent on the hippocampus and become stabilized through the neural reorganization of connections between the medial temporal lobe and neocortex. The exact time-course of these neural changes is not well established, although time-dependent changes in retrieval-related brain function can be detected across relatively short time periods in humans (e.g., hours to months). In a study involving older adults with normal cognition (N = 24), we investigated changes in brain activity and functional connectivity associated with the long-term memory consolidation of verbal material over one month. Participants studied fact-like, three-word sentences at 1-month, 1-week, 1-day, and 1-hour intervals before a recognition memory test inside an MRI scanner. Old/new recognition with confidence ratings and response times were recorded. We examined whole-brain changes in retrieval-related brain activity, as well as functional connectivity of the hippocampus and ventromedial prefrontal cortex (vmPFC), as memories aged from 1 hour to 1 month. Secondary analyses minimized the effect of confounding factors affected by memory age (i.e., changes in confidence and response time or re-encoding of targets). Memory accuracy, confidence ratings, and response times changed with memory age. A memory age network was identified where retrieval-related brain activity in cortical regions increased or decreased as a function of memory age. Hippocampal brain activity in an anatomical region of interest decreased with memory age. Importantly, these changes in retrieval-related activity were not confounded with changes in activity related to concomitant changes in behavior or encoding. Exploratory analyses of vmPFC functional connectivity as a function of memory age revealed increased connectivity with the posterior parietal cortex, as well as with the vmPFC itself. In contrast, hippocampal functional connectivity with the vmPFC and orbitofrontal cortex decreased with memory age. The observed changes in retrieval-related brain activity and functional connectivity align with the predictions of standard systems consolidation theory. These results suggest that processes consistent with long-term memory consolidation can be identified over short time periods using fMRI, particularly for verbal material.

A classification-based generative approach to selective targeting of global slow oscillations during sleep.

Given sleep's crucial role in health and cognition, numerous sleep-based brain interventions are being developed, aiming to enhance cognitive function, particularly memory consolidation, by improving sleep. Research has shown that Transcranial Alternating Current Stimulation (tACS) during sleep can enhance memory performance, especially when used in a closed-loop (cl-tACS) mode that coordinates with sleep slow oscillations (SOs, 0.5-1.5Hz). However, sleep tACS research is characterized by mixed results across individuals, which are often attributed to individual variability. This study targets a specific type of SOs, widespread on the electrode manifold in a short delay ("global SOs"), due to their close relationship with long-term memory consolidation. We propose a model-based approach to optimize cl-tACS paradigms, targeting global SOs not only by considering their temporal properties but also their spatial profile. We introduce selective targeting of global SOs using a classification-based approach. We first estimate the current elicited by various stimulation paradigms, and optimize parameters to match currents found in natural sleep during a global SO. Then, we employ an ensemble classifier trained on sleep data to identify effective paradigms. Finally, the best stimulation protocol is determined based on classification performance. Our study introduces a model-driven cl-tACS approach that specifically targets global SOs, with the potential to extend to other brain dynamics. This method establishes a connection between brain dynamics and stimulation optimization. Our research presents a novel approach to optimize cl-tACS during sleep, with a focus on targeting global SOs. This approach holds promise for improving cl-tACS not only for global SOs but also for other physiological events, benefiting both research and clinical applications in sleep and cognition.

The integrated stress response effector GADD34 is repurposed by neurons to promote stimulus-induced translation

Neuronal protein synthesis is required for long-lasting plasticity and long-term memory consolidation. Dephosphorylation of eukaryotic initiation factor 2α is one of the key translational control events that is required to increase de novo protein synthesis that underlies long-lasting plasticity and memory consolidation. Here, we interrogate the molecular pathways of translational control that are triggered by neuronal stimulation with brain-derived neurotrophic factor (BDNF), which results in eukaryotic initiation factor 2α (eIF2α) dephosphorylation and increases in de novo protein synthesis. Primary rodent neurons exposed to BDNF display elevated translation of GADD34, which facilitates eIF2α dephosphorylation and subsequent de novo protein synthesis. Furthermore, GADD34 requires G-actin generated by cofilin to dephosphorylate eIF2α and enhance protein synthesis. Finally, GADD34 is required for BDNF-induced translation of synaptic plasticity-related proteins. Overall, we provide evidence that neurons repurpose GADD34, an effector of the integrated stress response, as an orchestrator of rapid increases in eIF2-dependent translation in response to plasticity-inducing stimuli.

Regulation of long-term memory by a few clock neurons in Drosophila.

Identification of the neural circuits in the brain regulating animal behavior and physiology is critical for understanding brain functions and is one of the most challenging goals in neuroscience research. The fruitfly Drosophila melanogaster has often been used to identify the neural circuits involved in the regulation of specific behaviors because of the many neurogenetic tools available to express target genes in particular neurons. Neurons controlling sexual behavior, feeding behavior, and circadian rhythms have been identified, and the number of neurons responsible for controlling these phenomena is small. The search for a few neurons controlling a specific behavior is an important first step to clarify the overall picture of the neural circuits regulating that behavior. We previously found that the clock gene period (per), which is essential for circadian rhythms in Drosophila, is also essential for long-term memory (LTM). We have also found that a very limited number of per-expressing clock neurons in the adult brain are required for the consolidation and maintenance of LTM. In this review, we focus on LTM in Drosophila, introduce the concept of LTM regulation by a few clock neurons that we have recently discovered, and discuss how a few clock neurons regulate Drosophila LTM.

Sex-specific variations in spatial reference memory acquisition: Insights from a comprehensive behavioral test battery in C57BL/6JRj mice

Sex differences in declarative memory are described in humans, revealing a female or a male advantage depending on the task. Specifically, spatial memory (i.e., spatial navigation) is typically most efficient in men. This sexual dimorphism has been replicated in male rats but not clearly in mice. In this study, sex differences in spatial memory were assessed in thirty-six C57BL/6 J mice (Janvier Labs; i.e., C57BL/6JRj mice), a widely used mouse substrain. Both male and female mice (12 weeks-old) were subjected to standard behavioral paradigms: the elevated plus maze, the open field test, the novel object and place tests, the forced swimming test, and the water maze test for spatial navigation. Across assessment, no sex differences were found in measures of locomotor activity, emotional and behavioral responses, and object and place recognition memories. In the water maze, male mice were faster in learning the platform location in the reference memory training and used more spatial strategies during the first training days. However, both sexes reached a similar asymptotic performance and performed similarly in the probe trial for long-term memory consolidation. No sex differences were found in the cued training, platform inversion sessions, or spatial working memory sessions. Hippocampal expression of the brain-derived neurotrophic factor was similar in both sexes, either in basal conditions or after performing the behavioral training battery. Importantly, female mice were not more variable than males in any measure analyzed. This outcome encourages the investigation of sex differences in animal models and the usefulness of including female mice in behavioral research.

MRNA translation in astrocytes controls hippocampal long-term synaptic plasticity and memory.

Activation of neuronal protein synthesis upon learning is critical for the formation of long-term memory. Here, we report that learning in the contextual fear conditioning paradigm engenders a decrease in eIF2α (eukaryotic translation initiation factor 2) phosphorylation in astrocytes in the hippocampal CA1 region, which promotes protein synthesis. Genetic reduction of eIF2α phosphorylation in hippocampal astrocytes enhanced contextual and spatial memory and lowered the threshold for the induction of long-lasting plasticity by modulating synaptic transmission. Thus, learning-induced dephosphorylation of eIF2α in astrocytes bolsters hippocampal synaptic plasticity and consolidation of long-term memories.

5 Combining Neurophysiology and Behavioral Measures to Identify Biomarkers of Clinical and Preclinical Hippocampus-Dependent Memory Dysfunction

Objective:Memory is a critical piece of the human experience and impairments in neural memory networks can have devastating consequences for the affected person. A subtype of memory, episodic memory generates context for the present based on past experience and allows us to make predictions about the future. Episodic memories become stable fixtures through long-term memory consolidation. It is believed that consolidation of episodic memory requires a dynamic interplay between connected hippocampal-cortical networks, mainly during sleep. Sleep oscillations, slow oscillations and thalamocortical spindles, coupled with hippocampal sharp wave ripples (SWR) is proposed to be mechanistically involved in establishing the crucial cortical-subcortical dialog. The current study aimed to determine alterations in typical sleep oscillations and oscillation coupling in patients with and without structural hippocampal damage and correlate them with neuropsychological measures believed to be sensitive to hippocampal dysfunction, i.e., Rey Auditory Verbal Learning Task (RAVLT) and Verbal Paired Associates (VPA-II).Participants and Methods:We used intracranial electroencephalography (iEEG) in 14 patients with epilepsy to directly record hippocampal and neocortical oscillations and neuropsychological measures obtained prior to implantation. Half of the participants were diagnosed with mesial temporal sclerosis (MTS) in the left hippocampus and healthy tissue in the right hippocampus. The other half did not have MTS and had either mesial temporal epilepsy without MTS or extra-temporal seizures. We analyzed hippocampal SWR output from both hippocampi and characterized neocortical slow oscillations and spindles and their coupling for each participant. We correlated electrophysiological data with behavioral results of neuropsychological testing in order to characterize the clinical relevance.Results:SWR analysis revealed significant differences in the frequency, t(7639) = 15.52, p>.001, p > .001), amplitude, t(7664) = -23.93, p > .001, and waveforms (p > .001) of SWR in the sclerotic versus healthy hippocampi. Patients with a sclerotic hippocampus but relatively preserved verbal memory scores (RAVLT, VPA-II) showed increased SWR amplitudes in the contralateral hippocampus compared to patients with low verbal memory scores. Additionally, we found differences between hemispheres in phase amplitude coupling of SWRs to spindles and SOs (p > 0.001). Results of our correlational analysis were variable and dependent upon additional factors, such as age of onset and diagnosis duration.Conclusions:Results from this work will aid in establishing a criterion for characterizing a relationship between subcortical and cortical oscillations as they relate to memory performance. Besides aiding our understanding of the neural mechanisms underpinning memory consolidation this will ideally help with developing neurophysiological biomarkers that may predict possible memory decline in resective or ablative neurosurgery absent of structural lesion. In addition, this work may potentially provide first evidence of a neurophysiological biomarker directly recorded from the human hippocampus to support possible reorganization of memory functioning in the non-sclerotic hippocampus.

33 Associations Between Long-Term Forgetting and Slow Wave Activity in Autosomal-Dominant Alzheimer’s Disease: Findings from the Colombia-Boston (COLBOS) Biomarker Study

Objective:Sleep contributes to memory retention and recall. Alzheimer’s disease (AD) patients experience decreased slow wave activity (SWA) during sleep. This decrease in SWA is associated with impaired memory consolidation (Lee et al., 2020). Long-term forgetting (LTF) over days or weeks has been linked to memory consolidation deficits and has been suggested as an early marker of AD that could be useful for identifying at-risk individuals for preclinical AD trials (Weston et al., 2018). Here, we examined associations between LTF and SWA in a sample of Presenilin-1 (PSEN1) E280A mutation carriers with autosomal dominant Alzheimer’s disease and non-carrier family members. Carriers of this mutation usually develop dementia in their forties (Fuller et al., 2019).Participants and Methods:Fourteen cognitively unimpaired PSEN1-E280A mutation carriers and sixteen age-matched non-carriers (mean age: 34.2 years) from the Colombia-Boston (COLBOS) biomarker study were included. Participants completed an overnight polysomnogram (PSG) and memory testing (NEUROPSI Word List) at 3-time points: 1) the night before PSG: immediate recall (Day1-ImmRecall) and a 20-minute delayed recall (Day1-DelayedRecall), 2) recall the following day (Day2-recall), and 3) recall one week later (Day7-recall). SWA was measured as the ratio 0. 6-1Hz/0.6-4Hz in frontopolar and frontotemporal regions and was calculated for sleep stages N2+N3 (slow wave sleep) based on an automated staging algorithm. Each participant’s LTF was calculated as the percent retention between Day 1 immediate recall and Day 7 recall (Butler, 2009). Mann-Whitney U tests were used to compare differences in recall, SWA, and LTF between groups. Spearman’s correlation was used to examine the associations between memory recall at different time points and SWA, as well as between LTF and SWA.Results:On Day 1, carriers had lower performance in immediate recall (p=0.02), compared to non-carriers, but there were no group differences in the 20-minute delayed recall. Carriers also recalled fewer words on Day 2 (p=0.03) and Day 7 (p=0.009) and had greater LTF (p=0.03). There were no group differences in SWA. In our overall sample, worse performance on word list delayed recall on Day 1, Day 2, and Day 7 was associated with less SWA across both frontotemporal (Day1: p=0.04, Day2: p=0.02, Day7: p=0.02) and frontopolar (all Ps<0.01) regions. In carriers, only worse performance on Day 1 delayed recall was associated with lower SWA in the frontopolar region (r= 0.535; p=0.049). Memory recall on other days was not associated with SWA in any brain regions. Additionally, greater LTF was associated with less SWA across both frontopolar (r= 0.507; p=0.005) and frontotemporal regions (r= 0.463 p= 0.01).Conclusions:Preliminary findings suggest that long-term forgetting is associated with less slow- wave activity in preclinical autosomal dominant Alzheimer’s disease. These results also suggest that SWA may be related to pre-sleep learning and subsequent overnight memory consolidation processes. LTF testing may be useful in selecting individuals for preclinical AD trials. Future research on the impact of slow wave activity on LTF may be useful in identifying ways to enhance short- and long-term memory consolidation in individuals at greater risk for dementia.

Lipoic acid inhibits cognitive impairment induced by multiple cell phones in young male rats: role of Sirt1 and Atg7 pathway

The utilization of digital technology has grown rapidly in the past three decades. With this rapid increase, cell phones emit electromagnetic radiation; that is why electromagnetic field (EMF) has become a substantial new pollution source in modern civilization, mainly having adverse effects on the brain. While such a topic attracted many researchers’ scopes, there are still minimal discoveries made regarding chronic exposure to EMF. The extensive use of cell phones may affect children's cognition even indirectly if parents and guardians used their phones repeatedly near them. This study aims to investigate possible lipoic acid (LA) effects on cognitive functions and hippocampal structure in young male rats exposed to electromagnetic fields (EMF) emitted from multiple cell phones. Forty young male Wistar rats were randomly allocated into three groups: control, multiple cell phones-exposed and lipoic acid-treated rats. By the end of the experimental period, the Morris water maze was used as a cognitive test. The rats were sacrificed for the collection of serum and hippocampal tissue. These serum samples were then utilized for assessment of Liver function tests. The level ofglutamate, acetylcholine (Ach) and malondialdehyde (MDA) was estimated, in addition to evaluating the expression of autophagy-related protein-7 (Atg7) and Sirt1 genes. The left hippocampal specimens were used for histopathological studies. Results showed that multiple cell phone-exposed rats exhibited shorter latency time to reach the platform by the fifth day of training; additionally, there was a reduction in consolidation of spatial long-term memory. Correspondingly, there was an elevation of hippocampal Ach, glutamate, and MDA levels; accompanied by up-regulation of hippocampal Sirt1 and Atg7 gene expression. Compared to the EMF-exposed group, LA administration improved both learning and memory, this was proved by the significant decline in hippocampal MDA and Ach levels, the higher hippocampal glutamate, the downregulated hippocampal Sirt1 gene expression and the upregulated Atg7 gene expression. In conclusion, EMF exposure could enhance learning ability; however, it interfered with long-term memory consolidation shown by higher hippocampal Ach levels. Lipoic acid treatment improved both learning and memory by enhancing autophagy and hippocampal glutamate level and by the reduced Ach levels and Sirt1 gene expression.