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Background and purpose: Increasing evidence indicates that oxidative stress is an important factor in the pathogenesis and progression of Alzheimer’s disease (AD). Betaine is trimethylglycine with antioxidant and neuroprotective properties. The present study aimed to evaluate the possible beneficial effects of betaine on oxidative stress and memory deficits induced by intrahippocampal injection of amyloid beta (Aß) in an AD model. Experimental approach: Forty adult male Wistar rats were divided into 5 equal groups: the control and Aß groups which received oral gavage of saline (1 mL daily) for 14 days. The other 3 groups (betaine + Aß) received betaine (5, 10, and 15 mg/kg, orally) for 14 consecutive days. On the 15th day, all of the groups were injected bilaterallyintrahippocampal of Aß (5 µg/µL), except controls that were injected with normal saline as a vehicle. Seven days after the Aß injection, memory was assessed in a passive avoidance test. Changes in catalase activities and glutathione peroxidase, glutathione, and malondialdehyde concentrations were investigated to determine the antioxidant activity in the rat hippocampus. Findings/Results: Data showed that betaine pretreatment of Aß-injected rats improved memory in avoidance tasks. In addition, betaine pretreatment attenuated oxidative stress. Conclusion and implications: The current findings showed that oral administration of betaine could prevent Aß-induced impairment of memory possibly through suppression of oxidative stress in the hippocampus area of rats.

Ling Zheng,1– 3 Zhenjie Wang,2 Yujia Liu,4 Jiapei Zhao,5 Saie Huang1,3 1Rehabilitation Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China; 2College of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China; 3Fujian Key Laboratory of Rehabilitation Technology, Fuzhou, People’s Republic of China; 4College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China; 5Department of Rehabilitation Medicine, Xiamen Fifth Hospital, Xiamen, People’s Republic of ChinaCorrespondence: Saie Huang, Email saiehuang@fjtcm.edu.cnObjective: There is a relationship between non-rapid eye movement (NREM) sleep and Alzheimer’s disease (AD). The rostromedial tegmental nucleus (RMTg) is activated can enhance NREM. Therefore, our experiment was designed to investigate the effects of activation of RMTg by chemical genetic techniques on APP/PS1 mice learning and memory.Materials and Methods: After the AAV-hSyn-hM3Dq-mCherry virus was injected into the RMTg nucleus, CNO solution was intraperitoneally injected to activate RMTg. The new object test and Morris water maze were used to determine the learning and memory level; T2-weighted imaging (T2WI) scanning was performed to analyze the volume of hippocampus and entorhinal cortex of each group; The virus transfection status was determined by laser confocal microscope and use immunohistochemical detection to observe the deposition of Beta Amyloid 1– 42 (Aβ 42).Results: Activation of RMTg by chemical genetic techniques can reduce the escape latency and increase discrimination index (RI) and the number of crossing platform; Activation of RMTg by chemical genetic techniques reduced the atrophy of the entorhinal cortex. Aβ 42 deposition in the brain was decreased after activation of RMTg.Conclusion: Activation of the RMTg nucleus by chemogenetic techniques can improve the learning and memory impairment in APP/PS1 mice.Keywords: Alzheimer’s disease, chemical genetics, rostromedial tegmental nucleus, RMTg, learning and memory, amyloid-β, Aβ

Purpose: Hyperthyroidism causes adverse changes in hippocampal-dependent learning/memory functions in developmental and adult periods. In the present study, the healing effect of selenium was investigated on learning disability in offspring of mothers given L-thyroxine during lactation. Materials and Methods: 12 pregnant rats were used in the study. The pregnant rats were randomly assigned into three groups (n=8/group): Male offspring of dams administered L-thyroxine (0.2 mg/kg/day) during the lactation was formed as lactational hyper-thyroidism group (LHG), male offspring of dams administered selenium between 39-60 days after induced lactational hyperthyroid-ism was formed as lactational hyperthyroidism+selenium group (LH+SeG), male offspring of dams administered SF during the lacta-tion period was formed the control group (KG). Spatial learning/memory functions were measured with the Morris water maze (n=16/group). All measurements were made when offspring rats were 60-66 days. Results: Post-hoc test with one-way ANOVA revealed that LHG rats were found on the platform by traveling longer distances and swimming longer than the control group (p0.005). There was also not any significant difference between the groups in terms of the time spent in the target quadrant in the probe trial. Conclusion: The study findings show that high thyroid hormone levels in mother rats during lactation have long-term negative effects on hippocampal-dependent learning function in offspring rats, and selenium has a healing effect on these disorders.

IntroductionNeuroinflammation is a common feature of many psychiatric disorders as well as a common underlying mechanism of neurodegenerative diseases. Sex has been shown to strongly influence the development as well as the clinical expression of these pathologies. However, there is still a neglect regarding the consideration of sex effects in rodent experiments, and a substantial underrepresentation of females in studies. This work set out to expand our knowledge of neuroinflammatory mechanisms in female mice, at both a behavioral and molecular level.MethodsThis study used GFAP-IL6 mice, a model of chronic neuroinflammation, in which interleukin-6 (IL6) is overexpressed in the central nervous system under the control of the glial fibrillary acidic protein (GFAP) promoter. We evaluated aged (11-15-month-old) wild type-like (WT) and GFAP-IL6 female mice in behavioral tests assessing anxiety (elevated plus-maze, EPM, Light/dark box), and spatial learning and memory (Y-maze, YM and Barnes Maze, BM) and associative learning (fear conditioning, FC). We also examined gene expression of markers linked to neuroinflammation, neurodegeneration and neurotransmission via RT-qPCR in brain regions involved in motor control, anxiety, learning and memory.ResultsFemale GFAP-IL6 mice exhibited reduced anxiety-like behavior in the EPM, and hypolocomotion in the light-dark test and EPM. Short-term memory impairment was evident in the YM but associative learning in FC was intact in GFAP-IL6 mice, suggesting domain-specific cognitive deficits in female GFAP-IL6 mice. In the BM, all mice showed intact learning and memory, but GFAP-IL6 mice exhibited higher latencies to enter the escape hole than WT mice. We analyzed the search strategy and found differences in the way GFAP-IL6 mice searched for the escape hole compared to WTs. RT-qPCR showed increased mRNA levels for molecules involved in pro-inflammatory pathways in the cerebellum, motor cortex, hippocampus, and amygdala in GFAP-IL6 mice. Of the regions examined, the cerebellum and the hippocampus showed upregulation of neuroinflammatory makers as well as dysregulation of glutamatergic and GABAergic neurotransmission gene expression in GFAP-IL6 mice compared to WTs.ConclusionIn conclusion, we showed that chronic neuroinflammation via IL6 overexpression in aged female mice led to a less anxious-like phenotype, hypolocomotion and impaired intermediate-term spatial learning and memory in the YM.

At the end of the 20th century, analog systems in computer science have been widely replaced by digital systems due to their higher computing power. Nevertheless, the question keeps being intriguing until now: is the brain analog or digital? Initially, the latter has been favored, considering it as a Turing machine that works like a digital computer. However, more recently, digital and analog processes have been combined to implant human behavior in robots, endowing them with artificial intelligence (AI). Therefore, we think it is timely to compare mathematical models with the biology of computation in the brain. To this end, digital and analog processes clearly identified in cellular and molecular interactions in the Central Nervous System are highlighted. But above that, we try to pinpoint reasons distinguishing in silico computation from salient features of biological computation. First, genuinely analog information processing has been observed in electrical synapses and through gap junctions, the latter both in neurons and astrocytes. Apparently opposed to that, neuronal action potentials (APs) or spikes represent clearly digital events, like the yes/no or 1/0 of a Turing machine. However, spikes are rarely uniform, but can vary in amplitude and widths, which has significant, differential effects on transmitter release at the presynaptic terminal, where notwithstanding the quantal (vesicular) release itself is digital. Conversely, at the dendritic site of the postsynaptic neuron, there are numerous analog events of computation. Moreover, synaptic transmission of information is not only neuronal, but heavily influenced by astrocytes tightly ensheathing the majority of synapses in brain (tripartite synapse). At least at this point, LTP and LTD modifying synaptic plasticity and believed to induce short and long-term memory processes including consolidation (equivalent to RAM and ROM in electronic devices) have to be discussed. The present knowledge of how the brain stores and retrieves memories includes a variety of options (e.g., neuronal network oscillations, engram cells, astrocytic syncytium). Also epigenetic features play crucial roles in memory formation and its consolidation, which necessarily guides to molecular events like gene transcription and translation. In conclusion, brain computation is not only digital or analog, or a combination of both, but encompasses features in parallel, and of higher orders of complexity. [ABSTRACT FROM AUTHOR]

Over 38 million people worldwide are living with HIV/AIDS, and more than half of them are affected by HIV-associated neurocognitive disorders (HAND). Such disorders are characterized by chronic neuroinflammation, neurotoxicity, and central nervous system deterioration, which lead to short- or long-term memory loss, cognitive impairment, and motor skill deficits that may show gender disparities. However, the underlying mechanisms remain unclear. Our previous study suggested that HIV-1 infection and viral protein R (Vpr) upregulate the SUR1-TRPM4 channel associated with neuroinflammation, which may contribute to HAND. The present study aimed to explore this relationship in a mouse model of HAND. This study employed the HIV transgenic Tg26 mouse model, comparing Tg26 mice with wildtype mice in various cognitive behavioral and memory tests, including locomotor activity tests, recognition memory tests, and spatial learning and memory tests. The study found that Tg26 mice exhibited impaired cognitive skills and reduced learning abilities compared to wildtype mice, particularly in spatial memory. Interestingly, male Tg26 mice displayed significant differences in spatial memory losses (p < 0.001), while no significant differences were identified in female mice. Consistent with our early results, SUR1-TRPM4 channels were upregulated in Tg26 mice along with glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4), consistent with reactive astrocytosis and neuroinflammation. Corresponding reductions in neurosynaptic responses, as indicated by downregulation of Synapsin-1 (SYN1) and Synaptophysin (SYP), suggested synaptopathy as a possible mechanism underlying cognitive and motor skill deficits. In conclusion, our study suggests a possible relationship between SUR1-TRPM4-mediated neuroinflammation and synaptopathy with impairments of learning and memory in mice with HAND. These findings could help to develop new therapeutic strategies for individuals living with HAND. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of exogenous Ginsenoside Rd on the learing and memory in the brain of the neonatal periventricular leukomalacia (PVL) rat, in order to provide experimental evidence for clinical treatment of preterm infant with PVL. Methods In June 2021, A total of 120 2-day-old neonatal SD rats were selected as the experimental animals. All the experimental SD rats were caged and divided into the sham operation group, the PVL group (control group) and the PVL Ginsenoside Rd intervention group (Ginsenoside Rd intervention group) according to the principle of randomization, with 40 rats in each group. The PVL animal model was prepared by ligation of the left common carotid artery combined with hypoxia (8%O2+92%N2) for half an hour. The pathological changes of periventricular white matter area of the rats in the three groups were observed on 4, 7 and 14 days after the operation. Morris water maze experiment was conducted on 30 days after birth to explore the learning and memory ability of the rats in the three groups. Results No abnormal pathological changes were found in the white matter area of the sham operation group 4, 7 and 14 days after operation. In the control group, the tissue structure of the white matter area of the rats was obviously loose 4 days after operation, with cell swelling, necrosis and nuclear shrinkage. Both the control group and the Ginsenoside Rd intervention group had liquefaction necrosis and cyst formation in the periventricular white matter area 7 days after operation, and the left ventricle was slightly enlarged. 14 days after operation, the left ventricle of the control group was further enlarged, and the white matter around the ventricle was obviously softened. The changes of periventricular white matter in the Ginsenoside Rd intervention group were similar to those in the control group 4 to 14 days after operation, but the pathological changes of white matter were significantly lighter than those in the control group at each time point. At the same training time 30 days after birth, the escape latency of the three groups was statistically significant (P＜0. 05). There were significant differences in escape latency 3 days before training, 3 days after training and 5 days after training (P＜0. 05). There was no significant difference in escape latency between the three groups at the 4th and 5th day (P＞0. 05). There was statistical significance in the number of times of the three groups of rats passing through the circle within 120 s, that was the piercing index (P＜0. 05). Conclusion Ginsenoside Rd can reduce the damage of periventricular white matter and improve the learning and memory ability of PVL rats. [ABSTRACT FROM AUTHOR]

Many researchers are attempting to identify drugs that can be repurposed as effective therapies for Alzheimer's disease (AD). Several recent studies have highlighted epidermal growth factor receptor (EGFR) inhibitors approved for use as anti-cancer drugs as potential candidates for repurposing as AD therapeutics. In cancer, EGFR inhibitors target cell proliferation and angiogenesis, and studies in AD mouse models have shown that EGFR inhibitors can attenuate amyloid-beta (Aβ) pathology and improve cognitive function. In this review, we discuss the different functions of EGFR in cancer and AD and the potential of EGFR as a dual molecular target for AD diseases. In addition, we describe the effects of anti-cancer EGFR tyrosine kinase inhibitors (TKIs) on AD pathology and their prospects as therapeutic interventions for AD. By summarizing the physiological functions of EGFR in cancer and AD, this review emphasizes the significance of EGFR as an important molecular target for these diseases. [ABSTRACT FROM AUTHOR]

Introduction: Prolonged social isolation is a form of passive chronic stress that has consequences on human and animal behavior. The present study was undertaken to elucidate whether the long-term isolation would precipitate age-related changes in anxiety and spatial learning and memory in degus. Methods: We investigated the effects of long-term social isolation on anxiety levels in the light-dark test, and spatial orientation abilities in the Barnes maze. Middle-aged female Octodon degus were allocated to either group-housed (3 animals per cage) or individually-housed for 5 months. Results: Under this experimental condition, there were no significant group differences in the anxiety level tested in the light-dark test and in the motivation to escape from the Barnes maze. There were no significant differences in cortisol levels between individually- and group-housed animals. On the last acquisition training day of spatial learning, individually- housed animals had a significantly higher number of correct responses and a smaller number of reference and working memory errors than the group-housed animals. In addition, isolated animals showed a tendency for reference and working memory impairment on the retention trial, while group-housed degus showed improvement in these parameters. Discussion and conclusion: The present study indicates that prolonged social isolation during adulthood in female degus has a dual effect on spatial orientation. Specifically, it results in a significant improvement in acquisition skills but a slight impairment in memory retention. The obtained cognitive changes were not accompanied by modification in anxiety and cortisol levels. [ABSTRACT FROM AUTHOR]

Aims: Oxygen therapy plays a vital role in the development of bronchopulmonary dysplasia (BPD), which is the independent risk factor for neurodevelopment deficits in premature infants. However, the effect of hippocampal cyclin‐dependent kinase 5 (CDK5) on BPD‐associated neurodevelopment deficits is not fully understood. Methods: Mice were placed in a hyperoxia chamber from postnatal Day 1 to Day 7. Hematoxylin and eosin staining was used to evaluate the lung histomorphological characteristics. Learning and memory functions of mice were detected by Morris water maze. TUNEL staining was applied to measure the number of apoptotic cells. The expression of CDK5, apoptosis‐related protein, and neuroplasticity‐related proteins were analyzed by Western blot. Golgi staining was used to assess the structure of dendritic spines. Results: Hyperoxia‐induced BPD mice showed a long‐term learning and memory dysfunction, more severe neuronal apoptosis, and a decline of synaptic plasticity. Inhibition of CDK5 overactivation ameliorated cognitive deficits, neuronal apoptosis, and synaptic plasticity disorders in BPD mice. Conclusions: This study first found a vital role of CDK5 in BPD‐associated neurodevelopmental disorders. Inhibition of CDK5 overexpression could effectively improve cognitive dysfunctions in BPD mice, which indicated that hippocampal CDK5 may be a new target for prevention and treatment in learning and memory dysfunction of BPD. [ABSTRACT FROM AUTHOR]

Aim: Pulpal pain is a common orofacial health issue that has been linked to cognitive impairment. Because of its prominent role in pain modulation and cognitive impairment, apelin (Apl) is regarded as a promising target for clinical pain management. The role of Apl in orofacial pain, however, is unknown. The purpose of this study was to determine the effects of intra‐periaqueductal grey matter (PAG) administrations of Apl‐13 on capsaicin‐evoked pulpal nocifensive behaviour and capsaicin‐induced spatial learning and memory impairments in rats. Methodology: Forty‐nine male Wistar rats (200–250 g) were randomly divided into seven groups (n = 7 per group). The groups included: untreated intact, capsaicin (Caps) only, three Caps+Apl groups that received different dosages of intra‐PAG injection of Apl‐13 (1, 2 and 3 μg/rat) 20 min prior to capsaicin application, and two Apl+antagonist groups that received Apl receptor antagonist or naloxone (a μ opioid receptor) 20 min before Apl injection. Learning and memory were assessed using the Morris water maze test. One‐way analysis of variance followed by Tukey post hoc tests was used for statistical analysis. Results: Intra‐PAG administration of Apl‐13 significantly reduced the capsaicin‐induced nocifensive behaviour (p <.01). This antinociception effect was inhibited by F13A and naloxone. Apl‐13 inhibited nociception‐induced learning and memory deficits (p <.01). The cognitive effects were also blocked by pre‐treatment administration of F13A (3 μg/rat). Conclusions: These findings indicated that Apl‐13, via Apl receptors (AR or APJ) and μ opioid receptors, alleviated capsaicin‐induced dental nocifensive behaviour and protected against nociception‐induced learning and memory impairments. As a result of our findings, Apl appears to be a promising analgesic option for further research in orofacial pain models and clinical trials. [ABSTRACT FROM AUTHOR]

Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models and in humans suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals or in elderly humans before onset of disease symptoms. However, a pharmacological treatment that can reverse memory deficits in AD patients was thus far not identified. Importantly, AD disease-related dysfunctions have increasingly been associated with neuro-inflammatory mechanisms and searching for anti-inflammatory medication to treat AD seems promising. Like for other diseases, repurposing of FDA-approved drugs for treatment of AD is an ideally suited strategy to reduce the time to bring such medication into clinical practice. Of note, the sphingosine-1-phosphate analogue fingolimod (FTY720) was FDA-approved in 2010 for treatment of multiple sclerosis patients. It binds to the five different isoforms of Sphingosine-1-phosphate receptors (S1PRs) that are widely distributed across human organs. Interestingly, recent studies in five different mouse models of AD suggest that FTY720 treatment, even when starting after onset of AD symptoms, can reverse synaptic deficits and memory dysfunction in these AD mouse models. Furthermore, a very recent multi-omics study identified mutations in the sphingosine/ceramide pathway as a risk factor for sporadic AD, suggesting S1PRs as promising drug target in AD patients. Therefore, progressing with FDA-approved S1PR modulators into human clinical trials might pave the way for these potential disease modifying anti-AD drugs. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including impairment in social communication and restrictive and repetitive behaviors and interests. Music has emerged in the past decade as an intervention therapy for children with ASD. The aim of the present study was to evaluate the effects of music on cognition impairments in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism on embryonic day 12.5 (E12.5) (600 mg/kg). Male and female pups were sub divided into four main groups (Saline.Non‐music, VPA.Non‐music, Saline.Music, and VPA.Music). The rats in the music groups were exposed to Mozart's piano sonata K.448 for 30 days (4 h/day), from postnatal day (PND) 21 to 50. Autistic‐like behaviors were tested using a social interaction, the Morris water maze (MWM), and a passive avoidance tasks at the end of the PND 50. Our results demonstrated that VPA‐exposed rat pups had significantly lower sociability and social memory performance compared with the saline‐exposed rats in both sexes. VPA‐exposed rat pups exhibited learning and memory impairments in the MWM and passive avoidance tasks. Our results demonstrated that music improved sociability in VPA‐exposed rats, especially in males. Furthermore, our findings revealed that music improved learning impairments in VPA‐exposed male rats in MWM task. In addition, music improved spatial memory impairments in VPA‐exposed rats of both sexes. We also found that music improved passive avoidance memory impairments in VPA‐exposed rats of both sexes, especially in females. More investigation in future studies are needed. [ABSTRACT FROM AUTHOR]

Introduction: The aim of the current study was to investigate the probable mechanism and effect of crocin on brain oxidative damage and memory deficits induced by unpredictable chronic mild stress (UCMS). Materials and methods: Male Wistar rats were randomly divided into six groups consisting of one vehicle group (received normal saline), four groups included rats who received UCMS 4 weeks out of which three groups were pretreated with different doses of crocin (10, 20, and 30 mg/kg/day) concomitantly. To assess the pure effect of crocin, the last experimental group received a high dose of crocin (30 mg/kg/day) without exposure to the UCMS procedure. The behavioral tests including Morris water maze (MWM) and passive avoidance (PA) were performed and eventually they were sacrificed for the estimation of biochemical parameters. Results: The increase in Malondialdehyde (MDA) as an oxidative stress indicator and nitrite levels in the hippocampus were observed in UCMS rats, along with memory deficits in behavioral tests including passive avoidance and Morris water maze (MWM) test. Moreover, treatment with crocin decreased MDA, nitrite, pro-inflammatory cytokine such as TNF-α, and pathological hallmark of Alzheimer's disease including amyloid-β (Aβ), and glial fibrillary acidic protein (GFAP) in the hippocampus, whereas antioxidant agents including total thiol content, SOD, and catalase activity were increased. Also behavioral test demonstrated a positive effect of crocin on memory deficit induced by UCMS. Interlukin-10 as an important anti-inflammatory agent was increased as well. Interestingly, in some behavioral and biochemical findings, treatment with 30 mg/kg of crocin has given better results compared to vehicle group, which means the administration of crocin could have preventive effects on learning and memory impairment. Conclusion: The present study strongly confirmed the positive effect of crocin and has the potential as an antioxidant and anti-inflammatory agent that could improve memory impairment induced by UCMS. [ABSTRACT FROM AUTHOR]

Adolescence represents a distinctive vulnerable period when exposure to stressful situations including opioid exposure can entail lasting effects on brain and can change neural mechanisms involved in memory formation for drug‐associated cues, possibly increasing vulnerability of adolescents to addiction. Herein, the effects of acute adolescent morphine exposure (AAME, two injections of 2.5 mg/kg SC morphine on PND 31) were therefore investigated 6 weeks later (adulthood) on avoidance memory and hippocampal long‐term potentiation (LTP) at Schaffer collateral‐CA1 synapses in transvers slices from the ventral hippocampus in adult male rats using field recordings technique. Animal body weight was measured from PND 31 throughout PND 40 and also in four time points with 1 week intervals from adolescence to adulthood (PNDs 48, 55, 62 and 69) to evaluate the effect of AAME on the weight gain. We showed that there were no effects on body weight, anxiety‐like behaviour and locomotor activity, even until adulthood. There was an improved dark avoidance memory during adulthood. Finally, AAME had no effects on baseline synaptic responses and resulted in a decrease in the mean values of the field excitatory postsynaptic potential slopes required to evoke the half‐maximal population spike amplitude and an enhancement of LTP magnitude (%) in the ventral CA1 during adulthood. Briefly, our results suggest long‐lasting effects of acute adolescent morphine exposure on the ventral hippocampus, which begin the enhancing of synaptic plasticity and the improving of emotional memory in adulthood. [ABSTRACT FROM AUTHOR]

We propose a mechanism enabling the appearance of border cells—neurons firing at the boundaries of the navigated enclosures. The approach is based on the recent discovery of discrete complex analysis on a triangular lattice, which allows constructing discrete epitomes of complex-analytic functions and making use of their inherent ability to attain maximal values at the boundaries of generic lattice domains. As it turns out, certain elements of the discrete-complex framework readily appear in the oscillatory models of grid cells. We demonstrate that these models can extend further, producing cells that increase their activity toward the frontiers of the navigated environments. We also construct a network model of neurons with border-bound firing that conforms with the oscillatory models.

Cognitive impairment frequently coexists with diabetes. Trelagliptin is a once-weekly taking selective dipeptidyl peptidase-4 (DPP-4) inhibitor and a long-term effective hypoglycemic medicine; nonetheless, its effects for the treatment of diabetes-related cognitive impairment have only sometimes been explored. In this study, a DM model was built using streptozotocin (STZ) and a high-fat diet (HFD). The morris water maze test on DM rats revealed a considerably reduced capacity for spatial learning and memory, but trelagliptin was able to restore function. Trelagliptin could lower the mRNA expression of inflammatory factors such IL-1β, TNF-α, and IL-6 in DM rats. It could also reduce the ratio of p-IKKα/IKKα, and the immunofluorescence result of NF-κB also demonstrated a drop. Trelagliptin partially restored dendritic spines and prevented the loss or shrinkage of neurons, respectively, according to the results of Nissl's staining and golgi staining. Furthermore, PI3K/Akt/GSK-3β has been activated, and synaptic plasticity has been modified during this process. In conclusion, trelagliptin improved the cognitive lesion in DM rats by suppressing the activation of the inflammatory route and by activating the PI3K/Akt/GSK-3β pathway at the same time, as well as interacting with the pathways that protect neurons, which still need further research.

Background: Gamma sensory stimulation may reduce AD-specific pathology. Yet, the efficacy of alternating electrical current stimulation in animal models of AD is unknown, and prior research has not addressed intensity-dependent effects. Methods: The intensity-dependent effect of gamma electrical stimulation (GES) with a sinusoidal alternating current at 40 Hz on Aβ clearance and microglia modulation were assessed in 5xFAD mouse hippocampus and cortex, as well as the behavioral performance of the animals with the Morris Water Maze. Results: One hour of epidural GES delivered over a month significantly (1) reduced Aβ load in the AD brain, (2) increased microglia cell counts, decreased cell body size, increased length of cellular processes of the Iba1 + cells, and (3) improved behavioral performance (learning & memory). All these effects were most pronounced when a higher stimulation current was applied. Conclusion: The efficacy of GES on the reduction of AD pathology and the intensity-dependent feature provide guidance for the development of this promising therapeutic approach. [ABSTRACT FROM AUTHOR]

Introduction: Recombinant adeno-associated viruses (rAAVs) are widely used in genetic therapeutics. AAV5 has shown superior transduction efficiency, targeting neurons and glial cells in primate brains. Nonetheless, the comprehensive impact of AAV5 transduction on molecular and behavioral alterations remains unexplored. This study focuses on evaluating the effects of AAV5 transduction in the hippocampus, a critical region for memory formation and emotional processes. Methods: In this experiment, fluorescence-activated cell sorting (FACS) was utilized to isolate the mCherry-labeled pyramidal neurons in the hippocampus of CaMkIIα-cre mice following three different doses rAAV5-mCherry infusion after 3 weeks, which were then subjected to RNA sequencing (RNA-seq) to assess gene expression profiles. The cytokines concentration, mRNA expression, and glial response in hippocampi were confirmed by ELASA, digital droplet PCR and immunohistochemistry respectively. Locomotion and anxiety-like behaviors were elevated by Open Field Test and Elevated Plus Maze Test, while the Y-Maze were used to assessed spatial working memory. Recognition memory and fear responses were examined by the Novel Object Recognition Test and Fear Conditioning Test, respectively. Results: We found that 2.88 × 1010 v.g rAAV5 transduction significantly upregulated genes related to the immune response and apoptosis, and downregulated genes associated with mitochondrial function and synaptic plasticity in hippocampal pyramidal neurons, while did not induce neuronal loss and gliosis compared with 2.88 × 109 v.g and 2.88 × 108 v.g. Furthermore, the same doses impaired working memory and contextual fear memory, without effects on locomotion and anxiety-related behaviors. Discussion: Our findings highlight the detrimental impact of high-dose administration compared to median-dose or low-dose, resulting in increased neural vulnerability and impaired memory. Therefore, when considering the expression effectiveness of exogenous genes, it is crucial to also take potential side effects into account in clinical settings. However, the precise molecular mechanisms underlying these drawbacks of high-dose rAAV5-mCherry still require further investigation in future studies. [ABSTRACT FROM AUTHOR]

Activity-dependent changes in the number of AMPA-type glutamate receptors (AMPARs) at the synapse underpin the expression of LTP and LTD, cellular correlates of learning and memory. Post-translational ubiquitination has emerged as a key regulator of the trafficking and surface expression of AMPARs, with ubiquitination of the GluA1 subunit at Lys-868 controlling the post-endocytic sorting of the receptors into the late endosome for degradation, thereby regulating their stability at synapses. However, the physiological significance of GluA1 ubiquitination remains unknown. In this study, we generated mice with a knock-in mutation in the major GluA1 ubiquitination site (K868R) to investigate the role of GluA1 ubiquitination in synaptic plasticity, learning, and memory. Our results reveal that these male mice have normal basal synaptic transmission but exhibit enhanced LTP and deficits in LTD. They also display deficits in short-term spatial memory and cognitive flexibility. These findings underscore the critical roles of GluA1 ubiquitination in bidirectional synaptic plasticity and cognition in male mice. [ABSTRACT FROM AUTHOR]

The selective pressures leading to the elaboration of downstream, integrative processing centres, such as the mammalian neocortex or insect mushroom bodies, are often unclear. In Heliconius butterflies, the mushroom bodies are two to four times larger than those of their Heliconiini relatives, and the largest known in Lepidoptera. Heliconiini lay almost exclusively on Passiflora, which exhibit a remarkable diversity of leaf shape, and it has been suggested that the mushroom body expansion of Heliconius may have been driven by the cognitive demands of recognizing and learning leaf shapes of local host plants. We test this hypothesis using two complementary methods: (i) phylogenetic comparative analyses to test whether variation in mushroom body size is associated with the morphological diversity of host plants exploited across the Heliconiini; and (ii) shape-learning experiments using six Heliconiini species. We found that variation in the range of leaf morphologies used by Heliconiini was not associated with mushroom body volume. Similarly, we find interspecific differences in shape-learning ability, but Heliconius are not overall better shape learners than other Heliconiini. Together these results suggest that the visual recognition and learning of host plants was not a main factor driving the diversity of mushroom body size in this tribe. [ABSTRACT FROM AUTHOR]

BACKGROUND: Exercise helps prevent and retard cognitive decline related to Alzheimer’s disease, dementia, and age. However, whether exercise prevents cognitive decline in patients with Alzheimer’s disease is related to the neuromorphological changes of the hippocampus is still unclear. OBJECTIVE: To investigate the effects of long-term aerobic exercise on learning and memory ability and neuromorphology of the hippocampus in mice with Alzheimer’s disease and its neuromechanism on Alzheimer’s disease. METHODS: Twelve wild-type mice aged 3 months were divided into two groups (n=6 per group): a wild exercise group and a wild control group. Mice in the wild exercise group were given an exercise intervention for 5 months, and mice in the wild control group had no intervention. Twelve APP/PS1 double transgenic mice with Alzheimer’s disease were divided into two groups (n=6 per group): a model exercise group and a model control group. Mice in the model exercise group were given an exercise intervention for 5 months, and mice in the model control group had no intervention. After the exercise intervention, the memory ability of mice was tested through the eight-arm maze test. Neuromorphological changes of the hippocampus in mice were observed using Nissl staining under transmission electron microscope. RESULTS AND CONCLUSION: The results of the eight-arm maze test showed that the memory ability of mice in the wild exercise group was better than that in the wild control group and the model exercise group (P < 0.05), and the memory ability of mice in the model exercise group and the wild control group was better than that in the model control group (P < 0.05). The results of Nissl staining showed that the Nissl bodies with clear nuclei and nucleoli were clearly visible in the hippocampal dentate gyrus, CA3 and CA1 areas of mice in the wild exercise group and the wild control group. In the mice with Alzheimer’s disease, the Nissl bodies in the hippocampus, especially in the dentate gyrus and CA3 areas, were fuzzy, and the nuclei and nucleoli were difficult to distinguish. In particular, in the model control group, the structure of nerve cells was relatively fuzzy, some neurons were seriously damaged, nerve cells arranged loosely with large spacing interval. Under the transmission electron microscopy, the number of synapses in the hippocampal dentate gyrus was decreased in the model control group compared with the wild control group. Some synaptic clefts, presynaptic membrane, and postsynaptic membrane were blurred, and there were fewer vesicles in the presynaptic membrane. The density of postsynaptic dense zone was lower. Compared with the model control group, the number of synapses in the hippocampal dentate gyrus was increased in the model exercise group. The distribution of synaptic vesicles in the presynaptic membrane was dense and uniform, and the density of postsynaptic dense zone was increased. To conclude, exercise can improve the structure of hippocampal nerve cells in Alzheimer’s disease mice to a certain extent, which may be one of the neuromechanisms by which exercise improves the learning and memory ability of Alzheimer’s disease mice. [ABSTRACT FROM AUTHOR]

BACKGROUND: Acetylation, one of the post-translational modifications of proteins, can induce changes in gene expression related to synaptic connection and memory storage by regulating chromatin structure. Sodium butyrate, a deacetylase inhibitor, has been confirmed to play a neuroprotective effect in various neurological disease models, but it has not been confirmed in animal experiments in the field of fluorine neurotoxicity, and its targets are still not comprehensive. OBJECTIVE: To study the effect of sodium butyrate on brain injury induced by fluorosis in rats and to preliminarily explore its possible mechanism. METHODS: Newly weaned male Sprague-Dawley rats were randomly divided into three groups. Rats in fluorosis group and sodium butyrate treatment group were given distilled water containing fluorine for 10 weeks. After 10 weeks of fluoride exposure, rats in the sodium butyrate treatment group were given 1 000 mg/kg sodium butyrate daily for 4 weeks. Fluorosis group and control group were intragastrically given the same amount of normal saline. Morris water maze was used to test the learning and memory ability of rats in each group. Pathological changes of the cerebral cortex were observed by hematoxylin-eosin staining. The acetylated modified proteins were identified by performance liquid chromatography-tandem mass spectrometry and their biological information was analyzed. RESULTS AND CONCLUSION: Compared with the control group, the body mass of rats decreased and the whole brain coefficient increased in the fluorosis group. Compared with the fluorosis group, the body mass of rats increased in the sodium butyrate treatment group, and the whole brain coefficient of rats decreased. Hematoxylin-eosin staining results showed cytoplasmic vacuolation, nuclear pyknosis, and perinuclear space widening in nerve cells of the fluorosis group. In the sodium butyrate treatment group, the number of normal nerve cells increased, cytoplasmic vacuolation decreased, and nuclear pyknosis decreased. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that a large number of differential acetylated modified proteins were significantly enriched in the synaptic vesicle circulation, synaptic transmission, neurotransmitter transport, transmembrane material transport, and other pathways related to synaptic plasticity. The data of protein-protein interaction network were imported into Cytoscape software, and the top five key hub proteins were identified by different algorithms, which were Hsp8, Rab7a, Nsf, Ezr, and Cfl1. These proteins may be the pathogenic factors of fluorine neurotoxicity and the potential therapeutic targets of sodium butyrate. [ABSTRACT FROM AUTHOR]

Objective: To investigate the possible mechanism of microRNA-9-5p(miR-9-5p) and Ras homologous gene family A (RHOA) in aluminum-induced cognitive dysfunction in rats. Methods: According to the principle of randomization, 48 Wistar rats were randomly divided into four groups (n=12) of blank control, low dose, medium dose and high dose. The blank control group was gavaged daily saline, and the other three dose groups were given daily gavage AlCl3 aqueous solution at three doses of 25 mg/kg, 50 mg/kg, and 100 mg/kg to create a rat model of cognitive impairment for three months. The water maze (MWM) positioning navigation experiment was used to record the time t(s), namely, the incubation period, on the platform of rats, and the incubation period of each group was used to determine whether the rats in the infected group had learning and memory impairment. Hematoxylin-eosin (HE) and Nissl stains observed the pathological changes of nerve cells in the hippocampus of the four groups. Western blot detected the protein expression levels of RHOA and cranial neurotrophic factor (BDNF) in fresh rat hippocampal tissues. RT-qPCR detected the mRNA expression of miR-9-5p, RHOA, and BDNF in rat hippocampal tissues. Results: The results of Morris water maze positioning navigation test showed that the incubation period of each group was calculated on the 1st, 3rd and 5th days of the experiment, and the motor incubation period of the infected group was higher than that of the control group. The results of HE staining showed that the rat nerve cells in the control group were morphologically intact, the staining was clear, the nucleus was clearly visible, and the edge of the cell membrane was sharp. The rat neurons in the infected group were damaged to varying degrees, the nucleus gradually dissolved, the cytoplasmic staining became deeper, the edges of the cell membrane were blurred and disordered, and the cells were deformed and arranged disordered. The results of Nissl staining showed that the well-stained Nissl body particles were visible in the nerve cells of rats in the control group, and the dissipation of Nissl bodies in the nerve cells of the infected group was reduced, and the staining was shallow. The results of RT-qPCR showed that compared with the control group, the mRNA expression of miR-9-5p and BDNF was decreased in the infected group, and the mRNA expression of RHOA was increased (P<0.05 or P<0.001). The Western blot results showed that compared with the control group, the relative expression of BDNF in the three infected groups was decreased, and the relative expression of RHOA increased (P<0.05). Conclusion: In aluminum-induced cognitive impairment, miR-9-5p is downregulated and RHOA is upregulatd. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive impairment is the main symptom of Alzheimer's disease (AD). Accumulating evidence implicate that immunity plays an important role in AD. Here, we investigated the effect of Qi-fu-yin (QFY) on cognitive impairment and cytokine secretion of 5xFAD mice. Methods: We used 2.5-month-old 5xFAD transgenic mice for behavioral tests to observe the changes in cognitive function after QFY treatment. After the behavioral experiment, the whole brain, cortex and plasma of each mouse were collected for soluble Aβ analysis, immunohistochemical experiment and cytokine analysis. Results: Here we found that the treatment of QFY ameliorated the ability of object recognition, passive avoidance responses and the ability of spatial learning and memory in 5xFAD mice. The deposits of β1-42 and Aβ1-40 were alleviated and the ration of Aβ1-42/Aβ1-40 was decrease in the plasma and brain of 5xFAD mice administrated with QFY. The administration of QFY promoted the secretion of anti-inflammatory cytokines, IL-5, IL-10 and G-CSF, and reduced the content of proinflammatory cytokines IFN-γ in plasma of 5xFAD mice. Notably, we found that the treatment of QFY decreased the concentration of CCL11 in the brain and plasma of 5xFAD mice. Conclusion: This suggested that QFY improved cognition and reduced Aβ deposits in 5xFAD mice by regulating abnormal immunity in 5xFAD mice. QFY may be as a potential therapeutic agent for AD. [ABSTRACT FROM AUTHOR]

Panoramic views offer information on heading direction and on location to visually navigating animals. This review covers the properties of panoramic views and the information they provide to navigating animals, irrespective of image representation. Heading direction can be retrieved by alignment matching between memorized and currently experienced views, and a gradient descent in image differences can lead back to the location at which a view was memorized (positional image matching). Central place foraging insects, such as ants, bees and wasps, conduct distinctly choreographed learning walks and learning flights upon first leaving their nest that are likely to be designed to systematically collect scene memories tagged with information provided by path integration on the direction of and the distance to the nest. Equally, traveling along routes, ants have been shown to engage in scanning movements, in particular when routes are unfamiliar, again suggesting a systematic process of acquiring and comparing views. The review discusses what we know and do not know about how view memories are represented in the brain of insects, how they are acquired and how they are subsequently used for traveling along routes and for pinpointing places. [ABSTRACT FROM AUTHOR]

• The hyperactive ITPR1-D2594K mutation causes motor deficits and muscle weakness. • ITPR1 hyperactivity enhances the response to thermal and mechanical stimulation. • R-carvedilol attenuates the enhanced pain response in the ITPR1-D2594K mice. • The ITPR1-D2594K mutation has little effect on hippocampal learning and memory. Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) is an intracellular Ca2+ release channel important for a number of fundamental cellular functions. Consistent with its critical physiological significance, mutations in ITPR1 are associated with disease. Surprisingly, nearly all the disease-associated ITPR1 mutations characterized to date are loss of function. Despite the paucity of ITPR1 gain-of-function (GOF) mutations, enhanced ITPR1 function as a result of dysregulation by ITPR1 interacting proteins is thought to be associated with ataxia, learning and memory impairments, Alzheimer's disease (AD) progression, and chronic pain. However, direct evidence for the role of ITPR1 GOF in disease is lacking. To determine whether GOF in ITPR1 itself has pathological ramifications, we employed a newly developed mouse model expressing an ITPR1 mutation in the gating domain of the channel, D2594K, that markedly increased the channel's sensitivity to activation by IP 3. Behavioral studies showed that the ITPR1-D2594K+/- mutant mice displayed motor deficits and reduced muscle strength. However, the ITPR1-D2594K+/- mutation did not significantly alter hippocampal learning and memory and did not change learning and memory impairments when crossed with the 5xFAD AD model mice. On the other hand, ITPR1-D2594K+/- mice exhibited increased sensitivity to thermal and mechanical stimulation compared to WT. Interestingly, R-carvedilol treatment attenuated the enhanced thermal and mechanical nociception in ITPR1-D2594K+/- mice. Thus, the ITPR1-D2594K+/- mutation in the channel's gating domain has a marked impact on motor movements and pain perception, but little effect on hippocampal learning and memory. [ABSTRACT FROM AUTHOR]

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mRNA translation initiation plays a critical role in learning and memory. The eIF4F complex, composed of the cap-binding protein eIF4E, ATP-dependent RNA helicase eIF4A, and scaffolding protein eIF4G, is a pivotal factor in the mRNA translation initiation process. eIF4G1, the major paralogue of the three eIF4G family members, is indispensable for development, but its function in learning and memory is unknown. To study the role of eIF4G1 in cognition, we used an eIF4G1 haploinsufficient (eIF4G1-1D) mouse model. The axonal arborization of eIF4G1-1D primary hippocampal neurons was significantly disrupted, and the mice displayed impairment in hippocampus-dependent learning and memory. Translatome analysis showed that the translation of mRNAs encoding proteins of the mitochondrial oxidative phosphorylation (OXPHOS) system was decreased in the eIF4G1-1D brain, and OXPHOS was decreased in eIF4G1-silenced cells. Thus, eIF4G1-mediated mRNA translation is crucial for optimal cognitive function, which is dependent on OXPHOS and neuronal morphogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Glutamate excitotoxicity is causal in striatal neurodegeneration underlying motor dysfunction and cognitive deficits in Huntington's disease (HD). Excitatory amino acid transporter 2 (EAAT2), the predominant glutamate transporter accounting for >90% of glutamate transport, plays a key role in preventing excitotoxicity by clearing excess glutamate from the intrasynaptic cleft. Accordingly, EAAT2 has emerged as a promising therapeutic target for prevention of neuronal excitotoxicity underlying HD and other neurodegenerative diseases. Methods: We have previously designed novel EAAT2 positive allosteric modulator GT951, GTS467, and GTS551, with low nanomolar efficacy in glutamate uptake and favorable pharmacokinetic properties. In this study, we test the neuroprotective abilities of these novel EAAT2 activators in vivo using the robust Drosophila HD transgenic model expressing human huntingtin gene with expanded repeats (Htt128Q). Results: All three compounds significantly restored motor function impaired under HD pathology over a wide dose range. Additionally, treatment with all three compounds significantly improved HD-associated olfactory associative learning and short-term memory defects, while GT951 and GTS551 also improved middle-term memory in low-performing group. Similarly, treatment with GT951 and GTS551 partially protected against early mortality observed in our HD model. Further, treatment with all three EAAT2 activators induced epigenetic expression of EAAT2 Drosophila homolog and several cognition-associated genes. Conclusion: Together, these results highlight the efficacy of GT951, GTS467 and GTS551 in treating motor and cognitive impairments under HD pathology and support their development for treatment of HD. [ABSTRACT FROM AUTHOR]

Group I metabotropic glutamate receptors (mGluRI), including mGluR1 and mGluR5 subtypes, modulate essential brain functions by affecting neuronal excitability, intracellular calcium dynamics, protein synthesis, dendritic spine formation, and synaptic transmission and plasticity. Nowadays, it is well appreciated that the mGluRI-dependent long-term depression (LTD) of glutamatergic synaptic transmission (mGluRI-LTD) is a key mechanism by which mGluRI shapes connectivity in various cerebral circuitries, directing complex brain functions and behaviors, and that it is deranged in several neurological and psychiatric illnesses, including neurodevelopmental disorders, neurodegenerative diseases, and psychopathologies. Here, we will provide an updated overview of the physiopathology of mGluRI-LTD, by describing mechanisms of induction and regulation by endogenous mGluRI interactors, as well as functional physiological implications and pathological deviations. [ABSTRACT FROM AUTHOR]

Objective: Sleep deprivation has developed into a common phenomenon, which can lead to inflammatory responses and cognitive impairment, but the underlying mechanism is ambiguous. Emerging evidence shows that gut microbiota plays a crucial role in theoccurrence and development of inflammatory and psychiatric diseases, possibly through neuroinflammation and the brain-gut axis. The current study investigated the influence of sleep deprivation on gut microbiota composition, pro-inflammatory cytokines, learning and memory in mice. Further, it explored whether changes in gut microbiota increase pro-inflammatory cytokine and induce learning and memory impairment. Methods: Healthy 8-week-old male C57BL/6J mice were randomly divided into the regular control group (RC), environmental control group (EC), and sleep deprivation group (SD). The sleep deprivation model was established by the Modified Multiple Platform Method. The experimental mice were subjected to sleep deprivation for 6h/d (8:00 am∼14:00 pm) in a sleep deprivation chamber, and the duration of sleep deprivation was 8 weeks. Morris water maze test to assess learning and memory in mice. Enzyme-Linked Immunosorbent Assay determined the concentrations of inflammatory cytokines. The changes in gut microbiota in mice were analyzed by 16S rRNA sequencing. Results: We found that SD mice had elevated latency of exploration to reach the hidden platform (p>0.05) and significantly decreased traversing times, swimming distance, and swimming time in the target zone when the hidden platform was removed (p<0.05). Sleep deprivation caused dysregulated expression in serum IL-1b, IL-6, and TNF-a in mice, and the difference was significant (all p<0.001). Tannerellaceae, Rhodospirillales, Alistipes, and Parabacteroides were significantly increased in SD mice. Correlation analysis showed IL-1b was positively correlated with the abundance of Muribaculaceae (r=0.497, p<0.05) and negatively correlated with the abundance of Lachnospiraceae (r=-0.583, p<0.05). The TNF-a was positively correlated with the abundances of Erysipelotrichaceae, Burkholderiaceae, and Tannerellaceae (r=0.492, r=0.646, r=0.726, all p<0.05). Conclusion: Sleep deprivation can increase pro-inflammatory cytokine responses and learning and memory impairment in mice and may be caused by the disorder of the microbiota. These findings of this study may open avenues for potential interventions that can relieve the detrimental consequences of sleep loss. [ABSTRACT FROM AUTHOR]

Androgens are closely associated with functions of hippocampal learning, memory, and synaptic plasticity. The zinc transporter ZIP9 (SLC39A9) regulates androgen effects as a binding site distinct from the androgen receptor (AR). However, it is still unclear whether androgens regulate their functions in hippocampus of mice through ZIP9. Compared with wild-type (WT) male mice, we found that AR-deficient male testicular feminization mutation (Tfm) mice with low androgen levels had learning and memory impairment, decreased expression of hippocampal synaptic proteins PSD95, drebrin, SYP, and dendritic spine density. Dihydrotestosterone (DHT) supplementation significantly improved these conditions in Tfm male mice, although the beneficial effects disappeared after hippocampal ZIP9 knockdown. To explore the underlying mechanism, we first detected the phosphorylation of ERK1/2 and eIF4E in the hippocampus and found that it was lower in Tfm male mice than in WT male mice, it upregulated with DHT supplementation, and it downregulated after hippocampal ZIP9 knockdown. Next, we found that the expression of PSD95, p-ERK1/2, and p-eIF4E increased in DHT-treated mouse hippocampal neuron HT22 cells, and ZIP9 knockdown or overexpression inhibited or further enhanced these effects. Using the ERK1/2 specific inhibitor SCH772984 and eIF4E specific inhibitor eFT508, we found that DHT activated ERK1/2 through ZIP9, resulting in eIF4E phosphorylation, thus promoting PSD95 protein expression in HT22 cells. Finally, we found that ZIP9 mediated the effects of DHT on the expression of synaptic proteins PSD95, drebrin, SYP, and dendritic spine density in the hippocampus of APP/PS1 mice through the ERK1/2-eIF4E pathway and affected learning and memory. This study demonstrated that androgen affected learning and memory in mice through ZIP9, providing new experimental evidence for improvement in learning and memory in Alzheimer's disease with androgen supplementation. [ABSTRACT FROM AUTHOR]

It has been consistently found that exposure to ambient air pollution, such as particulate matter (PM), results in cognitive impairments and mental disorders. This study aimed to investigate the possible neuroprotective effects of curcumin, a polyphenol compound, on the neurobehavioral deficits and to identify the role of oxidative stress in dusty PM exposure rats. Rats received curcumin (50 mg/kg, daily, gavage, 2 weeks) 30 min before placing animals in a clean air chamber (≤ 150 µg/m3, 60 min daily, 2 weeks) or ambient dusty PM chamber (2000–8000 µg/m3, 60 min daily, 2 weeks). Subsequently, the cognitive and non-cognitive functions of the animals were evaluated using standard behavioral tests. Moreover, blood–brain barrier (BBB) permeability, brain water content (BWC), oxidative–antioxidative status, and histological changes were determined in the cerebral cortex and hippocampal areas of the rats. Our results showed that curcumin administration in dusty PM exposure rats attenuates memory impairment, decreases anxiety-/depression-like behaviors, and improves locomotor/exploratory activities. These findings were accompanied by reduced BBB permeability and BWC, decreasing oxidative stress, and lessening neuronal loss in the cerebral cortex and different hippocampal areas. The results of this study suggest that curcumin's antioxidant properties may contribute to its efficacy in improving neurobehavioral deficits and preventing neuronal loss associated with dusty PM exposure. [ABSTRACT FROM AUTHOR]

Introduction: Growing evidence clearly demonstrates that maternal rodents exposure to sleep deprivation (SD) during late pregnancy impairs learning and memory in their offspring. Epigenetic mechanisms, particularly histone acetylation, are known to be involved in synaptic plasticity, learning, and memory. We hypothesize that the cognitive decline induced by SD during late pregnancy is associated with histone acetylation dysfunction, and this effect could be reversed by an enriched environment (EE). Methods: In the present study, pregnant CD‐1 mice were exposed to SD during the third trimester of pregnancy. After weaning, all offspring were randomly assigned to two subgroups in either a standard environment or an EE. When offspring were 3 months old, the Morris water maze was used to evaluate hippocampal‐dependent learning and memory ability. Molecular biological techniques, including western blot and real‐time fluorescence quantitative polymerase chain reaction, were used to examine the histone acetylation pathway and synaptic plasticity markers in the hippocampus of offspring. Results: The results showed that the following were all reversed by EE treatment: maternal SD (MSD)‐induced cognitive deficits including spatial learning and memory; histone acetylation dysfunction including increased histone deacetylase 2 (HDAC2) and decreased histone acetyltransferase (CBP), and the acetylation levels of H3K9 and H4K12; synaptic plasticity dysfunction including decreased brain‐derived neurotrophic factor; and postsynaptic density protein‐95. Conclusions: Our findings suggested that MSD could damage learning ability and memory in offspring via the histone acetylation pathway. This effect could be reversed by EE treatment. [ABSTRACT FROM AUTHOR]

In order to investigate the effect of resveratrol on lanthanum -induced nerve injury and the expres sion of hypoxia inducible factor 1-a (HIF-1a) in the brain of offspring rats, a model of lanthanum exposure in 5 g/L LaCl, aqueous solution was established. After modeling, the offspring rats were randomly divided into control group, positive control group as well as low, medium and high dose resveratrol intervention groups. They were giv- en distilled water or different doses of resveratrol for 4 weeks, and the learning and memory ability of offspring rats in each group was detected the next day. The body mass, whole brain mass and hippocampus mass of offspring rats were measured before and after resveratrol intervention. The whole brain coefficient and hippocampus coefficient were calculated, and the HIF-1a mRNA and protein contents in hippocampus were determined. The results showed that the body mass of lanthanum-exposed offspring decreased and the brain development was impaired. After resveratrol intervention, the body mass, whole brain mass, hippocampus mass and tissue coefficient of lantha- num-exposed offspring rats increased gradually. With the increase of resveratrol intervention dose, the swimming distance and average escape latency of the offspring rats in the directional navigation experiment were gradually shortened (P<0.05), and the swimming distance and the time of staying in the target quadrant, the number of crossing the target quadrant and the hidden platform in the space exploration experiment were gradually increased (P<0.05). The expression level of HIF-1a mRNA in hippocampus was significantly increased (P<0.05), and the content of HIF-1a protein was significantly increased (P<0.05). Therefore, lanthanum can accumulate in the brain tissue of offspring rats, resulting in decreased learning and memory ability. Resveratrol can alleviate nerve injury caused by lanthanum exposure. The mechanism may be related to the increase of HIF-1a gene con- tent in hippocampus. [ABSTRACT FROM AUTHOR]

Racial stereotypes exert pernicious effects on decision-making and behavior, yet little is known about how stereotypes disrupt people's ability to learn new associations. The current research interrogates a fundamental question about the boundary conditions of probabilistic learning by examining whether and how learning is influenced by preexisting associations. Across three experiments, participants learned the probabilistic outcomes of different card combinations based on feedback in either a social (e.g., forecasting crime) or nonsocial (e.g., forecasting weather) learning context. During learning, participants were presented with either task-irrelevant social (i.e., Black or White faces) or nonsocial (i.e., darker or lighter clouds) stimuli that were stereotypically congruent or incongruent with the learning context. Participants exhibited learning disruptions in the social compared to nonsocial learning context, despite repeated instructions that the stimuli were unrelated to the outcome (Studies 1 and 2). We also found no differences in learning disruptions when participants learned in the presence of negatively (Black and criminal) or positively valenced stereotypes (Black and athletic; Study 3). Finally, we tested whether learning decrements were due to "first-order" stereotype application or inhibition at the trial level, or due to "second-order" cognitive load disruptions that accumulate across trials due to fears of appearing prejudiced (aggregated analysis). We found no evidence of first-order disruptions and instead found evidence for second-order disruptions: participants who were more internally motivated to respond without prejudice, and thus more likely to self-monitor their responses, learned less accurately over time. We discuss the implications of the influence of stereotypes on learning and memory. [ABSTRACT FROM AUTHOR]

When making decisions based on probabilistic outcomes, people guide their behavior using knowledge gathered through both indirect descriptions and direct experience. Paradoxically, how people obtain information significantly impacts apparent preferences. A ubiquitous example is the description-experience gap: individuals seemingly overweight low probability events when probabilities are described yet underweight them when probabilities must be experienced firsthand. A leading explanation for this fundamental gap in decision-making is that probabilities are weighted differently when learned through description relative to experience, yet a formal theoretical account of the mechanism responsible for such weighting differences remains elusive. We demonstrate how various learning and memory retention models incorporating neuroscientifically motivated learning mechanisms can explain why probability weighting and valuation parameters often are found to vary across description and experience. In a simulation study, we show how learning through experience can lead to systematically biased estimates of probability weighting when using a traditional cumulative prospect theory model. We then use hierarchical Bayesian modeling and Bayesian model comparison to show how various learning and memory retention models capture participants' behavior over and above changes in outcome valuation and probability weighting, accounting for description and experience-based decisions in a within-subject experiment. We conclude with a discussion of how substantive models of psychological processes can lead to insights that heuristic statistical models fail to capture. [ABSTRACT FROM AUTHOR]

Novel monoterpene-based hydroxamic acids of two structural types were synthesized for the first time. The first type consisted of compounds with a hydroxamate group directly bound to acyclic, monocyclic and bicyclic monoterpene scaffolds. The second type included hydroxamic acids connected with the monoterpene moiety through aliphatic (hexa/heptamethylene) or aromatic linkers. An in vitro analysis of biological activity demonstrated that some of these molecules had powerful HDAC6 inhibitory activity, with the presence of a linker area in the structure of compounds playing a key role. In particular, it was found that hydroxamic acids containing a hexa- and heptamethylene linker and (-)-perill fragment in the Cap group exhibit excellent inhibitory activity against HDAC6 with IC50 in the submicromolar range from 0.56 ± 0.01 µM to 0.74 ± 0.02 µM. The results of the study of antiradical activity demonstrated the presence of moderate ability for some hydroxamic acids to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2ROO• radicals. The correlation coefficient between the DPPH radical scavenging activity and oxygen radical absorbance capacity (ORAC) value was R2 = 0.8400. In addition, compounds with an aromatic linker based on para-substituted cinnamic acids, having a monocyclic para-menthene skeleton as a Cap group, 35a, 38a, 35b and 38b, demonstrated a significant ability to suppress the aggregation of the pathological β-amyloid peptide 1-42. The 35a lead compound with a promising profile of biological activity, discovered in the in vitro experiments, demonstrated neuroprotective effects on in vivo models of Alzheimer's disease using 5xFAD transgenic mice. Together, the results obtained demonstrate a potential strategy for the use of monoterpene-derived hydroxamic acids for treatment of various aspects of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

This study explored the potential contribution of Orx1R within vlPAG to the learning and memory of animals with chronic migraine-like pain. Migraine was induced by repeated i.p. administration of nitroglycerin (5 mg/kg). Passive avoidance adeptness was evaluated in the shuttle box maze. The spatial memory performance was estimated using MWM tests. In the MWM task, NTG-injected rats revealed an imperative increase in escape latency and traveled the distance to catch the stage and a decrease in the time spent to pass into the goal zone in comparison to the control animals. Such NTG-evoked responses were attenuated by the post-treating intra-vlPAG injection of orexin A at 100 but not 25 and 50 pM. Furthermore, in the shuttle box test, NTG-treated rats showed eversion memory retrieval impairment as reflected by decreased phase through latency and longer time spent in the black chambers of the maze. Administration of orexin A at 50 and 100 pM could suppress NTG-related eversion memory deficiency in rats. However, orexin A (100 pM) aptitude to preserve memory performance, in both MWM and shuttle box tasks, was significantly prevented by SB334867 (20 nM) as an Orx1R antagonist. Overall, these data support the role of Orx1R within vlPAG to modulate migraine-related cognition deficits in rats. [ABSTRACT FROM AUTHOR]

Mutations in genes encoding amyloid precursor protein (APP) and presenilins (PSs) cause familial forms of Alzheimer's disease (AD), a neurodegenerative disorder strongly associated with aging. It is currently unknown whether and how AD risks affect early brain development, and to what extent subtle synaptic pathology may occur prior to overt hallmark AD pathology. Transgenic mutant APP/PS1 over-expression mouse lines are key tools for studying the molecular mechanisms of AD pathogenesis. Among these lines, the 5XFAD mice rapidly develop key features of AD pathology and have proven utility in studying amyloid plaque formation and amyloid β (Aβ)-induced neurodegeneration. We reasoned that transgenic mutant APP/PS1 over-expression in 5XFAD mice may lead to neurodevelopmental defects in early cortical neurons, and performed detailed synaptic physiological characterization of layer 5 (L5) neurons from the prefrontal cortex (PFC) of 5XFAD and wild-type littermate controls. L5 PFC neurons from 5XFAD mice show early APP/Aβ immunolabeling. Whole-cell patch-clamp recording at an early post-weaning age (P22–30) revealed functional impairments; although 5XFAD PFC-L5 neurons exhibited similar membrane properties, they were intrinsically less excitable. In addition, these neurons received smaller amplitude and frequency of miniature excitatory synaptic inputs. These functional disturbances were further corroborated by decreased dendritic spine density and spine head volumes that indicated impaired synapse maturation. Slice biotinylation followed by Western blot analysis of PFC-L5 tissue revealed that 5XFAD mice showed reduced synaptic AMPA receptor subunit GluA1 and decreased synaptic NMDA receptor subunit GluN2A. Consistent with this, patch-clamp recording of the evoked L23>L5 synaptic responses revealed a reduced AMPA/NMDA receptor current ratio, and an increased level of AMPAR-lacking silent synapses. These results suggest that transgenic mutant forms of APP/PS1 overexpression in 5XFAD mice leads to early developmental defects of cortical circuits, which could contribute to the age-dependent synaptic pathology and neurodegeneration later in life. [ABSTRACT FROM AUTHOR]

Genistein (GEN) is a non-steroidal phytoestrogen that belongs to the isoflavone class. It is abundantly found in soy. Soy and its products are used as food components in many countries including India. The present review is focused to address roles of GEN in brain functions in the context of learning and memory as a function of aging and neurological disorders. Memory decline is one of the most disabling features observed during normal aging and age-associated neurodegenerative disorders namely Alzheimer's disease (AD) and Parkinson's disease (PD), etc. Anatomical, physiological, biochemical and molecular changes in the brain with advancement of age and pathological conditions lead to decline of cognitive functions. GEN is chemically comparable to estradiol and binds to estrogen receptors (ERs). GEN acts through ERs and mimics estrogen action. After binding to ERs, GEN regulates a plethora of brain functions including learning and memory; however detailed study still remains elusive. Due to the neuroprotective, anti-oxidative and anti-inflammatory properties, GEN is used to restore or improve memory functions in different animal models and humans. The present review may be helpful to understand roles of GEN in learning and memory during aging and neurological disorders, its direction of research and therapeutic perspectives. [ABSTRACT FROM AUTHOR]

Nutrient supplementation during gestation and lactation is the basis for neurodevelopment, improving brain development including the learning and memory function of the offspring. Maternal supplementation with edible bird’s nest (EBN) has beneficial roles in the brain development of the offspring, but the mechanism has not been elucidated. In the current study, pregnant rats were given EBN (4.5 g/kg, 9 g/kg) and sialic acid (45 mg/kg) until the offspring were weaned. EBN was more effective at increasing learning and memory and hippocampal development than sialic acid of the offspring. In detail, EBN increased the synaptic plasticity of existing neurons and enhanced hippocampal neurogenesis of offspring, as well as upregulated the ERK-CREB-BDNF signaling pathway. It was concluded that maternal administration of EBN improved the learning and memory function of the offspring by accelerating hippocampus development by regulating the ERK-CREB-BDNF signaling pathway. Overall, EBN might be a potential maternal supplement in promoting neurodevelopment in offspring.

Perinatal exposure to bifenthrin (BF) alters neurodevelopment. However, the most susceptible time period to BF exposure and the possible mechanisms are not clear. In the current study, pregnant female mice were treated with BF (0.5 mg/kg/d) at three different stages [gestational day (GD) 0–5, 6–15 and 16-birth (B)] and neurologic deficits were evaluated in offspring mice. BF exposure at GD 16-B significantly altered the locomotor activity and caused learning and memory impairments in 6-week-old offspring. Gestational BF exposure also caused neuronal loss in the region of cornu ammonis of hippocampi of 6-week-old offspring. Interestingly, neurobehavioral impairments and neuronal loss were not observed in offspring at 10-week-old. BF exposure at GD 16-B also decreased protein levels of VGluT1, NR1 and NR2A while increased the protein levels of NR2B and VGAT1, as well as the gene levels of Il-1β, Il-6 and Tnf-α in hippocampi of 6-week-old offspring. Collectively, these data demonstrate that gestational exposure to a low dose BF causes neurodevelopmental deficits that remit with the age and the late-stage of pregnancy is the most susceptible time window to BF exposure. Imbalance in excitatory/inhibitory neuronal transmission, altered expression levels of NMDA receptors and increased neural inflammation may be associated with BF prenatal exposure-triggered neurobehavioral impairments.

The mechanisms underlying the formation and retrieval of memories are still an active area of research and discussion. Manifold models have been proposed and refined over the years, with most assuming a dichotomy between memory processes involving non-conscious and conscious mechanisms. Despite our incomplete understanding of the underlying mechanisms, tests of memory and learning count among the most performed behavioral experiments. Here, we will discuss available protocols for testing learning and memory using the example of the most prevalent animal species in research, the laboratory mouse. A wide range of protocols has been developed in mice to test, e.g., object recognition, spatial learning, procedural memory, sequential problem solving, operant- and fear conditioning, and social recognition. Those assays are carried out with individual subjects in apparatuses such as arenas and mazes, which allow for a high degree of standardization across laboratories and straightforward data interpretation but are not without caveats and limitations. In animal research, there is growing concern about the translatability of study results and animal welfare, leading to novel approaches beyond established protocols. Here, we present some of the more recent developments and more advanced concepts in learning and memory testing, such as multi-step sequential lockboxes, assays involving groups of animals, as well as home cage-based assays supported by automated tracking solutions; and weight their potential and limitations against those of established paradigms. Shifting the focus of learning tests from the classical experimental chamber to settings which are more natural for rodents comes with a new set of challenges for behavioral researchers, but also offers the opportunity to understand memory formation and retrieval in a more conclusive way than has been attainable with conventional test protocols. We predict and embrace an increase in studies relying on methods involving a higher degree of automatization, more naturalistic- and home cage-based experimental setting as well as more integrated learning tasks in the future. We are confident these trends are suited to alleviate the burden on animal subjects and improve study designs in memory research.

The brain is complex and metabolically active, and the detection of metabolites plays an important role in brain development and diseases. Currently, there is a lack of research on the metabolic spectrum changes in learning and memory impairment, and hippocampal damage induced by microwave radiation from the metabolic perspective. Aiming to provide sensitive indicators for microwave radiation-induced brain damage and establish a foundation for understanding its injury mechanisms, this study employed non-targeted metabolomics to investigate metabolic fluctuations and key metabolic pathway alterations in rats’ hippocampal tissue after microwave radiation. The memory and spatial exploration abilities of rats decreased after radiation. The postsynaptic densities were thickened in the MW group. The cholesterol sulfate, SM(d16:1/24:1(15Z)), and linoelaidylcarnitine were significantly increased after radiation, whereas etrahydrocorticosterone, L-phenylalanine, and histamine were significantly decreased after radiation. These metabolites were enriched in signaling pathways related to the inflammatory mediator regulation of transient receptor potential (TRP) channels, neuroactive ligand–receptor interaction, steroid hormone biosynthesis, and phenylalanine, tyrosine, and tryptophan biosynthesis. These findings indicate that microwave radiation causes spatial learning and memory dysfunction in rats and structural damage to hippocampal tissue.

Novelty detection, crucial to episodic memory formation, is impaired in epileptic patients with mesial temporal lobe resection. Mismatch novelty detection, that activates the hippocampal CA1 area in humans and is vital for memory reformulation and reconsolidation, is also impaired in patients with hippocampal lesions. In this work, we investigated the response to mismatch novelty, as occurs with the new location of known objects in a familiar environment, in the Li2+-pilocarpine rat model of TLE and its correlation with hippocampal monoaminergic markers. Animals showing spontaneous recurrent seizures (SRSs) for at least 4 weeks at the time of behavioural testing showed impaired spatial learning in the radial arm maze, as described. Concurrently, SRS rats displayed impaired exploratory responses to mismatch novelty, yet novel object recognition was not significantly affected in SRS rats. While the levels of serotonin and dopamine transporters were mildly decreased in hippocampal membranes from SRS rats, the levels on the norepinephrine transporter, tyrosine hydroxylase and dopamine-β-hydroxylase were enhanced, hinting for an augmentation, rather than an impairment in noradrenergic function in SRS animals. Altogether, this reveals that mismatch novelty detection is particularly affected by hippocampal damage associated to the Li2+-pilocarpine model of epilepsy 4–8 weeks after the onset of SRSs and suggests that deficits in mismatch novelty detection may substantially contribute to cognitive impairment in MTLE. As such, behavioural tasks based on these aspects of mismatch novelty may prove useful in the development of cognitive therapy strategies aiming to rescue cognitive deficits observed in epilepsy.