Radial Arm Water Maze Research Articles

Swimming exercise protective effect on waterpipe tobacco smoking-induced impairment of memory and oxidative stress

Waterpipe tobacco smoking (WP) is associated with a vast range of detrimental health effects, including memory impairment and anti-oxidative scavenging dysfunction. Forced swimming exercise (FSE) is known to improve cognitive function and general wellbeing. In this study, we evaluated the neuroprotective effect of FSE on memory impairment induced by exposure to WP in the rat model. Wistar male rats were divided into four groups: fresh air (control), WP exposure, FSE, and WP/FSE. Animals were exposed to WP for 1 h/day, 5 days/week for 4 weeks. At the same time, animals were forced to swim 1 h/day as 5 min swimming followed by 5 min rest, 5 days/ week for 4 weeks. Spatial learning and memory was assessed using Radial Arm Water Maze (RAWM). Additionally, hippocampal oxidative stress biomarkers including reduced glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG ratio, glutathione peroxidase (GPx), Catalase, and TBARS were analyzed. Key findings: this study showed that WP exposure impaired both short- and long-term memory (P < 0.05). On the other hand, FSE prevented memory impairment induced by WP exposure (P < 0.05). Moreover, WP exposure reduced activity of catalase, GPx, and GSH/GSSG ratio (P < 0.05) in the hippocampus, which were also normalized by FSE. However, no changes were detected in GSH and TBARS levels in WP exposure and/or FSE groups. In conclusion, WP exposure induced both short- and long- term memory impairments, which was prevented by FSE. This improvement in memory function might be attributed to oxidative stress biomarkers pathways.

Vitamin E prevents the cognitive impairments in post-traumatic stress disorder rat model: behavioral and molecular study.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder developed after an exposure to severe traumatic events. Patients with PTSD suffer from different symptoms including memory impairment. In addition, PTSD is associated with oxidative stress. Vitamin E, a fat-soluble vitamin, possesses cognition protective effects via its antioxidative properties. To investigate the impact of vitamin E on memory impairment induced by PTSD in animals. A rat model of PTSD-like behavior and the radial arm water maze (RAWM) for testing of learning and memory paradigm were used. Rats were divided into 4 groups: control, vitamin E, PTSD, and vitamin E + PTSD. In the learning phase, results showed no significant differences among experimental groups, indicating that PTSD-like behavior did not impair learning ability in rats. However, memory tests in the RAWM showed that PTSD-like animals had impairment in both short-term and long-term memories. Vitamin E, on the other hand, prevented this impairment of memory. With respect to oxidative stress, significant decreases were detected in reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, glutathione peroxidase (GPx) and catalase enzyme activities, global histone 3 acetylation, and brain derived neurotrophic factor (BDNF) levels in the PTSD-like animals group compared with other groups (P < 0.05). Vitamin E protected the reduction of these oxidative stress biomarkers, global histone 3 acetylation, and BDNF levels. Vitamin E prevented memory impairment associated with PTSD-like behavior in animals, probably via its antioxidative properties, and preservation of epigenetic changes induced in PTSD-like animals.

Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

Age-related decline in circulating levels of insulin-like growth factor (IGF)-1 is associated with reduced cognitive function, neuronal aging, and neurodegeneration. Decreased mitochondrial function along with increased reactive oxygen species (ROS) and accumulation of damaged macromolecules are hallmarks of cellular aging. Based on numerous studies indicating pleiotropic effects of IGF-1 during aging, we compared the central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function using an inducible liver IGF-1 knockout (LID). Circulating levels of IGF-1 (~ 75%) were depleted in adult male Igf1f/f mice via AAV-mediated knockdown of hepatic IGF-1 at 5 months of age. Cognitive function was evaluated at 18 months using the radial arm water maze and glucose and insulin tolerance assessed. Mitochondrial function was analyzed in hippocampus, muscle, and visceral fat tissues using high-resolution respirometry O2K as well as redox status and oxidative stress in the cortex. Peripherally, IGF-1 deficiency did not significantly impact muscle mass or mitochondrial function. Aged LID mice were insulin resistant and exhibited ~ 60% less adipose tissue but increased fat mitochondrial respiration (20%). The effects on fat metabolism were attributed to increases in growth hormone. Centrally, IGF-1 deficiency impaired hippocampal-dependent spatial acquisition as well as reversal learning in male mice. Hippocampal mitochondrial OXPHOS coupling efficiency and cortex ATP levels (~ 50%) were decreased and hippocampal oxidative stress (protein carbonylation and F2-isoprostanes) was increased. These data suggest that IGF-1 is critical for regulating mitochondrial function, redox status, and spatial learning in the central nervous system but has limited impact on peripheral (liver and muscle) metabolism with age. Therefore, IGF-1 deficiency with age may increase sensitivity to damage in the brain and propensity for cognitive deficits. Targeting mitochondrial function in the brain may be an avenue for therapy of age-related impairment of cognitive function. Regulation of mitochondrial function and redox status by IGF-1 is essential to maintain brain function and coordinate hippocampal-dependent spatial learning. While a decline in IGF-1 in the periphery may be beneficial to avert cancer progression, diminished central IGF-1 signaling may mediate, in part, age-related cognitive dysfunction and cognitive pathologies potentially by decreasing mitochondrial function.

Vitamin C attenuates memory loss induced by post-traumatic stress like behavior in a rat model

Oxidative stress is associated with neuronal damage in many brain regions including the hippocampus; an area in the brain responsible of memory processing. Oxidative stress is also linked with many psychiatric conditions including post-traumatic stress disorder (PTSD). PTSD is triggered by traumatic experience and many PTSD patients show signs of memory impairment. Vitamin C is a water-soluble vitamin with antioxidant properties. Herein, we hypothesized that memory impairment observed during PTSD could be a result of oxidative stress in hippocampal tissues and that prophylactic vitamin C administration may reduce oxidative stress in the hippocampus and prevent memory impairment. The above hypothesis was tested in a rat model where PTSD-like behavior was induced through single prolonged stress (SPS). Short and long-term memory was tested using a radial arm water maze (RAWM). We found that SPS induced a significant increase in the oxidized glutathione levels of the hippocampus. This reduction was accompanied with a significant decrease in glutathione peroxidase and catalase enzyme activity, and a significant increase in lipid peroxidation. Intriguingly, vitamin C administration successfully attenuated memory impairment and all of the changes observed in oxidative stress markers. Our findings demonstrate that vitamin C could prevent oxidative stress and memory impairment induced by SPS model of PTSD-like behavior in rat.

Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice.

Cognitive impairment is one of the most common co-occurring chronic conditions among elderly heart failure patients (incidence: up to ~ 80%); however, the underlying mechanisms are not completely understood. It is hypothesized that in addition to decreased cardiac output, increases in central-and consequentially, cerebral-venous pressure (backward failure) also contribute significantly to the genesis of cognitive impairment. To test this hypothesis and elucidate the specific pathogenic role of venous congestion in the brain, we have established a novel model of increased cerebral venous pressure: mice with jugular vein ligation (JVL). To test the hypothesis that increased venous pressure in the brain contributes to the development of cognitive deficits by causing blood-brain barrier disruption, dysregulation of blood flow, and/or promoting neuroinflammation, in C57BL/6 mice, the internal and external jugular veins were ligated. Cognitive function (radial arm water maze), gait function (CatWalk), and motor coordination (rotarod) were tested post-JVL. Neurovascular coupling responses were assessed by measuring changes in cerebral blood flow in the whisker barrel cortex in response to contralateral whisker stimulation by laser speckle contrast imaging through a closed cranial window. Blood-brain barrier integrity (IgG extravasation) and microglia activation (Iba1 staining) were assessed in brain slices by immunohistochemistry. Neuroinflammation-related gene expression profile was assessed by a targeted qPCR array. After jugular vein ligation, mice exhibited impaired spatial learning and memory, altered motor coordination, and impaired gait function, mimicking important aspects of altered brain function observed in human heart failure patients. JVL did not alter neurovascular coupling responses. In the brains of mice with JVL, significant extravasation of IgG was detected, indicating blood-brain barrier disruption, which was associated with histological markers of neuroinflammation (increased presence of activated microglia) and a pro-inflammatory shift in gene expression profile. Thus, cerebral venous congestion per se can cause blood-brain barrier disruption and neuroinflammation, which likely contribute to the genesis of cognitive impairment. These findings have relevance to the pathogenesis of cognitive decline associated with heart failure as well as increased cerebal venous pressure due to increased jugular venous reflux in elderly human patients.

Chronic Calcineurin Inhibition via Cyclosporine A Impairs Visuospatial Learning After Isoflurane Anesthesia.

Clinical studies implicate the perioperative period in cognitive complications, and increasing experimental evidence shows that the anesthetic agents can affect neuronal processes that underpin learning and memory. Calcineurin, a Ca-dependent phosphatase critically involved in synaptic plasticity, is activated after isoflurane exposure, but its role in the neurological response to anesthesia is unclear. We investigated the effect of chronic calcineurin inhibition on postanesthetic cognitive function. Mice were treated with 30 minutes of isoflurane anesthesia during a chronic cyclosporine A regimen. Behavioral end points during the perianesthesia period were quantified. Visuospatial learning was assessed with the water radial arm maze. Total and biotinylated surface protein expression of the α5β3γ2 γ-aminobutyric acid (GABA) type A receptors was measured. Expression of the GABA synthesis enzyme glutamate decarboxylase (GAD)-67 was also measured. Mice treated with cyclosporine A before anesthesia showed significant deficits in visuospatial learning compared to sham and cyclosporine A-treated mice (n = 10 per group, P = .0152, Tukey post hoc test). Induction and emergence were unaltered by cyclosporine A. Analysis of hippocampal protein expression revealed an increased surface expression of the α5 GABA type A receptor subunit after isoflurane treatment (P = .019, Dunnett post hoc testing), as well as a decrease in GAD-67 expression. Cyclosporine A did not rescue either effect. Our results confirm the work of others that isoflurane induces changes to inhibitory network function and exclude calcineurin inhibition via cyclosporine A as an intervention. Further, our studies suggest that calcineurin mediates a protective role in the neurological response to anesthesia, and patients receiving cyclosporine A may be an at-risk group for memory problems related to anesthesia.

Withania somnifera root powder protects againist post-traumatic stress disorder-induced memory impairment.

Post-traumatic stress disorder (PTSD) is precipitated by exposure to severe traumatic events such as wars, natural disasters, catastrophes, or other traumatic events. Withania somnifera (WS) Dunal (family: Solanaceae) known traditionally as "Ashwaghanda" is used widely in ayurvedic medicine, and known to have positive role in neurodegenerative diseases. In this study, WS effect on impairment of memory due to PTSD was studied in animal models. Single-prolonged stress rat model, which consisted of restrain for 2h, forced swimming for 20min, rest for 15min, and diethyl ether exposure for 1-2min, was used to induce PTSD animals. The WS root powder extract was administered orally at a dose of 500mg/kg/day. The radial arm water maze (RAWM) was used to assess spatial learning and memory. Enzymatic assays were used to evaluate changes in oxidative stress biomarkers in the hippocampus following treatments. The result showed that PTSD resulted in short- and long- term memory impairments. Administration of WS prevented this impairment of memory induced by PTSD. Furthermore, WS prevented PTSD induced changes in oxidative stress biomarker in the hippocampus. For quality assessment, the methanolic extract for WS was subjected to UHPLC analysis. A calibration curve for isowithanone as a marker compound was constructed. WS roots content of isowithanone was found to be 0.23% (w/w). In conclusion, WS administration prevented PTSD induced memory impairment probably through preserving changes in antioxidant mechanisms in the hippocampus.

Neuroprotective effects of lipopolysaccharide and naltrexone co‑preconditioning in the photothrombotic model of unilateral selective hippocampal ischemia in rat.

Preconditioning with lipopolysaccharide (LPS) or opioid antagonists has a neuroprotective effect in ischemic insults. However, the co‑preconditioning effect of toll‑like receptor ligands and opioid antagonists has not been investigated. In this study we examined the neuroprotective effect of LPS and naltrexone (NTX) preconditioning and co‑preconditioning in unilateral selective hippocampal ischemia in rats to assess for possible synergistic protective effects. LPS and NTX were injected unilaterally into the left cerebral ventricle of male rats. Forty‑eight hours after LPS and twenty‑four hours after NTX injection, ipsilateral selective hippocampal ischemia was induced using a modified version of the photothrombotic method. Protective effects for LPS and NTX were assessed by evaluating infarct volume (using 2,3,5‑triphenyltetrazolium chloride staining), and cognitive function (using radial arm water maze and passive avoidance tests). Animals in the ischemic group had an infarct lesion and considerable cognitive impairment, compared with the sham group. LPS or NTX preconditioning significantly reduced the infarct size and improved cognitive function. Moreover, co‑preconditioning with LPS and NTX increased the protective effect compared with preconditioning with LPS or NTX alone. Our data showed that LPS and NTX preconditioning resulted in a neuroprotective effect in hippocampal ischemia. Furthermore, co‑preconditioning with LPS and NTX resulted in a synergistic protective effect.

High fat diet alters gut microbiota but not spatial working memory in early middle-aged Sprague Dawley rats.

As the global population ages, and rates of dementia rise, understanding lifestyle factors that play a role in the development and acceleration of cognitive decline is vital to creating therapies and recommendations to improve quality of later life. Obesity has been shown to increase risk for dementia. However, the specific mechanisms for obesity-induced cognitive decline remain unclear. One potential contributor to diet-induced cognitive changes is neuroinflammation. Furthermore, a source of diet-induced inflammation to potentially increase neuroinflammation is via gut dysbiosis. We hypothesized that a high fat diet would cause gut microbe dysbiosis, and subsequently: neuroinflammation and cognitive decline. Using 7-month old male Sprague Dawley rats, this study examined whether 8 weeks on a high fat diet could impact performance on the water radial arm maze, gut microbe diversity and abundance, and microgliosis. We found that a high fat diet altered gut microbe populations compared to a low fat, control diet. However, we did not observe any significant differences between dietary groups on maze performance (a measure of spatial working memory) or microgliosis. Our data reveal a significant change to the gut microbiome without subsequent effects to neuroinflammation (as measured by microglia characterization and counts in the cortex, hippocampus, and hypothalamus) or cognitive performance under the parameters of our study. However, future studies that explore duration of the diet, composition of the diet, age of animal model, and strain of animal model, must be explored.

The Noonan Syndrome-linked Raf1L613V mutation drives increased glial number in the mouse cortex and enhanced learning.

RASopathies are a family of related syndromes caused by mutations in regulators of the RAS/Extracellular Regulated Kinase 1/2 (ERK1/2) signaling cascade that often result in neurological deficits. RASopathy mutations in upstream regulatory components, such as NF1, PTPN11/SHP2, and RAS have been well-characterized, but mutation-specific differences in the pathogenesis of nervous system abnormalities remain poorly understood, especially those involving mutations downstream of RAS. Here, we assessed cellular and behavioral phenotypes in mice expressing a Raf1L613V gain-of-function mutation associated with the RASopathy, Noonan Syndrome. We report that Raf1L613V/wt mutants do not exhibit a significantly altered number of excitatory or inhibitory neurons in the cortex. However, we observed a significant increase in the number of specific glial subtypes in the forebrain. The density of GFAP+ astrocytes was significantly increased in the adult Raf1L613V/wt cortex and hippocampus relative to controls. OLIG2+ oligodendrocyte progenitor cells were also increased in number in mutant cortices, but we detected no significant change in myelination. Behavioral analyses revealed no significant changes in voluntary locomotor activity, anxiety-like behavior, or sociability. Surprisingly, Raf1L613V/wt mice performed better than controls in select aspects of the water radial-arm maze, Morris water maze, and cued fear conditioning tasks. Overall, these data show that increased astrocyte and oligodendrocyte progenitor cell (OPC) density in the cortex coincides with enhanced cognition in Raf1L613V/wt mutants and further highlight the distinct effects of RASopathy mutations on nervous system development and function.

Effect of waterpipe tobacco smoke exposure during lactation on learning and memory of offspring rats: Role of oxidative stress

AimsThe prevalence of waterpipe tobacco smoking is increasing among breastfeeding women. Herein, the effect of maternal waterpipe tobacco smoke (WTS) exposure during lactation on learning and memory of adult offspring rats was examined. Main methodsLactating rats received either fresh air or mainstream WTS (1 h twice daily) from day 4 to day 21. Learning and memory was examined by the radial arm water maze and the levels of brain derived neurotrophic factor (BDNF) and oxidative stress biomarkers superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase and thiobarbituric acid reactive substances (TBARS) were assessed in the hippocampus of adult male offspring rats. Key findingsMaternal exposure to WTS during lactation impaired the long-term memory and reduced levels of BDNF (P < 0.05) in hippocampus in adult male offspring rats. The activity of SOD, GPx and catalase were reduced (P < 0.05) while level of TBARS was increased (P < 0.05). SignificanceMaternal WTS exposure during lactation impaired the long-term memory of adult male offspring that was associated with low levels of BDNF and altered oxidative stress balance. Therefore, careful measures should be taken to enhance waterpipe smoking cessation during breastfeeding.

Omega-3 fatty acids protects against chronic sleep-deprivation induced memory impairment

AimsThe current study aims to evaluate the possible protective effect of omega-3 fatty acids on memory impairment induced by sleep-deprivation in rats. Materials and methodsAnimals were chronically sleep deprived using the modified multiple platform model (8 h/day for 8 weeks). Omega-3 fatty acids were administered as fish oil via oral gavage at a daily dose of 100 mg omega-3 PUFA/100 g BWT. The spatial learning and memory were evaluated using the radial arm water maze (RAWM). Additionally, the following oxidative stress biomarkers were measured in the hippocampus: glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG, glutathione peroxidase (GPx), catalase, superoxide dismutase (SOD), and thiobarbituric acid reactive substance (TBARS). Key findingsAnimals in the SD group committed significantly more errors in both short- and long- term memory tests of the RAWM compared to other groups. On the other hand, animals that were sleep deprived and treated with omega-3 fatty acids committed similar number of errors compared to the control group. This indicates that SD impaired both short- and long- term memories, and that chronic omega-3 fatty acids administration prevented these effects. Omega-3 fatty acids also prevented the decreases in hippocampal GPx, catalase and GSH/GSSG ratio and normalized the increases in GSSG levels, which were impaired by SD model. No changes were observed on hippocampal TBARS levels, or activity of SOD among experimental groups. SignificanceIn conclusion, a protective effect of omega-3 fatty acids administration has been observed against chronic SD-induced memory impairment probably via improving hippocampus antioxidant effects.

Edaravone prevents memory impairment in an animal model of post-traumatic distress.

Post-traumatic stress disorder (PTSD) is a mental health problem that develops in a proportion of individuals after experiencing a potential life-threatening traumatic stress event. Edaravone is a free radical scavenger, with a neuroprotective effect against cognitive impairment in several animal models. In the present study, the protective effect of edaravone on PTSD-induced memory impairment was investigated. Single prolonged stress was used as an animal model of PTSD, comprising 2 h of restrain, 20-min forced swimming, 15-min rest, and 1-2-min diethyl ether exposure. Concurrently, edaravone was given at a dose of 6 mg/kg/day, intraperitoneally, for 21 days. The radial arm water maze was used to assess learning and memory. Antioxidant biomarkers were measured in hippocampus tissues. Chronic administration of edaravone prevented impairment of short-term and long-term memory. Edaravone also prevented the stress-induced decrease in the ratio of reduced glutathione/oxidized glutathione and the activities of glutathione peroxidase and catalase enzymes in the hippocampus, as well as increases in the levels of oxidized glutathione and thiobarbituric acid reactive substances. In conclusion, edaravone ameliorated oxidative stress and cognitive impairment associated with a PTSD model, probably by supporting antioxidant mechanism in the hippocampus.

The effect of cilostazol on hippocampal memory and oxidative stress biomarkers in rat model of diabetes mellitus

Diabetes is a global public health crisis worldwide, particularly in developing countries. Diabetes is characterized by a consistent elevation in blood glucose level which leads to several complications including cognitive impairment. Hippocampus, a brain structure responsible for memory, is vulnerable to damage caused by hyperglycemia-induced oxidative stress. In this study, we evaluated the effect of cilostazol, a selective phosphodiesterase 3 inhibitor, on hippocampal memory and oxidative stress biomarkers in streptozotocin-induced diabetes model. Cilostazol was administered to rats intraperitoneally at dose 3 mg/kg. Spatial learning and memory were tested using radial arm water maze (RAWM). BDNF protein, TBARS levels and different antioxidant biomarkers were assessed after dissection of the hippocampus. The diabetic rats showed an increase in the number of the errors during RAWM performance. However, treatment with cilostazol could not showed an improvement in animal’s learning and memory performance. The results revealed that diabetic rats showed an increase in TBARS levels and a decrease in an antioxidant enzyme activities (superoxide dismutase (SOD) and glutathione peroxidase (GPx)). Moreover, cilostazol was able to normalize diabetes-induced reduction in the hippocampus activity of SOD and GPx. Moreover, administration of cilostazol normalized diabetes-induced increase in TBARS level, without any significant effect on BDNF level or catalase activity. In conclusion, cilostazol showed no improvement in the learning and memory functions which could be due to the lack of significant cognitive impairment induced by streptozotocin administration. However, cilostazol had shown antioxidant activity through normalization of hippocampal oxidative stress biomarkers.

Omega-3 Fatty Acids Prevent Post-Traumatic Stress Disorder-Induced Memory Impairment.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that can happen after exposure to a traumatic event. Post-traumatic stress disorder is common among mental health disorders that include mood and anxiety disorders. Omega-3 fatty acids (OMGs) are essential for the maintenance of brain function and prevention of cognition dysfunctions. However, the possible effect of OMG on memory impairment induced by PTSD has not been studied. In here, such an effect was explored using a rat model of PTSD. The PTSD-like behavior was induced in animals using a single-prolonged stress (SPS) rat model of PTSD (2 h restraint, 20 min forced swimming, 15 min rest, 1–2 min diethyl ether exposure). The OMG was administered orally at a dose of 100 mg omega-3 polyunsaturated fatty acid (PUFA)/100 g body weight/day. Spatial learning and memory were assessed using the radial arm water maze (RAWM) method. Changes in oxidative stress biomarkers, thiobarbituric acid reactive substances (TBARS), and brain derived neuroptrophic factor (BDNF) in the hippocampus following treatments were measured. The results revealed that SPS impaired both short- and long-term memory (p < 0.05). Use of OMG prevented memory impairment induced by SPS. Furthermore, OMG normalized SPS induced changes in the hippocampus that reduced glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG ratios, the activity of catalase, glutathione peroxidase (GPx), and TBARSs levels. In conclusion, the SPS model of PTSD-like behavior generated memory impairment, whereas OMG prevented this impairment, possibly through normalizing antioxidant mechanisms in the hippocampus.

Neuregulin1 attenuates cognitive deficits and hippocampal CA1 neuronal apoptosis partly via ErbB4 receptor in a rat model of chronic cerebral hypoperfusion.

Neuregulin1 (NRG1) is an effective neuroprotectant. Previously we demonstrated that the expression of hippocampal NRG1/ErbB4 gradually decreased and correlates with neuronal apoptosis during chronic cerebral hypoperfusion (CCH). Here we aimed to further investigate the protective role of NRG1 in CCH. AG1478, an ErbB4 inhibitor, was used to explore the involvement of ErbB4 receptors in NRG1's action. Permanent bilateral common carotid artery occlusion (2VO) or sham operation was performed in Sprague-Dawley rats. NRG1 (100 μM) and AG1478 (50 mM) was administered intraventricularly. Eight weeks post-surgery, cognitive impairment was analyzed using Morris water maze (MWM) and radial arm water maze (RAWM) tests, followed by histological assessment of the survival and apoptosis of hippocampal CA1 neurons using NeuN and TUNEL immunostaining respectively. Expression of apoptosis-related proteins and ErbB4 activation (pErbB4/ErbB4) was evaluated by Western blotting. The results showed that NRG1 significantly improved the performances in MWM (spatial learning and memory) and RAWM (spatial working and reference memory), attenuated hippocampal CA1 neuronal loss and apoptosis, upregulated the expression of pErbB4/ErbB4 and the anti-apoptotic protein Bcl-2, and downregulated the expression of pro-apoptotic proteins of Cleaved (Cl)-caspase3 and Bax. In addition, the protective effects of NRG1 could be partly abolished by AG1478. Taken together, our study suggested that NRG1 ameliorates cognitive impairment and neuronal apoptosis partly via ErbB4 receptors in rats with CCH.

Blueberries Improve Neuroinflammation and Cognition differentially Depending on Individual Cognitive baseline Status.

Daily supplementation of blueberries (BBs) reverses age-related deficits in behavior in aged rats. However, it is unknown whether BB is more beneficial to one subset of the population dependent on baseline cognitive performance and inflammatory status. To examine the effect of individual differences on the efficacy of BB, aged rats (17 months old) were assessed for cognition in the radial arm water maze (RAWM) and divided into good, average, and poor performers based on navigation errors. Half of the rats in each cognitive group were then fed a control or a 2% BB diet for 8 weeks before retesting. Serum samples were collected, pre-diet and post-diet, to assess inflammation. Latency in the radial arm water maze was significantly reduced in the BB-fed poor performers (p < .05) and preserved in the BB-fed good performers. The control-fed good performers committed more working and reference memory errors in the post-test than pretest (p < .05), whereas the BB-fed good performers showed no change. An in vitro study using the serum showed that BB supplementation attenuated lipopolysaccharide (LPS)-induced nitrite and tumor necrosis factor-alpha, and cognitive performance was associated with innate anti-inflammatory capability. Therefore, consumption of BB may reverse some age-related deficits in cognition, as well as preserve function among those with intact cognitive ability.

White matter lesions, cerebral inflammation and cognitive function in a mouse model of cerebral hypoperfusion

Development of specific treatments for vascular dementia requires appropriate animal models. Bilateral carotid artery stenosis (BCAS) employs metal coils wrapped around both common carotid arteries to induce cerebral hypoperfusion, white matter lesions and memory impairment in mice. We focused on the relationship of memory impairment induced by BCAS to white matter lesions demonstrated by ex vivo magnetic resonance imaging (MRI). We found a significant effect of BCAS on perceptual learning in the novel object recognition test and on number of errors and latency to platform in the radial arm water maze. MRI analysis revealed a significant effect of BCAS on diffusion tensor imaging (DTI) parameters in white matter areas. After correction for multiple testing, significantly lower fractional anisotropy (FA) values were found in the corpus callosum and anterior commissure and significantly higher mean diffusivity values in the internal capsule. Focusing on the corpus callosum, we found that correlations between FA and number of errors on the RAWM test were significant after controlling for treatment. We further found that the effects of BCAS on cognition were partly mediated by its effects on white matter integrity. Immunofluorescence studies demonstrated significantly higher microglia cell density and soma size in the corpus callosum of BCAS mice compared to controls, and these parameters were correlated with the imaging data. The results of this study indicate that cognitive deficits induced by cerebral hypoperfusion due to BCAS result in part from microglia activation and disruption of white matter integrity, supporting the face and construct validity of this unique model of vascular dementia.

Age-Related Cognitive Impairment: Role of Reduced Synaptobrevin-2 Levels in Deficits of Memory and Synaptic Plasticity.

Cognitive impairment in the aging population is quickly becoming a health care priority, for which currently no disease-modifying treatment is available. Multiple domains of cognition decline with age even in the absence of neurodegenerative diseases. The cellular and molecular changes leading to cognitive decline with age remain elusive. Synaptobrevin-2 (Syb2), the major vesicular SNAP receptor protein, highly expressed in the cerebral cortex and hippocampus, is essential for synaptic transmission. We have analyzed Syb2 protein levels in mice and found a decrease with age. To investigate the functional consequences of lower Syb2 expression, we have used adult Syb2 heterozygous mice (Syb2+/-) with reduced Syb2 levels. This allowed us to mimic the age-related decrease of Syb2 in the brain in order to selectively test its effects on learning and memory. Our results show that Syb2+/- animals have impaired learning and memory skills and they perform worse with age in the radial arm water maze assay. Syb2+/- hippocampal neurons have reduced synaptic plasticity with reduced release probability and impaired long-term potentiation in the CA1 region. Syb2+/- neurons also have lower vesicular release rates when compared to WT controls. These results indicate that reduced Syb2 expression with age is sufficient to cause cognitive impairment.

Male/female Differences in Radial Arm Water Maze Execution After Chronic Exposure to Noise.

Introduction:Noise is one of the main sources of discomfort in modern societies. It affects physiology, behavior, and cognition of exposed subjects. Although the effects of noise on cognition are well known, gender role in noise-cognition relationship remains controversial.Aim:We analyzed the effects of noise on the ability of male and female rats to execute the Radial Arm Water Maze (RAWM) paradigm.Materials and Methods:Male and female Wistar rats were exposed to noise for 3 weeks, and the cognitive effects were assessed at the end of the exposure. RAWM execution included a three-day training phase and a reversal-learning phase conducted on the fourth day. Escape latency, reference memory errors, and working memory errors were quantified and compared between exposed and non-exposed subjects.Results:We found that male rats were in general more affected by noise. Execution during the three-day learning phase evidenced that male exposed rats employed significantly more time to acquire the task than the non-exposed. On the other hand, the exposed females solved the paradigm in latencies similar to control rats. Both, males and females diminished their capacity to execute on the fourth day when re-learning abilities were tested.Conclusion:We conclude that male rats might be less tolerable to noise compared to female ones and that spatial learning may be a cognitive function comparably more vulnerable to noise.