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Background: The mutually beneficial coevolutionary relationships between rodents and plant seeds have been a theme of research in plant-animal relationships. Seed tannins are important secondary metabolites of plants that regulate the food-hoarding behavior of rodents; however, the underlying molecular mechanisms are not yet clear. In this study, we investigated whether and how seed tannins improve spatial memory and regulate the hoarding behavior of Tamias sibiricus by altering their gut microbiota., Results: We showed that acorn tannins not only improved spatial memory but also enhanced scatter-hoarding in T. sibiricus. Changes in the composition and function of the gut microbiota in response to tannins from acorns are closely related to these improvements. Metabonomic analyses revealed the role of gut isovaleric acid and isobutyric acid as well as serum L-tryptophan in mediating the spatial memory of T. sibiricus via the gut microbiota. The hippocampal proteome provides further evidence that the microbiota-gut-brain axis regulates spatial memory and scatter-hoarding in animals. Our study is likely the first to report that plant secondary metabolites improve hippocampal function and spatial memory and ultimately modulate food-hoarding behavior via the microbiota-gut-brain axis., Conclusion: Our findings may have resolved the long-standing puzzle about the hidden role of plant secondary metabolites in manipulating food-hoarding behavior in rodents via the microbiota-gut-brain axis. Our study is important for better understanding the mutualistic coevolution between plants and animals. Video Abstract., (© 2024. The Author(s).)

Most research on visual search has used simple tasks presented on a computer screen. However, in natural situations visual search almost always involves eye, head, and body movements in a three-dimensional (3D) environment. The different constraints imposed by these two types of search tasks might explain some of the discrepancies in our understanding concerning the use of memory resources and the role of contextual objects during search. To explore this issue, we analyzed a visual search task performed in an immersive virtual reality apartment. Participants searched for a series of geometric 3D objects while eye movements and head coordinates were recorded. Participants explored the apartment to locate target objects whose location and visibility were manipulated. For objects with reliable locations, we found that repeated searches led to a decrease in search time and number of fixations and to a reduction of errors. Searching for those objects that had been visible in previous trials but were only tested at the end of the experiment was also easier than finding objects for the first time, indicating incidental learning of context. More importantly, we found that body movements showed changes that reflected memory for target location: trajectories were shorter and movement velocities were higher, but only for those objects that had been searched for multiple times. We conclude that memory of 3D space and target location is a critical component of visual search and also modifies movement kinematics. In natural search, memory is used to optimize movement control and reduce energetic costs.

Glutamate is involved in fundamental functions, including neuronal plasticity and memory. Astrocytes are integral elements involved in synaptic function, and the GLT-1 transporter possesses a critical role in glutamate uptake. Here, we study the role of GLT-1, specifically located in astrocytes, in the consolidation, expression, reconsolidation and persistence of spatial object recognition memory in rats. Administration of dihydrokainic acid (DHK), a selective GLT-1 inhibitor, into the dorsal hippocampus around a weak training which only induces short-term memory, promotes long-term memory formation. This promotion is prevented by hippocampal administration of protein-synthesis translation inhibitor, blockade of Activity-regulated cytoskeleton-associated protein (Arc) translation or Brain-Derived Neurotrophic Factor (BDNF) action, which are plasticity related proteins necessary for memory consolidation. However, DHK around a strong training, which induces long-term memory, does not affect memory consolidation. Administration of DHK before the test session impairs the expression of long-term memory, and this effect is dependent of Arc translation. Furthermore, DHK impairs reconsolidation if applied before a reactivation session, and this effect is independent of Arc translation. These findings reveal specific consequences on spatial memory stages developed under hippocampal GLT-1 blockade, shedding light on the intricate molecular mechanisms, governed in part for the action of glia., (© 2024. The Author(s).)

Background: Patients with breast cancer (BC) exhibit circadian rhythm disruptions, mainly of rest-activity rhythm (RAR), of which sleep is an essential component, and cortisol rhythm. Sleep complaints such as insomnia and cognitive impairments are prevalent in BC. In general population, sleep is known to contribute greatly to cognition. Thus, improving RAR (and particularly sleep) could help limiting cognitive impairments in BC patients. It has recently been suggested that, in addition to its essential role in spatial memory, the vestibular system contributes to RAR synchronization. Its stimulation could therefore limit both sleep disturbances and spatial memory deficits in BC., Objectives: The main aim of the ICANSLEEP-2 study is to assess the effects of galvanic vestibular stimulation (GVS) on circadian rhythms. The secondary aim is to assess whether GVS improves sleep and spatial memory in BC patients., Methods: Two groups with insomnia complaints (Insomnia Severity Index > 7) will be included: a patients' group with BC (n = 50) and a healthy control group without history of cancer (n = 25). There will be two assessment sessions, before and after 2 weeks of GVS. Patients will be randomly assigned to either a GVS group or a sham group (noneffective stimulation). Controls will receive GVS. GVS effects will be quantified and compared between groups. Assessments will include actigraphy, salivary cortisol, polysomnography, a cognitive test battery (including a computer-based task for spatial memory) and validated questionnaires (for psychological functioning and sleep complaints)., Discussion: Current methods for improving sleep in BC have had controversial outcomes regarding sleep structure. We expect GVS to offer a new mean of directly targeting RAR disruptions in BC patients, with beneficial effects on sleep structure. Given the crucial impact of sleep on cognitive functioning, notably spatial memory, improving sleep of BC patients should enhance their cognitive functioning., Ethics and Dissemination: This study received ethical approval from the Ile de France IV institutional review board on 19 April 2022 (no. ID-RCB: 2022-A00437-36). The findings yielded by this protocol will be presented at various conferences and in peer-reviewed journals., Clinicaltrials.gov Registration Number: NCT05414357., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Galin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Brain pathological changes impair cognition early in disease etiology. There is an urgent need to understand aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2 is a mitochondrial-resident protein regulating Ca 2+ fluxes to and from mitochondria impacting overall health. We previously reported that Tusc2 female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, -/- female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2 -/- female mice demonstrated a pro-inflammatory increase in astrocytes, expression of IFN-γ in CD4 + T cells and Granzyme-B in CD8 + T cells. We also found fewer FOXP3 + T-regulatory cells and Ly49G + NK and Ly49G + NKT cells in female Tusc2 -/- brains, suggesting a dampened anti-inflammatory response. Moreover, Tusc2 -/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca 2+ dynamics. Overall, the data suggest that dysregulation of Ca 2+ -dependent processes and a heightened pro-inflammatory brain microenvironment in Tusc2 -/- mice could underlie cognitive impairment. Thus, strategies to modulate the mitochondrial Tusc2- and Ca 2+ - signaling pathways in the brain should be explored to improve cognitive health.

Background: Impaired mitochondrial dynamics have been identified as a significant contributing factor to reduced neurogenesis under pathological conditions. However, the relationship among mitochondrial dynamics, neurogenesis, and spatial memory during normal development remains unclear. This study aims to elucidate the role of mitophagy in spatial memory mediated by neurogenesis during development., Methods: Adolescent and adult male mice were used to assess spatial memory performance. Immunofluorescence staining was employed to evaluate levels of neurogenesis, and mitochondrial dynamics were assessed through western blotting and transmission electron microscopy. Pharmacological interventions further validated the causal relationship among mitophagy, neurogenesis, and behavioral performance during development., Results: The study revealed differences in spatial memory between adolescent and adult mice. Diminished neurogenesis, accompanied by reduced mitophagy, was observed in the hippocampus of adult mice compared to adolescent subjects. Pharmacological induction of mitophagy in adult mice with UMI-77 resulted in enhanced neurogenesis and prolonged spatial memory retention. Conversely, inhibition of mitophagy with Mdivi-1 in adolescent mice led to reduced hippocampal neurogenesis and impaired spatial memory., Conclusion: The observed decline in spatial memory in adult mice is associated with decreased mitophagy, which affects neurogenesis in the dentate gyrus. This underscores the therapeutic potential of enhancing mitophagy to counteract age- or disease-related cognitive decline., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

In their natural environment, animals face a variety of ecological and social challenges, which might be linked to the emergence of different cognitive skills. To assess inter-specific variation in cognitive skills, we used ungulates as a study model, testing a total of 26 captive individuals across 5 different species (i.e., dwarf goats, Capra aegagrus hircus, llamas, Lama glama, guanacos, Lama guanicoe, zebras, Equus grevyi, and rhinos, Diceros bicornis michaeli). Across species, we used the same well-established experimental procedures to test individuals' performance in naïve physics tasks, i.e. object permanence, short-term spatial memory, causality, understanding of object properties, and gravity. Our results revealed that study subjects showed object permanence, were able to remember the position of hidden food after up to 60 s, and inferred the position of hidden food from the sound produced or not produced when shaking containers. Moreover, they showed an understanding of basic object properties, being able to locate objects hidden behind occluders based on their size and inclination, and could reliably follow the trajectory of falling objects across different conditions. Finally, inter-specific differences were limited to the understanding of object properties, and suggest that domesticated species as goats might perform better than non-domesticated ones in tasks requiring these skills. These results provide new information on the cognitive skills of a still understudied taxon and confirm ungulates as a promising taxon for the comparative study of cognitive evolution., (© 2024. The Author(s).)

Aims: Synaptic dysfunction is a hallmark pathology of Alzheimer's disease (AD) and is strongly associated with cognitive impairment. Abnormal phagocytosis by the microglia is one of the main causes of synapse loss in AD. Previous studies have shown that the absence of melanoma 2 (AIM2) inflammasome activity is increased in the hippocampus of APP/PS1 mice, but the role of AIM2 in AD remains unclear., Methods: Injection of Aβ 1-42 into the bilateral hippocampal CA1 was used to mimic an AD mouse model (AD mice). C57BL/6 mice injected with AIM2 overexpression lentivirus and conditional knockout of microglial AIM2 mice were used to confirm the function of AIM2 in AD. Cognitive functions were assessed with novel object recognition and Morris water maze tests. The protein and mRNA expression levels were evaluated by western blotting, immunofluorescence staining, and qRT-PCR. Synaptic structure and function were detected by Golgi staining and electrophysiology., Results: The expression level of AIM2 was increased in AD mice, and overexpression of AIM2 induced synaptic and cognitive impairments in C57BL/6 mice, similar to AD mice. Elevated expression levels of AIM2 occurred in microglia in AD mice. Conditional knockout of microglial AIM2 rescued cognitive and synaptic dysfunction in AD mice. Excessive microglial phagocytosis activity of synapses was decreased after knockout of microglial AIM2, which was associated with inhibiting complement activation., Conclusion: Our results demonstrated that microglial AIM2 plays a critical role in regulating synaptic plasticity and memory deficits associated with AD, providing a new direction for developing novel preventative and therapeutic interventions for this disease., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Abstract Background The mutually beneficial coevolutionary relationships between rodents and plant seeds have been a theme of research in plant-animal relationships. Seed tannins are important secondary metabolites of plants that regulate the food-hoarding behavior of rodents; however, the underlying molecular mechanisms are not yet clear. In this study, we investigated whether and how seed tannins improve spatial memory and regulate the hoarding behavior of Tamias sibiricus by altering their gut microbiota. Results We showed that acorn tannins not only improved spatial memory but also enhanced scatter-hoarding in T. sibiricus. Changes in the composition and function of the gut microbiota in response to tannins from acorns are closely related to these improvements. Metabonomic analyses revealed the role of gut isovaleric acid and isobutyric acid as well as serum L-tryptophan in mediating the spatial memory of T. sibiricus via the gut microbiota. The hippocampal proteome provides further evidence that the microbiota-gut-brain axis regulates spatial memory and scatter-hoarding in animals. Our study is likely the first to report that plant secondary metabolites improve hippocampal function and spatial memory and ultimately modulate food-hoarding behavior via the microbiota-gut-brain axis. Conclusion Our findings may have resolved the long-standing puzzle about the hidden role of plant secondary metabolites in manipulating food-hoarding behavior in rodents via the microbiota-gut-brain axis. Our study is important for better understanding the mutualistic coevolution between plants and animals. Video Abstract

The medial entorhinal cortex (MEC) is hypothesized to function as a cognitive map for memory-guided navigation. How this map develops during learning and influences memory remains unclear. By imaging MEC calcium dynamics while mice successfully learned a novel virtual environment over ten days, we discovered that the dynamics gradually became more spatially consistent and then stabilized. Additionally, grid cells in the MEC not only exhibited improved spatial tuning consistency, but also maintained stable phase relationships, suggesting a network mechanism involving synaptic plasticity and rigid recurrent connectivity to shape grid cell activity during learning. Increased c-Fos expression in the MEC in novel environments further supports the induction of synaptic plasticity. Unsuccessful learning lacked these activity features, indicating that a consistent map is specific for effective spatial memory. Finally, optogenetically disrupting spatial consistency of the map impaired memory-guided navigation in a well-learned environment. Thus, we demonstrate that the establishment of a spatially consistent MEC map across learning both correlates with, and is necessary for, successful spatial memory., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Storing and accessing memories is required to successfully perform day-to-day tasks, for example for engaging in a meaningful conversation. Previous studies in both rodents and primates have correlated hippocampal cellular activity with behavioral expression of memory. A key role has been attributed to awake hippocampal replay - a sequential reactivation of neurons representing a trajectory through space. However, it is unclear if awake replay impacts immediate future behavior, gradually creates and stabilizes long-term memories over a long period of time (hours and longer), or enables the temporary memorization of relevant events at an intermediate time scale (seconds to minutes). In this study, we aimed to address the uncertainty around the timeframe of impact of awake replay by collecting causal evidence from behaving rats. We detected and disrupted sharp wave ripples (SWRs) - signatures of putative replay events - using electrical stimulation of the ventral hippocampal commissure in rats that were trained on three different spatial memory tasks. In each task, rats were required to memorize a new set of locations in each trial or each daily session. Interestingly, the rats performed equally well with or without SWR disruptions. These data suggest that awake SWRs - and potentially replay - does not affect the immediate behavior nor the temporary memorization of relevant events at a short timescale that are required to successfully perform the spatial tasks. Based on these results, we hypothesize that the impact of awake replay on memory and behavior is long-term and cumulative over time., Competing Interests: LD, FK No competing interests declared, (© 2024, Deceuninck and Kloosterman.)

Widespread release of norepinephrine (NE) throughout the forebrain fosters learning and memory via adrenergic receptor (AR) signaling, but the molecular mechanisms are largely unknown. The β2 AR and its downstream effectors, the trimeric stimulatory Gs-protein, adenylyl cyclase (AC), and the cAMP-dependent protein kinase A (PKA), form a unique signaling complex with the L-type Ca2+ channel (LTCC) CaV1.2. Phosphorylation of CaV1.2 by PKA on Ser1928 is required for the upregulation of Ca2+ influx on β2 AR stimulation and long-term potentiation induced by prolonged theta-tetanus (PTT-LTP) but not LTP induced by two 1-s-long 100-Hz tetani. However, the function of Ser1928 phosphorylation in vivo is unknown. Here, we show that S1928A knock-in (KI) mice of both sexes, which lack PTT-LTP, express deficiencies during initial consolidation of spatial memory. Especially striking is the effect of this mutation on cognitive flexibility as tested by reversal learning. Mechanistically, long-term depression (LTD) has been implicated in reversal learning. It is abrogated in male and female S1928A knock-in mice and by β2 AR antagonists and peptides that displace β2 AR from CaV1.2. This work identifies CaV1.2 as a critical molecular locus that regulates synaptic plasticity, spatial memory and its reversal, and LTD.SIGNIFICANCE STATEMENT We show that phosphorylation of the Ca2+ channel CaV1.2 on Ser1928 is important for consolidation of spatial memory and especially its reversal, and long-term depression (LTD). Identification of Ser1928 as critical for LTD and reversal learning supports the model that LTD underlies flexibility of reference memory.

Physical exercise studies are generally underrepresented in young adulthood. Seventeen subjects were randomized into an intervention group (24.2 ± 3.9 years; 3 trainings/week) and 10 subjects into a passive control group (23.7 ± 4.2 years), over a duration of 6 months. Every two months, performance diagnostics, computerized spatial memory tests, and 3 Tesla magnetic resonance imaging were conducted. Here we find that the intervention group, compared to controls, showed increased cardiorespiratory fitness, spatial memory performance and subregional hippocampal volumes over time. Time-by-condition interactions occurred in right cornu ammonis 4 body and (trend only) dentate gyrus, left hippocampal tail and left subiculum. Increases in spatial memory performance correlated with hippocampal body volume changes and, subregionally, with left subicular volume changes. In conclusion, findings support earlier reports of exercise-induced subregional hippocampal volume changes. Such exercise-related plasticity may not only be of interest for young adults with clinical disorders of hippocampal function, but also for sedentary normal cohorts., (© 2024. The Author(s).)

Previous research has demonstrated that 40-Hz audiovisual stimulation can improve pathological conditions and promote cognitive function in mouse models of Alzheimer's disease. However, limited research has been conducted on humans, and the results have been inconsistent. In our study, we divided participants into an experimental group and a control group to investigate whether 40-Hz stimulation could enhance performance in visual threshold tasks and working memory task. In Experiment 1, we used a light bulb as the stimulus source and found a general practice effect, but no difference between the groups. In Experiment 2, we used a computer screen as the stimulus source and set the stimulation frequency to 48 Hz. In Experiment 3 , we used a computer screen and audio as stimulus sources, simultaneously applying a 40-Hz stimulation to both visual and auditory modalities. Both experiments only revealed the disappearance of practice effects in the 40-Hz (48-Hz) group. Experiment 4 focused on testing visual spatial memory, but did not identify any significant differences between or within groups. In Experiment 5, we tested various visual spatial frequencies; yet again, no significant differences were found. Based on the comprehensive results, we conclude that a 40-Hz stimulation does not have a promoting effect on visual threshold or visual spatial memory.

Competing Interests: Competing interests statement:The authors declare no competing interest.

Studies have shown ketogenic diets (KD) started from early middle-age improved health span and longevity in mice. KDs started later in life or administered intermittently may be more feasible and promote compliance. Therefore, this study sought to test if continuous or intermittent KDs started in late-middle-aged mice would improve cognition and motor function at advanced age. Eighteen-month-old male C57BL/6JN mice were assigned to an isocaloric control (CD), KD, or intermittent ketogenic (IKD, 3-day KD/week) diet. A panel of behavior tests were performed to assess cognitive and motor functions with aging. Y-maze alternation rate was higher for both IKD and KD mice at 23 months of age and for KD mice at 26 months indicating an improved spatial working memory. Twenty-six-month-old KD mice also showed better spatial learning memory in Barnes maze when compared to the CD. Improved grid wire hang performance was observed in aged IKD and KD versus CD mice indicating better muscle endurance under isometric contraction. A reduced level of circulating proinflammatory cytokines in aged KD (IL-6 and TNF-α) and IKD (IL-6) mice may contribute to the phenotypic improvements observed with these interventions. This study demonstrates that when initiated at late-middle age, the KD improved measures of spatial memory and grid wire hang performance in aged male mice, with IKD showing results intermediate to the CD and KD groups.

The examination of the influence of morphine on behavioral processes, specifically learning and memory, holds significant importance. Additionally, microtubule proteins play a pivotal role in cellular functions, and the dynamics of microtubules contribute to neural network connectivity, information processing, and memory storage. however, the molecular mechanism of morphine on microtubule dynamics, learning, and memory remains uncovered. In the present study, we examined the effects of chronic morphine administration on memory formation impairment and the kinetic alterations in microtubule proteins induced by morphine in mice. Chronic morphine administration at doses of 5 and 10 mg/kg dose-dependently decreased subjects' performance in spatial memory tasks, such as the Morris Water Maze and Y-maze spontaneous alternation behavior. Furthermore, morphine was found to stabilize microtubule structure, and increase polymerization, and total polymer mass. However, it simultaneously impaired microtubule dynamicity, stemming from structural changes in tubulin dimer structure. These findings emphasize the need for careful consideration of different doses when using morphine, urging a more cautious approach in the administration of this opioid medication.

IntroductionThe vestibular system’s contribution to spatial learning and memory abilities may be clarified using the virtual Morris Water Maze Task (vMWMT). This is important because of the connections between the vestibular system and the hippocampus area. However, there is ongoing debate over the role of the vestibular system in developing spatial abilities. This study aimed to evaluate the relationship between Dynamic Visual Acuity (DVA) across three planes and spatial abilities.MethodsThis cross-sectional study was conducted with 50 healthy adults aged 18 to 55 with normal stress levels and mental health and no neurological, audiological, or vestibular complaints. The Trail-Making Test (TMT) Forms A and B for the assessment of executive functions, the DVA test battery for the evaluation of visual motor functions, and the Virtual Morris Water Maze Test (vMWMT) for the assessment of spatial learning and spatial memory were performed. All participants also underwent the Benton Face Recognition Test (BFRT) and Digit Symbol Substitution Tests (DSST) to assess their relation with spatial memory.ResultsDVA values in horizontal (H-DVA), vertical (V-DVA), and sagittal (S-DVA) planes ranged from (−0.26) to 0.36 logMAR, (−0.20) to 0.36 logMAR, and (−0.28) to 0.33 logMAR, respectively. The latency of three planes of DVA was affected by vMWMT (Horizontal, Vertical, and Sagittal; Estimate: 22.733, 18.787, 13.341, respectively p < 0.001). Moreover, a moderately significant correlation was also found, with a value of 0.571 between the Virtual MWM test and BFRT and a value of 0.539 between the DSST (p < 0.001).ConclusionSpatial abilities in healthy adults were significantly influenced by dynamic visual functions across horizontal, vertical, and sagittal planes. These findings are expected to trigger essential discussions about the mechanisms that connect the vestibular-visual system to the hippocampus. The original vMWMT protocol is likely to serve as a model for future studies utilizing this technology.

Spatial cognition is fundamental to human behavior, but people differ in how they remember spatial relations, variably using body-based (egocentric) and environment-based (allocentric) spatial reference frames. Despite decades of study, the causes of this variation and flexibility in spatial memory remain unclear. Here we show that people spontaneously use different reference frames on different spatial axes at the same time. When remembering the placement of a target object in a 2-dimensional array, Indigenous Tsimane' adults preferentially used allocentric space to determine lateral placement and egocentric space to determine sagittal placement in the same action. This effect of axis was also significant among US university students, whose overall preference for egocentric space was stronger on the sagittal than lateral axis. These findings support a novel account of spatial cognitive diversity and suggest that people across cultures habitually integrate egocentric and allocentric spatial reference frames into the same action.

Objective To preliminarily investigate the role of thalamic nucleus reuniens (RE) on medial entorhinal cortex (MEC)-related spatial memory and its mechanism. Methods Retrobeads-mediated retrograde tracing and anterograde tracing were used to identify the morphological connections between RE and MEC brain regions. Then in vivo fiber photometry was used to record and analyze the activities of REMEC-projecting neurons when mice were exploring in the open field. Chemical genetics was utilized to explore the effects of RE-MEC pathway inhibition on spatial memory. Results Retrograde and anterograde tracing confirmed that RE sent neuronal fibers to MEC, which were mainly distributed in the superficial layers. Optical fiber recording showed that the activities of REMEC-projecting neurons were increased when the mice were rearing and looking up, but were decreased when the mice were stationary and grooming (R2=0.077 3, P < 0.01). And the calcium signal of these neurons was positively correlated with movement speed. Compared with the control group, chemogenetic inhibition of the RE-MEC pathway significantly prolonged the exploration distance of the mice in the treatment group in the open field (P < 0.01), but showed no effects on the center time, rearing time, number of head ups and number of grooming. Conclusion RE-MEC pathway is activated during spatial exploratory behaviors and participates in spatial learning and memory. Chemogenetic inhibition of RE-MEC pathway impairs spatial memory and extends the exploration distance to represent the spatial information of novel environment, and has no effects on emotions. [Key words] thalamic nucleus reuniens , medial entorhinal cortex , spatial memory , open field ,

New neurones are generated throughout life in the mammalian brain in a process known as adult hippocampal neurogenesis (AHN). Since this phenomenon grants a high degree of neuroplasticity influencing learning and memory, identifying factors that regulate AHN may be important for ameliorating age-related cognitive decline. Calorie restriction (CR) has been shown to enhance AHN and improve memory, mediated by the stomach hormone, ghrelin. Intermittent fasting (IF), a dietary strategy offering more flexibility than conventional CR, has also been shown to promote aspects of AHN. The 5:2 diet is a popular form of IF; however, its effects on AHN are not well characterised. To address this, we quantified AHN in adolescent and adult wild-type and ghrelin-receptor-deficient mice following 6 weeks on a 5:2 diet. We report an age-related decline in neurogenic processes. However, the 5:2 diet does not increase AHN nor enhance memory performance, suggesting that this specific form of IF is ineffective in promoting brain plasticity to support learning., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Background and Aim: Centella asiatica (L.) Urb. (Apiaceae) is a renowned medicinal plant being used in the Ayurvedic system for its pharmacological effects on the central nervous system such as rejuvenating, sedative, anxiolytic and memory-enhancing properties. The present study was designed to investigate the effect of Centella asiatica (CA) extract on inflammatory responses induced by lipopolysaccharide (LPS) and resulting changes in cognitive behavior., Materials and Methods: Adult male Sprague-Dawley rats were divided into 4 groups as control, LPS, CA and LPS + CA. The treatments with LPS (5 mg/kg) were intraperitoneally (i.p) injected on day 4 and CA ethanol extract (200 mg/kg) were given orally for 14 days. Morris Water Maze (MWM) test was performed to assess spatial learning and memory performance. Acute oral toxicity of the extract at the highest dose of 5000 mg/kg was also conducted., Results: Single administration of LPS was able to significantly elicit learning and memory impairment ( p  < .05) when compared to the control groups. Treatment with CA significantly improved the impaired learning ability in which the LPS + CA rats took the shortest time and route to find the hidden platform (15.85 ± 2.68 s ( p  < .001); 352.43 ± 88.10 cm ( p  < .001) on day 5) and induced differential cytokine responses in the blood. No mortality and no significant variation in the body and organ weights between the control and the treated group was observed after 14 days of acute toxicity study. Hematological analysis and biochemical parameters revealed no toxic effects of the extract. Pathologically, neither gross abnormalities nor histopathological changes were observed., Discussion and Conclusion: Centella asiatica extract exhibited significant learning and memory enhancement potential in animal model. Hence, indicating its putative preventive therapeutic effects in neuroinflammation related diseases.KEY MESSAGEA single dose of lipopolysaccharide (LPS) (5 mg/kg) administered systemically to mimic the consequences of LPS-induced inflammatory responses was able to affect some behavioral modification of spatial memory at the time point of study.The study showed that the learning capability during the training trial was restored or ameliorated with the pre-emptive treatment of Centella asiatica extract (200 mg/kg). Centella asiatica extract improves spatial memory, learning deficits and regulates proinflammatory responses in systemic LPS-treated rats.

Sleep facilitates hippocampal-dependent memories, supporting the acquisition and maintenance of internal representation of spatial relations within an environment. In humans, however, findings have been mixed regarding sleep's contribution to spatial memory and navigation, which may be due to task designs or outcome measurements. We developed the Minecraft Memory and Navigation (MMN) task for the purpose of disentangling how spatial memory accuracy and navigation change over time, and to study sleep's independent contributions to each. In the MMN task, participants learned the locations of objects through free exploration of an open field computerized environment. At test, they were teleported to random positions around the environment and required to navigate to the remembered location of each object. In study 1, we developed and validated four unique MMN environments with the goal of equating baseline learning and immediate test performance. A total of 86 participants were administered the training phases and immediate test. Participants' baseline performance was equivalent across all four environments, supporting the use of the MMN task. In study 2, 29 participants were trained, tested immediately, and again 12 h later after a period of sleep or wake. We found that the metric accuracy of object locations, i.e., spatial memory, was maintained over a night of sleep, while after wake, metric accuracy declined. In contrast, spatial navigation improved over both sleep and wake delays. Our findings support the role of sleep in retaining the precise spatial relationships within a cognitive map; however, they do not support a specific role of sleep in navigation.

Brain oscillations in humans play a role in a wide range of cognitive processes, including navigation and memory. The oscillatory dynamics contributing to successful spatial memory recall in humans are not well-understood. To investigate specific oscillatory frequency bands during the recall process in human navigation, we recorded electroencephalographic (EEG) activity during a recall trial in healthy young adults (n = 15) following the learning of a goal location in a Virtual Water Maze task. We compared this to the activity during the same trial length, in a group of participants who did not learn a target location and navigated freely but were time-matched to the learning group (non-learning, n = 15). We compared relative power in Delta (2-4Hz), Theta (5-7Hz), Alpha (8-12Hz), Beta (15-29Hz), and Gamma (30-40Hz) bands across the scalp. We found that delta and theta activity were greater during recall in our learning group, as opposed to our non-learning group. We also demonstrated clear suppression in the alpha band at posterior sites during memory-guided navigation compared to our non-learning group. Additionally, when goal-directed navigation switches to focused searching behavior, power becomes greater at the frontal region; with increases in the delta and theta bands reflecting this strategy change. There was also greater beta and gamma activity at posterior sites in our learning group. We discuss the results further in terms of the possible roles and functions of these oscillations during human navigation and hope this exploratory analysis can provide hypotheses for future spatial navigation and memory work. [ABSTRACT FROM AUTHOR]

This study examined the influence of genetic background on cognitive performance in a selectively bred high nicotine-preferring (NP) rat line. Using the novel object recognition (NOR), novel location recognition (NLR), and Morris water maze (MWM) tests, we evaluated object memory, spatial memory, and spatial navigation in nicotine-naive NP rats compared to controls. Our results demonstrate that in the NOR test, both male and female NP rats spent more time exploring the novel object (higher discrimination index) compared to sex-matched controls. In the NLR, the discrimination index differed significantly from zero chance (no preference) in both NP males and females but not in controls, indicating enhanced spatial memory in the NP line. During MWM acquisition, the NP groups and control males took a shorter path to reach the platform compared to control females. On the probe trial, the distance traveled in the target quadrant was longer for NP males and females compared to their respective controls, suggesting enhanced spatial navigation and learning in the NP rats. The interesting preference for novel objects and locations displayed by NP rats may indicate a potential novelty-seeking phenotype in this line. These results highlight the complex interplay between genetic factors, cognitive function, and nicotine preference. [ABSTRACT FROM AUTHOR]

Introduction: The positive effects of exercise on spatial memory and learning have been demonstrated in research. The olfactory sensory neurons (OSNs) respond to mechanical stimulation induced by nasal airflow which is associated with airflow intensity. Accordingly, nasal breathing can modulate brain oscillations in nonolfactory areas, and respiration-entrained oscillations aid the improvement of cognitive abilities. Given that aerobic exercise increases the rate of respiration and intensity of nasal airflow, this study evaluates the role of OSNs in mediating the effects of aerobic exercise on memory. Methods: We examined spatial memory following exercise in animal models of olfactory sensory neuron impairment (methimazole injection 300 mg/kg/week). Results: Destroying OSNs significantly reduces olfactory bulb (OB) activity at delta and theta frequency bands as well as its coupling to respiration. More importantly, it abolished the positive effect of exercise on spatial memory (P<0.05). Conclusion: The OB activity is one of the probable mechanisms for improving spatial memory following exercise. [ABSTRACT FROM AUTHOR]

Lactate has emerged as a key player in regulating neural functions and cognitive processes. Beyond its function as an energy substrate and signal molecule, recent research has revealed lactate to serve as an epigenetic regulator in the brain. However, the molecular mechanisms by which lactate regulates spatial memory and its role in the prevention of cognitive disorders remain unclear. Herein, we injected L-lactate (10 μmol/kg/d for 6 d) into the mouse's hippocampus, followed by the Morris water maze (MWM) test and molecular analyses. Improved spatial memory performances were observed in mice injected with lactate. Besides, lactate upregulated the expression of synaptic proteins post-synaptic density 95 (PSD95), synaptophysin (SYP), and growth associated protein 43 (GAP43) in hippocampal tissues and HT22 cells, suggesting a potential role in synaptic transmission and memory formation. The facilitative role of monocarboxylate transporter 2 (MCT2), a neuron-specific lactate transporter, in this process was confirmed, as MCT2 antagonists attenuated the lactate-induced upregulation of synaptic proteins. Moreover, lactate induced protein lactylation, a post-translational modification, which could be suppressed by MCT2 inhibition. RNA sequencing of lactated-injected hippocampal tissues revealed a comprehensive gene expression profile influenced by lactate, with significant changes in genes associated with transcriptional progress. These data demonstrate that hippocampal lactate injection enhances spatial memory in mice, potentially through the upregulation of synaptic proteins and induction of protein lactylation, with MCT2 playing a crucial role in these processes. Our findings shed light on the multi-faceted role of lactate in neural function and memory regulation, opening new avenues for therapeutic interventions targeting cognitive disorders. [ABSTRACT FROM AUTHOR]

Abstract Background Deficits in spatial memory, orientation, and navigation are often neglected early signs of cognitive impairment or loss of vestibular function. Real-world navigation tests require complex setups. In contrast, simple pointing at targets in a three-dimensional environment is a basic sensorimotor ability which provides an alternative measure of spatial orientation and memory at bedside. The aim of this study was to test the reliability of a previously established 3D-Real-World Pointing Test (3D-RWPT) in patients with cognitive impairment due to different neurodegenerative disorders, bilateral vestibulopathy, or a combination of both compared to healthy participants. Methods The 3D-RWPT was performed using a static array of targets in front of the seated participant before and, as a transformation task, after a 90-degree body rotation around the yaw-axis. Three groups of patients were enrolled: (1) chronic bilateral vestibulopathy (BVP) with normal cognition (n = 32), (2) cognitive impairment with normal vestibular function (n = 28), and (3) combined BVP and cognitive impairment (n = 9). The control group consisted of age-matched participants (HP) without cognitive and vestibular deficits (n = 67). Analyses focused on paradigm-specific mean angular deviation of pointing in the azimuth (horizontal) and polar (vertical) spatial planes, of the preferred pointing strategy (egocentric or allocentric), and the resulting shape configuration of the pointing array relative to the stimulus array. Statistical analysis was performed using age-corrected ANCOVA-testing with Bonferroni correction and correlation analysis using Spearman’s rho. Results Patients with cognitive impairment employed more egocentric pointing strategies while patients with BVP but normal cognition and HP used more world-based solutions (pBonf 5.78 × 10-3**). Differences in pointing accuracy were only found in the azimuth plane, unveiling unique patterns where patients with cognitive impairment showed decreased accuracy in the transformation tasks of the 3D-RWPT (pBonf

This work presents an Augmented Reality application based on SLAM (Simultaneous Localization and Mapping) for the assessment of spatial memory involving olfactory stimuli. A study was carried with twenty-five adults. The participants of the study completed two phases (a learning phase and an evaluation phase). In the learning phase, the participants physically walk around a real environment and have to remember the location of olfactory stimuli. In the evaluation phase, the participants have to remember the location of olfactory stimuli learned in the previous phase. The data of this study is compared with those obtained in a previous study involving visual and tactile stimuli (N = 47). The results indicate that the olfactory stimuli did not offer significant differences with respect to the visual stimuli for the correct placement of stimuli and the number of attempts in the evaluation phase. The olfactory stimuli had better results compared to the tactile stimuli for the correct placement of the stimuli in the evaluation phase and there was a significantly lower number of attempts. The time required in the learning and evaluation phases was greater for the olfactory stimuli compared to the other two stimuli, which is justified by the physical and mechanical characteristics of each of the stimuli. The results show that this type of memory task for the olfactory stimuli is independent of gender and age. All of these results suggest that olfactory stimuli are valid stimuli for assessing the memorization of olfactory-spatial associations and are similar to the level of visual stimuli and better than tactile stimuli.

Being able to represent and remember verbally-encoded information about spatial environments from different perspectives is important for numerous daily activities. The present study examined how frequently individuals spontaneously engage in visual mental imagery and verbal rehearsal strategies in memory recall of spatial descriptions, and whether using certain strategies is associated with better recall performance. Memory recall for route (person-centred) and survey (object-centred) spatial descriptions was examined in a sample of 105 neurotypical individuals, who also reported to what extent they used route- and survey-based mental imagery and verbal rehearsal strategies in each description. Results showed that participants favoured a path visualisation strategy to recall the route description and a map visualisation strategy to recall the survey description. Regression models further showed that employing both imagery and verbal strategies was associated with better recall for both route and survey descriptions, although imagery strategies held a higher predictive power. The present findings highlight the fact that the spontaneous use of internal strategies in the form of visual imagery and verbal rehearsal is ubiquitous when recalling spatial descriptions and a core part of efficient spatial memory functioning. [ABSTRACT FROM AUTHOR]

The aim of this study is to reveal how exchangees construct their public spaces for collective practices in a built environment that is abandoned and analyse these places along with collective practices retrospectively through changing daily life practices. Exchangees migrated from Greece to Turkey because of the population exchange decision which was taken in the Treaty of Lausanne in 1923. Due to the fact that the exchangee's identity and culture are visible through collective practices in public spaces, eight collective practices, which are weddings, hıdrellez, religious celebrations, official holiday celebrations, seeing-soldiers-off, seasonal preparations, funeral ceremonies, and public announcements of bad news are selected. These places, where collective practices are performed, are the subject of the research. The first-generation exchanges, for their collective practices, besides building spaces of their own, also settled in places that were left by the Greeks. The study focuses on these public spaces. The sample group of this study is the exchangees in Bursa, Görükle village who migrated from Greece. The methods of the study are analysing archive materials in the form of text, photo and maps and memory interviews conducted with the second and third generation exchangees who still use these public places. As a result of the study, it was revealed that the exchangees restructured the collective practice places in order to establish a sense of belonging and reinterpreting their culture and identity in the new settlement. The study concluded that the places of collective practices, spatial memory, the identity of the exchangee and the public spaces left by the Greeks have been transferred by spatial memory. This study reveals the influence of spatial memory, the relevance of belonging, reinterpreting of exchangees’ culture and identity over the restructuring of the physical environment and the transfer of these between generations.

Part-set cuing facilitation and impairment effects are rarely found in spatial memory, which is a challenge to the theories of part-set cuing effects based on lexical stimulus. This study aims to investigate whether there part-set cuing facilitation and impairment effects are present in spatial memory by constructing two types of memory scenes with high and low degrees of interitem associations, achieved by manipulating the presentation of miniatures. This study examined the effects of different part-set cues on free recall, recognition, and reconstruction tasks. The results of two experiments revealed that matrix cues impaired the performance of three recall tasks in memory scenes with a high degree of interitem associations, and scene cues facilitated the reconstruction performance (Experiment 1). Conversely, in memory scenes with a low degree of interitem associations, the impairment effect of matrix cues was not observed in the three recall tasks, but scene cues still facilitated the reconstruction performance (Experiment 2). These findings supported the retrieval strategy disruption hypothesis, the two-mechanism and the multi-mechanism accounts, demonstrating the significance of interitem associations in spatial memory. Furthermore, the results provided direct evidence for the importance of the encoding-retrieval strategy matching principle in spatial memory tasks.

IntroductionDespite its importance for navigation, very little is known about how the normal aging process affects spatial exploration behavior. We aimed to investigate: (1) how spatial exploration behavior may be altered early in the aging process, (2) the relationship between exploration behavior and subsequent spatial memory, and (3) whether exploration behavior can classify participants according to age.MethodsFifty healthy young (aged 18–28) and 87 healthy midlife adults (aged 43–61) freely explored a desktop virtual maze, learning the locations of nine target objects. Various exploration behaviors (object visits, distance traveled, turns made, etc.) were measured. In the test phase, participants navigated from one target object to another without feedback, and their wayfinding success (% correct trials) was measured.ResultsIn the exploration phase, midlife adults exhibited less exploration overall compared to young adults, and prioritized learning target object locations over maze layout. In the test phase, midlife adults exhibited less wayfinding success when compared to the young adults. Furthermore, following principal components analysis (PCA), regression analyses indicated that both exploration quantity and quality components were associated with wayfinding success in the midlife group, but not the young adults. Finally, we could classify participants according to age with similar accuracy using either their exploration behavior or wayfinding success scores.DiscussionOur results aid in the understanding of how aging impacts spatial exploration, and encourages future investigations into how pathological aging may affect spatial exploration behavior.

Brain oscillations in humans play a role in a wide range of cognitive processes, including navigation and memory. The oscillatory dynamics contributing to successful spatial memory recall in humans are not well-understood. To investigate specific oscillatory frequency bands during the recall process in human navigation, we recorded electroencephalographic (EEG) activity during a recall trial in healthy young adults (n = 15) following the learning of a goal location in a Virtual Water Maze task. We compared this to the activity during the same trial length, in a group of participants who did not learn a target location and navigated freely but were time-matched to the learning group (non-learning, n = 15). We compared relative power in Delta (2–4 Hz), Theta (5–7 Hz), Alpha (8–12 Hz), Beta (15–29 Hz), and Gamma (30–40 Hz) bands across the scalp. We found that delta and theta activity were greater during recall in our learning group, as opposed to our non-learning group. We also demonstrated clear suppression in the alpha band at posterior sites during memory-guided navigation compared to our non-learning group. Additionally, when goal-directed navigation switches to focused searching behavior, power becomes greater at the frontal region; with increases in the delta and theta bands reflecting this strategy change. There was also greater beta and gamma activity at posterior sites in our learning group. We discuss the results further in terms of the possible roles and functions of these oscillations during human navigation and hope this exploratory analysis can provide hypotheses for future spatial navigation and memory work.

Abstract Glutamate is involved in fundamental functions, including neuronal plasticity and memory. Astrocytes are integral elements involved in synaptic function, and the GLT–1 transporter possesses a critical role in glutamate uptake. Here, we study the role of GLT-1, specifically located in astrocytes, in the consolidation, expression, reconsolidation and persistence of spatial object recognition memory in rats. Administration of dihydrokainic acid (DHK), a selective GLT-1 inhibitor, into the dorsal hippocampus around a weak training which only induces short-term memory, promotes long-term memory formation. This promotion is prevented by hippocampal administration of protein-synthesis translation inhibitor, blockade of Activity-regulated cytoskeleton-associated protein (Arc) translation or Brain-Derived Neurotrophic Factor (BDNF) action, which are plasticity related proteins necessary for memory consolidation. However, DHK around a strong training, which induces long-term memory, does not affect memory consolidation. Administration of DHK before the test session impairs the expression of long-term memory, and this effect is dependent of Arc translation. Furthermore, DHK impairs reconsolidation if applied before a reactivation session, and this effect is independent of Arc translation. These findings reveal specific consequences on spatial memory stages developed under hippocampal GLT-1 blockade, shedding light on the intricate molecular mechanisms, governed in part for the action of glia.

Abstract Background The over-activation of adenosine A2A receptors (A2AR) is closely implicated in cognitive impairments of Alzheimer's disease (AD). Growing evidence shows that A2AR blockade possesses neuroprotective effects on AD. Spatial navigation impairment is an early manifestation of cognitive deficits in AD. However, whether A2AR blockade can prevent early impairments in spatial cognitive function and the underlying mechanism is still unclear. Methods A transgenic APP/PS1 mouse model of AD amyloidosis was used in this study. Behavioral tests were conducted to observe the protective effects of A2AR blockade on early spatial memory deficits in 4-month old APP/PS1 mice. To investigate the underlying synaptic mechanism of the protective effects of A2AR blockade, we further examined long-term potentiation (LTP) and network excitation/inhibition balance of dentate gyrus (DG) region, which is relevant to unique synaptic functions of immature adult-born granule cells (abGCs). Subsequently, the protective effects of A2AR blockade on dendritic morphology and synaptic plasticity of 6-week-old abGCs was investigated using retrovirus infection and electrophysiological recordings. The molecular mechanisms underlying neuroprotective properties of A2AR blockade on the synaptic plasticity of abGCs were further explored using molecular biology methods. Results APP/PS1 mice displayed DG-dependent spatial memory deficits at an early stage. Additionally, impaired LTP and an imbalance in network excitation/inhibition were observed in the DG region of APP/PS1 mice, indicating synaptic structural and functional abnormalities of abGCs. A2AR was found to be upregulated in the hippocampus of the APP/PS1 mouse model of AD. Treatment with the selective A2AR antagonist SCH58261 for three weeks significantly ameliorated spatial memory deficits in APP/PS1 mice and markedly restored LTP and network excitation/inhibition balance in the DG region. Moreover, SCH58261 treatment restored dendritic morphology complexity and enhanced synaptic plasticity of abGCs in APP/PS1 mice. Furthermore, SCH58261 treatment alleviated the impairment of synaptic plasticity in abGCs. It achieved this by remodeling the subunit composition of NMDA receptors and increasing the proportion of NR2B receptors in abGCs of APP/PS1 mice. Conclusions Blockade of A2AR improves early spatial memory deficits in APP/PS1 mice, possibly by reversing synaptic defects of abGCs. This finding suggests that A2AR blockade could be a potential therapy for AD.

Neuropeptide orexin mainly exists in neurons within and around the lateral hypothalamus and exhibits high affinity to orexin 1 and 2 receptors (OX1R and OX2R, respectively). Orexinergic neurons send their axons to the nucleus accumbens (NAc), which expresses OX1Rs. Previous studies have shown the involvement of orexins and their role in learning and memory processes in the dorsal raphe nucleus and hippocampus. However, no study has examined the effects of orexins in the NAc on memory. The present study examined the effect of the post-training and pre-probe trial intra-NAc administration of SB-33486-A (OX1R antagonist, 12 μg/0.5μl) and TCS-OX2-29 (OX2R antagonist, 10 μg/0.5 μl) on the consolidation and retrieval of memory in the Morris Water Maze (MWM) task. In experiment 1, rats were trained in the MWM and, immediately after every training, received bilateral injections of dimethyl sulfoxide (DMSO) (control group), SB-334867-A (SB), and TCS-OX2-29 (TCS) into the NAc. Experiment 2 was similar to experiment 1, except that the rats received DMSO, SB, and TCS 15 min before the probe test. Probe and visible tests were performed after the last training, and the distance moved, escape latency, and velocity were recorded. In experiment 3, rats trained in experiments 1 and 2, immediately after the probe test, were given the trials for visuomotor coordination assessment on the visible platform. According to the results, the injection of SB increased the distance moved and escape latency in the treated groups, compared to the control group, in the consolidation phase of spatial memory ( P <0.05) but not in its retrieval phase ( P >0.05). However, TCS-OX2-29 had no effect. These results suggest that the inactivation of the NAc OX1Rs, but not OX2Rs, impairs the consolidation but not the retrieval of spatial memory in rats., Competing Interests: The authors declare that they have no conflict of interest.

Memory is a fundamental brain function that can be affected by a variety of external factors including environmental pollutants. One of these pollutants is methyl vinyl ketone (MVK), a hazardous substance found in cigarettes, industrial wastes, and car exhaust. Humans can be exposed to MVK under many circumstances; however, it is unclear whether MVK affects higher-order brain functions such as memory. Here, we examined the memory performances of mice receiving systemic MVK administration. We found that 1 mg/kg of MVK impaired spatial memory. We also showed that 1 mg/kg MVK activated glial cells and altered glial functions in several subregions of the hippocampus, a brain region involved in learning and memory. These results suggest that MVK induces memory deficits and activates glial cells in hippocampal subregions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Widespread release of norepinephrine (NE) throughout the forebrain fosters learning and memory via adrenergic receptor (AR) signaling, but the molecular mechanisms are largely unknown. The β 2 AR and its downstream effectors, the trimeric stimulatory G s -protein, adenylyl cyclase (AC), and the cAMP-dependent protein kinase A (PKA), form a unique signaling complex with the L-type Ca 2+ channel (LTCC) Ca V 1.2. Phosphorylation of Ca V 1.2 by PKA on Ser 1928 is required for the upregulation of Ca 2+ influx on β 2 AR stimulation and long-term potentiation induced by prolonged theta-tetanus (PTT-LTP) but not LTP induced by two 1-s-long 100-Hz tetani. However, the function of Ser 1928 phosphorylation in vivo is unknown. Here, we show that S1928A knock-in (KI) mice of both sexes, which lack PTT-LTP, express deficiencies during initial consolidation of spatial memory. Especially striking is the effect of this mutation on cognitive flexibility as tested by reversal learning. Mechanistically, long-term depression (LTD) has been implicated in reversal learning. It is abrogated in male and female S1928A knock-in mice and by β 2 AR antagonists and peptides that displace β 2 AR from Ca V 1.2. This work identifies Ca V 1.2 as a critical molecular locus that regulates synaptic plasticity, spatial memory and its reversal, and LTD. SIGNIFICANCE STATEMENT We show that phosphorylation of the Ca 2+ channel Ca V 1.2 on Ser 1928 is important for consolidation of spatial memory and especially its reversal, and long-term depression (LTD). Identification of Ser 1928 as critical for LTD and reversal learning supports the model that LTD underlies flexibility of reference memory., (Copyright © 2023 the authors.)

Schema knowledge can dramatically affect how we encode and retrieve memories. Current models propose that schema information is combined with episodic memory at retrieval to influence memory decisions, but it is not known how the strength or type of episodic memory (i.e., unconscious memory versus familiarity versus recollection) influences the extent to which schema information is incorporated into memory decisions. To address this question, we had participants search for target objects in semantically expected (i.e., congruent) locations or in unusual (i.e., incongruent) locations within scenes. In a subsequent test, participants indicated where in each scene the target had been located previously, then provided confidence-based recognition memory judgments that indexed recollection, familiarity strength, and unconscious memory for the scenes. In both an initial online study (n = 133) and replication (n = 59), target location recall was more accurate for targets that had been located in schema-congruent rather than incongruent locations; importantly, this effect was strongest for new scenes, decreased with unconscious memory, decreased further with familiarity strength, and was eliminated entirely for recollected scenes. Moreover, when participants recollected an incongruent scene but did not correctly remember the target location, they were still biased away from congruent regions-suggesting that detrimental schema bias was suppressed in the presence of recollection even when precise target location information was not remembered. The results indicate that episodic memory modulates how schemas are used: Schema knowledge contributes to spatial memory judgments primarily when episodic memory fails to provide precise information, and recollection can override schema bias completely.