Impaired Spatial Memory Research Articles

Schisandrin A Alleviates Spatial Learning and Memory Impairment in Diabetic Rats by Inhibiting Inflammatory Response and Through Modulation of the PI3K/AKT Pathway.

Clinical and epidemiological research shows that people with diabetes mellitus frequently experience diabetic cognitive impairment. Schisandrin A (SchA), one of the lignans found in the dried fruit of Schisandra chinensis, has a variety of pharmacological effects on immune system control, apoptosis suppression, anti-oxidation and anti-inflammation. The goal of the current investigation was to clarify the probable neuro-protective effects of SchA against streptozotocin-induced diabetes deficiencies of the spatial learning and memory in rats. The outcomes show that SchA therapy effectively improved impaired glucose tolerance, fasting blood glucose level and serum insulin level in diabetic rats. Additionally, in the Morris water maze test, diabetic rats showed deficits in spatial learning and memory that were ameliorated by SchA treatment. Moreover, giving diabetic rats SchA reduced damage to the hippocampus structure and increased the production of synaptic proteins. Further research revealed that SchA therapy reduced diabetic-induced hippocampus neuron damage and the generation of Aβ, as demonstrated by the upregulated phosphorylation levels of insulin signaling pathway connected proteins and by the decreased expression levels of inflammatory-related factors. Collectively, these results suggested that SchA could improve diabetes-related impairments in spatial learning and memory, presumably by reducing inflammatory responses and regulating the insulin signaling system.

Transplanting old organs promotes senescence in young recipients

In clinical organ transplantation, donor and recipient ages may differ substantially. Old donor organs accumulate senescent cells that have the capacity to induce senescence in naïve cells. We hypothesized that the engraftment of old organs may induce senescence in younger recipients, promoting age-related pathologies. When performing isogeneic cardiac transplants between age-mismatched C57BL/6 old donor (18 months) mice and young and middle-aged C57BL/6 (3- or 12- month-old) recipients , we observed augmented frequencies of senescent cells in draining lymph nodes, adipose tissue, livers, and hindlimb muscles 30 days after transplantation. These observations went along with compromised physical performance and impaired spatial learning and memory abilities. Systemic levels of the senescence-associated secretory phenotype factors, including mitochondrial DNA (mt-DNA), were elevated in recipients. Of mechanistic relevance, injections of mt-DNA phenocopied effects of age-mismatched organ transplantation on accelerating aging. Single treatment of old donor animals with senolytics prior to transplantation attenuated mt-DNA release and improved physical capacities in young recipients. Collectively, we show that transplanting older organs induces senescence in transplant recipients, resulting in compromised physical and cognitive capacities. Depleting senescent cells with senolytics, in turn, represents a promising approach to improve outcomes of older organs.

Quantitative susceptibility mapping in rats with minimal hepatic encephalopathy: Does iron overload aggravate cognitive impairment by promoting neuroinflammation?

Background and aimsMinimal hepatic encephalopathy (MHE) is a mild form of hepatic encephalopathy that lacks observable signs and symptoms. Nevertheless, MHE can cause neurocognitive dysfunction, although the neurobiological mechanisms are not fully understood. Here, the effects of hippocampal iron deposition on cognitive function and its role in MHE were investigated. Materials and methodsEighteen rats were assigned to experimental and control groups. MHE was induced by thioacetamide. Spatial memory and exploratory behavior were assessed by the Morris water and elevated plus mazes. Hippocampal susceptibility was measured by quantitative susceptibility mapping, iron deposition in the hippocampus and liver by Prussian blue staining, and inflammatory cytokine and ferritin levels in the hippocampus were measured by ELISA. ResultsMHE rats showed impaired spatial memory and exploratory behavior (P < 0.05 for all parameters). The bilateral hippocampal susceptibility values were significantly raised in MHE rats, together with evidence of neuroinflammation (increased pro-inflammatory and reduced anti-inflammatory cytokine levels (all P < 0.05). Further analysis indicated good correlations between hippocampal susceptibility values with latency time and inflammatory cytokine levels in MHE but not in control rats. ConclusionMHE induced by thioacetamide was associated with hippocampal iron deposition and inflammation, suggesting that iron overload may be an important driver of neuroinflammatory responses.

Mitochondrial OPA1 Deficiency Is Associated to Reversible Defects in Spatial Memory Related to Adult Neurogenesis in Mice.

Mitochondria are integrative hubs central to cellular adaptive pathways. Such pathways are critical in highly differentiated postmitotic neurons, the plasticity of which sustains brain function. Consequently, defects in mitochondria and in their dynamics appear instrumental in neurodegenerative diseases and may also participate in cognitive impairments. To directly test this hypothesis, we analyzed cognitive performances in a mouse mitochondria-based disease model, because of haploinsufficiency in the mitochondrial optic atrophy type 1 (OPA1) protein involved in mitochondrial dynamics. In males, we evaluated adult hippocampal neurogenesis parameters using immunohistochemistry. We performed a battery of tests to assess basal behavioral characteristics and cognitive performances, and tested putative treatments. While in dominant optic atrophy (DOA) mouse models, the known main symptoms are late onset visual deficits, we discovered early impairments in hippocampus-dependent spatial memory attributable to defects in adult neurogenesis. Moreover, less connected adult-born hippocampal neurons showed a decrease in mitochondrial content. Remarkably, voluntary exercise or pharmacological treatment targeting mitochondrial dynamics restored spatial memory in DOA mice. Altogether, our study identifies a crucial role for OPA1-dependent mitochondrial functions in adult neurogenesis, and thus in hippocampal-dependent cognitive functions. More generally, our findings show that adult neurogenesis is highly sensitive to mild mitochondrial defects, generating impairments in spatial memory that can be detected at an early stage and counterbalanced by physical exercise and pharmacological targeting of mitochondrial dynamics. Thus, amplification of mitochondrial function at an early stage appears beneficial for late-onset neurodegenerative diseases.

The impact of early life stress and schizophrenia on motor and cognitive functioning: an experimental study

BackgroundEarly life stress (ELS) and parental psychopathology, such as schizophrenia (SZ), have been associated with altered neurobiological and behavioral outcomes later in life. Previous studies have investigated the effects of ELS and parental SZ on various aspects of behavior, however, we have studied the combined effects of these stressors and how they interact, as individuals in real-life situations may experience multiple stressors simultaneously.ObjectiveThe aim of this study was to investigate the impact of ELS and schizophrenia on locomotor activity, anxiety-like behavior, exploratory tendencies, and spatial memory in Sprague Dawley (SD) rats.MethodsMale and female SD pups were randomly assigned to eight groups: control, ELS, schizophrenia, and ELS + schizophrenia. ELS was induced by prenatal stress (maternal stress) and maternal separation (MS) during the first 2 weeks of life, while SZ was induced by subcutaneous administration of ketamine. Behavioral tests included an open field test (OFT) for motor abilities and a Morris water maze (MWM) for cognitive abilities. ANOVA and post hoc Tukey tests were utilized to analyze the data.ResultsOur results show that ELS and parental psychopathology had enduring effects on SZ symptoms, particularly psychomotor retardation (p &amp;lt; 0.05). The OFT revealed increased anxiety-like behavior in the ELS group (p = 0.023) and the parental psychopathology group (p = 0.017) compared to controls. The combined ELS and parental psychopathology group exhibited the highest anxiety-like behavior (p = 0.006). The MWM analysis indicated impaired spatial memory in the ELS group (p = 0.012) and the combined ELS and parental psychopathology group (p = 0.003) compared to controls. Significantly, the exposure to ELS resulted in a decrease in the population of glial fibrillary acidic protein-positive (GFAP+) astrocytes. However, this effect was reversed by positive parental mental health.ConclusionOur findings highlight the interactive effects of ELS and parental psychopathology on anxiety-like behavior and spatial memory in rats. ELS was linked to increased anxiety-like behavior, while SZ was associated with anhedonia-like behavior. Positive parenting augments neuroplasticity, synaptic function, and overall cognitive capacities.

Extracellular proteins as potential biomarkers in Sepsis-related cerebral injury.

Sepsis can cause brain damage known as septic encephalopathy (SAE), which is linked to higher mortality and poorer outcomes. Objective clinical markers for SAE diagnosis and prognosis are lacking. This study aimed to identify biomarkers of SAE by investigating genes and extracellular proteins involved in sepsis-induced brain injury. Extracellular protein differentially expressed genes (EP-DEGs) from sepsis patients' brain tissue (GSE135838) were obtained from Gene Expression Omnibus (GEO) and evaluated by protein annotation database. The function and pathways of EP-DEGs were examined using GO and KEGG. Protein-protein interaction (PPI) networks were built and crucial EP-DEGs were screened using STRING, Cytoscape, MCODE, and Cytohubba. The diagnostic and prognostic accuracy of key EP-DEGs was assessed in 31 sepsis patients' blood samples and a rat cecal ligation and puncture (CLP)-induced sepsis model. Cognitive and spatial memory impairment was evaluated 7-11 days post-CLP using behavioral tests. Blood and cerebrospinal fluid from 26 rats (SHAM n=14, CLP n=12) were collected 6 days after CLP to analyze key EP-DEGs. Thirty-one EP-DEGs from DEGs were examined. Bone marrow leukocytes, neutrophil movement, leukocyte migration, and reactions to molecules with bacterial origin were all enhanced in EP-DEGs. In comparison to the sham-operated group, sepsis rats had higher levels of MMP8 and S100A8 proteins in their venous blood (both p<0.05) and cerebrospinal fluid (p=0.0506, p<0.0001, respectively). Four important extracellular proteins, MMP8, CSF3, IL-6, and S100A8, were identified in clinical peripheral blood samples. MMP8 and S100A8 levels in the peripheral blood of sepsis patients were higher in SAE than in non-SAE. In comparison to MMP8, S100A8 had a higher area under the curve (AUC: 0.962, p<0.05) and a higher sensitivity and specificity (80% and 100%, respectively) than MMP8 (AUC: 0.790, p<0.05). High levels of S100A8 strongly correlated with 28-day mortality and the Glasgow Coma Scale (GCS) scores. The extracellular proteins MMP8, CSF3, IL-6, and S100A8 may be crucial in the pathophysiology of SAE. S100A8 and MMP8 are possible biomarkers for SAE's onset and progression. This research may help to clarify the pathogenesis of SAE and improve the diagnosis and prognosis of the disease.

Effects of FB1 and HFB1 on Autonomous Exploratory and Spatial Memory and Learning Abilities in Mice.

Fumonisin B1 (FB1) is a representative form of fumonisin and is widely present in food and feed. Hydrolyzed fumonisin B1 (HFB1) emerges as a breakdown product of FB1, which is accompanied by FB1 alterations. While previous studies have primarily focused on the liver or kidney toxicity of FB1, with limited studies existing on its neurotoxicity and even fewer on the toxicity of HFB1, this study focuses on the neurotoxicity of FB1 and HFB1 exposure in mice investigated by the open field test, Morris water maze test, histopathological analysis, and nontargeted metabolomics. Further, the levels of oxidative stress-related indices, neurotransmitters, and sphingolipids in the brain were measured to analyze their correlation with behavioral outcomes. The results showed that both FB1 (5 mg/kg) and HFB1 (2.8 mg/kg) reduced autonomous exploratory behavior in mice, impaired spatial learning and memory, and caused mild abnormalities in the brain structure. Quantitative analysis further indicated that exposure to FB1 and HFB1 disrupted neurotransmitter homeostasis, exacerbated oxidative stress, and significantly increased the sphinganine/sphingosine (Sa/So) ratio. Moreover, HFB1 exhibited neurotoxic effects similar to those of FB1, emphasizing the need to pay attention to the neurotoxicity effect of HFB1. These findings underscore the importance of understanding the risks and potential neurological damage associated with FB1 and HFB1 exposure, highlighting the necessity for further research in this crucial field.

Ketamine evoked disruption of entorhinal and hippocampal spatial maps

Ketamine, a rapid-acting anesthetic and acute antidepressant, carries undesirable spatial cognition side effects including out-of-body experiences and spatial memory impairments. The neural substrates that underlie these alterations in spatial cognition however, remain incompletely understood. Here, we used electrophysiology and calcium imaging to examine ketamine’s impacts on the medial entorhinal cortex and hippocampus, which contain neurons that encode an animal’s spatial position, as mice navigated virtual reality and real world environments. Ketamine acutely increased firing rates, degraded cell-pair temporal firing-rate relationships, and altered oscillations, leading to longer-term remapping of spatial representations. In the reciprocally connected hippocampus, the activity of neurons that encode the position of the animal was suppressed after ketamine administration. Together, these findings demonstrate ketamine-induced dysfunction of the MEC-hippocampal circuit at the single cell, local-circuit population, and network levels, connecting previously demonstrated physiological effects of ketamine on spatial cognition to alterations in the spatial navigation circuit.

27-Hydroxycholesterol impairs learning and memory ability via decreasing brain glucose uptake mediated by the gut microbiota

Brain glucose hypometabolism is a significant manifestation of Alzheimer’s disease (AD). 27-hydroxycholesterol (27-OHC) and the gut microbiota have been recognized as factors possibly influencing the pathogenesis of AD. This study aimed to investigate the link between 27-OHC, the gut microbiota, and brain glucose uptake in AD. Here, 6-month-old male C57BL/6 J mice were treated with sterile water or antibiotic cocktails, with or without 27-OHC and/or 27-OHC synthetic enzyme CYP27A1 inhibitor anastrozole (ANS). The gut microbiota, brain glucose uptake levels, and memory ability were measured. We observed that 27-OHC altered microbiota composition, damaged brain tissue structures, decreased the 2-deoxy-2-[18 F] fluorodeoxyglucose (18F-FDG) uptake value, downregulated the gene expression of glucose transporter type 4 (GLUT4), reduced the colocalization of GLUT1/glial fibrillary acidic protein (GFAP) in the hippocampus, and impaired spatial memory. ANS reversed the effects of 27-OHC. The antibiotic-treated mice did not exhibit similar results after 27-OHC treatment. This study reveals a potential molecular mechanism wherein 27-OHC-induced memory impairment might be linked to reduced brain glucose uptake, mediated by the gut microbiota.

Parental folic acid deficiency delays neurobehavioral development in rat offspring by inhibiting the differentiation of neural stem cells into neurons

Maternal folate status during pregnancy is associated with the neurodevelopment of offspring; however, study results on the association between paternal folate status and offspring neurodevelopment are inconsistent. This study aimed to explore whether parental folic acid deficiency affects the neurobehavioral development of offspring by affecting the differentiation of neural stem cells (NSCs) into neurons. In the present study, the offspring were divided into four groups: parental folic acid deficient group (D-D), maternal folic acid deficient and paternal folic acid normal group (D-N), maternal folic acid normal and paternal folic acid deficient group (N-D), and parental folic acid normal group (N-N). For in vivo study, neurobehavioral indexes, and neuron-specific nuclear protein (NeuN) and glial fibrillary acidic protein (GFAP) expression in the brain hippocampus and cerebral cortex of offspring were measured at different time points. For in vitro study, NSCs were cultured from the hippocampus and striatum, and neuronal and astrocytic differentiation were measured. The results demonstrated that parental folic acid deficiency decreased the brain folate level in offspring, delayed early sensory-motor reflex development, impaired spatial learning and memory ability in adolescence and adulthood, decreased differentiation of NSCs into neurons and increased differentiation of NSCs into astrocytes in vivo and in vitro. These impacts on the neurodevelopment of offspring were most pronounced in D-D group, followed by D-N group and N-D group. In conclusion, parental folic acid deficiency inhibits the neurobehavioral development of offspring, possibly by inhibiting the differentiation of NSCs into neurons.

Zingiber officinale Exhibits Neuroprotective Properties against Tramadol-Induced Spatial Memory Impairment and Histopathological Changes

Drug abuse has been on the increase in recent years. Tramadol is one of such drug commonly misused and reported to have neurotoxic effects. However, Zingiber officinale has been reported to have neuroprotective properties. This study aimed to evaluate the neuroprotective effects of Z. officinale on spatial memory deficits in tramadol-treated Wistar rats. Thirty adult male Wistar rats were divided into five groups, and respectively, orally administered the following for 21 days: the control group (2 ml/kg of distilled water), tramadol (Tram, 50 mg/kg), tramadol (50 mg/kg)+naltrexone (12.5 mg/kg), and tramadol (50 mg/kg)+Z. officinale (500 mg/kg+1000 mg/kg, respectively). A Morris water maze test was conducted for the assessment of spatial memory. The rats were euthanized by transcardiac perfusion, and the brains were harvested, fixed, and processed using haematoxylin and eosin stain for histology. A remarkable decrease in latency time and an increase in distance covered to locate the platform were observed in the tramadol-treated group compared to the control in the acquisition phase. The probe test showed a remarkable decrease in the time spent in the escape platform quadrant in the tramadol-treated group compared with the control. Neurodegenerative changes were observed in the hippocampus of the tramadol group, presenting as karyorrhexis, gliosis, and perineural vacuolation. These neurodegenerative changes were attenuated in Z. officinale-treated groups in a dose-dependent manner. Z. officinale improved the learning and memory of tramadol-treated rats. Findings from this study suggest that Z. officinale attenuated tramadol-induced neurotoxicity in Wistar rats

Effects of HMGB1/RAGE/cathespin B inhibitors on alleviating hippocampal injury by regulating microglial pyroptosis and caspase activation in neonatal hypoxic-ischemic brain damage.

Microglia play a crucial role in regulating neuroinflammation in the pathogenesis of neonatal hypoxic-ischemic brain damage (HIBD). Pyroptosis, an inflammatory form of programmed cell death, has been implicated in HIBD; however, its underlying mechanism remains unclear. We previously demonstrated that high-mobility group box 1 protein (HMGB1) mediates neuroinflammation and microglial damage in HIBD. In this study, we aimed to investigate the association between HMGB1 and microglial pyroptosis and elucidate the mechanism involved in rats with HIBD (both sexes were included) and in BV2 microglia subjected to oxygen-glucose deprivation. Our results showed that HMGB1 inhibition by glycyrrhizin (20 mg/kg) reduced the expression of microglial pyroptosis-related proteins, including caspase-1, the N-terminus fragment of gasdermin D (N-GSDMD), and pyroptosis-related inflammatory factors, such as interleukin (IL) -1β and IL-18. Moreover, HMGB1 inhibition resulted in reduced neuronal damage in the hippocampus 72 h after HIBD and ultimately improved neurobehavior during adulthood, as evidenced by reduced escape latency and path length, as well as increased time and distance spent in the target quadrant during the Morris water maze test. These results revealed that HIBD-induced pyroptosis is mediated by HMGB1/receptor for advanced glycation end products (RAGE) signaling (inhibition by FPS-ZM1, 1 mg/kg) and the activation of cathespin B (cat B). Notably, cat B inhibition by CA074-Me (5 mg/kg) also reduced hippocampal neuronal damage by suppressing microglial pyroptosis, thereby ameliorating learning and memory impairments caused by HIBD. Lastly, we demonstrated that microglial pyroptosis may contribute to neuronal damage through the HMGB1/RAGE/cat B signaling pathway in vitro. In conclusion, these results suggest that HMGB1/RAGE/cat B inhibitors can alleviate hippocampal injury by regulating microglial pyroptosis and caspase activation in HIBD, thereby reducing the release of proinflammatory mediators that destroy hippocampal neurons and induce spatial memory impairments.

TgF344-AD Rat Model of Alzheimer's Disease: Spatial Disorientation and Asymmetry in Hemispheric Neurodegeneration.

The TgF344-AD ratline represents a transgenic animal model of Alzheimer's disease. We previously reported spatial memory impairment in TgF344-AD rats, yet the underlying mechanism remained unknown. We, therefore, set out to determine if spatial memory impairment in TgF344-AD rats is attributed to spatial disorientation. Also, we aimed to investigate whether TgF344-AD rats exhibit signs of asymmetry in hemispheric neurodegeneration, similar to what is reported in spatially disoriented AD patients. Finally, we sought to examine how spatial disorientation correlates with working memory performance. TgF344-AD rats were divided into two groups balanced by sex and genotype. The first group underwent the delayed match-to-sample (DMS) task for the assessment of spatial orientation and working memory, while the second group underwent positron emission tomography (PET) for the assessment of glucose metabolism and microglial activity as in-vivo markers of neurodegeneration. Rats were 13 months old during DMS training and 14-16 months old during DMS testing and PET. In the DMS task, TgF344-AD rats were more likely than their wild-type littermates to display strong preference for one of the two levers, preventing working memory testing. Rats without lever-preference showed similar working memory, regardless of their genotype. PET revealed hemispherically asymmetric clusters of increased microglial activity and altered glucose metabolism in TgF344-AD rats. TgF344-AD rats display spatial disorientation and hemispherically asymmetrical neurodegeneration, suggesting a potential causal relationship consistent with past clinical research. In rats with preserved spatial orientation, working memory remains intact.

Vitamin D3 supplementation improves spatial memory, muscle function, pain score, and modulates different functional physiological biomarkers in vitamin D3 deficiency diet (VDD)-induced rats model

BackgroundVitamin D Deficiency is recognized as a pandemic, which is associated with high mortality. An inadequate level of vitamin D is associated with autoimmune diseases, hypertension, and cancer. The study was aimed to assess the pharmacological effects of chronic vitamin D3 supplementation on the manipulation diet regiment of deprived cholecalciferol (vitamin D3 deficient diet, VDD) rats.MethodsMemory performance (Y-maze task), muscular function (muscle grip strength), and pain score (pressure application measurement meter) were measured. Functional biomarkers were measured using ELISA method in different matrix viz. in serum (parathyroid hormone; PTH, calcitonin, thyroxine, and C-reactive protein; CRP, 25-OH Vit D3), and in CSF (klotho and β-endorphin). 25-OH Vit D3 was also estimated in liver and kidney homogenate using ELISA. Vitamin D receptor (VDR) was measured spectrophotometrically in liver and adipose tissue.ResultsVDD-induced rats showed a decrease in number of entries and time spent in the novel arm and spontaneous alternations in the Y-maze task. Significant improvements of neuromuscular function and pain score after addition of vitamin D3. In comparison to the VDD group, VDR expression (liver) and active metabolites of vitamin D3 (25-OH vit.D3) in serum were significantly higher by 48.23% and 280%, respectively. The PTH and CRP levels were significantly reduced by 32.5% and 35.27%, respectively, whereas calcitonin was increased by 36.67% compared with the VDD group. Klotho and β-endorphin expressions in cerebrospinal fluid were significantly elevated by 19.67% and 133.59%, respectively, compared to VDD group.ConclusionsOverall, the results indicate that supplementation of cholecalciferol significantly improved spatial memory impairment, VDR expression, and may provide an opportunity to manage vitamin D deficiencies.

Effects and mechanisms of salidroside on the behavior of SPS-induced PTSD rats

Post-traumatic stress disorder (PTSD) is a complex mental disorder, closely associated with stress and traumatic events. Salidroside (Sal) has been reported to possess neuroprotective effects. However, the behavioral effects and mechanisms of Sal on PTSD remain unknown. In this study, we utilized a rat model of PTSD induced by single prolonged stress (SPS) and administered Sal intraperitoneally (25, 50, 75 mg/kg/d) for 14 days. We then examined the behavioral effects and underlying mechanisms of Sal on SPS-induced PTSD rats. Our findings demonstrated that Sal alleviated anxiety-like behavior and spatial learning and memory impairment in SPS-induced PTSD rats. Furthermore, Sal treatment preserved the histomorphology of the hippocampal region. It was observed that Sal protected against hippocampal neuronal apoptosis in PTSD rats by reducing the number of TUNEL-positive cells and modulating apoptosis-related proteins (Bcl-2 and Bax). Additionally, Sal inhibited the activation of the NF-κB/iNOS/COX-2 signaling pathway in the hippocampus of PTSD rats, thereby suppressing the release of inflammatory factors (TNF-α and IL-1β) and the activation of microglia. Notably, Sal increased the expression of synapse-associated proteins PSD95 and Synapsin I in the hippocampus, while also enhancing dendritic density in the region. In conclusion, our results demonstrated that Sal could attenuate SPS-induced PTSD-like behaviors by inhibiting hippocampal neuronal apoptosis, enhancing hippocampal synaptic plasticity, and reducing neuroinflammatory responses. These findings may provide a foundation for the potential clinical application of Sal in the treatment of PTSD.

Multilevel meta-analysis and dose-response analysis for bisphenol A (BPA) exposure on metabolic and neurobehavioral effects

Evidence suggests that oral exposure to bisphenol A (BPA) may result in adverse metabolic and neurobehavioral effects. The aim of the present meta-analysis is to examine this association based on systematically selected laboratory rodent studies published from 2012 to 2021 and sourced from Scopus, Web of Science, EmBase, and PubMed. Articles satisfying eligibility and inclusion criteria were included for the calculation of the summary standardised mean difference (SMD). Subgroup analysis and subsequent dose-response analysis were conducted if applicable. In total, 32 studies were analysed for 6 metabolic endpoints (cholesterol, triglycerides, insulin, glucose, leptin, and adiponectin) and 6 neurobehavioral endpoints (locomotor activity, exploratory, anxiety, depression, spatial learning and memory, non-spatial learning and memory). Summary SMDs implied that no significant effects were observed in endpoints considered. The dose was not determined as a significant moderator with regards to medium or high heterogeneity; however, there was significant impairment of spatial learning and memory at health-based guidance value (‘HBGV’) (0.05–9 mg (kg bw)−1 day−1) and ‘High’ (>9 mg (kg bw)−1 day−1) dose group. As a result, an indicative toxicological reference dose value of 0.034 mg (kg bw)−1 day−1 was proposed due to large variability. Potential harm to spatial learning and memory from BPA exposure requires further investigation. This study has provided some additional information on potential adverse metabolic and neurobehavioral effects of BPA from the perspective of meta-analysis which can inform the public, regulatory authorities, and policymakers.

Low prepulse inhibition predicts lower social interaction, impaired spatial working memory, reference memory and cognitive flexibility in genetically heterogeneous rats

The “Genetically Heterogeneous National Institutes of Health (NIHHS)” stock rat (hereafter HS) shows a wide phenotypic variation, as a result of having been derived from eight inbred rat strains. Thus, these rats may be a conceivable parallel model of a healthy human sample. In order to evaluate whether HS rats have face validity as an animal model of schizophrenia-relevant features, it should be demonstrated that they present behavioural traits that may model negative and cognitive symptoms of the disorder. Previous studies on HS rats have shown that prepulse inhibition (PPI, a measure of sensorimotor gating processes), which is impaired in schizophrenic patients, is correlated with their working memory performance. In this study, we evaluated whether low PPI in the HS stock rat predicts impairments of spatial working memory (SWM), spatial reference memory and cognitive flexibility in the Morris water maze (MWM) test, and we evaluated HS rats for social interaction (SI) in a social investigation task. HS rats were stratified into 2 different groups according to their PPI scores, i.e. low- and high-PPI. In the SI task, low-PPI rats showed decreased social behaviour compared to high-PPI rats. In addition, relative to high-PPI HS rats, the low-PPI group displayed poorer SWM performance, impaired cognitive flexibility (in a reversal task) and worsened long-term spatial memory. Such differential behaviours in social and cognitive paradigms provide evidence on the face validity of low-PPI HS rats as a model of negative-like and cognitive schizophrenia-relevant traits.

Stress effects on spatial memory retrieval and brain c-Fos expression pattern in adults are modulated by early nicotine exposure

The cognitive effects of nicotine are linked to persistent modifications in extended neural systems that regulate cognitive and emotional processes, and these changes occur during development. Additionally, acute stress has modulatory effects on cognition that involve broad neural systems and can be influenced by prior environmental challenges. The effects of nicotine and stress may be interconnected, leading to modifications in a network of shared brain substrates. Here, we explored the interaction between nicotine and stress by evaluating the effects of acute stress exposure in spatial memory retrieval for animals pretreated with nicotine during adolescence or adulthood. Adolescent (35 days old) and adult (70 days old) male Wistar rats were treated for 21 days with one daily subcutaneous injection of nicotine 0.14 mg/ml (free base). 30 days after the last injection, rats were trained in the Barnes maze and tested 24 h later, half the rats were tested under regular conditions, and half of them were exposed to 1 h of restraining stress before the retrieval test, and brain samples were collected and c-Fos immunopositive cells were stained. Prolonged nicotine withdrawal or acute stress improved spatial memory retrieval. Acute stress in nicotine pretreated adults impaired spatial memory retrieval. Nicotine exposure during early adulthood resulted in long-lasting brain adaptations that amplified emotional responses to acute stress after prolonged drug withdrawal.

The role of the gut–microbiota–brain axis via the subdiaphragmatic vagus nerve in chronic inflammatory pain and comorbid spatial working memory impairment in complete Freund's adjuvant mice

Chronic inflammatory pain (CIP) is a common public medical problem, often accompanied by memory impairment. However, the mechanisms underlying CIP and comorbid memory impairment remain elusive. This study aimed to examine the role of the gut–microbiota–brain axis in CIP and comorbid memory impairment in mice treated with complete Freund's adjuvant (CFA). 16S rRNA analysis showed the altered diversity of gut microbiota from day 1 to day 14 after CFA injection. Interestingly, fecal microbiota transplantation (FMT) from healthy naive mice ameliorated comorbidities, such as mechanical allodynia, thermal hyperalgesia, spatial working memory impairment, neuroinflammation, and abnormal composition of gut microbiota in the CFA mice. Additionally, subdiaphragmatic vagotomy (SDV) blocked the onset of these comorbidities. Interestingly, the relative abundance of the bacterial genus or species was also correlated with these comorbidities after FMT or SDV. Therefore, our results suggest that the gut–microbiota–brain axis via the subdiaphragmatic vagus nerve is crucial for the development of CIP and comorbid spatial working memory impairment in CFA mice.

RETRACTED: Cladribine induces apoptosis, neuroinflammation, mitochondrial oxidative stress, tau phosphorylation and Aβ (1−42) pathway in the hippocampus: An in vivo approach

Cladribine is a purine nucleoside found to enhance toxic amyloid protein and cause memory impairment. Patients following chemotherapy treatment commonly suffer from cognitive deficits more prevalent in the elderly than adults. A previous research study revealed that cladribine has a high affinity to the brain, increases the level of amyloid precursor protein, and results in learning deficits. The study was designed to validate an animal model of cladribine administration to rats through mitochondrial oxidative stress, inflammation, apoptosis, tau phosphorylation, and amyloid-β (1–42) accumulation. In this study, all rats were orally given cladribine (0.5 and 1 mg/kg) for 28 days, resulting in impaired spatial memory confirmed by behavioural activity. On day 29, all rats were euthanized, and the hippocampal tissues were isolated and used for the estimation of neuroinflammatory markers, biochemicals parameters (glutathione, catalase, lipid peroxidation, and nitrite), amyloid-β (1–42) level, neurotransmitters, and nuclear factor kappa B analysis. Cladribine administration significantly elevated cytokines release, dysbalanced neurotransmitter concentration, and promoted the Aβ accumulation and hyperphosphorylation of tau protein. Our study outcome confirmed that cladribine produces cognitive impairment via activation of Nuclear factor kappa B, mitochondrial oxidative stress and dysbalanced of the endogenous antioxidant defence system.