Long-term Object Memory Research Articles

Maternal ingestion of cannabidiol (CBD) in mice leads to sex-dependent changes in memory, anxiety, and metabolism in the adult offspring, and causes a decrease in survival to weaning age

RationaleThe consequences of perinatal cannabidiol (CBD) exposure are severely understudied, but are important, given its widespread use and believed safety as a natural supplement. ObjectiveThe objective of this study was to test the health, metabolic, and behavioral consequences of perinatal CBD exposure on dams and their offspring raised to adult. MethodsPrimiparous female C57BL/6 J mice were orally administered 100 mg/kg CBD in strawberry jam to expose offspring during gestation, lactation, or both using a cross-fostering design. Adult offspring were metabolically profiled using indirect calorimetry and intraperitoneal glucose tolerance testing. Adults were behaviorally phenotyped, video recorded, and mouse position tracked using DeepLabCut. ResultsCBD was detected in maternal plasma using LC-MS 10-min post consumption (34.2 ± 1.7 ng/ul) and peaked within 30 min (371.0 ± 34.0 ng/ul). Fetal exposure to CBD significantly decreased survival of the pups, and decreased male postnatal development, but did not alter litter size, maternal body weight or pup birth weight. We observed many sex-dependent effects of perinatal CBD exposure. Exposure to CBD during gestation and lactation increased meal size, caloric intake, and respiratory exchange ratio for adult male offspring, while exposure during lactation decreased fasting glucose, but had no effect on clearance. Adult female offspring exposed to CBD during lactation showed increased drink size. Perinatal CBD exposure increased obsessive compulsive- and decreased anxiety-like behaviors (marble burying, light-dark box, elevated-plus maze) in female mice, decreased long-term object memory in male mice, and had no effect on attention tasks for either sex. ConclusionsWe conclude that orally-administered CBD during pregnancy affects behavior and metabolism in a sex-dependent manner, and mice are differentially sensitive to exposure during gestation vs. lactation, or both. Because long-term changes are observed following perinatal exposure to the drug, and exposure significantly decreases survival to weaning, more research during development is warranted.

N1-Acetyl-5-methoxykynuramine, which decreases in the hippocampus with aging, improves long-term memory via CaMKII/CREB phosphorylation.

Melatonin is a molecule ubiquitous in nature and involved in several physiological functions. In the brain, melatonin is converted to N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK)and then to N1-acetyl-5-methoxykynuramine (AMK),which has been reported to strongly enhance long-term object memory formation. However, the synthesis of AMK in brain tissues and the underlying mechanisms regarding memory formation remain largely unknown. In the present study, young and old individuals from a melatonin-producing strain, C3H/He mice, were employed. The amount of AMK in the pineal gland and plasma was very low compared with those of melatonin at night; conversely, in the hippocampus, the amount of AMK was higher than that of melatonin. Indoleamine 2, 3-dioxygenase (Ido) mRNA was expressed in multiple brain tissues, whereas tryptophan 2,3-dioxygenase (Tdo) mRNA was expressed only in the hippocampus, and its lysate had melatonin to AFMK conversion activity, which was blocked by the TDO inhibitor. The expression levels of phosphorylated cAMP response element binding protein (CREB)and PSD-95in whole hippocampal tissue were significantly increased with AMK treatment. Before increasing in the whole tissue, CREB phosphorylation was significantly enhanced in the nuclear fraction. In the Kyoto Encyclopedia of Genes and Genomes (KEGG)pathway analysis, we found that downregulated genes in hippocampus of old C3H/He mice were more enriched for long-term potentiation (LTP)pathway. Gene set enrichment analysis showed that LTP and neuroactive receptor interaction gene sets were enriched in hippocampus of old mice. In addition, Ido1 and Tdo mRNA expression was significantly decreased in the hippocampus of old mice compared with young mice, and the decrease in Tdo mRNA was more pronounced than Ido1. Furthermore, there was a higher decrease in AMK levels, which was less than 1/10 that of young mice, than in melatonin levels in the hippocampus of old mice. In conclusion, we first demonstrated the Tdo-related melatonin to AMK metabolism in the hippocampus and suggest a novel mechanism of AMK involved in LTP and memory formation. These results support AMK as a potential therapeutic agent to prevent memory decline.

Long-term memory for objects in real-world scenes: The effects of semantic consistency and task priorities

Long-term memory for objects in real-world scenes: The effects of semantic consistency and task priorities

A signal-detection model evaluates feature dependence in visual long-term memory for real-world objects

A signal-detection model evaluates feature dependence in visual long-term memory for real-world objects

Memory recovery through gene therapy with a single chain antibody fragment selective for Aβ oligomers in a model of Alzheimer’s disease in rats

Strong evidence supports the hypothesis that synapse damage and memory impairment in early Alzheimer disease (AD) might be due to synaptic failure caused by amyloid beta oligomers (AβOs). We demonstrated the preclinical efficacy of a single-chain variable-fragment (scFv) antibody NUsc1 that selectively targets a subpopulation of AβOs; NUsc1 prevented AβO-induced inhibition of long-term potentiation in hippocampal slices and short-term memory impairment in mice. Since specific targeting of AβOs by NUsc1 may be a substantial improvement in target engagement and efficacy for AD therapy, we developed an adeno-associated virus (AAV) vector to drive neuronal expression of NUsc1 within the brain. AAV-NUsc1 rescued short-term memory (STM) for objects and congeners interaction in mice AD models. Purpose: In heterozygous McGill-R-Thy1-APP transgenic (Tg+/–) rat model of AD, progressive amyloid pathology is accompanied by cognitive impairment involving long-term memory (LTM) decline. LTM in a novel-object-recognition (NOR) task was impaired in 4-month-old (Tg+/–) male rats, suggesting that they are unable to form/evoke such discriminative memories. Hence, we investigated if AAV-NUsc1 treatment could rescued this memory. Methods: 10-12 weeks-old either Tg or wild type male rats were i.c.v. infused with AAV-NUsc1. Two months later, short-term exploratory behavior, habituation to an open field (OF), object discrimination and LTM for objects were assessed. Results: AAV-NUsc1 treated Tg rats were able to successfully perform the task 24 h after training, denoting recovery of LT discrimination capacity and LTM formation. Wild type rats successfully performed the task either treated or not with AAV-NUsc1. Also, exploration and short-term habituation to an open field was preserved in Tg+/– rats either treated or not. Conclusions: Our present and previous results suggest that AAV-NUsc1 represents a significant advance in gene therapy, supporting the feasibility of immunotherapy using viral vector-mediated NUsc1 gene delivery as a potential therapeutic approach in AD.

Single cannabidiol administration affects anxiety-, obsessive compulsive-, object memory-, and attention-like behaviors in mice in a sex and concentration dependent manner

RationaleThe behavioral effects of cannabidiol (CBD) are understudied, but are important, given its therapeutic potential and widespread use as a natural supplement. ObjectiveThe objective of this study was to test whether a single injection of CBD affected anxiety-like or attention-like behavior, or memory in wildtype mice or mice with reported trait anxiety due to a targeted gene-deletion in a voltage-dependent potassium channel, Kv1.3. MethodsWildtype C57BL/6 J and Kv1.3−/− mice of both sexes were reared to adulthood and then administered an intraperitoneal injection of 10 or 20 mg/kg CBD. Mice were behaviorally-phenotyped using the marble-burying test, the light-dark box (LDB), short (1 h) and long-term (24 h) object memory test, the elevated-plus maze (EPM), and the object-based attention task in order to assess obsessive compulsive-, anxiety-, and attention-like behaviors, and memory. ResultsWe discovered that acute CBD treatment reduced marble burying in male, but not female mice. CBD was effective in lessening anxiety-like behaviors determined by the LDB test in both male and female wildtype mice, whereby the effective dose required to observe the effect in females was less. In Kv1.3−/− mice, CBD increased anxiety-like behaviors in the LDB in both sexes at the higher concentration of CBD and it similarly increased anxiety-like behavior in females in the EPM at the lower concentration of CBD. Long-term object memory was reduced in male wildtype mice at the lower concentration of CBD. Finally, ADHD- or attention-like behaviors were not altered by CBD in wildtype mice, but in Kv1.3−/− mice, females were observed to have a loss in attention while males demonstrated improved attention. ConclusionsWe conclude that administration of a single dose of CBD has immediate effects on mouse behavior that is dose, sex, and anxiety-state dependent – and that these behavioral outcomes are important to examine in parallel human trials.

Hippocampal oxytocin is involved in spatial memory and synaptic plasticity deficits following acute high-fat diet intake in juvenile rats.

The hippocampus undergoes maturation during juvenility, a period of increased vulnerability to environmental challenges. We recently found that acute high-fat diet (HFD) impaired hippocampal long-term potentiation (LTP) and hippocampal-dependent spatial memory. We also recently reported that similar HFD exposure affected prefrontal plasticity and social memory through decreased oxytocin levels in the prefrontal cortex. In the present study, we therefore evaluated whether hippocampal oxytocin levels are also affected by juvenile HFD and could mediate deficits of hippocampal LTP and spatial memory. We found that postweaning HFD decreased oxytocin levels in the CA1 of the dorsal hippocampus. Interestingly, systemic injection of high, but not low, dose of oxytocin rescued HFD-induced LTP impairment in CA1. Moreover, deficits in long-term object location memory (OLM) were prevented by systemic injection of both high and low dose of oxytocin as well as by intra-CA1 infusion of oxytocin receptor agonist. Finally, we found that blocking oxytocin receptors in CA1 impaired long-term OLM in control-fed juvenile rats. These results suggest that acute HFD intake lowers oxytocin levels in the CA1 that lead to CA1 plasticity impairment and spatial memory deficits in juveniles. Further, these results provide the first evidence for the regulatory role of oxytocin in spatial memory.

Two distinct ways to form long-term object recognition memory during sleep and wakefulness

Memory consolidation is promoted by sleep. However, there is also evidence for consolidation into long-term memory during wakefulness via processes that preferentially affect nonhippocampal representations. We compared, in rats, the effects of 2-h postencoding periods of sleep and wakefulness on the formation of long-term memory for objects and their associated environmental contexts. We employed a novel-object recognition (NOR) task, using object exploration and exploratory rearing as behavioral indicators of these memories. Remote recall testing (after 1 wk) confirmed significant long-term NOR memory under both conditions, with NOR memory after sleep predicted by the occurrence of EEG spindle-slow oscillation coupling. Rats in the sleep group decreased their exploratory rearing at recall testing, revealing successful recall of the environmental context. By contrast, rats that stayed awake after encoding showed equally high levels of rearing upon remote testing as during encoding, indicating that context memory was lost. Disruption of hippocampal function during the postencoding interval (by muscimol administration) suppressed long-term NOR memory together with context memory formation when animals slept, but enhanced NOR memory when they were awake during this interval. Testing remote recall in a context different from that during encoding impaired NOR memory in the sleep condition, while exploratory rearing was increased. By contrast, NOR memory in the wake rats was preserved and actually superior to that after sleep. Our findings indicate two distinct modes of long-term memory formation: Sleep consolidation is hippocampus dependent and implicates event-context binding, whereas wake consolidation is impaired by hippocampal activation and strengthens context-independent representations.

Effects of Post-natal Dietary Milk Fat Globule Membrane Polar Lipid Supplementation on Motor Skills, Anxiety, and Long-Term Memory in Adulthood.

Early life nutrition critically impacts post-natal brain maturation and cognitive development. Post-natal dietary deficits in specific nutrients, such as lipids, minerals or vitamins are associated with brain maturation and cognitive impairments. Specifically, polar lipids (PL), such as sphingolipids and phospholipids, are important cellular membrane building blocks and are critical for brain connectivity due to their role in neurite outgrowth, synaptic formation, and myelination. In this preclinical study, we assessed the effects of a chronic supplementation with a source of PL extracted from an alpha-lactalbumin enriched whey protein containing 10% lipids from early life (post-natal day (PND) 7) to adulthood (PND 72) on adult motor skills, anxiety, and long-term memory. The motor skills were assessed using open field and rotarod test. Anxiety was assessed using elevated plus maze (EPM). Long-term object and spatial memory were assessed using novel object recognition (NOR) and Morris water maze (MWM). Our results suggest that chronic PL supplementation improved measures of spatial long-term memory accuracy and cognitive flexibility in the MWM in adulthood, with no change in general mobility, anxiety and exploratory behavior. Our results indicate memory specific functional benefits of long-term dietary PL during post-natal brain development.

The Black Box effect: sensory stimulation after learning interferes with the retention of long-term object location memory in rats

Reducing sensory experiences during the period that immediately follows learning improves long-term memory retention in healthy humans, and even preserves memory in patients with amnesia. To date, it is entirely unclear why this is the case, and identifying the neurobiological mechanisms underpinning this effect requires suitable animal models, which are currently lacking. Here, we describe a straightforward experimental procedure in rats that future studies can use to directly address this issue. Using this method, we replicated the central findings on quiet wakefulness obtained in humans: We show that rats that spent 1 h alone in a familiar dark and quiet chamber (the Black Box) after exploring two objects in an open field expressed long-term memory for the object locations 6 h later, while rats that instead directly went back into their home cage with their cage mates did not. We discovered that both visual stimulation and being together with conspecifics contributed to the memory loss in the home cage, as exposing rats either to light or to a cage mate in the Black Box was sufficient to disrupt memory for object locations. Our results suggest that in both rats and humans, everyday sensory experiences that normally follow learning in natural settings can interfere with processes that promote long-term memory retention, thereby causing forgetting in form of retroactive interference. The processes involved in this effect are not sleep-dependent because we prevented sleep in periods of reduced sensory experience. Our findings, which also have implications for research practices, describe a potentially useful method to study the neurobiological mechanisms that might explain why normal sensory processing after learning impairs memory both in healthy humans and in patients suffering from amnesia.

Investigation of the relationship between visual feature binding in short- and long-term memory in healthy aging.

Binding visual features into coherent object representations is essential both in short- and long-term memory. However, the relationship between feature binding processes at different memory delays remains unexplored. Here, we addressed this question by using the Mnemonic Similarity Task and a delayed-estimation working memory task on a large sample of older adults. The results revealed that higher propensity to misbind object features in working memory is associated with lower lure discrimination performance in the mnemonic similarity task, suggesting that shared feature binding processes underlie the formation of coherent short- and long-term visual object memory representations.

Neutral ceramidase is a marker for cognitive performance in rats and monkeys

BackgroundCeramides are lipid molecules determining cell integrity and intercellular signaling, and thus, involved in the pathogenesis of several psychiatric and neurodegenerative disorders. However, little is known about the role of particular enzymes of the ceramide metabolism in the mechanisms of normal behavioral plasticity. Here, we studied the contribution of neutral ceramidase (NC), one of the main enzymes mediating ceramide degradation, in the mechanisms of learning and memory in rats and non-human primates.MethodsNaïve Wistar rats and black tufted-ear marmosets (Callithrix penicillata) were tested in several tests for short- and long-term memory and then divided into groups with various memory performance. The activities of NC and acid ceramidase (AC) were measured in these animals. Additionally, anxiety and depression-like behavior and brain levels of monoamines were assessed in the rats.ResultsWe observed a predictive role of NC activity in the blood serum for superior performance of long-term object memory tasks in both species. A brain area analysis suggested that high NC activity in the ventral mesencephalon (VM) predicts better short-term memory performance in rats. High NC activity in the VM was also associated with worse long-term object memory, which might be mediated by an enhanced depression-like state and a monoaminergic imbalance.ConclusionsAltogether, these data suggest a role for NC in short- and long-term memory of various mammalian species. Serum activity of NC may possess a predictive role in the assessing the performance of certain types of memory.

The Influence of Poststudy Action Congruency on Memory Consolidation.

. The actions associated with objects are thought to be automatically activated when processing object names. Recent studies, however, have failed to find evidence for a role of the motor system in long-term memory for objects. One exception is a study by van Dam et al. (2013) in which participants studied object names associated with pressing (e.g., doorbell) or twisting (e.g., jar), followed by pressing or twisting actions in a seemingly unrelated task. In the final memory test, performance for action congruent words was better than for action incongruent words. We aimed to generalize these findings. In Experiments 1 and 2, we found no effect of action congruency on repetition priming in lexical decision and man-made/natural decision. In Experiment 3, the action congruency manipulation was administered immediately after initial study or a day later, just prior to the recognition memory test. We found no effects of action congruency and timing of the action. Finally, Experiment 4 was a direct replication of Experiment 1 of van Dam et al. (2013). Again, we failed to find an effect of poststudy action congruency. Thus, we obtained no evidence for the view that motor actions play a role in long-term memory for objects.

β-Lactolin, a Whey-Derived Lacto-Tetrapeptide, Prevents Alzheimer's Disease Pathologies and Cognitive Decline.

The prevention of age-related memory decline and dementia has been becoming a high priority because of the rapid growth in aging populations. Accumulating epidemiological and clinical studies indicate that intake of fermented dairy products rich in β-lactolin improves memory retrieval and executive function and attenuates cognitive decline in the elderly. However, the effects of long-term consumption of β-lactolin on Alzheimer’s disease (AD) pathologies have not been investigated. In the present study, we examined the effects of β-lactolin and whey digestion rich in β-lactolin on AD pathology in 5×FAD transgenic mice and PS19 tauopathy mice. Intake of β-lactolin and whey digestion rich in β-lactolin reduced the levels of inflammatory cytokines, suppressed the infiltration of activated microglia, decreased the levels of amyloid-β, ameliorated impaired long-term object memory, and attenuated decreased synaptophysin, dopamine, brain-derived neurotrophic factor, and insulin-like growth factor 1 levels in the cortex in 5×FAD transgenic mice. In addition, intake of β-lactolin and whey digestion rich in β-lactolin improved behavioral abnormality and reduced the ratio of phosphorylated tau to total tau in the cortex in PS19 tauopathy mice. These findings indicate that consumption with β-lactolin and whey digestion rich in β-lactolin suppresses inflammation and attenuates AD pathology and cognitive impairment.

Rolipram treatment during consolidation ameliorates long-term object location memory in aged male mice

Normal aging is accompanied by cognitive and memory impairments that negatively impact quality of life for the growing elderly population. Hippocampal function is most vulnerable to the deleterious effects of aging, and deficits in hippocampus-dependent memories are common amongst aged individuals. Moreover, signaling networks such as the cAMP/PKA/CREB pathway, which are critical for memory consolidation, are dampened in healthy aged subjects. Phosphodiesterase (PDE) enzymes that break down cAMP are also affected by aging, and increased break down of cAMP by PDEs may contribute to reduced activity of the cAMP/PKA/CREB signaling network in the brain of aged individuals. Here, we report that the PDE4 inhibitor rolipram administered during consolidation of hippocampus-dependent object location memory improves aged-related spatial memory deficits in aged mice.

Exercise opens a temporal window for enhanced cognitive improvement from subsequent physical activity.

The beneficial effects of exercise on cognition are well established; however specific exercise parameters regarding the frequency and duration of physical activity that provide optimal cognitive health have not been well defined. Here, we explore the effects of the duration of exercise and sedentary periods on long-term object location memory (OLM) in mice. We use a weak object location training paradigm that is subthreshold for long-term memory formation in sedentary controls, and demonstrate that exercise enables long-term memories to form. We show that 14- and 21-d of running wheel access enables mice to discriminate between familiar and novel object locations after a 24 h delay, while 2- or 7-d running wheel access provides insufficient exercise for such memory enhancement using the subthreshold learning paradigm. After 14- and 21-d of wheel running, exercise-induced cognitive enhancement then decays back to baseline performance following 3-d of sedentary activity. However, exercise-induced cognitive enhancement can be reactivated by an additional period of just 2 d exercise, previously shown to be insufficient to induce cognitive enhancement on its own. The reactivating period of exercise is capable of enhancing memory after three- or seven-sedentary days, but not 14-d. These data suggest a type of “molecular memory” for the exercise stimulus, in that once exercise duration reaches a certain threshold, it establishes a temporal window during which subsequent low-level exercise can capitalize on the neurobiological adaptations induced by the initial period of exercise, enabling it to maintain the benefits on cognitive function. These findings provide new information that may help to guide future clinical studies in exercise.

Central Histamine Boosts Perirhinal Cortex Activity and Restores Forgotten Object Memories

BackgroundA method that promotes the retrieval of lost long-term memories has not been well established. Histamine in the central nervous system is implicated in learning and memory, and treatment with antihistamines impairs learning and memory. Because histamine H3 receptor inverse agonists upregulate histamine release, the inverse agonists may enhance learning and memory. However, whether the inverse agonists promote the retrieval of forgotten long-term memory has not yet been determined. MethodsHere, we employed multidisciplinary methods, including mouse behavior, calcium imaging, and chemogenetic manipulation, to examine whether and how the histamine H3 receptor inverse agonists, thioperamide and betahistine, promote the retrieval of a forgotten long-term object memory in mice. In addition, we conducted a randomized double-blind, placebo-controlled crossover trial in healthy adult participants to investigate whether betahistine treatment promotes memory retrieval in humans. ResultsThe treatment of H3 receptor inverse agonists induced the recall of forgotten memories even 1 week and 1 month after training in mice. The memory recovery was mediated by the disinhibition of histamine release in the perirhinal cortex, which activated the histamine H2 receptor. Histamine depolarized perirhinal cortex neurons, enhanced their spontaneous activity, and facilitated the reactivation of behaviorally activated neuronal ensembles. A human clinical trial revealed that treatment of H3 receptor inverse agonists is specifically more effective for items that are more difficult to remember and subjects with poorer performance. ConclusionsThese results highlight a novel interaction between the central histamine signaling and memory engrams.

Sucrose or sucrose and caffeine differentially impact memory and anxiety-like behaviours, and alter hippocampal parvalbumin and doublecortin

Caffeinated sugar-sweetened "energy" drinks are a subset of soft drinks that are popular among young people worldwide. High sucrose diets impair cognition and alter aspects of emotional behaviour in rats, however, little is known about sucrose combined with caffeine. Rats were allocated to 2 h/day 10% sucrose (Suc), 10% sucrose plus 0.04% caffeine (CafSuc) or control (water) conditions. The addition of caffeine to sucrose appeared to increase the rewarding aspect of sucrose, as the CafSuc group consumed more solution than the Suc group. After 14 days of intermittent Suc or CafSuc access, anxiety was assessed in the elevated plus maze (EPM) prior to their daily solution access, whereby CafSuc and Suc rats spent more time in the closed arms, indicative of increased anxiety. Following daily solution access, CafSuc, but not Suc, rats showed reduced anxiety-like behaviour in the open-field. Control and CafSuc rats displayed intact place and long-term object memory, while Suc showed impaired memory performance. Sucrose reduced parvalbumin immunoreactivity in the hippocampus, but no differences were observed between Control and CafSuc conditions. Parvalbumin reactivity in the basolateral amygdala did not differ between conditions. Reduced doublecortin immunoreactivity in the dentate gyrus relative to controls was seen in the CafSuc, but not Suc, treatment conditions. These findings indicate that the addition of caffeine to sucrose attenuated cognitive deficits. However, the addition of caffeine to sucrose evoked anxiety-like responses under certain testing conditions, suggesting that frequent consumption of caffeinated energy drinks may promote emotional alterations and brain changes compared to standard soft drinks.

Face processing skills predict faithfulness of portraits drawn by novices.

Individuals show astonishing variability in their face recognition abilities, and the causes and consequences of this heterogeneity are unclear. Special expertise with faces, for example in portraitists, is associated with advantages on face processing tasks, especially those involving perceptual abilities. Do face processing skills improve through practice, or does drawing skill reflect pre-existing individual differences? If the latter, then the association between face processing skills and production of faithful portraits should also exist in people without practice in drawing. Two exploratory studies and one follow-up confirmatory study provide support for this hypothesis. Drawing ability of novices was predicted by their performance on face recognition tasks involving perceptual discrimination and visual short-term memory, but not by those that rely more heavily on long-term memory or memory for non-face objects. By examining non-experts, we show that expertise with faces might build upon pre-existing individual differences in face processing skills.

Effects of grasp compatibility on long-term memory for objects

Previous studies have shown action potentiation during conceptual processing of manipulable objects. In four experiments, we investigated whether these motor actions also play a role in long-term memory. Participants categorized objects that afforded either a power grasp or a precision grasp as natural or artifact by grasping cylinders with either a power grasp or a precision grasp. In all experiments, responses were faster when the affordance of the object was compatible with the type of grasp response. However, subsequent free recall and recognition memory tasks revealed no better memory for object pictures and object names for which the grasp affordance was compatible with the grasp response. The present results therefore do not support the hypothesis that motor actions play a role in long-term memory.