Spatial Memory Performance Research Articles

Neuroprotective Effects of Chemerin on a Mouse Stroke Model: Behavioral and Molecular Dimensions.

The present study was conducted to investigate the effects of different doses of recombinant human Chemerin (rhChemerin) on brain damage, spatial memory, blood-brain barrier (BBB) disruption and cellular and molecular mechanisms in a mouse stroke model. The mouse stroke model was developed by blocking the middle cerebral artery for 1h and performing reperfusion for 23h. Immediately, one and three hours after the stroke, 200, 400 and 800ng/mouse of intranasal rhChemerin was administered. Neuronal and BBB damage, spatial memory and neurological performance were examined 24h after the stroke. Western blotting and immunofluorescence were utilized to determine the effects of rhChemerin on the expressions of nuclear factor kappa B (NF-κB), pro-inflammatory cytokines such as TNF-α and IL-1β, anti-inflammatory cytokines such as IL-10 and TGF-β and vascular endothelial growth factor (VEGF). Administering 400 and 800ng/mouse of rhChemerin in the mice immediately and one hour after ischemia minimized the infarct size, BBB opening, spatial memory and neurological impairment (P < 0.001). Furthermore, 800ng/mouse of rhChemerin significantly diminished terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive (apoptotic) cells, suppressed the expressions of NF-kB, TNF-α and IL-1β and upregulated IL-10 and VEGF in the cortex and hippocampus of the mice. The present findings showed that rhChemerin administered immediately and one hour after stroke alleviates neuronal and BBB injures and improves spatial memory. These effects of rhChemerin may be mediated by inhibiting inflammatory pathways and apoptotic machinery.

Spatial working memory is disparately interrelated with social status through different developmental stages in rats

Social life necessitates cognitive competence to meet the dynamic demands of social development. The formation of dominance hierarchy is a general phenomenon in social groups. As an essential element of executive and cognitive function, working memory could influence and be influenced by social status in a dominance hierarchy. However, the direction and degree of the association between them through different developmental stages remain unclear. To address this issue and clarify the “cause or consequence” problem, we investigated the spatial working memory performance in a Y-maze and Morris water maze in home-caged sibling Wistar rats (N = 26 cages, three rats/cage) through three stages of their life: before (week 7), during (week 10), and after (week 20) assumed timings of the social dominance hierarchy formation (SDHF). We used the social dominance tube test during the assumed time of hierarchy formation (weeks 9–11) to measure the relative dominance status in each cage. Here, we found that higher working memory index before SDHF could be predictive of later acquisition of higher social status. Working memory performance declined for all animals during SDHF, in which agonistic conflicts are increased. However, living within an established hierarchical social network for several weeks deteriorated the working memory performance of dominant and middle-ranked animals, while the performance of subordinates improved and got significantly better than higher-ranked animals. In conclusion, while working memory and social status were correlated positively before dominance hierarchy formation, there was a trade-off between them after the formation of it. In contrast to the common view, these results highlight the adverse effect of higher social status on cognitive behavior.

Zeb2/Axin2-Enriched BMSC-Derived Exosomes Promote Post-Stroke Functional Recovery by Enhancing Neurogenesis and Neural Plasticity.

Exosomes harvested from bone marrow-derived mesenchymal stromal cells (BMSCs) have shown treatment potential in many diseases. In vitro, Zeb2/Axin2 stimulated endogenous neurogenesis, which induced functional recovery after stroke. Here, we investigated whether the Zeb2/Axin2-enriched exosomes harvested from BMSCs transfected with a Zeb2/Axin2 overexpression plasmid would enhance neurological recovery. Compared with the control, both exosome treatments significantly improved functional recovery, and Zeb2/Axin2-enriched exosomes had significantly more improved effects on neurological function, neurogenesis, and neurite remodeling/neuronal dendrite plasticity than the control BMSC exosome treatment in a middle cerebral artery occlusion MCAO rat model. After stimulation with Zeb2/Axin2-enriched BMSC exosomes, the spatial memory and nerve function of MCAO rats showed marked recovery. The number of neurons was increased in the subventricularzone (SVZ), hippocampus, and cortex area, while the expression of nerve growth factors (NGF, BDNF, etc.) was upregulated. In the ischemic boundary zone, Zeb2/Axin2-enriched exosomes promoted synaptic remodeling by increasing the number of synapses and reversed the axonal loss of phosphorylated neurofilament (SMI-31) and synaptophysin (SYN) caused by ischemic injury, thus alleviating axonal demise and promoting synaptic proliferation. In vitro, Zeb2/Axin2-enriched exosomes significantly increased neurite branching and elongation of cultured cortical embryonic rat neurons under oxygen- and glucose-deprived (OGD) conditions. Moreover, Ex-Zeb2/Axin2-enriched exosomes downregulated the protein level of SOX10, endothelin-3/EDNRB, and Wnt/β-catenin expression. In conclusion, exosomes harvested from Ex-Zeb2/Axin2 BMSC could improve post-stroke neuroplasticity and functional recovery in MCAO rats by promoting proliferation and differentiation of neural stem cells. The mechanism may be related to the SOX10, Wnt/β-catenin, and endothelin-3/EDNRB pathways.

Early-life stress does not alter spatial memory performance, hippocampal neurogenesis, neuroinflammation, or telomere length in 20-month-old male mice

Early-life stress (ES) increases the risk for psychopathology and cognitive decline later in life. Because the neurobiological substrates affected by ES (i.e., cognition, neuroplasticity, and neuroinflammation) are also altered in aging, we set out to investigate if and how ES in the first week of life affects these domains at an advanced age, and how ES modulates the aging trajectory per se. We subjected C57BL/6j mice to an established ES mouse model from postnatal days 2–9. Mice underwent behavioral testing at 19 months of age and were sacrificed at 20 months to investigate their physiology, hippocampal neuroplasticity, neuroinflammation, and telomere length. ES mice, as a group, did not perform differently from controls in the open field or Morris water maze (MWM). Hippocampal neurogenesis and synaptic marker gene expression were not different in ES mice at this age. While we find aging-associated alterations to neuroinflammatory gene expression and telomere length, these were unaffected by ES. When integrating the current data with those from our previously reported 4- and 10-month-old cohorts, we conclude that ES leads to a ‘premature’ shift in the aging trajectory, consisting of early changes that do not further worsen at the advanced age of 20 months. This could be explained e.g. by a ‘floor’ effect in ES-induced impairments, and/or age-induced impairments in control mice. Future studies should help understand how exactly ES affects the overall aging trajectory.

Cognitive Impairment and Mossy Fiber Sprouting in a Rat Model of Drug-resistant Epilepsy Induced by Lithium-pilocarpine.

The mossy fiber sprouting (MFS) in the dentate gyrus is a common pathological change of epilepsy. Previous studies suggested that it is associated with drug-resistant epilepsy, and mossy cells control spontaneous seizures and spatial memory. We investigated the correlations among cognitive impairment, MFS, seizure frequency and drug resistance in a rat model of epilepsy induced by lithium-pilocarpine. Phenytoin and phenobarbital were used to screen drug resistance. Cognitive function and MFS were detected through the novel object recognition (NOR) test, Morris water maze (MWM) test and Timm staining. The results showed that object memory and spatial memory functions were both significantly impaired in rats with epilepsy, and only spatial memory impairment was more severe in rats with drug-resistant epilepsy. More frequent spontaneous seizures and more obvious MFS were observed in the drug-resistant rats. The seizure frequency was significantly associated with the MWM performance but not with the NOR performance in rats with epilepsy. The degree of MFS was significantly associated with seizure frequency and spatial memory function. Taken together, these correlations among drug resistance, seizure frequency, spatial memory impairment and MFS suggested the possibility of a common pathological mechanism. More studies are needed to clarify the underlying mechanism behind these correlations and the detailed role of MFS in epilepsy. The mechanism of mossy cell change may be an important target for the treatment of seizures, drug resistance and cognitive dysfunction in patients with epilepsy.

The Effects Of Long-term Treadmill Running Exercise On Nek7 Expression In Hippocampus Of AD Model Mouse

PURPOSE: The effects of treadmill running for 20 weeks intervention on the memory abilities and the expression of NEK7, IL-1β and IL-10 in hippocampus of Alzheimer's disease (AD) model mouse. METHODS: Twenty male APP/PS1 (three months old) mouse (C57BL/6JNju) were randomly divided into two groups: AD control group (AC, n = 10) and AD exercise group (AE, n = 10). Following acclimation to laboratory conditions for one week. The AE group was intervened by treadmill exercise for 20 weeks (12 m/min, 30 min/day, 5 days/week), the AC group was normally fed for 20 weeks. The Morris water maze experiment lasted for one week at week 20, to evaluate the spatial learning and memory function of the mice. Then brain tissue was taken, immunofluorescence was used to detect IL-1β and IL-10 deposition, and Western Blot were used to detect NEK7 deposition in hippocampus of mouse. The experimental data was reported as mean ± SE, and processed with one-way ANOVA, level of significance was set at α = 0.05. RESULTS: (1) Water maze navigation trial showed that the average escape latency of each group showed a downward trend. Compared with AC group, the decreasing trend of AE group was more significant. In the space exploration experiment, the average frequency of crossing the platform in AC group were significantly less than those in AE group (P < 0.01, AC = 1.48 ± 0.89, AE = 3.89 ± 1.20). (2) Immunofluorescence showed that the expression level of IL-1β of AE group was significantly lower than that of AC group(P < 0.01), but IL-10 of AE group was significantly higher than that of AC group (P < 0.01) in the hippocampus. (3) Western blot results showed that NEK7 expression level in AE group was significantly lower than that in AC group (P < 0.01, AC = 0.45 ± 0.02, AE = 0.19 ± 0.03). CONCLUSION: Long-term treadmill running exercise can improve the spatial learning and memory function of AD model mice. The mechanism may be due to inhibition Nek7 protein, thus inhibition IL-1β, promotion the expression of IL-10. These results indicate that long-term treadmill running exercise alleviation brain inflammation and prevent the impairment of spatial learning and memory function of AD.

Spatial Memory and Microglia Activation in a Mouse Model of Chronic Neuroinflammation and the Anti-inflammatory Effects of Apigenin.

Chronic neuroinflammation characterized by microglia reactivity is one of the main underlying processes in the initiation and progression of neurodegenerative diseases such as Alzheimer’s disease. This project characterized spatial memory during healthy aging and prolonged neuroinflammation in the chronic neuroinflammatory model, glial fibrillary acidic protein-interleukin 6 (GFAP-IL6). We investigated whether chronic treatment with the natural flavonoid, apigenin, could reduce microglia activation in the hippocampus and improve spatial memory. GFAP-IL6 transgenic and wild-type-like mice were fed with apigenin-enriched or control chow from 4 months of age and tested for spatial memory function at 6 and 22 months using the Barnes maze. Brain tissue was collected at 22 months to assess microgliosis and morphology using immunohistochemistry, stereology, and 3D single cell reconstruction. GFAP-IL6 mice showed age-dependent loss of spatial memory recall compared with wild-type-like mice. Chronic apigenin treatment decreased the number of Iba-1+ microglia in the hippocampus of GFAP-IL6 mice and changed microglial morphology. Apigenin did not reverse spatial memory recall impairment in GFAP-IL6 mice at 22 months of age. GFAP-IL6 mice may represent a suitable model for age-related neurodegenerative disease. Chronic apigenin supplementation significantly reduced microglia activation, but this did not correspond with spatial memory improvement in the Barnes Maze.

Filgrastim Improved Spatial Memory functions in Rat Model of scopolamine induced Alzheimer type memory dysfunction

Filgrastim is a granulocyte colony-stimulating factor (G-CSF), which also showed effects on memory and cholinergic activity. This study was conducted to determine the effect of filgrastim on memory in Rat Model of scopolamine induced memory dysfunction. Materials and Methods: 24 male Wistar rats were divided into four groups: Group I: control rats receiving normal saline. Group II: rats induced Alzheimer disease by injection of Scopolamine. Groups III and IV: AD rats treated with 50 and 70 μg/kg/day intraperitoneally (i.p) filgrastim over a period of two weeks. Then, rats trained with four trials per day for 5 consecutive days in the Morris water maze (MWM) to find a hidden platform. Time elapsed for finding the hidden platform were considered as criteria for learning. On the 6th day, memory retention was evaluated by time spent in target quadrant.Results: In Scopolamine groups, escape latency during training trials showed a significant decrease (P< 0.001) and these rats spent shorter time in the target quadrant in probe trials compared to controls(P< 0.001). treatment of scopolamine group by filgrastim in doses of 50 and 70 μg/kg/day significantly reduced the latency time to finding the escape platform (P< 0.01). And in probe trials, on the last day of training, the filgrastim –treated group spent significantly longer time in the platform quadrant when compared with the scopolamine induced AD animals (P< 0.01).Conclusion: filgrastim acted as a memory enhancer in scopolamine induced Alzheimer rats. This cognitive enhancer effect of filgrastim may be attributed to its cholinergic effect.

Space Radiation-Induced Alterations in the Hippocampal Ubiquitin-Proteome System.

Exposure of rodents to <20 cGy Space Radiation (SR) impairs performance in several hippocampus-dependent cognitive tasks, including spatial memory. However, there is considerable inter-individual susceptibility to develop SR-induced spatial memory impairment. In this study, a robust label-free mass spectrometry (MS)-based unbiased proteomic profiling approach was used to characterize the composition of the hippocampal proteome in adult male Wistar rats exposed to 15 cGy of 1 GeV/n 48Ti and their sham counterparts. Unique protein signatures were identified in the hippocampal proteome of: (1) sham rats, (2) Ti-exposed rats, (3) Ti-exposed rats that had sham-like spatial memory performance, and (4) Ti-exposed rats that impaired spatial memory performance. Approximately 14% (159) of the proteins detected in hippocampal proteome of sham rats were not detected in the Ti-exposed rats. We explored the possibility that the loss of the Sham-only proteins may arise as a result of SR-induced changes in protein homeostasis. SR-exposure was associated with a switch towards increased pro-ubiquitination proteins from that seen in Sham. These data suggest that the role of the ubiquitin-proteome system as a determinant of SR-induced neurocognitive deficits needs to be more thoroughly investigated.

Neurotoxic Effect of Fipronil in Male Wistar Rats: Ameliorative Effect of L-Arginine and L-Carnitine.

Simple SummaryInsecticides are widely used in agricultural and household environments. They induce wide range of deleterious effects. Fipronil is one of the most widely used phenylpyrazoles insecticides. The neurotoxic effect of such insecticide was tested in the present study with special emphasis on cognitive deficit as well as testing the possible ameliorative impacts of L-arginine and L-carnitine. The study proposed fipronil-induced cognitive deficit as a reflection to oxidative stress and neuro-inflammation. Moreover, L-arginine and L-carnitine exerted ameliorative influence on fipronil induced oxidative stress and neuro-inflammation. Therefore, L-arginine and L-carnitine can be considered as prospective candidates for mitigation of pesticide induced neurotoxicity especially in people with high-risk exposure to pesticide.The ameliorative effect of L-arginine (LA) and L-carnitine (LC) against fipronil (FPN)-induced neurotoxicity was explored. In this case, 36 adult male rats were randomly divided into six groups: group I received distilled water, group II received 500 mg/kg LA, group III received 100 mg/kg LC, group IV received 4.85 mg/kg FPN, group V received 4.85 mg/kg FPN and 500 mg/kg LA and group VI received 4.85 mg/kg FPN and 100 mg/kg LC for 6 weeks. Cognitive performance was assessed using Barnes maze (BM). Serum corticosterone, brain total antioxidant capacity (TAC), malondialdehyde (MDA) and dopamine were measured. Histopathology and immunohistochemistry of ionized calcium-binding adaptor (Iba-1), doublecortin (DCX) and serotonin (S-2A) receptors were performed. Fipronil induced noticeable deterioration in spatial learning and memory performance. In addition, FPN significantly (p < 0.05) diminished brain antioxidant defense system and dopamine coincide with elevated serum corticosterone level. Histopathological examination revealed degenerative and necrotic changes. Furthermore, Iba-1 and DCX were significantly expressed in cortex and hippocampus whereas S-2A receptors were significantly lowered in FPN group. However, administration of LA or LC alleviated FPN-induced deteriorations. In conclusion, LA and LC could be prospective candidates for mitigation of FPN-induced neurotoxicity via their antioxidant, anti-inflammatory and neuropotentiating effects.

The Prostate Cancer Therapy Enzalutamide Compared with Abiraterone Acetate/Prednisone Impacts Motivation for Exploration, Spatial Learning and Alters Dopaminergic Transmission in Aged Castrated Mice

Simple SummaryCognitive side effects and fatigue after cancer treatment now constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are next-generation therapies improving metastatic castration-resistant prostate cancer (mCRPC) patient survival, but also associated with neurological disturbances. We developed a behavioral 17 months-aged and castrated mouse model receiving AAP or ENZ for 5 days per week for six weeks. We establish that ENZ impacts locomotor and explorative behaviors, and strength capacity likely by preventing binding of central synthetized androgens to androgen receptors expressed by dopamine neurons of the Substantia Nigra and the Ventral Tegmentum. ENZ also reduces the cognitive score, associated with less neuronal activity in dorsal hippocampal areas. This demonstrates ENZ-specific consequences on motivation to exploration and cognition, being of particular importance for future management of elderly prostate cancer patients and their quality of life.Cognitive side effects after cancer treatment threatening quality of life (QoL) constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are examples of next-generation therapy (NGT) administered to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment were reported. We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ for 5 days per week for six consecutive weeks. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH+-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus highlighted ENZ-induced dopaminergic regulation within the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN+-neurons in the dorsal hippocampus. The consequences of the mCRPC treatment ENZ on aged castrated mouse motivation to exploration and cognition should make reconsider management strategy of elderly prostate cancer patients.

Thymoquinone improves cognitive and hippocampal long-term potentiation deficits due to hepatic encephalopathy in rats.

Objective(s):Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that causes brain disturbances. Thymoquinone (TQ) has a wide spectrum of activities such as antioxidant, anti-inflammatory, and anticancer. This study aimed to evaluate the effects of TQ on spatial memory and hippocampal long-term potentiation (LTP) in rats with thioacetamide (TAA)-induced liver injury and hepatic encephalopathy. Materials and Methods:Adult male Wistar rats were divided into six groups randomly: 1) Control; 2) HE, received TAA (200 mg/kg); 3-5) Treated groups (HE+TQ5, HE+TQ10, and HE+TQ20). TQ (5, 10, and 20 mg/kg) was injected intraperitoneally (IP) for 12 consecutive days from day 18 to 29. Subsequently, spatial memory performance was evaluated by the Morris water maze paradigm and hippocampal LTP was recorded from the dentate gyrus (DG) region. Activity levels of Malondialdehyde (MDA) and superoxide dismutase (SOD) were measured in the hippocampal tissue.Results:Data showed that the hippocampal content of MDA was increased while SOD activities were decreased in TAA-induced HE. TQ treatment significantly improved spatial memory and LTP. Moreover, TQ restored the levels of MDA and SOD activities in the hippocampal tissue in HE rats. Conclusion:Our data confirm that TQ could attenuate cognitive impairment and improve LTP deficit by modulating the oxidative stress parameters in this model of HE, which leads to impairment of spatial cognition and LTP deficit. Thus, these results suggest that TQ may be a promising agent with positive therapeutic effects against liver failure and HE defects.

Ocimum sanctum Linn. Extract Improves Cognitive Deficits in Olfactory Bulbectomized Mice via the Enhancement of Central Cholinergic Systems and VEGF Expression.

This study aimed to clarify the antidementia effects of ethanolic extract of Ocimum sanctum Linn. (OS) and its underlying mechanisms using olfactory bulbectomized (OBX) mice. OBX mice were treated daily with OS or a reference drug, donepezil (DNP). Spatial and nonspatial working memory performance was measured using a modified Y maze test and a novel object recognition test, respectively. Brain tissues of the animals were subjected to histochemical and neurochemical analysis. OS treatment attenuated OBX-induced impairment of spatial and nonspatial working memories. OBX induced degeneration of septal cholinergic neurons, enlargement of the lateral ventricles, and suppression of hippocampal neurogenesis. OS and DNP treatment also depressed these histological damages. OS administration reduced ex vivo activity of acetylcholinesterase in the brain. OBX diminished the expression levels of genes coding vascular endothelial growth factor (VEGF) and VEGF receptor type 2 (VEGFR2). Treatment with OS and DNP reversed OBX-induced decrease in VEGF gene and protein expression levels without affecting the expression of the VEGFR2 gene. These results demonstrate that the administration of OS can lessen the cognitive deficits and neurohistological damages of OBX and that these actions are, at least in part, mediated by the enhancement of central cholinergic systems and VEGF expression.

The olfactory bulb modulates entorhinal cortex oscillations during spatial working memory

Cognitive functions such as working memory require integrated activity among different brain regions. Notably, entorhinal cortex (EC) activity is associated with the successful working memory task. Olfactory bulb (OB) oscillations are known as rhythms that modulate rhythmic activity in widespread brain regions during cognitive tasks. Since the OB is structurally connected to the EC, we hypothesized that OB could modulate EC activity during working memory performance. Herein, we explored OB–EC functional connectivity during spatial working memory performance by simultaneous recording local field potentials when rats performed a Y-maze task. Our results showed that the coherence of delta, theta, and gamma-band oscillations between OB and EC was increased during correct trials compared to wrong trials. Cross-frequency coupling analyses revealed that the modulatory effect of OBs low-frequency phase on EC gamma power and phase was enhanced when animals correctly performed working memory task. The influx of information from OB to EC was also increased at delta and gamma bands within correct trials. These findings indicated that the modulatory influence of OB rhythms on EC oscillations might be necessary for successful working memory performance.

The Neuropathological and Biological Impacts of Alzheimer’s Disease on Spatial Memory: A Literature Review

Introduction: The effects of spatial memory on Alzheimer’s disease (AD) pose a great hazard to the emotional and physical wellbeing of the patient and their families, affecting more than 60% of individuals with AD. This review explores the neuropathological and biological foundations of spatial memory with relation to AD. Methods: The results in the 11 papers (7 animal studies, 4 clinical studies) will be described, examined, and compared with each other, and attempt to pinpoint areas for future research. Results: Results from animal studies showed that neurotransmitter function, protein function, and calcium regulation are all impaired by AD, which lowers the spatial memory and cognition in animals. In clinical studies, it was found that the medial temporal lobe (MTL) regions, including the hippocampus, amygdala, and entorhinal cortex, are compromised by AD and relate to spatial memory performance. Discussion: This review concluded that more clinical research should be conducted around spatial memory, and animal research can explore the role of protein function given the relevance of neuropathology in AD. Conclusion: With the information collected in this review, future steps can be taken to explore the intricacies of spatial memory and AD. Moreover, this review also poses a useful reference for other researchers examining the relation between spatial memory and AD.

Anxiolytic effects of administration of a commercially available prebiotic blend of galacto-oligosaccharides and beta glucans in Sprague-Dawley rats.

Prebiotics are nondigestible food agents that stimulate the growth of bacteria in the gut, whereas probiotics are live microorganisms that replace or restore beneficial bacteria in the digestive tract. Both agents have been shown to have beneficial qualities within the microbiota-gut-brain axis, but the behavioural effects of prebiotics have been less studied than probiotics. Whereas several studies have shown that prebiotics reduce inflammation and modulate anxiety in animals that are injected with lipopolysacccharides or chronically stressed animals, respectively, it is not yet known how they affect a healthy organism. Here, we tested the behavioural effects of galacto-oligosaccharides and beta glucan as a commercially available prebiotic blend in healthy, naïve Sprague-Dawley rats. We used the open field test and elevated plus maze to assess anxiety-like behaviour in controls and in rats that ingested the prebiotic blend in their drinking water. We also used the Morris Water Maze to assess spatial memory performance in controls and prebiotic treated rats. Rats treated with prebiotics spent more time in the intermediate zone of the open field test and in the open arms of the elevated plus maze, and exhibited a shorter latency to enter each of these zones. No significant differences between groups were found in the Morris Water Maze. Our results suggest that whereas prebiotics significantly reduced anxiety-like behaviours, it had no effect on spatial memory performance. Altogether, our data indicate that commercially available prebiotic beta glucan blends have anxiolytic effects in healthy rats.

Methotrexate Neurotoxicity Is Related to Epigenetic Modification of the Myelination Process.

With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways.

Behavioral and biochemical investigations to explore the efficacy of quercetin and folacin in experimental diabetes induced vascular endothelium dysfunction and associated dementia in rats.

Vascular dementia (VaD), being strongly associated with metabolic conditions is a major health concern around the world. Diabetes is a major risk factor for the development of VaD. This study investigates the efficacy of quercetin and folacin in diabetes induced vascular endothelium dysfunction and related dementia. Single dose streptozotocin (STZ) (50mg/kg i.p) was administered to albino Wistar rats (male, 200-250g) by dissolving in citrate buffer. Morris water maze (MWM) and attentional set shifting tests were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains' oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), mitochondrial enzyme complex (I, II, and IV), inflammatory markers (interleukin-IL-6, IL-10, tumor necrosis factor-TNF-α, and myeloperoxidase-MPO), and acetylcholinesterase activity-AChE were also assessed. Quercetin (30mgkg-1/60mgkg-1) and folacin (30mgkg-1/60mgkg-1) were used as the treatment drugs. Donepezil (0.5mgkg-1) was used as a positive control. STZ administered rats showed reduction in learning, memory, reversal learning, executive functioning, impairment in endothelial function, increase in brains' oxidative stress; inflammation; AChE activity, and decrease in mitochondrial complex (I, II, and IV) activity. Administration of quercetin and folacin in two different doses, significantly attenuated the STZ induced diabetes induced impairments in the behavioral, endothelial, and biochemical parameters. STZ administration caused diabetes and VaD which was attenuated by the administration of quercetin and folacin. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced VaD conditions.

Anterior Thalamic Inputs Are Required for Subiculum Spatial Coding, with Associated Consequences for Hippocampal Spatial Memory.

Just as hippocampal lesions are principally responsible for “temporal lobe” amnesia, lesions affecting the anterior thalamic nuclei seem principally responsible for a similar loss of memory, “diencephalic” amnesia. Compared with the former, the causes of diencephalic amnesia have remained elusive. A potential clue comes from how the two sites are interconnected, as within the hippocampal formation, only the subiculum has direct, reciprocal connections with the anterior thalamic nuclei. We found that both permanent and reversible anterior thalamic nuclei lesions in male rats cause a cessation of subicular spatial signaling, reduce spatial memory performance to chance, but leave hippocampal CA1 place cells largely unaffected. We suggest that a core element of diencephalic amnesia stems from the information loss in hippocampal output regions following anterior thalamic pathology.SIGNIFICANCE STATEMENT At present, we know little about interactions between temporal lobe and diencephalic memory systems. Here, we focused on the subiculum, as the sole hippocampal formation region directly interconnected with the anterior thalamic nuclei. We combined reversible and permanent lesions of the anterior thalamic nuclei, electrophysiological recordings of the subiculum, and behavioral analyses. Our results were striking and clear: following permanent thalamic lesions, the diverse spatial signals normally found in the subiculum (including place cells, grid cells, and head-direction cells) all disappeared. Anterior thalamic lesions had no discernible impact on hippocampal CA1 place fields. Thus, spatial firing activity within the subiculum requires anterior thalamic function, as does successful spatial memory performance. Our findings provide a key missing part of the much bigger puzzle concerning why anterior thalamic damage is so catastrophic for spatial memory in rodents and episodic memory in humans.

Possible involvement of agmatine in neuropharmacological actions of metformin in diabetic mice

The risk of psychiatric and neurological disorders is significantly higher in patients with diabetes mellitus. Diabetic patients are more susceptible to depression, anxiety and memory impairment as compared with non-diabetic individuals. Metformin, a biguanide used for the management of type 2 diabetes mellitus (T2DM), promotes neurogenesis, enhances spatial memory function and protects the brain against oxidative imbalance beyond its effect on glucose metabolism. However, the exact mechanism of its neuropharmacological actions in T2DM is not known. We investigated the role of the agmatinergic system in neuropharmacological actions of metformin in diabetic mice. Diabetes was induced by the streptozotocin (STZ) injection and confirmed by high blood glucose levels. After 28 days, STZ treated mice exhibited memory impairment in radial arm maze, depression-like behavior in forced swim test and anxiety-like behavior in elevated plus maze along with increased expression of pro-inflammatory cytokines like TNF-α, IL-1β, IL-6, IL-10 also, reduced agmatine and BDNF levels in the hippocampus and prefrontal cortex compared to the control animals. Metformin and agmatine alone or in combination, by once-daily administration during 14–27 day of the protocol significantly reversed the STZ induced high blood glucose levels, memory impairment, depression and anxiety-like behaviors. It also reduced neuro-inflammatory markers and increased agmatine and BDNF levels in the hippocampus and prefrontal cortex. The present study suggests the importance of endogenous agmatine in the neuropharmacological action of metformin in diabetic mice. The data projects agmatine and metformin combination as a potential therapeutic strategy for diabetes associated memory impairment, depression, anxiety, and other comorbidities.