Cognitive Performance Of Mice Research Articles

Impact and Interrelationships of Striatal Proteins, EPHB2, OPRM1, and PER2 on Mild Cognitive Impairment.

With the global increase in life expectancy, there has been a rise in the incidence of cognitive impairments attributed to diverse etiologies. Notably, approximately 50% of individuals diagnosed with mild cognitive impairment (MCI) progress to dementia within 3years. However, the precise mechanisms underlying MCI remain elusive. Therefore, this study aimed to elucidate potential mechanisms implicated in MCI utilizing Per2 knockout (KO) mice, which have previously been shown to have cognitive deficits. Behavioral (Y-maze, Barnes maze) and molecular (electrophysiology, RNA sequencing, western blot, and immunofluorescence) experiments were conducted in Per2 KO and wild-type (WT) mice. Per2 KO mice exhibited impaired spatial working memory in the Y-maze and Barnes maze. However, there were no significant group differences in hippocampal long-term potentiation (LTP) between Per2 KO and WT mice, whereas striatal LTP in Per2 KO mice was lower compared to WT mice. In RNA sequencing analysis, 58 genes were downregulated and 64 genes were upregulated in the striatum of Per2 KO mice compared to WT mice. Among the differentially expressed genes, four genes (Chrm2, EphB2, Htr1b, Oprm1) were identified. Optimal expression levels of EPHB2 and OPRM1 were found to significantly enhance cognitive performance in mice. Additionally, Per2 KO mice exhibited reduced EPHB2-NMDAR-LTP and OPRM-mTOR signaling, along with elevated amyloid beta (Aβ) levels, when compared to WT mice. However, these alterations were reversed upon administration of morphine treatment. Striatal OPRM1-mTOR signaling, EPHB2-NMDAR-LTP signaling, and Aβ expression levels may exert a combined effect on MCI under the control of Per2 expression.

Cognitive training of mice attenuates age-related decline in associative learning and behavioral flexibility.

Identifying factors that influence age-related cognitive decline is crucial, given its severe personal and societal impacts. However, studying aging in human or animal models is challenging due to the significant variability in aging processes among individuals. Additionally, longitudinal and cross-sectional studies often produce differing results. In this context, home-cage-based behavioral analysis over lifespans has emerged as a significant method in recent years. This study aimed to explore how prior experience affects cognitive performance in mice of various age groups (4, 12, and 22 months) using a home-cage-based touchscreen test battery. In this automated system, group-housed, ID-chipped mice primarily obtain their food during task performance throughout the day, motivated by their own initiative, without being subjected to food deprivation. Spatial working memory and attention were evaluated using the trial unique non-matching to location (TUNL) and the five-choice serial reaction time task (5-CSRTT), respectively. The same set of mice learned both of these demanding tasks. While signs of cognitive decline were already apparent in middle-aged mice, older mice exhibited poorer performance in both tasks. Mice at both 12 and 22 months displayed an increase in perseverance and a decrease in the percentage of correct responses in the TUNL test compared to the 4-month-old mice. Furthermore, during the 5-CSRTT, they exhibited higher rates of omissions and premature responses compared to their younger counterparts. Additionally, the correct response rate in 22-month-old mice was lower than that of the 4-month-old ones. However, mice that had undergone cognitive training at 4 months maintained high-performance levels when re-tested at 12 months, showing an increase in correct responses during TUNL testing compared to their untrained controls. In the 5-CSRTT, previously trained mice demonstrated higher correct response rates, fewer omissions, and reduced premature responses compared to naive control mice. Notably, even when assessed on a visual discrimination and behavioral flexibility task at 22 months, experienced mice outperformed naive 4-month-old mice. These findings highlight the advantages of early-life cognitive training and suggest that its benefits extend beyond the cognitive domains primarily targeted during early training. The success of this study was significantly aided by the fully automated home-cage-based testing system, which allows for high throughput with minimal human intervention.

Aβ oligomers reduce neuronal plasticity in an aged animal model of Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the extracellular accumulation of senile plaques composed of beta‐amyloid (Aβ). Aβ oligomers (AβO) induce damage beginning with loss of synapses, followed by neurite network disorganization and neuronal death. The hippocampus is a cerebral structure and a major place of neuroplasticity and a key structure for memory processing and consolidation. Hippocampal atrophy is well documented in AD. Neuronal plasticity persists during ageing and could adaptative response to cognitive decline during ageing or dementia.Alterations in adult neuronal plasticity and synaptic dysfunctions are detected in rodent models of Alzheimer’s disease. Thus, early dysfunction in neural stem cell production and neuronal differentiation could be linked to reduced neuronal plasticity in AD.MethodIn this study, to investigate the effect of age on neurogenesis, in young (12 weeks), aged and healthy (16 months) mice and in an in vivo model of AD, based on intra‐hippocampal injection of a AβO/protofibril preparation in aged (16 months) mice.Proliferation of cells (BrdU, Ki67), differentiation (DCX) and maturation (NeuN) into neurons were studied in the dendate gyrus of mice. Activation of glial cells was also assessed by immunohistochemistry. In addition, cognitive performance of mice were assessed using the Y‐maze test (short‐term spatial memory) in the same animal.ResultOur results show a decrease in neurogenesis in aged mice compared to young mice. Injection of AβO in the CA1 area was also associated with decreased neurogenesis in the dentate gyrus, neuroinflammation and to reduce performance in the Y‐maze test.This reduction in neuroblast generation was revealed by a decrease in the number of BrdU(+), Ki67(+) and DCX(+) cells in the dentate gyrus.ConclusionWe evidenced a decreased in neuronal plasticity in aging which is exacerbated in our in vivo model of AD and connected to cognitive decline.

Infant gut microbiota contributes to cognitive performance in mice

Gut microbiota has been linked to infant neurodevelopment. Here, an association between infant composite cognition and gut microbiota composition is established as soon as 6months. Higher diversity and evenness characterize microbial communities of infants with composite cognition above (Inf-aboveCC) versus below (Inf-belowCC) median values. Metaproteomic and metabolomic analyses establish an association between microbial histidine ammonia lyase and infant histidine metabolome with cognition. Fecal transplantation from Inf-aboveCC versus Inf-belowCC donors into germ-free mice shows that memory, assessed by a novel object recognition test, is a transmissible trait. Furthermore, Inf-aboveCC mice are enriched in species belonging to Phocaeicola, as well as Bacteroides and Bifidobacterium, previously linked to cognition. Finally, Inf-aboveCC mice show lower fecal histidine and urocanate:histidine and urocanate:glutamate ratios in the perirhinal cortex compared to Inf-belowCC mice. Overall, these findings reveal a causative role of gut microbiota on infant cognition, pointing at the modulation of histidine metabolite levels as a potential underlying mechanism.

SARS‐CoV2 Nucleocapsid Protein induces Tau pathological changes in the mouse hippocampus

AbstractBackgroundNeurologic manifestations are emerging as an immediate consequence of SARS‐CoV2 infection, the etiologic agent of COVID19. Although little is known about the long‐term consequences of SARS‐CoV2 infection, there is the possibility that infection may trigger long‐term neurological effects. Exposure to pathogens in fact triggers inflammation in the brain and exacerbates Tau pathological changes in animal models of Alzheimer disease. Reports of the presence of SARS‐CoV2 in the brains of subjects with COVID19 are emerging and a study in brain organoids revealed that SARS‐CoV2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to recruitment of Tau into stress granules (SG) operated by the Nucleocapsid protein (NP) of SARS‐CoV2.MethodTo address whether exposure to SARS‐CoV2 may predispose to develop dementia, we investigated whether NP interacts with Tau and induces hyperphosphorylation and aggregation of Tau in human iPSC cells and hippocampal neurons in vivo. We tested whether NP interacts with Tau by co‐immunoprecipitation experiments. Mechanistically, we tested whether posttranslational modification of NP and Tau by SUMO2 modulates their distribution in SG and their pathological interaction. We expressed NP for 2 months, with or without SUMO2, in the hippocampus of 6 months old wild type and JNPL3 mice, before performing Y‐maze. After behavioral assessment, the mice were sacrificed and brains were isolated to perform biochemical and immunofluorescence analyses.ResultWe found that NP and Tau co‐localize and physically interact in human cells. We also found that NP induces hyperphosphorylation of Tau and reduces the amount of synaptic proteins in neurons. This is also paralleled by a reduction in the cognitive abilities of mice infected with NP in their hippocampus. Finally we found that modulation of SUMOylation dramatically affects SG induced by NP in cells, Tau hyperphoshorylation, as well as cognitive performance in mice infected with NP.ConclusionOur data demonstrate that NP induces pathological changes in cells and animals expressing wild type Tau, and aggravates the pathology in neurons expressing mutant forms of Tau, both in vitro and in vivo. Moreover we demonstrate that SUMO2 conjugation ameliorates NP‐induced Tau pathology.

Aerobic exercise combined with chlorogenic acid exerts neuroprotective effects and reverses cognitive decline in Alzheimer's disease model mice (APP/PS1) via the SIRT1/ /PGC-1α/PPARγ signaling pathway.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease account for 60-80% of the total number of people with dementia, but its treatment and prevention strategies are still in a long process of exploration. It has been reported that a healthy lifestyle may be an effective non-pharmacological intervention for the prevention and treatment of AD, including increased physical activity and the consumption of polyphenol-rich foods. This study, therefore, investigated the effects of 8 weeks of moderate-intensity aerobic exercise (EX), administration of chlorogenic acid administration (GCA), and a combination of both (EX+GCA) on β-amyloid (Aβ) deposition, inflammatory factors, oxidative stress markers, neuronal damage, and cognitive performance in the brains of AD model mice (APP/PS1) and which signaling pathways may be responsible for these effects. The study used Western blot to detect the expression of signaling pathway-related proteins, enzyme-linked immunosorbent assay to detect the expression of inflammatory factors, hematoxylin-eosin staining to detect hippocampal neuronal morphology, immunohistochemistry to detect changes in Aβ deposition in the hippocampus, an oxidative stress marker kit to detect oxidative stress status and the Morris water maze to detect changes in cognitive performance. This study showed that an 8-week intervention (EX/GCA/EX+GCA) activating the SIRT1/PGC-1α signaling pathway improved oxidative stress, neuroinflammation, Aβ deposition, and cognitive performance in mice. However, there was no obvious difference between the EX and GCA groups. In contrast, the combined EX+GCA intervention was significantly better than phase EX or GCA. Our study suggests that although relief of Aβ deposition, neuroinflammation, oxidative stress, neuronal damage, and cognitive decline could also be achieved with EX or GCA, the combined EX+GCA intervention showed better results. These relief effects on AD-related conditions may be obtained by mediating the activation of the SIRT1/PGC-1α signaling pathway. This study is the first to explore the improvement of AD-related conditions with a combined lifestyle of EX+GCA. This healthy lifestyle could be a candidate option for the treatment of AD.

Klotho increases antioxidant defenses in astrocytes and ubiquitin–proteasome activity in neurons

Klotho is an antiaging protein, and its levels decline with age and chronic stress. The exogenous administration of Klotho can enhance cognitive performance in mice and negatively modulate the Insulin/IGF1/PI3K/AKT pathway in terms of metabolism. In humans, insulin sensitivity is a hallmark of healthy longevity. Therefore, this study aimed to determine if exogenous Klotho, when added to neuronal and astrocytic cell cultures, could reduce the phosphorylation levels of certain insulin signaling effectors and enhance antioxidant strategies in these cells. Primary cell cultures of cortical astrocytes and neurons from mice were exposed to 1 nM Klotho for 24 h, with or without glucose. Klotho decreased pAKT and mTOR levels. However, in astrocytes, Klotho increased FOXO-3a activity and catalase levels, shielding them from intermediate oxidative stress. In neurons, Klotho did not alter FOXO-3 phosphorylation levels but increased proteasome activity, maintaining lower levels of PFKFB3. This study offers new insights into the roles of Klotho in regulating energy metabolism and the redox state in the brain.

An Open-Field-Based Unimodal Object Recognition Test (OF-UORT) for Assessment of Chronic Stress Effects on Visual and Tactile Unimodal Cognition in Mice.

The open field (OF) test is a widely used behavioral assay in animal studies to assess locomotion, emotion, and cognition. In open-field-based object recognition tasks, the open arena is equipped with combinations of objects to allow the examination of various aspects of learning and memory. In this article, we provide a protocol for open-field-based unimodal memory tests that assess tactile or visual unimodal cognitive behavior in mice. These tests do not require mice to be restricted from eating or drinking and do not involve aversive stimuli, such as electric shock, high-decibel sound waves, bright light, or forced swimming. Inside the apparatus, mice can freely and spontaneously explore the objects and the environment. Sniffing of, or direct contact with, objects is considered a cognitive exploration of the objects, and the timing and number of such behaviors can be recorded. During the acquisition phase, two identical objects are provided. After an intertrial interval, the retrieval phase is initiated, during which one object is replaced with a new object that is different from the previous one. Decorative clear domes are used prevent direct tactile contact with the objects, whereas infrared illumination is used to block visual information from the objects. By alternating the access to visual or tactile features of the objects in the acquisition and retrieval phases, the experimenters can assess visual or tactile unimodal cognition. Here, we describe our own instrumentation and application for experiments, and demonstrate that the modified device is capable of testing visual or tactile unimodal cognition in mice. Although easy to perform, this task/test can accurately reflect unimodal cognitive performance in mice, which can provide solid and reproducible data support to related studies. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Validation of the open-field-based unimodal object recognition test Basic Protocol 2: Evaluation of chronic stress effects on unimodal cognition using the open-field-based unimodal cognitive test.

Pneumoviruses can impair the central nervous system by different mechanisms

Abstract Pneumoviruses such as the respiratory syncytial virus (hRSV) and the human metapneumovirus (hMPV) are the leading cause of acute lower tract respiratory infection, mainly in infants, elderly and immunocompromised individuals, causing high morbidity and mortality rates. However, these viruses can cause neurological alterations, such as encephalitis and encephalopathy. Viral RNA and pro-inflammatory molecules have been found in patients with neurological signs, supporting the notion of neuroinvasion and/or neuroinflammation caused by hRSV and hMPV. Therefore, this work seeks to evaluate the effects of these viruses on the brain. Accordingly, mice were infected with either hRSV or hMPV or treated with non-infectious controls (mock). Despite detecting viral load in the lungs of hMPV-infected mice, no viral load was detected in their brains, as it was shown for hRSV. However, pro-inflammatory cytokines such as IL-6 and IFN-g were increased only in the sera of hMPV-infected mice. Also, we observed differential patterns in the increase of cytokines in the brain of hRSV or hMPV-infected mice, including IL-6, TNF-a, and IL-4. Moreover, increased blood-brain barrier permeability was observed in mice infected with both viruses. Additionally, after several weeks post-infection, a Marble Burying (MB) test was performed, and we observed an impaired cognitive performance in mice infected with both viruses. All these results suggest that infection with these pneumoviruses can cause long-term behavioral impairment in mice. Our work provides new insight into the effect of hRSV and hMPV on the central nervous system and underscores the need to further understand how respiratory virus can damage brain function in humans. This work was supported by ANID/FONDECYT grants #11221280; #1190830, ANID scholarship # 21210662, the Millennium Institute on Immunology and Immunotherapy ACE 210015, ICN09_016 / ICN 2021_045; former P09/016-F.

Bioactive nutraceuticals oligo-lactic acid and fermented soy extract alleviate cognitive decline in mice in part via anti-neuroinflammation and modulation of gut microbiota.

Cognition decline is associated with aging and certain diseases, such as neurodegenerative or neuropsychiatric disorders, diabetes and chronic kidney disease. Inflammation/neuroinflammation is considered an important causal factor, and experimental evidence suggests that anti-inflammatory natural compounds may effectively prevent cognitive decline. The goal of this study was to evaluate the effects of two natural bioactive agents, oligo-lactic acid (LAP) and fermented soy extract (ImmunBalance, IMB), on cognition in an adenine-induced cognitive impairment mouse model and to investigate the modulation of related biomarkers. Male C57 black mice were randomly assigned into the following experimental groups and received the corresponding treatments for 2 weeks before the use of adenine for model development: (1) negative control; (2) model control: injection of adenine at 50 mg/kg daily for 4 weeks; (3, 4) IMB groups: adenine injection and IMB oral gavage at 250 and 1,000 mg/kg BW, respectively; and (5) LAP group: adenine injection and LAP oral gavage at 1,000 mg/kg BW. One week after the model was developed, mice were evaluated for cognitive performances by using Y maze test, novel object recognition test, open field test, and Barnes maze tests. At the end of the experiment, brain tissues and cecum fecal samples were collected for analysis of gene expression and gut microbiota. Mice treated with LAP or IMB had significantly improved spatial working memory, spatial recognition memory (LAP only), novel object recognition, and spatial learning and memory, compared with those in the model group. Gene expression analysis showed that, among a panel of cognition related genes, six of them (ELOVL2, GLUT4, Nestein, SNCA, TGFB1, and TGFB2) were significantly altered in the model group. LAP treatment significantly reversed expression levels of inflammatory/neuroinflammatory genes (SNCA, TGFB1), and IMB significantly reversed expression levels of genes related to inflammation/neuroinflammation, neurogenesis, and energy metabolism (ELOVL2, GLUT4, Nestin, TGFB1, and TGFB2). The altered microbiome was attenuated only by IMB. In conclusion, our data showed that LAP improved cognition associated with regulating biomarkers related to neuroinflammation and energy metabolism, whereas IMB improved cognition associated with regulating biomarkers related to neuroinflammation, energy metabolism, and neurogenesis, and modulating gut microbiota. Our results suggest that LAP and IMB may improve cognitive performance in mice via distinct mechanisms of action.

SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy.

Tau is a microtubule-associated protein predominantly expressed in neurons, which participates in microtubule polymerization and axonal transport. Abnormal tau metabolism leads to neurodegenerative diseases named tauopathies, such as Alzheimer’s disease and frontotemporal dementia. The alternative splicing of exon 10 (E10) in the primary transcript produces tau protein isoforms with three (3R) or four (4R) microtubule binding repeats, which are found in equal amounts in the normal adult human brain. Several tauopathies are associated with abnormal E10 alternative splicing, leading to an imbalance between 3R and 4R isoforms, which underlies disease. Correction of such imbalance represents a potential disease-modifying therapy for those tauopathies. We have previously optimized a trans-splicing RNA reprogramming strategy to modulate the 3R:4R tau content in a mouse model of tauopathy related to tau mis-splicing (htau mice), and showed that local modulation of E10 inclusion in the prefrontal cortex prevents cognitive decline, neuronal firing impairments and hyperphosphorylated tau accumulation. Furthermore, local shifting of 3R–4R tau into the striatum of htau mice prevented motor coordination deficits. However, a major bottleneck of our previous work is that local splicing regulation was performed in young mice, before the onset of pathological phenotypes. Here we tested whether regulation of tau E10 splicing could rescue tau pathology phenotypes in htau mice, after the onset of cognitive and motor impairments, comparable to early stages of human tauopathies. To determine phenotypic time course and affected brain nuclei, we assessed htau mice using behavioural tests and microPET FDG imaging over time, similarly to diagnosis methods used in patients. Based on these analyses, we performed local delivery of pre-trans splicing molecules to regulate E10 inclusion either into the medial prefrontal cortex (mPFC) or the striatum at 6-month-old once behavioral phenotypes and metabolic changes were detected. Tau isoforms modulation into the mPFC restored cognitive performance in mice that previously showed mild to severe memory impairment while motor coordination deficit was rescued after striatal injection of trans-splicing molecules. Our data suggest that tau regulation could recover pathological phenotypes early after phenotypic onset, raising promising perspectives for the use of RNA based therapies in tauopathies related to MAPT abnormal splicing.

Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer's disease pathology in mice.

All drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer’s disease (AD) patients. In this study, we repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting synaptic formation (i.e., Wnt signaling) and cellular clearance (i.e., autophagic) pathways respectively, to test their therapeutic potential for attenuating AD-related pathology. We characterized our 3xTg AD mouse colony to select timepoints for separate and combinatorial treatment of both drugs while collecting cerebrospinal fluid (CSF) using an optimized microdialysis method. We found that treatment with Fasudil reduced Aβ at early and later stages of AD, whereas administration of Lonafarnib had no effect on Aβ, but did reduce tau, at early stages of the disease. Induction of autophagy led to increased size of amyloid plaques when administered at late phases of the disease. We show that combinatorial treatment with both drugs was effective at reducing intraneuronal Aβ and led to improved cognitive performance in mice. These findings lend support to regulating Wnt and autophagic pathways in order to attenuate AD-related pathology.

Soy isoflavones protects against cognitive deficits induced by chronic sleep deprivation via alleviating oxidative stress and suppressing neuroinflammation

Mounting evidence suggests that there is a close association between chronic sleep deprivation (CSD) and cognitive deficits. The animal model of CSD-induced cognitive deficits is commonly used to seek potential treatments. Soy isoflavones (SI) have been reported to possess antioxidant, anti-inflammation, and neuroprotective effects. In the present study, the effects of SI on CSD-induced memory impairment were investigated. The mice were subjected to the sleep interruption apparatus and continuously sleep deprived for 2 weeks, while orally administrated with SI (10, 20, and 40 mg/kg) or Modafinil (MOD,100 mg/kg) during the CSD process. Immediately after the SD protocol, cognitive performance of mice was evaluated by the object location recognition (OLR) test, the novel object recognition (NOR) test, and the Morris water maze (MWM) task, as well as the hippocampus, was extracted for evaluation of oxidative stress parameters and inflammation levels through biochemical parameter assay and western blotting analysis. The results showed that SI administration remarkably improved the cognitive performance of CSD-treated mice in OLR, NOR, and MWM tests. In addition, SI significantly elevated total antioxidant capacity and superoxide dismutase enzyme activities, decreased malondialdehyde level, promoting antioxidant element nuclear erythroid-2-related factor 2, and its downstream targets, including heme oxygenase 1, and quinone oxidoreductase 1 protein expressions. Moreover, SI treatment significantly suppressed nuclear factor kappa B p65, nitric oxide synthase, and cyclooxygenase 2 activation, as well as the pro-inflammatory cytokines (Tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1β [IL-1β]) release in the hippocampus of CSD-treated mice. In summary, the current study provides an insight into the potential of SI in treatment of cognitive deficits by CSD.

Neonatal Supplementation of Oleamide During Suckling Promotes Learning Ability and Memory in Adolescent Mice

BackgroundFatty acid amides (FAMs) are present in breast milk. Oleamide (ODA), a member of the FAM family, has been reported to affect learning and memory-related abilities in animal experiments. ObjectivesThis study aimed to characterize the temporal changes of FAMs in human milk and sought to examine the effect of ODA supplementation during suckling on postweaning cognitive performance in mice. MethodsFAMs were measured in human milk (postpartum 1–24 wk) by ultra-performance liquid chromatography-triple quadruple mass spectrometry (UPLC-TQ-MS) analysis. We supplemented neonatal C57BL/6J mice of both sexes with vehicle (control), 5 mg/(kg · day) ODA (L-ODA), or 25 mg/(kg · day) ODA (H-ODA) throughout suckling by oral gavage. After weaning, the Morris water maze test and novel object recognition test were performed. Neurogenesis, spinal morphogenesis in the dentate gyrus (DG) region, and hippocampal expression of synaptic markers were analyzed. Data were analyzed by ANOVA and repeated-measures ANOVA. ResultsODA (0.566–1.31 mg/L) was the most abundant FAM in breast milk, followed by palmitamide (0.135–0.269 mg/L) and linoleamide (0.046–0.242 mg/L). Compared with the control group, the H-ODA group demonstrated shorter escape latency, shorter travel distance, 113% more platform crossing, and 48% greater discrimination index in behavioral tests (P < 0.05). Additionally, the H-ODA group showed a higher density of 5-ethynyl-2’-deoxyuridine (EdU)+ and EdU+& doublecortin (DCX)+ cells (62% and 53%, respectively), and 52% greater spine density in the DG region than the control group (P < 0.05). The synaptic markers, postsynaptic density protein 95 (PSD95) and synaptophysin (SYP), were upregulated in the H-ODA group compared with the control group (P < 0.05). The L-ODA group also showed shorter escape latency in behavioral tests and 27% greater spine density in the DG region than the control group (P < 0.05). ConclusionsODA is the most common FAM in human milk. ODA supplementation during suckling promotes learning and memory-related abilities in adolescent mice by augmenting hippocampal neuronal proliferation and boosting synaptic plasticity.

The role of 5-HT7R in the memory impairment of mice induced by long-term isoflurane anesthesia

General anesthesia is widely utilized in the clinic for surgical and diagnostic procedures. However, growing evidence suggests that anesthetic exposure may affect cognitive function negatively. Unfortunately, little is known about the underlying mechanisms and efficient prevention and therapeutic strategies for the anesthesia-induced cognitive dysfunction. 5-HT7R, a serotonin receptor family member, is functionally associated with learning and memory. It has recently become a potential therapeutic target in various neurological diseases as its ligands have a wide range of neuropharmacological effects. However, it remains unknown the role of 5-HT7R in the long-term isoflurane anesthesia-induced memory impairment and whether prior activation or blockade of 5-HT7R before anesthesia has modulating effects on this memory impairment. In this study, 5-HT7R selective agonist LP-211 and 5-HT7R selective antagonist SB-269970 were pretreated intraperitoneally to mice before anesthesia; their effects on the cognitive performance of mice were assessed using fear conditioning test and novel object recognition test. Furthermore, the transcriptional level of 5-HT7R in the hippocampus was detected using qRT-PCR, and proteomics was conducted to probe the underlying mechanisms. As a result, long-term exposure to isoflurane anesthesia caused memory impairment and an increase in hippocampal 5-HT7R mRNA expression, which could be attenuated by SB-269970 pretreatment but not LP-211pretreatment. According to the proteomics results, the antiamnestic effect of SB-269970 pretreatment was probably attributed to its action on the gene expression of Slc6a11, Itpka, Arf3, Srcin1, and Epb41l2, and synapse organization in the hippocampus. In conclusion, 5-HT7R is involved in the memory impairment induced by long-term isoflurane anesthesia, and the prior blockade of 5-HT7R with SB-269970 protects the memory impairment. This finding may help to improve the understanding of the long-term isoflurane anesthesia-induced memory impairment and to construct potential preventive and therapeutic strategies for the adverse effects after long-term isoflurane exposure.

Impaired Cognitive Performance in Mice Exposed to Prolonged Hyperoxia.

Supplementation of oxygen at concentrations significantly above environmental level for prolonged periods may lead to hyperoxia and tissue toxicity. The mammalian brain undergoes structural and functional changes during adaptation to hypoxia and hyperoxia. In this study we investigated the effect of prolonged hyperoxic exposure on cognitive and motor performance in mice. Two-month-old male mice were placed in either hyperoxic (50% O2) or normoxic conditions for 3weeks. Cognitive function was measured using the Y-maze test. High alteration rate between the three arms of the maze is indicative of sustained memory and cognitive function. Motor function was measured using the grip strength and rotarod tests. In the rotarod test high speed and long latency are indicative of coordination and resistance. After 3weeks of exposure, hematocrit levels were significantly decreased in the hyperoxia group compared to normoxic control littermates (%, mean±SD, 37.8±1.3, n=15 vs. 49.9±5.1, n=15, p<0.05). In the Y-maze test, chronic hyperoxic exposure resulted in a statistically significant decrease in alteration rate compared to normoxic control (%, mean±SD, 53.4±9.9, n=30 vs. 61.2±9.5, n=15, p<0.05). The rotarod and grip strength tests did not show statistically significant changes between the two groups. Our data suggest that chronic hyperoxia may lead to decreased cognitive performance in adult mice, which may be secondary to structural and functional changes in the brain.

Amino Acid Nanofibers Improve Glycemia and Confer Cognitive Therapeutic Efficacy to Bound Insulin.

Diabetes poses a high risk for debilitating complications in neural tissues, regulating glucose uptake through insulin-dependent and predominantly insulin-independent pathways. Supramolecular nanostructures provide a flexible strategy for combinatorial regulation of glycemia. Here, we compare the effects of free insulin to insulin bound to positively charged nanofibers comprised of self-assembling amino acid compounds (AACs) with an antioxidant-modified side chain moiety (AAC2) in both in vitro and in vivo models of type 1 diabetes. Free AAC2, free human insulin (hINS) and AAC2-bound-human insulin (AAC2-hINS) were tested in streptozotocin (STZ)-induced mouse model of type 1 diabetes. AAC2-hINS acted as a complex and exhibited different properties compared to free AAC2 or hINS. Mice treated with the AAC2-hINS complex were devoid of hypoglycemic episodes, had improved levels of insulin in circulation and in the brain, and increased expression of neurotransmitter taurine transporter, Slc6a6. Consequently, treatment with AAC2-hINS markedly advanced both physical and cognitive performance in mice with STZ-induced and genetic type 1 diabetes compared to treatments with free AAC2 or hINS. This study demonstrates that the flexible nanofiber AAC2 can serve as a therapeutic platform for the combinatorial treatment of diabetes and its complications.

Effects of Acute and Chronic Exposure to a Mixed Field of Neutrons and Photons and Single or Fractionated Simulated Galactic Cosmic Ray Exposure on Behavioral and Cognitive Performance in Mice.

During space missions, astronauts experience acute and chronic low-dose-rate radiation exposures. Given the clear gap of knowledge regarding such exposures, we assessed the effects acute and chronic exposure to a mixed field of neutrons and photons and single or fractionated simulated galactic cosmic ray exposure (GCRsim) on behavioral and cognitive performance in mice. In addition, we assessed the effects of an aspirin-containing diet in the presence and absence of chronic exposure to a mixed field of neutrons and photons. In C3H male mice, there were effects of acute radiation exposure on activity levels in the open field containing objects. In addition, there were radiation-aspirin interactions for effects of chronic radiation exposure on activity levels and measures of anxiety in the open field, and on activity levels in the open field containing objects. There were also detrimental effects of aspirin and chronic radiation exposure on the ability of mice to distinguish the familiar and novel object. Finally, there were effects of acute GCRsim on activity levels in the open field containing objects. Activity levels were lower in GCRsim than sham-irradiated mice. Thus, acute and chronic irradiation to a mixture of neutrons and photons and acute and fractionated GCRsim have differential effects on behavioral and cognitive performance of C3H mice. Within the limitations of our study design, aspirin does not appear to be a suitable countermeasure for effects of chronic exposure to space radiation on cognitive performance.

Impaired Cognitive Flexibility Induced by Chronic Cerebral Hypoperfusion in the 5XFAD Transgenic Mouse Model of Mixed Dementia.

Cerebrovascular lesions are widely prevalent in patients with Alzheimer’s disease (AD), but their relationship to the pathophysiology of AD remains poorly understood. An improved understanding of the interaction of cerebrovascular damage with AD is crucial for the development of therapeutic approaches. Herein, we investigated the effects of chronic cerebral hypoperfusion (CCH) in a 5XFAD transgenic (Tg) mouse model of AD. We established CCH conditions in both Tg and non-Tg mice by inducing unilateral common carotid artery occlusion (UCCAO). Cognitive performance in mice was evaluated, and their brain tissue was examined for amyloid-beta (Aβ) pathology to elucidate possible mechanisms. We found that UCCAO-operated Tg mice showed impaired cognitive flexibility in the reversal phase of the hidden-platform water maze task compared to sham-operated Tg mice. Interestingly, UCCAO-operated Tg mice used fewer spatial cognitive strategies than sham-operated Tg mice during reversal learning. These cognitive deficits were accompanied by increased Aβ plaque burden and Aβ42 levels in the hippocampus and prefrontal cortex, 2 regions that play essential roles in the regulation of cognitive flexibility. Furthermore, changes in cognitive flexibility are strongly correlated with the expression levels of enzymes related to Aβ clearance, such as neprilysin and insulin-degrading enzymes. These findings suggest that, in 5XFAD mice, impaired cognitive flexibility is related to CCH, and that Aβ clearance might be involved in this process.

Subchronic N-acetylcysteine Treatment Decreases Brain Kynurenic Acid Levels and Improves Cognitive Performance in Mice.

The tryptophan (Trp) metabolite kynurenic acid (KYNA) is an α7-nicotinic and N-methyl-d-aspartate receptor antagonist. Elevated brain KYNA levels are commonly seen in psychiatric disorders and neurodegenerative diseases and may be related to cognitive impairments. Recently, we showed that N-acetylcysteine (NAC) inhibits kynurenine aminotransferase II (KAT II), KYNA’s key biosynthetic enzyme, and reduces KYNA neosynthesis in rats in vivo. In this study, we examined if repeated systemic administration of NAC influences brain KYNA and cognitive performance in mice. Animals received NAC (100 mg/kg, i.p.) daily for 7 days. Redox markers, KYNA levels, and KAT II activity were determined in the brain. We also assessed the effect of repeated NAC treatment on Trp catabolism using brain tissue slices ex vivo. Finally, learning and memory was evaluated with and without an acute challenge with KYNA’s bioprecursor L-kynurenine (Kyn; 100 mg/kg). Subchronic NAC administration protected against an acute pro-oxidant challenge, decreased KYNA levels, and lowered KAT II activity and improved memory both under basal conditions and after acute Kyn treatment. In tissue slices from these mice, KYNA neosynthesis from Trp or Kyn was reduced. Together, our data indicate that prolonged treatment with NAC may enhance memory at least in part by reducing brain KYNA levels.