Spatial Object Recognition Research Articles

A hypothalamic circuit mechanism underlying the impact of stress on memory and sleep.

Stress profoundly affects sleep and memory processes. Stress impairs memory consolidation, and similarly, disruptions in sleep compromise memory functions. Yet, the neural circuits underlying stress-induced sleep and memory disturbances are still not fully understood. Here, we show that activation of CRH PVN neurons, similar to acute restraint stress, decreases sleep and impairs memory in a spatial object recognition task. Conversely, inhibiting CRH PVN neurons during stress reverses stress-induced memory deficits while slightly increasing the amount of sleep. We found that both stress and stimulation of CRH PVN neurons activate neurons in the lateral hypothalamus (LH), and that their projections to the LH are critical for mediating stress-induced memory deficits and sleep disruptions. Our results suggest a pivotal role for CRH PVN neuronal pathways in regulating the adverse effects of stress on memory and sleep, an important step towards improving sleep and ameliorating the cognitive deficits that occur in stress-related disorders.

Enhancing spatial memory and pattern separation: Long-term effects of stimulant treatment in individuals with ADHD

This study explores the under-researched domain of long-term stimulant treatment in children and adolescents diagnosed with attention deficit hyperactivity disorder (ADHD). The necessity for extended treatment duration, often accompanied by safety concerns and side effects leading to treatment discontinuation, underscores the significance of this investigation. Concurrently, comparative studies have revealed adverse impacts on vulnerable regions within the hippocampal formation, accompanied by behavioral perturbations. We employed computerized tests and virtual reality to assess spatial memory, pattern separation, and object recognition memory in a cohort of children diagnosed with ADHD receiving stimulant treatment. We compared their performance to a group of neurotypical peers. Our findings indicate that the ADHD group exhibited a lower performance in spatial memory, pattern separation, and object recognition memory than ND group. Intriguingly, a positive relationship emerged between the duration of stimulant treatment and performance in these variables. Notably, this improvement was not immediate to MPH treatment but becomes significant after 24 months of treatment. In contrast to previous comparative investigations, our study did not reveal a detrimental impact on spatial navigation, object recognition memory, or pattern separation, despite the known interplay of these cognitive processes with the hippocampal formation. These results shed new light on the nuanced effects of stimulant treatment in ADHD, underscoring the need for a more comprehensive understanding of long-term treatment outcomes.

Arc and BDNF mediated effects of hippocampal astrocytic glutamate uptake blockade on spatial memory stages

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.

Leveraging Mobile Net and Yolo Algorithm for Enhanced Perception in Autonomous Driving

This project presents a cutting-edge autonomous navigation system designed to enhance spatial understanding and object recognition for vehicles. Equipped with cameras on both the left and right sides, by capturing comprehensive view of the surroundings, utilizing stereo vision for crucial depth information. The integration of Mobile Net and YOLO (You Only Look Once) algorithms is central to achieving real-time object detection and recognition. Mobile Net is employed for efficient feature extraction, ensuring optimal computational efficiency. Simultaneously, YOLO plays a pivotal role in rapid and accurate identification of objects within the captured images, contributing to the robustness of spatial understanding crucial for autonomous navigation. The result is a comprehensive and reliable autonomous navigation system, showcasing the effectiveness of combining cutting-edge technologies for improved real time decision making.

Acute Administration of HIV-1 Tat Protein Drives Glutamatergic Alterations in a Rodent Model of HIV-Associated Neurocognitive Disorders

HIV-1-associated neurocognitive disorders (HAND) are a major comorbidity of HIV-1 infection, marked by impairment of executive function varying in severity. HAND affects nearly half of people living with HIV (PLWH), with mild forms predominating since the use of anti-retroviral therapies (ART). The HIV-1 transactivator of transcription (Tat) protein is found in the cerebrospinal fluid of patients adherent to ART, and its administration or expression in animals causes cognitive symptoms. Studies of Tat interaction with the N-methyl-D-aspartate receptor (NMDAR) suggest that glutamate toxicity contributes to Tat-induced impairments. To identify changes in regional glutamatergic circuitry underlying cognitive impairment, we injected recombinant Tat86 or saline to medial prefrontal cortex (mPFC) of male Sprague–Dawley rats. Rats were assessed with behavioral tasks that involve intact functioning of mPFC including the novel object recognition (NOR), spatial object recognition (SOR), and temporal order (TO) tasks at 1 and 2 postoperative weeks. Following testing, mPFC tissue was collected and analyzed by RT-PCR. Results showed Tat86 in mPFC-induced impairment in SOR, and upregulation of Grin1 and Grin2a transcripts. To further understand the mechanism of Tat toxicity, we assessed the effects of full-length Tat101 on gene expression in mPFC by RNA sequencing. The results of RNAseq suggest that glutamatergic effects of Tat86 are maintained with Tat101, as Grin2a was upregulated in Tat101-injected tissue, among other differentially expressed genes. Spatial learning and memory impairment and Grin2a upregulation suggest that exposure to Tat protein drives adaptation in mPFC, altering the function of circuitry supporting spatial learning and memory.

TAAR1 in dentate gyrus is involved in chronic stress-induced impairments in hippocampal plasticity and cognitive function

Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.

Dnmt3a1 regulates hippocampus-dependent memory via the downstream target Nrp1

Epigenetic factors are well-established players in memory formation. Specifically, DNA methylation is necessary for the formation of long-term memory in multiple brain regions including the hippocampus. Despite the demonstrated role of DNA methyltransferases (Dnmts) in memory formation, it is unclear whether individual Dnmts have unique or redundant functions in long-term memory formation. Furthermore, the downstream processes controlled by Dnmts during memory consolidation have not been investigated. In this study, we demonstrated that Dnmt3a1, the predominant Dnmt in the adult brain, is required for long-term spatial object recognition and contextual fear memory. Using RNA sequencing, we identified an activity-regulated Dnmt3a1-dependent genomic program in which several genes were associated with functional and structural plasticity. Furthermore, we found that some of the identified genes are selectively dependent on Dnmt3a1, but not its isoform Dnmt3a2. Specifically, we identified Neuropilin 1 (Nrp1) as a downstream target of Dnmt3a1 and further demonstrated the involvement of Nrp1 in hippocampus-dependent memory formation. Importantly, we found that Dnmt3a1 regulates hippocampus-dependent memory via Nrp1. In contrast, Nrp1 overexpression did not rescue memory impairments triggered by reduced Dnmt3a2 levels. Taken together, our study uncovered a Dnmt3a-isoform-specific mechanism in memory formation, identified a novel regulator of memory, and further highlighted the complex and highly regulated functions of distinct epigenetic regulators in brain function.

Synergistic effects of tilapia head protein hydrolysate and walnut protein hydrolysate on the amelioration of cognitive impairment in mice.

Cognitive impairment (CI) is a significant public health concern, and bioactive peptides have shown potential as therapeutic agents. However, information about their synergistic effects on cognitive function is still limited. Here, we investigated the synergistic effects of tilapia head protein hydrolysate (THPH) and walnut protein hydrolysate (WPH) in mitigating CI induced by scopolamine in mice. The results showed that the combined supplementation of THPH and WPH (mass ratio, 1:1) was superior to either individual supplement in enhancing spatial memory and object recognition abilities in CI mice, and significantly lessened brain injury in CI mice by alleviating neuronal damage, reducing oxidative stress and stabilizing the cholinergic system. In addition, the combined supplementation was found to be more conducive to remodeling the gut microbiota structure in CI mice by not only remarkably reducing the ratio of Firmicutes to Bacteroidota, but also specifically enriching the genus Roseburia. On the other hand, the combined supplementation regulated the disorders of sphingolipid and amino acid metabolism in CI mice, particularly upregulating glutathione and histidine metabolism, and displayed a stronger ability to increase the expression of genes and proteins related to the brain-derived neurotrophic factor (BDNF)/TrkB/CrEB signaling pathway in the brain. These findings demonstrate that tilapia head and walnut-derived protein hydrolysates exerted synergistic effects in ameliorating CI, which was achieved through modulation of gut microbiota, serum metabolic pathways and BDNF signaling pathways. © 2024 Society of Chemical Industry.

Whole body vibration ameliorates anxiety-like behavior and memory functions in 30 months old senescent male rats

Whole body vibration (WBV) is a form of passive exercise that offers an alternative physical training to aged individuals with limitations in their physical and mental capabilities. The aim of the present study was to explore the therapeutic potential of five weeks of WBV on anxiety-like behaviors as well as learning and memory abilities in senescent thirty months old rats. Animals were exposed to 5 min vibration twice per day, five times per week during the five consecutive weeks. Pseudo WBV treated animals served as controls. After five weeks of WBV treatment, animals were tested for anxiety-like behavior by the open field test and for spatial and object memory functions by the novel and spatial object recognition tests, respectively. As a result, anxiety-like and exploratory behaviors were significantly improved in the WBV treated group compared to the pseudo WBV group. Furthermore, WBV treatment increased discrimination performance in both spatial and object memory function testing. These results indicate that WBV treatment in thirty months old rats seems to have comparable beneficial effects on age-related emotional and cognitive performance as what has been reported in younger age groups.

Behavioral characterization of early nicotine withdrawal in the mouse: a potential model of acute dependence

BackgroundClinical and preclinical research have demonstrated that short-term exposure to nicotine during the initial experimentation stage can lead to early manifestation of withdrawal-like signs, indicating the state of “acute dependence”. As drug withdrawal is a major factor driving the progression toward regular drug intake, characterizing and understanding the features of early nicotine withdrawal may be important for the prevention and treatment of drug addiction. In this study, we corroborate the previous studies by showing that withdrawal-like signs can be precipitated after short-term nicotine exposure in mice, providing a potential animal model of acute dependence on nicotine.ResultsTo model nicotine exposure from light tobacco use during the initial experimentation stage, mice were treated with 0.5 mg/kg (-)-nicotine ditartrate once daily for 3 days. On the following day, the behavioral tests were conducted after implementing spontaneous or mecamylamine-precipitated withdrawal. In the open field test, precipitated nicotine withdrawal reduced locomotor activity and time spent in the center zone. In the elevated plus maze test, the mecamylamine challenge increased the time spent in the closed arm and reduced the number of entries irrespective of nicotine experience. In the examination of the somatic aspect, precipitated nicotine withdrawal enhanced the number of somatic signs. Finally, nicotine withdrawal did not affect cognitive functioning or social behavior in the passive avoidance, spatial object recognition, or social interaction test.ConclusionsCollectively, our data demonstrate that early nicotine withdrawal-like signs could be precipitated by the nicotinic antagonist mecamylamine in mice, and that early withdrawal from nicotine primarily causes physical symptoms.

Modulation of memory reconsolidation by adjacent novel tasks: timing defines the nature of change

Reconsolidation turns memories into a responsive state that allows their modulation until they stabilize again. This phenomenon attracted remarkable attention due to its potential impact on therapeutics and education. Recent evidence revealed that different memories undergo reconsolidation via a behavioral tagging process. Thus, their re-stabilization involves setting “reconsolidation-tags” and synthesizing plasticity-related proteins for their capture at the tagged sites. Here, we studied the possibility of affecting these fundamental mechanisms to modulate reconsolidation. Our findings, in laboratory rats, indicate that exploring a novel environment 60 min before or after memory reactivation improves spatial object recognition memory by promoting protein synthesis. Conversely, experiencing novelty immediately after reactivation impairs the reconsolidation by affecting the tags. Similar effects, but with a different optimal time window for improvement, occur in inhibitory avoidance memory. These results highlight the possibility of modulating existing memories using non-invasive interventions that selectively affect the fundamental mechanisms of behavioral tagging during their reconsolidation.

Intermittent fasting disrupts hippocampal-dependent memory and norepinephrine content in aged male and female mice

Intermittent fasting (IMF) is associated with many health benefits in animals and humans. Yet, little is known if an IMF diet affects mood and cognitive processing. We have previously identified that IMF in diet-induced obese males increases norepinephrine and dopamine content in the hypothalamus and increases arcuate neuropeptide Y (NPY) gene expression more than in ad libitum control males. This suggests that IMF may improve cognition through activation of the hindbrain norepinephrine neuronal network and reverse the age-dependent decline in NPY expression. Less is known about the association between anxiety and IMF. Although, in humans, IMF during Ramadan may alleviate anxiety. Here, we address the impact of IMF on anxiety-like behavior using the open field test, hippocampal-dependent memory using the Y-maze and spatial object recognition, and hippocampal-independent memory using novel object recognition in middle-aged male and female (12 mo) and aged male and female (18 mo) mice. Using ELISA, we determined norepinephrine (NE) content in the dorsal hippocampus (DH) and prefrontal cortex (PFC). We also investigated gene expression in the arcuate nucleus (ARC), the lateral hypothalamus (LH), and the locus coeruleus (LC). In IMF-treated females at both ages, we observed an improvement in spatial navigation although an impairment in spatial object orientation. IMF-treated females (12 mo) had a reduction and IMF-treated males (12 mo) displayed an improvement in novel object recognition memory. IMF-treated females (18 mo) exhibited anxiolytic-like behavior and increased locomotion. In the DH, IMF-treated males (12 mo) had a greater amount of NE content and IMF-treated males (18 mo) had a reduction. In the ARC, IMF-treated males (12 mo) exhibited an increase in Agrp and Npy and a decrease in Adr1a. In the ARC, IMF-treated males (18 mo) exhibited an increase in Npy and a decrease in Adr1a; females had a trending decrease in Cart. In the LH at 12 months, IMF-treated males had a decrease in Npy5r, Adr1a, and Adr1b; both males and females had a reduction in Npy1r. In the LH, IMF-treated females (18 mo) had a decrease in Hcrt. In the LC at both ages, mice largely exhibited sex effects. Our findings indicate that IMF produces alterations in mood, cognition, DH NE content, and ARC, LH, and LC gene expression depending on sex and age.

Chaperone interventional therapy restores proteostasis, improves cognition and increases ADAM10 in young and aged APP knockin mice

AbstractBackgroundTwo distinct phenotypes of Alzheimer’s disease are deficits in cognition and proteostasis, including chronic activation of the unfolded protein response (UPR) and aberrant Aβ production. The UPR is a signal transduction pathway activated in the endoplasmic reticulum (ER) at the onset of proteostatic stress. With age the UPR is less efficient and the expression of the key regulator, the chaperone BiP / Hspa5, also declines. It is unknown if restoring proteostasis by reducing chronic and aberrant UPR activation in AD can improve pathology and cognition. Here, we present data using an APP knock‐in mouse model of AD and several small molecule chaperone supplementation paradigms, including an early and late‐stage intervention.MethodTransgenic APP knock‐in mice were used as a model for AD. Two groups of mice and their wildtype littermates, (treatment starting early at 1‐2 mos old and late at 12 mos old) were administered the chemical chaperone 4‐phenyl butyrate (PBA) by weekly I.P. for 10 weeks. Controls were given I.P. injections of sterile saline. After 10 weeks of PBA or saline treatment, mice were subjected to the Spatial Object Recognition (SOR) cognitive tasks. A third group of APP knock‐in mice and wildtype littermates were given stereotaxic local hippocampal AAV‐BiP overexpression or AAV‐mCherry control injections. Following recovery and viral expression, mice were subjected to the SOR test. All mice were perfused, and tissue was collected for both immunohistochemistry and biochemical analyses.ResultPBA treatment improved performance in the SOR test both with early and late‐stage PBA interventions. AAV‐BiP overexpression recapitulated those results. Histological data indicates that chaperone treatment, both with PBA injections and AAV‐BiP overexpression, reduced hippocampal ER stress and was correlated with increased pCREB. Chronic PERK activation which leads to inhibition of protein translation was reduced, while XBP1s levels were increased with chaperone treatment. This was coupled with increased ADAM10, which is associated with non‐amyloidogenic cleavage of APPConclusionReducing proteostatic stress even at a late age improves cognition in a mouse model of Alzheimer’s disease. The implications of these results could have an impact on the development of therapies to inform the development of potential treatments for Alzheimer’s disease.

Volume of the posterior and not anterior hippocampus predicts spatial memory performance in Alzheimer´s Disease

AbstractBackgroundHippocampal volume atrophy is one of the most acknowledged supportive biomarkers for Alzheimer´s disease (AD). However, how hippocampal volumes along the anterior‐posterior axis mediate memory in aging and dementia is still subject of ongoing research. This study aimed to investigate the difference in volume of the hippocampus and its anterior and posterior subregions in a healthy young and senior control group as well as in mild cognitive impairment (MCI) due to AD and its ability to predict performance in spatial memory tasks.MethodThirteen healthy young controls (24.9 ± 2.8 years), fourteen healthy senior controls (66.6 ± 8.2 years) as well as fifteen MCI patients (71.1 ± 6.0 years) with biomarkers typical for AD were included in this study. Subject‐specific manual tracing of hippocampi according to the EADC‐ADNI Harmonized Protocol for Hippocampal Segmentation (HarP) was performed on high‐resolution T1‐weighted MRI. Following the segmentation into anterior and posterior hippocampal parts, volumetry of anterior, posterior and total hippocampus was computed. Every subject performed a combined spatial memory and object recognition paradigm. Brain‐behavior correlations were conducted in order to explore prediction of spatial memory performance.ResultVolume measures of the hippocampi significantly differentiated healthy from pathological aging. Larger volume of posterior hippocampus in MCI patients correlated with higher performance scores in the spatial memory task (mean percentage of successfully retrieved object locations) whereas total and anterior hippocampal volume did not predict performance in the spatial memory task.ConclusionThese results support a functional hippocampal anterior‐posterior differentiation in memory processes and further stress the importance of integrating the dissociation of the hippocampus along its long‐axis concerning functional connectivity in memory processes and dementia.

Repeated multi-domain cognitive training prevents cognitive decline, anxiety and amyloid pathology found in a mouse model of Alzheimer disease

Education, occupation, and an active lifestyle, comprising enhanced social, physical, and mental components are associated with improved cognitive functions in aged people and may delay the progression of various neurodegenerative diseases including Alzheimer’s disease. To investigate this protective effect, 3-month-old APPNL-G-F/NL-G-F mice were exposed to repeated single- or multi-domain cognitive training. Cognitive training was given at the age of 3, 6, & 9 months. Single-domain cognitive training was limited to a spatial navigation task. Multi-domain cognitive training consisted of a spatial navigation task, object recognition, and fear conditioning. At the age of 12 months, behavioral tests were completed for all groups. Then, mice were sacrificed, and their brains were assessed for pathology. APPNL-G-F/NL-G-F mice given multi-domain cognitive training compared to APPNL-G-F/NL-G-F control group showed an improvement in cognitive functions, reductions in amyloid load and microgliosis, and a preservation of cholinergic function. Additionally, multi-domain cognitive training improved anxiety in APPNL-G-F/NL-G-F mice as evidenced by measuring thigmotaxis behavior in the Morris water maze. There were mild reductions in microgliosis in the brain of APPNL-G-F/NL-G-F mice with single-domain cognitive training. These findings provide causal evidence for the potential of certain forms of cognitive training to mitigate the cognitive deficits in Alzheimer disease.

Effects of heterozygous deletion of autism-related gene Cullin-3 in mice.

Autism Spectrum Disorder (ASD) is a developmental disorder in which children display repetitive behavior, restricted range of interests, and atypical social interaction and communication. CUL3, coding for a Cullin family scaffold protein mediating assembly of ubiquitin ligase complexes through BTB domain substrate-recruiting adaptors, has been identified as a high-risk gene for autism. Although complete knockout of Cul3 results in embryonic lethality, Cul3 heterozygous mice have reduced CUL3 protein, demonstrate comparable body weight, and display minimal behavioral differences including decreased spatial object recognition memory. In measures of reciprocal social interaction, Cul3 heterozygous mice behaved similarly to their wild-type littermates. In area CA1 of hippocampus, reduction of Cul3 significantly increased mEPSC frequency but not amplitude nor baseline evoked synaptic transmission or paired-pulse ratio. Sholl and spine analysis data suggest there is a small yet significant difference in CA1 pyramidal neuron dendritic branching and stubby spine density. Unbiased proteomic analysis of Cul3 heterozygous brain tissue revealed dysregulation of various cytoskeletal organization proteins, among others. Overall, our results suggest that Cul3 heterozygous deletion impairs spatial object recognition memory, alters cytoskeletal organization proteins, but does not cause major hippocampal neuronal morphology, functional, or behavioral abnormalities in adult global Cul3 heterozygous mice.

Effects of Caloric Restriction on Spatial Object Recognition Memory, Hippocampal Neuron Loss and Neuroinflammation in Aged Rats

Age-related neurobiological changes significantly affect hippocampal structure and function, such that the main cognitive impairments associated with aging are related to the integrity of this brain structure, including the deterioration in spatial object recognition (SOR) memory. Previous studies have shown that intrinsic factors such as neuroinflammation, as well as lifestyle factors such as diet, can affect aging-associated brain functions and cognitive performance. In this regard, caloric restriction (CR) produces beneficial effects on health and life expectancy, although its ability to slow down age-dependent effects on cognitive decline and hippocampus (HPC) functioning remains unclear. Therefore, we set out to evaluate the effects of CR on SOR memory in aged male Wistar rats, as well as those on hippocampal neuron loss, neurogenesis and inflammation. The data show that CR in aged rats attenuates the decline in SOR memory, age-associated hippocampal neuron loss, and age-dependent microglial activation. Furthermore, we found a significant reduction in neurogenesis in the dentate gyrus of the old animals relative to adult rats. These findings support the positive effect of CR on SOR memory, suggesting that it dampens hippocampal neuronal loss and reduces proinflammatory activity.

Protective effect of glutamic-oxaloacetic transaminase on hippocampal neurons in Alzheimer's disease using model mice

Alzheimer's disease (AD), a neurodegenerative disease affecting the elderly, frequently causes cognitive impairment and memory decline, and there are currently no effective therapeutic drugs available. Glutamate excitotoxicity is one of the pathogeneses of AD, and there is evidence that glutamic-oxaloacetic transaminase (GOT) can significantly reduce glutamate concentrations in the hippocampi of mice, but its role in APP/PS1 transgenic mice is unknown. We investigated the improvement of neurological function and related protein expression following subcutaneous injection of GOT in mice with AD. We performed immunohistochemical staining on the brain tissue of 3-, 6-, and 12-month-old mice and found that the content of the β-amyloid protein Aβ1-42 in the 6 months old GOT treatment group was significantly reduced. Meanwhile, the APP-GOT group outperformed the APP group in the water maze and spatial object recognition experiments. The number of neurons in the hippocampal CA1 area of the APP-GOT group increased when compared to the APP group according to Nissl staining. Electron microscopic examination of the hippocampal CA1 area demonstrated that the number of synapses in the APP-GOT group was more than that in the APP group, and the mitochondrial structure was relatively complete. Finally, the protein content of the hippocampus was detected. In comparison to the APP group, SIRT1 content increased in the APP-GOT group whereas Aβ1-42 content decreased, and Ex527 could reverse this trend. These results suggest that GOT can significantly improve the cognitive function of mice in the early stage of AD, and the underlying mechanism may be through decreasing Aβ1-42 and increasing SIRT1 expressions.

Environmental Enrichment Engages Vesicular Zinc Signaling to Enhance Hippocampal Neurogenesis.

Zinc is highly concentrated in synaptic vesicles throughout the mammalian telencephalon and, in particular, the hippocampal dentate gyrus. A role for zinc in modulating synaptic plasticity has been inferred, but whether zinc has a particular role in experience-dependent plasticity has yet to be determined. The aim of the current study was to determine whether vesicular zinc is important for modulating adult hippocampal neurogenesis in an experience-dependent manner and, consequently, hippocampal-dependent behaviour. We assessed the role of vesicular zinc in modulating hippocampal neurogenesis and behaviour by comparing ZnT3 knockout (KO) mice, which lack vesicular zinc, to wild-type (WT) littermates exposed to either standard housing conditions (SH) or an enriched environment (EE). We found that vesicular zinc is necessary for a cascade of changes in hippocampal plasticity following EE, such as increases in hippocampal neurogenesis and elevations in mature brain-derived neurotrophic factor (mBDNF), but was otherwise dispensable under SH conditions. Using the Spatial Object Recognition task and the Morris Water task we show that, unlike WT mice, ZnT3 KO mice showed no improvements in spatial memory following EE. These experiments demonstrate that vesicular zinc is essential for the enhancement of adult hippocampal neurogenesis and behaviour following enrichment, supporting a role for zincergic neurons in contributing to experience-dependent plasticity in the hippocampus.

0300 Early Life Sleep Fragmentation Impairs Hippocampal-Dependent Learning and Sleep-Dependency in Hippocampal Calcium Transients

Abstract Introduction Sleep deprivation impairs hippocampal-dependent memory, and hippocampal-dependent memory impairments occur in some dementias, including Alzheimer’s disease. As our population continues to age, understanding the molecular basis for memory impairments is increasingly important. We hypothesized that early life sleep fragmentation would result in lasting increases in hippocampal calcium transient activity. Methods B6 mice were randomized to 12wk of sleep fragmentation or rested control conditions at age 8wk. Mice were microinjected with AAV9-CamKII-GCamp6F into the hippocampus and later implanted with a GRIN Lens into CA1 secured to a baseplate along with chronic EEG/EMG electrodes and recording connector. Calcium recordings were obtained two to three months after injection and recordings were obtained across sleep-wake cycles>4mins of wake and NREM sleep. Individual cells across animal were combined into sleep fragmented (n = 521 cells) or rested (n = 443 cells) groups during wake or sleep. Average FFx was analyzed by group and condition by T-tests, paired for within and unpaired across groups. A spatial object recognition assay was also performed on all mice (n=16 for both groups) and performance across group was analyzed by paired T-tests. Results Rested mice showed normal spatial object recognition (n = 16, p<0.05). In contrast, SF mice showed impaired spatial object recognition (n = 16, N.S.). There were no differences across sleep conditions in calcium transient FFx for waking (p>0.05). However, in sleep, cells in SF mice had significantly higher average FFx values than cells in rested mice (p<0.0001). Conclusion Early-life sleep fragmentation has long-lasting impacts on memory. Since spatial memory is dependent on hippocampal function, the calcium transient FFx data suggests that a driver of this hippocampal memory impairment may be higher firing rates in sleep and/or greater calcium exposure in hippocampal CamKII neurons in sleep, both of which may perturb microglial maintenance of synapses. Understanding the molecular drivers behind this calcium dysfunction will be essential in our understanding of neurodegeneration, dementia, and Alzheimer’s disease. Support (If Any) NIH AG054104; AG064231