Long-term Memory Consolidation Research Articles

Behavioural tagging: Effect of novelty exploration on plasticity related molecular signatures.

Learning and memory are one of those frontier areas of neurobiology which attract us to investigate the intricacy of this process. Here, we aimed to investigate the general mechanism of "Behavioural Tagging and Capture" in long term memory (LTM) formation and to find the key factors playing role in consolidation of LTM. In this study, we've shown that not only plasticity related proteins (PRPs) but neurotransmitters and immediate early genes (IEGs) also play an important role in memory formation process. It's very well evident that memory traces can last longer if close in time novelty is introduced around memory encoding. Here our results point out that this novelty exploration acts as a modulator in memory consolidation by providing PRPs such as brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), enhancing neurotransmitters (Dopamine), IEGs (cFos) and some enzymes such as acetylcholinesterase (AChE), monoamine oxidase (MAO), sodium-potassium ATPase (Na+K+-ATPase). Therefore, by using a Novel Object Recognition task (NOR) in combination with novel task exposure, we evaluated the role of molecular markers in memory consolidation employing a behavioural tagging model. The purpose of the current study was first to evaluate the effect of novelty exposure around a single trail of NOR task in a critical time window on memory consolidation in rats after 24h and second to determine the expression of BDNF, CREB, c-fos, AChE, MAO, Na+K+-ATPase as potential markers in the medial prefrontal cortex (mPFC) during memory formation. In the present study, to identify and validate the role of these molecular signatures in memory consolidation, infusion of the protein synthesis inhibitor Anisomycin (Ani) was done around the training session that causes a deficit in the formation of LTM when tested 24h after weak encoding. Altogether, here we are providing the first comprehensive set of evidences indicating that BDNF, CREB, dopamine, some enzymes and c-fos role in modulating LTM by employing behavioural tagging model.

Intermittent fasting enhances long-term memory consolidation, adult hippocampal neurogenesis, and expression of longevity gene Klotho

Daily calorie restriction (CR) and intermittent fasting (IF) enhance longevity and cognition but the effects and mechanisms that differentiate these two paradigms are unknown. We examined whether IF in the form of every-other-day feeding enhances cognition and adult hippocampal neurogenesis (AHN) when compared to a matched 10% daily CR intake and ad libitum conditions. After 3 months under IF, female C57BL6 mice exhibited improved long-term memory retention. IF increased the number of BrdU-labeled cells and neuroblasts in the hippocampus, and microarray analysis revealed that the longevity gene Klotho (Kl) was upregulated in the hippocampus by IF only. Furthermore, we found that downregulating Kl in human hippocampal progenitor cells led to decreased neurogenesis, whereas Kl overexpression increased neurogenesis. Finally, histological analysis of Kl knockout mice brains revealed that Kl is required for AHN, particularly in the dorsal hippocampus. These data suggest that IF is superior to 10% CR in enhancing memory and identifies Kl as a novel candidate molecule that regulates the effects of IF on cognition likely via AHN enhancement.

The selective 5-HT1A receptor biased agonists, F15599 and F13714, show antidepressant-like properties after a single administration in the mouse model of unpredictable chronic mild stress

RationaleThe prevalence of depression is ever-increasing throughout the population. However, available treatments are ineffective in around one-third of patients and there is a need for more effective and safer drugs.ObjectivesThe antidepressant-like and procognitive effects of the “biased agonists” F15599 (also known as NLX-101) which preferentially targets postsynaptic 5-HT1A receptors and F13714, which targets 5-HT1A autoreceptors, were investigated in mice.MethodsAntidepressant-like properties of the compounds and their effect on cognitive functions were assessed using the forced swim test (FST) and the novel object recognition (NOR), respectively. Next, we induced a depressive-like state by an unpredictable chronic mild stress (UCMS) procedure to test the compounds’ activity in the depression model, followed by measures of sucrose preference, FST, and locomotor activity. Levels of phosphorylated cyclic AMP response element-binding protein (p-CREB) and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) were also determined.ResultsF15599 reduced immobility time in the FST over a wider dose-range (2 to 16 mg/kg po) than F13714 (2 and 4 mg/kg po), suggesting accentuated antidepressant-like properties in mice. F15599 did not disrupt long-term memory consolidation in the NOR at any dose tested, while F13714 impaired memory formation, notably at higher doses (4–16 mg/kg). In UCMS mice, a single administration of F15599 and F13714 was sufficient to robustly normalize depressive-like behavior in the FST but did not rescue disrupted sucrose preference. Both F15599 and F13714 rescued cortical and hippocampal deficits in p-ERK1/2 levels of UCMS mice but did not influence the p-CREB levels.ConclusionsOur studies showed that 5-HT1A receptor biased agonists such as F13714 and especially F15599, due to its less pronounced side effects, might have potential as fast-acting antidepressants.

Patterns of Cellular Overlap in Expression of c‐Fos and Arc Activity‐Regulated Genes in the Mouse Brain Regions During Acquisition and Retrieval of Contextual Conditioned Fear

Consolidation of long-term memory requires expression of immediate early genes (IEGs) encoding regulatory and effector proteins, such as inducible transcription factor c-Fos and activity-regulated cytoskeleton-associated protein Arc/Arg3.1. Since these IEGs are involved in various forms of behavioral and stimulus-induced plasticity, their products are often used to label active neurons, and their promoters are employed to tag and manipulate active engram cells. However, little is still known as to whether c-Fos and Arc proteins are induced identically and in the same neurons of different brain structures under various behavioral conditions. In the present work we compared expression patterns of c-Fos and Arc proteins in the mouse brain after acquisition and retrieval of contextual fear and analyzed cellular overlap of their expression in both conditions. Our hypothesis was that the activity patterns of two genes would not be identical though would substantially overlap according to similarities and differences in signaling cascades driving their expression. Both cohorts of mice were subjected to standard contextual fear conditioning with an electric footshock. One group of animals was sacrificed 90 minutes after the training session and the other was tested for retrieval of contextual memory on the next day and sacrificed 90 minutes later. The percentage of freezing in the conditioning context was measured as an index of memory. Brain sections were collected from hippocampus, amygdala and associative cortices of experimental mice, active control mice and home cage control mice. Double immunohistochemical staining with anti-Fos and anti-Arc antibodies was performed, and stained sections were scanned with a confocal microscope. The cell count showed behavioral induction of both c-Fos and Arc in all the examined brain structures. However, there was only a partial overlap of about 30% between the two labelled cell populations. Arc-positive cells predominated over c-Fos-positive cells in the hippocampus regardless of cognitive task, and in cingulate and parietal cortex Arc prevalence was stronger in after memory retrieval compared to learning. Moreover, within the above structures localization of c-Fos- and Arc-positive cells had different distribution across cortical layers and hippocampal subfields. Our results indicate that c-Fos and Arc proteins are not equivalent markers of stimulus-induced neural activity, as they are expressed in cell populations that differ by more than 60%. This data imposes a significant restraint on the use of these IEGs as interchangeable markers of neuronal activity/plasticity and calls for a further study of the differences in their regulation during behavior and learning.

Amphetamine Modulation of Long-Term Object Recognition Memory in Rats: Influence of Stress.

Amphetamine is a potent psychostimulant that increases brain monoamine levels. Extensive evidence demonstrated that norepinephrine is crucially involved in the regulation of memory consolidation for stressful experiences. Here, we investigated amphetamine effects on the consolidation of long-term recognition memory in rats exposed to different intensities of forced swim stress immediately after training. Furthermore, we evaluated whether such effects are dependent on the activation of the peripheral adrenergic system. To this aim, male adult Sprague Dawley rats were subjected to an object recognition task and intraperitoneally administered soon after training with amphetamine (0.5 or 1 mg/kg), or its corresponding vehicle. Rats were thereafter exposed to a mild (1 min, 25 ± 1°C) or strong (5 min, 19 ± 1°C) forced swim stress procedure. Recognition memory retention was assessed 24-h after training. Our findings showed that amphetamine enhances the consolidation of memory in rats subjected to mild stress condition, while it impairs long-term memory performance in rats exposed to strong stress. These dichotomic effects is dependent on stress-induced activation of the peripheral adrenergic response.

Herpes Simplex Virus Type 1 Neuronal Infection Triggers the Disassembly of Key Structural Components of Dendritic Spines.

Herpes simplex virus type 1 (HSV-1) is a widespread neurotropic virus. Primary infection of HSV-1 in facial epithelium leads to retrograde axonal transport to the central nervous system (CNS) where it establishes latency. Under stressful conditions, the virus reactivates, and new progeny are transported anterogradely to the primary site of infection. During the late stages of neuronal infection, axonal damage can occur, however, the impact of HSV-1 infection on the morphology and functional integrity of neuronal dendrites during the early stages of infection is unknown. We previously demonstrated that acute HSV-1 infection in neuronal cell lines selectively enhances Arc protein expression - a major regulator of long-term synaptic plasticity and memory consolidation, known for being a protein-interaction hub in the postsynaptic dendritic compartment. Thus, HSV-1 induced Arc expression may alter the functionality of infected neurons and negatively impact dendritic spine dynamics. In this study we demonstrated that HSV-1 infection induces structural disassembly and functional deregulation in cultured cortical neurons, an altered glutamate response, Arc accumulation within the somata, and decreased expression of spine scaffolding-like proteins such as PSD-95, Drebrin and CaMKIIβ. However, whether these alterations are specific to the HSV-1 infection mechanism or reflect a secondary neurodegenerative process remains to be determined.

The histone H3 lysine 9 methyltransferase G9a/GLP complex activity is required for long-term consolidation of spatial memory in mice

The G9a/G9a-like protein (GLP) histone lysine dimethyltransferase complex and downstream histone H3 lysine 9 dimethylation (H3K9me2) repressive mark have recently emerged as key transcriptional regulators of gene expression programs necessary for long-term memory (LTM) formation in the dorsal hippocampus. However, the role for hippocampal G9a/GLP complex in mediating the consolidation of spatial LTM remains largely unknown. Using a water maze competition task in which both dorsal hippocampus-dependent spatial and striatum-dependent cue navigation strategies are effective to solve the maze, we found that pharmacological inhibition of G9a/GLP activity immediately after learning disrupts long-term consolidation of previously learned spatial information in male mice, hence producing cue bias on the competition test performed 24 h later. Importantly, the inhibition of hippocampal G9a/GLP did not disrupt short-term memory retention. Immunohistochemical analyses revealed increases in global levels of permissive histone H3K9 acetylation in the dorsal hippocampus and dorsal striatum at 1 h post-training, which persisted up to 24 h in the hippocampus. Conversely, H3K9me2 levels were either unchanged in the dorsal hippocampus or transiently decreased at 15 min post-training in the dorsal striatum. Finally, the inhibition of G9a/GLP activity further increased global levels of H3K9 acetylation while decreasing H3K9me2 in the hippocampus at 1 h post-training. However, both marks returned to vehicle control levels at 24 h. Together, these findings support the possibility that G9a/GLP in the dorsal hippocampus is required for the transcriptional switch from short-term to long-term spatial memory formation.

Glyphosate-based herbicides affect behavioural patterns of the livebearer Jenynsia multidentata.

Roundup® is one of the most widely marketed glyphosate-based herbicides in the world. There are many different formulations of this brand that differ from each other in glyphosate concentration, salts and adjuvants, including surfactants, which are labelled as "inert" compounds. Several studies have shown that these formulations are highly toxic to fish, even compared with pure glyphosate. However, mechanisms underlying this toxicity are not fully understood. In this context, this study evaluated the effects of exposure to Roundup Original® (RO), Roundup Transorb® (RT), and Roundup WG® (RWG) on the behavioural patterns of the livebearer Jenynsia multidentata. This fish naturally inhabits agricultural areas in southern Brazil and Argentina where glyphosate is used extensively. In the experiment, animals were exposed to the herbicides for 96 h, at the environmentally relevant concentration of 0.5 mg/L of glyphosate. Swimming performance, anxiety, aggressiveness, long-term memory and male sexual activity were recorded. The formulation RWG negatively affected swimming performance, thigmotaxia and long-term memory consolidation. Conversely, RT reduced the sexual performance of males. These results confirm that Roundup® formulations are extremely harmful and also that they have different targets of toxicity, affecting behaviours that are essential for fish survival.

Accelerated long-term forgetting in focal epilepsy: Do interictal spikes during sleep matter?

Accelerated long-term forgetting (ALF) is a particular form of amnesia mostly encountered in focal epilepsy, particularly in temporal lobe epilepsy. This type of memory loss is characterized by an impairment of long-term consolidation of declarative memory, and its mechanisms remain poorly understood. In particular, the respective contribution of lesion, seizures, interictal epileptic discharges, and sleep is still debated. Here, we provide an overview of the relationships intertwining epilepsy, sleep, and memory consolidation and, based on recent findings from intracranial electroencephalographic recordings, we propose a model of ALF pathophysiology that integrates the differential role of interictal spikes during wakefulness and sleep. This model provides a framework to account for the different timescales at which ALF may occur.

Acute exercise following skill practice promotes motor memory consolidation in Parkinson’s disease

Acute cardiovascular exercise has shown to promote neuroplastic processes supporting the consolidation of newly acquired motor skills in healthy adults. First results suggest that this concept may be transferred to populations with motor and cognitive dysfunctions. In this context, Parkinson’s disease (PD) is highly relevant since patients demonstrate deficits in motor learning. Hence, in the present study we sought to explore the effect of a single post-practice exercise bout on motor memory consolidation in PD.For this purpose, 17 patients with PD (Hoehn and Yahr: 1 – 2.5, age: 60.1 ± 7.9 y) practiced a whole-body skill followed by either (i) a moderate-intense bout of cycling, or (ii) seated rest for a total of 30 min. The motor skill required the participants to balance on a tiltable platform (stabilometer) for 30 s. During skill practice, participants performed 15 trials followed by a retention test 1 day and 7 days later. We calculated time in balance (platform within ± 5° from horizontal) for each trial and within- and between-group differences in memory consolidation (i.e. offline learning = skill change from last acquisition block to retention tests) were analyzed.Groups revealed similar improvements during skill practice (F4,60 = 0.316, p = 0.866), but showed differences in offline learning, which were only evident after 7 days (F1,14 = 5.602, p = 0.033).Our results suggest that a single post-practice exercise bout is effective in enhancing long-term motor memory consolidation in a population with motor learning impairments. This may point at unique promoting effects of exercise on dopamine neurotransmission involved in memory formation. Future studies should investigate the potential role of exercise-induced effects on the dopaminergic system.

Exploration of a novel virtual environment improves memory consolidation in ADHD

Experimental evidence in rodents and humans suggests that long-term memory consolidation can be enhanced by the exploration of a novel environment presented during a vulnerable early phase of consolidation. This memory enhancing effect (behavioral tagging) is caused by dopaminergic and noradrenergic neuromodulation of hippocampal plasticity processes. In translation from animal to human research, we investigated whether behavioral tagging with novelty can be used to tackle memory problems observed in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). 34 patients with ADHD and 34 typically developing participants (age 9–15 years) explored either a previously familiarized or a novel virtual environment 45 min after they had learned a list of 20 words. Participants took a free recall test both immediately after learning the word list and after 24 h. Patients who explored a familiar environment showed significantly impaired memory consolidation compared to typically developing peers. Exploration of a novel environment led to significantly better memory consolidation in children and adolescents with ADHD. However, we did not observe a beneficial effect of novel environment exploration in typically developing participants. Our data rather suggested that increased exploration of a novel environment as well as higher feelings of virtual immersion compromised memory performance in typically developing children and adolescents, which was not the case for patients with ADHD. We propose that behavioral tagging with novel virtual environments is a promising candidate to overcome ADHD related memory problems. Moreover, the discrepancy between children and adolescents with and without ADHD suggests that behavioral tagging might only be able to improve memory consolidation for weakly encoded information.

A Study of the Participation of NMDA Glutamate Receptors in the Mechanisms of Specific Anterograde Amnesia Reversion

We studied the involvement of NMDA glutamate receptors in the mechanisms of anterograde amnesia. It was found that repeated training of amnestic animals treated with D-cycloserine, a potent agonist of the glycine site of NMDA receptors, did not lead to consolidation of long-term memory, while expression of short-term memory was more pronounced in comparison with control animals that received saline before repeated training. It was shown that D-cycloserine in amnestic snails did not affect the food reactions caused by the presentation of a conditioned stimulus during the reminder (without combination with the unconditioned stimulus). It is assumed that NMDA glutamate receptors in amnestic animals are involved in the neural plasticity mechanisms that underlie short-term memory, but their activation does not influence the anterograde amnesia processes and does not lead to the formation or recovery of long-term memory.

Sleep-dependent memory consolidation in children with self-limited focal epilepsies

ObjectiveChildren with self-limited focal epilepsies of childhood (SLFE) are known to show impaired memory functions, particularly in the verbal domain. Interictal epileptiform discharges (IED) in these epilepsies are more pronounced in nonrapid eye movement (NREM) sleep. Nonrapid eye movement sleep is crucial for consolidation of newly-encoded memories. Therefore, we hypothesize that sleep-dependent memory consolidation is altered in relation to IED in children with SLFE. MethodsWe conducted a prospective case–control study. We applied a verbal (word pair) and a visuospatial (two-dimensional [2D] object location) learning task, both previously shown to benefit from sleep in terms of memory consolidation. Learning took place in the evening, and retrieval was tested in the morning after a night of sleep. Electroencephalogram (EEG) was recorded across night. After sleep-stage scoring, the spike–wave index (SWI) was assessed at the beginning and the end of sleep. Fourteen patients with SLFE (age: 5.5 to 11.6 years) were compared with 15 healthy controls (age: 6.8 to 9.1 years) examined in a previous study. ResultsIn contrast to healthy controls (mean: +12.9% recalled word pairs, p = .003, standard deviation (SD) = 12.4%), patients did not show overnight performance gains in the verbal memory task (mean: +6.4% recalled word pairs, p > .05, SD = 17.3) Neither patients nor controls showed significant overnight changes in visuospatial task performance. Spike–wave index was negatively correlated with recall performance in the verbal but not in the visuospatial task. SignificanceWe found evidence for impaired overnight improvement of performance in children with SLFE in a verbal learning task, with high SWI rates predicting low recall performance. We speculate that spike–waves hamper long-term memory consolidation by interfering with NREM sleep.

Amygdala inhibitory neurons as loci for translation in emotional memories.

To survive in a dynamic environment, animals need to identify and appropriately respond to stimuli that signal danger1. Survival also depends on suppressing the threat-response during a stimulus that predicts absence of threat, i.e. safety2–5. Understanding the biological substrates of emotional memories in which animals learn to flexibly execute defensive responses to a threat-predictive cue and a safety cue is critical for developing treatments for memory disorders such as PTSD5. A key brain area for processing and storing threat memories is the centrolateral amygdala (CeL), which is an important node in the neuronal circuit mediating defensive responses6–9. Here, we applied intersectional chemogenetic strategies in CeL inhibitory neurons (INs) to block cell-type-specific translation programs that are sensitive to depletion of eukaryotic initiation factor 4E (eIF4E) and phosphorylation of eukaryotic initiation factor 2α (p-eIF2α), respectively. We show that de novo translation in CeL Somatostatin-expressing (SOM) INs is necessary for long-term storage of conditioned-threat response whereas de novo translation in CeL protein kinase Cδ (PKCδ)-expressing INs is necessary for conditioned-response inhibition to a safety cue. Our results provide new insight into the role of de novo protein synthesis in distinct CeL inhibitory neuron populations during consolidation of long-term memories.

Perinatal exposure to nicotine disrupts circadian locomotor and learning efficiency rhythms in juvenile mice.

The increased rates of nicotine exposure by electronic nicotine delivery systems (vaping), ingestion, or patches during pregnancy as an alternative to the smoking of tobacco arise concerns about the neurodevelopmental, cognitive, and behavioral long-term consequences in the juvenile offspring. Nowadays, the use of electronic cigarettes as supposed a safer smoking alternative has been increased mainly in young females at reproductive age, due to the "safety" misconception. However, previous studies suggest that exposure to nicotine during pregnancy and prenatal development may lead to detrimental effects in the postnatal lifespan. Nicotine, as an alkaloid, alters the reward system acting as acetylcholine (ACh) agonist on nicotinic cholinergic receptors (nAChRs). In early brain development, the cholinergic system is also involved in neurite outgrowth, cell survival, proliferation, differentiation, neurogenesis, and many other critical processes being considered as a developmental signal marker. The nicotine noxious effect at those early stages may impact the system programming and plasticity in the long-term postnatal life. In this study, we analyze the circadian locomotor activity and learning efficiency rhythms in the juvenile male offspring of mice exposed to nicotine through pregnancy and lactation. Attenuated rhythm amplitude and relative power of the circadian component were found in the nicotine exposed offspring (pN). The acrophase (the best performance during a 24-h cycle) of learning efficiency was delayed and the long-term memory consolidation task failed after 8days of learning experience. The aforementioned results suggest nicotine exposurein uterusmodifies the circadian modulation related to the memory consolidation and locomotor systems as well as its environmental temporal synchronization.

Dopamine is associated with prioritization of reward-associated memories in Parkinson's disease.

Patients with Parkinson's disease have reduced reward sensitivity related to dopaminergic neuron loss, which is associated with impairments in reinforcement learning. Increasingly, however, dopamine-dependent reward signals are recognized to play an important role beyond reinforcement learning. In particular, it has been shown that reward signals mediated by dopamine help guide the prioritization of events for long-term memory consolidation. Meanwhile, studies of memory in patients with Parkinson's disease have focused on overall memory capacity rather than what is versus what isn't remembered, leaving open questions about the effect of dopamine replacement on the prioritization of memories by reward and the time-dependence of this effect. The current study sought to fill this gap by testing the effect of reward and dopamine on memory in patients with Parkinson's disease. We tested the effect of dopamine modulation and reward on two forms of long-term memory: episodic memory for neutral objects and memory for stimulus-value associations. We measured both forms of memory in a single task, adapting a standard task of reinforcement learning with incidental episodic encoding events of trial-unique objects. Objects were presented on each trial at the time of feedback, which was either rewarding or not. Memory for the trial-unique images and for the stimulus-value associations, and the influence of reward on both, was tested immediately after learning and 2 days later. We measured performance in Parkinson's disease patients tested either ON or OFF their dopaminergic medications and in healthy older control subjects. We found that dopamine was associated with a selective enhancement of memory for reward-associated images, but that it did not influence overall memory capacity. Contrary to predictions, this effect did not differ between the immediate and delayed memory tests. We also found that while dopamine had an effect on reward-modulated episodic memory, there was no effect of dopamine on memory for stimulus-value associations. Our results suggest that impaired prioritization of cognitive resource allocation may contribute to the early cognitive deficits of Parkinson's disease.

Pain memory in patients with chronic pain versus asymptomatic individuals: A prospective cohort study.

The main objective of this study was to assess pain memory as well as long-term episodic memory, both in patients with chronic pain (CP) and in asymptomatic participants (AP). A prospective cohort study design was used. Sixty-eight participants were divided into two groups: CP (n=34) and AP (n=34). The protocol consisted of taking eight tests, four painful provocation tests and four distracting tests, and completing a memory test on the order of the tests at the end of the experiment and at 1-month post-experiment. Patients with CP showed acceptable concordance in the classification, in ascending order from lower to higher pain perception, both post-experiment and 1-month post-experiment (κ=0.41-0.60, p<.001). No differences were found regarding recall of the order of the tests, but differences were found in painful tests isolated only post-experiment in the CP group with a moderate effect size (p<.05, d=0.77). Patients with CP had a more reliable memory than AP in relation to the memory of the pain caused experimentally until at least 1month after the experiment. Interspersing distraction tests appeared to result in increased complexity and difficulty in coding and decoding information in patients with CP, leading to similar reliable long-term memory consolidation in comparison with AP. Treatments directed towards chronic pain should consider the influence of painful memories and their establishment towards long-term explicit episodic memories in patients with chronic pain, as well as the influence of cognitive-evaluative and affective-motivational variables on memory. Not causing pain while implementing a treatment whose objective is to reduce pain could reduce the probability of developing new painful memories in patients with chronic pain.

Drosophila as a Model to Study the Relationship Between Sleep, Plasticity, and Memory.

Humans spend nearly a third of their life sleeping, yet, despite decades of research the function of sleep still remains a mystery. Sleep has been linked with various biological systems and functions, including metabolism, immunity, the cardiovascular system, and cognitive functions. Importantly, sleep appears to be present throughout the animal kingdom suggesting that it must provide an evolutionary advantage. Among the many possible functions of sleep, the relationship between sleep, and cognition has received a lot of support. We have all experienced the negative cognitive effects associated with a night of sleep deprivation. These can include increased emotional reactivity, poor judgment, deficit in attention, impairment in learning and memory, and obviously increase in daytime sleepiness. Furthermore, many neurological diseases like Alzheimer’s disease often have a sleep disorder component. In some cases, the sleep disorder can exacerbate the progression of the neurological disease. Thus, it is clear that sleep plays an important role for many brain functions. In particular, sleep has been shown to play a positive role in the consolidation of long-term memory while sleep deprivation negatively impacts learning and memory. Importantly, sleep is a behavior that is adapted to an individual’s need and influenced by many external and internal stimuli. In addition to being an adaptive behavior, sleep can also modulate plasticity in the brain at the level of synaptic connections between neurons and neuronal plasticity influences sleep. Understanding how sleep is modulated by internal and external stimuli and how sleep can modulate memory and plasticity is a key question in neuroscience. In order to address this question, several animal models have been developed. Among them, the fruit fly Drosophila melanogaster with its unparalleled genetics has proved to be extremely valuable. In addition to sleep, Drosophila has been shown to be an excellent model to study many complex behaviors, including learning, and memory. This review describes our current knowledge of the relationship between sleep, plasticity, and memory using the fly model.

0119 The Role of Aging and Working Memory in Emotional-Long Term Memory Formation

Abstract Introduction It is widely accepted that “offline” processes during sleep contributes to memory. Working Memory (WM) capacity, which reflects “online” memory processing, is an important factor influencing cognitive functioning, which declines with age. In younger individuals, a positive association is reported between WM-capacity and declarative memory improvement. Methods We examined the relation between WM and long-term memory consolidation, among younger [N=105, 18-25yr] and older adults (N=119, 60-85yr). Subjects completed an OSPAN WM task, encoded a Word-Paired Association (WPA) task in the morning (Test1), and were tested on the WPA in the afternoon (Test2) after a 90-minute polysomnographically-recorded nap or wake. Half of the subjects were exposed to negatively valenced word-pairs (EWPA) while the other half were exposed to neutral word-pairs (NWPA). Subjects rated valence of the word-pairs at Test1 and Test2. We compared the four groups (young-EWPA, young-NWPA, old-EWPA and old-NWPA) on WM and WPA in both wake and sleep. Results In both wake and sleep, in the WPA, ageXword-condition interaction was found (p=.004). Post-hoc analysis revealed that in wake, younger-EWPA had higher performance (p=.03) than younger-NWPA, however, older-EWPA had lower performance (p=.03) than older-NWPA. Additionally, we found an ageXword-condition interaction whereby youngers showed no change in ratings, while older adults rated word-pairs more positively both in wake (p=.03) and sleep (p=.002) at Test 2. Youngers had higher WM performance (p=.007), also their WM performance was positively associated with WPA both for Neutral (p=.03) and Emotional (p=.01). WM and WPA among older adults was not related. In younger-EWPA, Stage2-sleep-minutes was positively associated to WPA improvement (p=.03) where this association was negative among older-EWPA (p=.02). In older-NWPA, Stage2-sleep-minutes was positively associated with WPA (p=.004). Conclusion Our findings indicate an association between WM and emotionally-salient memory formation that is modulated by age. Older adults, but not younger, showed the emotional bias previously reported. WM was higher in younger adults related to memory improvement. Stage2-sleep was related to memory improvement in both groups, but in opposite directions. In sum, the role of sleep in memory consolidation changes with aging and WM may play a role in this process. Support Fenn et al.,2012

Hippocampal Interictal Spikes during Sleep Impact Long-Term Memory Consolidation.

Non-rapid eye movement (NREM) sleep is supposed to play a key role in long-term memory consolidation transferring information from hippocampus to neocortex. However, sleep also activates epileptic activities in medial temporal regions. This study investigated whether interictal hippocampal spikes during sleep would impair long-term memory consolidation. We prospectively measured visual and verbal memory performance in 20 patients with epilepsy investigated with stereoelectroencephalography (SEEG) at immediate, 30-minute, and 1-week delays, and studied the correlations between interictal hippocampal spike frequency during waking and the first cycle of NREM sleep and memory performance, taking into account the number of seizures occurring during the consolidation period and other possible confounding factors, such as age and epilepsy duration. Retention of verbal memory over 1 week was negatively correlated with hippocampal spike frequency during sleep, whereas no significant correlation was found with hippocampal interictal spikes during waking. No significant result was found for visual memory. Regression tree analysis showed that the number of seizures was the first factor that impaired the verbal memory retention between 30 minutes and 1 week. When the number of seizures was below 5, spike frequency during sleep higher than 13 minutes was associated with impaired memory retention over 1 week. Our results show that activation of interictal spikes in the hippocampus during sleep and seizures specifically impair long-term memory consolidation. We hypothesize that hippocampal interictal spikes during sleep interrupt hippocampal-neocortical transfer of information. ANN NEUROL 2020;87:976-987.