Impaired Learning Ability Research Articles

Astragaloside protects rat brain from microwave-induced functional injuries via restoring acetylcholine and normalizing electroencephalogram.

Studies from our group and others have reported that 30mW/cm2 microwave could damage the structures of rat hippocampus, as well as impair the neuronal functions. The neuroprotective effects of astragaloside, purified from Astragalus membranaceus, have been demonstrated in animal models of neurodegenerative diseases. In this study, we found that 30mW/cm2 microwave impaired spatial learning and memory ability in rats, while astragaloside could significantly alleviate the injuries. The pathological analysis also showed that astragaloside protected neurons from microwave-induced damages, such as mitochondrial swelling and cavitation, rough endoplasmic reticulum swelling and dilation, synaptic gap disappearing, and vesicle aggregation. Moreover, microwave-induced structural damage of synapse resulted in downregulation of acetylcholine, an important neurotransmitter for information transmission, while astragaloside could protect the structure of synapse, as well as restore the acetylcholine level in rat hippocampus. Furthermore, astragaloside also accelerated the recovery of brain electroencephalogram (EEG) after microwave exposure, indicating that astragaloside could promote the normalization of neuronal functions. In conclusion, astragaloside protected the morphological structures and restored acetylcholine level in rat hippocampus, which could improve brain functions via normalizing brain EEG. Therefore, astragaloside might be a promising candidate to treat microwave-induced injuries of central nervous system (CNS).

Complications resulting from encephalitis and health care needs at Vietnam National Children’s Hospital (2018-2019)

ABSTRACT: We conducted research at the Vietnam National Children’s Hospital to describe the characteristics of sequelae after encephalitis at Children's Hospital. The study describes the progress of 270 pediatric encephalopathy patients treated at the Vietnam National Children’s Hospital from August 1, 2018 to July 31, 2019 to identify sequelae and care needs for patients with sequelae of encephalitis. Results: There were 78/270 (28.8%) patients discharged from hospital with sequelae. In particular, the percentage of patients who needed to walk practice was 84.6%, followed by the percentage of patients who had speech disabilities and hand movement practice was 73.1%, the percentage of patients with behavior changes was 60.3%, and the percentage of patients with impaired learning and working ability was 61.6%, while 55.2% of the patients had seizures, and finally 35.9% of the patients needed hearing aids. Children with sequelae had other care needs depending on the degree of sequelae.
 Key word: Acute Encephalitis, Sequale of Encephalitis

Key miRNAs associated with memory and learning disorder upon exposure to sevoflurane determined by RNA sequencing.

The study aimed to identify differentially expressed microRNAs (miRNAs/miRs) and explore the mechanisms governing impaired memory and learning ability in developing brains exposed to sevoflurane. A total of six 7-day-old male ICR mice were randomly assigned into the sevoflurane anesthesia group (treated with 2.4% sevoflurane) or control group (treated with normal saline solution at the same dose). After 14 days, the mice were subjected to a Morris water maze experiment. Then, the animals were sacrificed and hippocampus tissues were isolated. RNAs in hippocampus tissues were sequenced and the differential miRNA expression profiles were identified by a bioinformatics approach. The learning and memory function of mice were significantly affected by sevoflurane exposure. A total of 18 miRNAs were found to be significantly affected by sevoflurane administration. Their target genes clustered into different functional groups, such as ‘dephosphorylation’, ‘vesicle localization’ and the ‘Wnt signaling pathway’. miR-101b-3p was closely related with ‘chromatin binding’ and ‘protein serine/threonine kinase activity’. The most represented pathways for miRNAs included ‘neuroactive ligand-receptor interaction’ (miR-1187), ‘long-term depression’ (miR-425-5p), ‘FoxO signaling pathway’ (miR-425-5p) and the ‘neurotrophin signaling pathway’ (miR-467a-3p). miR-467a-3p (degree=89), miR-101b-3p (degree=59), and miR-1187 (degree=51) were the hub nodes in the miRNA regulatory network. The Wnt signaling pathway, miR-467a-3p, miR-1187 and miR-101b-3p may be therapeutic targets for preventing cognitive impairments induced by sevoflurane.

Tea polyphenols protect learning and memory in sleep-deprived mice by promoting AMPA receptor internalization.

Chronic sleep loss caused lots of health problems, also including cognition impairment. Tea is one of the most popular drinks when people stay up late. Nevertheless, the effects of tea on sleep deprivation-induced cognition impairment are still unclear. In the present study, we found 24-h sleep deprivation (S-DEP) increased membrane α-amino-3-hydroxy-5-methyl-4-isoxa-zolep-propionate (AMPA) receptor level through a tumor necrosis factor α (TNFα)-dependent pathway in hippocampi. Blocking elevated TNFα level can protect S-DEP mice from impaired learning ability according to behavioral test. Tea polyphenols, major active compounds in green tea, suppressed TNFα production through downregulating TNFα converting enzyme (TACE) level. Meanwhile, tea polyphenols treatment could ameliorate recognition impairment and anxiety-like behaviors in S-DEP mice. The aforementioned results demonstrate cognition protective effects of tea polyphenols in S-DEP mice model, which provide a theoretical basis for the treatments of S-DEP-induced cognition impairment by targeting the TACE/TNFα/AMPA pathway.

Lanthanum Chloride Causes Neurotoxicity in Rats by Upregulating miR-124 Expression and Targeting PIK3CA to Regulate the PI3K/Akt Signaling Pathway

Background Lanthanum (La) exposure can cause central nervous system (CNS) damage and dysfunction in children, seriously affecting intellectual development. miR-124 plays an important role in the development of the nervous system. We exposed rats to a La environment then observed the rats' learning and memory damage and neurotoxicity and the relationship with miR-124. Methods Rats were exposed to LaCl3 via drinking water. The rats' offspring were exposed to LaCl3 from their mother before weaning, then from La water for 28 days. A Morris water maze was used to observe spatial memory capabilities. H&E staining and TUNEL assays were used to observe pathological changes and apoptosis in the hippocampus. miR-124 was detected by RT-qPCR, and its targeting was confirmed by luciferase assay. The HT22 cell line was cultured with LaCl3 and treated with miR-124 mimics or inhibitors; then, expression of PI3K/Akt-related proteins was detected by western blot. Results La exposure can lead to impaired learning and memory ability in offspring. Offspring with La accumulations in the hippocampus showed severe damage, disordered cells, and increased neurocyte apoptosis. In vitro, the postsynaptic density protein 95 was downregulated under La exposure and apoptosis increased. This effect of La can be attenuated by miR-124 inhibitors and enhanced by miR-124 mimics. LaCl3 exposure increased miR-124 expression and targeting on PIK3CA, downregulating PI3K, p-Akt, and p-NF-κB p65. Conclusion La causes neurotoxicity by upregulating miR-124 expression and targeting PIK3CA through the PI3K/Akt signaling pathway.

Effects of an Adaptogenic Extract on Electrical Activity of the Brain in Elderly Subjects with Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled, Two-Armed Cross-Over Study.

Background: The current and potential uses of adaptogens are mainly related to treatment of stress-induced fatigue, impaired cognitive function, mental illness, and behavioral- and age-related disorders. However, clinical evidence regarding the efficacy of adaptogens is limited. The primary aim of this study is to determine whether a combination of adaptogenic plant extracts from Andrographis paniculata and Withania somnifera (Adaptra® Forte) could be used as effective and safe treatment for impaired cognitive, memory, or learning ability functions and sleep disorders. Methods: The changes in electroencephalogram (EEG) frequency ranges in 17 different brain regions, psychometric tests of cognitive performance, as well as standard questionnaires of assessment of mood and sleep were measured after single and repeated administration of Adaptra® or placebo for four weeks and after a two-week treatment-free follow-up period within a randomized, double-blind, placebo-controlled two-armed cross-over study. Results: Adaptra® Forte significantly improved cognitive performance in the d2-Test for attention and the concentration performance test after four weeks’ treatment, and was positively correlated with increases in δ and θ power in the quantitative EEG compared with placebo during cognitive challenges. Conclusion: The results of this study suggest that Adaptra® Forte exhibits a calming and anxiolytic effect without sedation, and is associated with overall stress-protective activity.

Endothelial-specific deficiency of megalin in the brain protects mice against high-fat diet challenge

BackgroundThe increasing risk of obesity and diabetes among other metabolic disorders are the consequence of shifts in dietary patterns with high caloric-content food intake. We previously reported that megalin regulates energy homeostasis using blood-brain barrier (BBB) endothelial megalin-deficient (EMD) mice, since these animals developed obesity and metabolic syndrome upon normal chow diet administration. Obesity in mid-life appears to be related to greater dementia risk and represents an increasing global health issue. We demonstrated that EMD phenotype induced impaired learning ability and recognition memory, neurodegeneration, neuroinflammation, reduced neurogenesis, and mitochondrial deregulation associated with higher mitochondrial mass in cortical tissues.MethodsEMD mice were subjected to normal chow and high-fat diet (HFD) for 14 weeks and metabolic changes were evaluated.ResultsSurprisingly, BBB megalin deficiency protected against HFD-induced obesity improving glucose tolerance and preventing hepatic steatosis. Compared to wild type (wt), the brain cortex in EMD mice showed increased levels of the mitochondrial biogenesis regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2), a thermogenic protein involved in the regulation of energy metabolism. This agreed with the previously found increased mitochondrial mass in the transgenic mice. Upon HFD challenge, we demonstrated these two proteins were found elevated in wt mice but reported no changes over the already increased levels in EMD animals.ConclusionWe propose a protective role for megalin on diet-induce obesity, suggesting this could be related to metabolic disturbances found in dementia through brain endocrine system communications.

Lanthanum Chloride Impairs Learning and Memory and Induces Dendritic Spine Abnormality by Down-Regulating Rac1/PAK Signaling Pathway in Hippocampus of Offspring Rats.

Lanthanum (La) is a natural rare earth element. It has neurotoxic effects which can impair learning and memory in humans. However, its mechanism of neurotoxicity is unclear. Learning and memory are coordinated by dendritic spines which form tiny protruding structures on the dendritic branches of neurons. This study investigated the effect of LaCl3 exposure to pregnant and lactating rats on the offspring rats' learning and memory ability. In this study, rats were divided into 4 groups and given distilled water solution containing 0%, 0.125%, 0.25%, 0.5% LaCl3, respectively, and this was done from conception to the end of the location. The effects of LaCl3 on spatial learning and memory ability in offspring rats and in the development of dendritic spines in CA1 pyramidal cells were investigated. The results showed that LaCl3 impaired spatial learning and memory ability in offspring rats, and decreased dendritic spine density during development. In addition, LaCl3 can affect the expression of CaMKII, miRNA132, p250GAP, Tiam1, PARD3, and down-regulated the activation of Rac1 which led to a decrease in the expression of Rac1/PAK signaling pathway and downstream regulatory proteins Cortactin and actin-related protein 2/3 complex (Arp2/3 complex). This study indicated that the learning and memory impairment and the decrease of dendritic spine density in the offspring of LaCl3 exposure may be related to the down-regulation of the Rac1/PAK signaling pathway regulated by Tiam1 and p250GAP.

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.

Effects of early postnatal exposure to fine particulate matter on emotional and cognitive development and structural synaptic plasticity in immature and mature rats.

IntroductionFine particulate matter (PM2.5) is closely associated with many neurological disorders including neurodegenerative disease, stroke, and brain tumors. However, the toxic effects of PM2.5 on neurodevelopment remain unclear. In this study, we aimed to determine the neurotoxic effects of early postnatal exposure to PM2.5 in immature and mature rats.MethodsWe exposed neonatal rats to PM2.5 (2 or 10 mg/kg body weight) through intranasal instillation from postnatal day (PND) 3–15, once a day. Emotional and cognitive development were evaluated using the elevated plus maze, forced swimming, and Morris water maze tests. Hippocampal tissue was collected and subjected to transmission electron microscopy observation and western blot analysis.ResultsRats had lower body weight after exposure to high dose of PM2.5. The behavioral test results indicated that high‐dose PM2.5 exposure led to increased anxiety‐like symptoms in immature and mature rats, apparent depressive‐like behaviors in mature rats, and impaired spatial learning and memory abilities in immature rats, and low‐dose PM2.5 exposure increased anxiety‐like behaviors in immature rats. Further, high‐dose PM2.5 exposure contributed to fewer synapses, thinner postsynaptic density, and shorter active zone in immature and mature rats, and also decreased expressions of synaptophysin (SYP), growth associated protein‐43 (GAP43), and postsynaptic density‐95 (PSD95) in immature rats, SYP and PSD95 in mature rats. Moreover, low‐dose PM2.5 exposure diminished the expression of PSD95 in immature rats. In addition, high‐dose PM2.5 exposure reduced brain‐derived neurotrophic factor (BDNF) expression and cAMP response element binding protein (CREB) phosphorylation in both immature and mature rats, and low‐dose PM2.5 exposure lessened BDNF expression and CREB phosphorylation in immature rats.ConclusionsOur findings indicate that PM2.5 impairs emotional and cognitive development by disrupting structural synaptic plasticity, possibly via the CREB/BDNF signaling pathway.

Potential biomarkers for neuroinflammation and neurodegeneration at short and long term after neonatal hypoxic-ischemic insult in rat

BackgroundHypoxic-ischemic (HI) encephalopathy causes life-long morbidity and premature mortality in term neonates. Therapies in addition to whole-body cooling are under development to treat the neonate at risk for HI encephalopathy, but are not a quickly measured serum inflammatory or neuronal biomarkers to rapidly and accurately identify brain injury in order to follow the efficacy of therapies.MethodsIn order to identify potential biomarkers for early inflammatory and neurodegenerative events after neonatal hypoxia-ischemia, both male and female Wistar rat pups at postnatal day 7 (P7) were used and had their right carotid artery permanently doubly occluded and exposed to 8% oxygen for 90 min. Sensory and cognitive parameters were assessed by open field, rotarod, CatWalk, and Morris water maze (MWM) test. Plasma and CSF biomarkers were investigated on the acute (24 h and 72 h) and chronic phase (4 weeks). Brains were assessed for gene expression analysis by quantitative RT-PCR Array.ResultsWe found a delay of neurological reflex maturation in HI rats. We observed anxiolytic-like baseline behavior in males more than females following HI injury. HI rats held on the rotarod for a shorter time comparing to sham. HI injury impaired spatial learning ability on MWM test. The CatWalk assessment demonstrated a long-term deficit in gait parameters related to the hind paw. Proinflammatory biomarkers such as IL-6 in plasma and CCL2 and TNF-α in CSF showed an upregulation at 24 h after HI while other cytokines, such as IL-17A and CCL5, were upregulated after 72 h in CSF. At 24 h post-injury, we observed an increase of Edn1, Hif1-α, and Mmp9 mRNA levels in the ipsilateral vs the contralateral hemisphere of HI rats. An upregulation of genes involved with clotting and hematopoietic processes was observed 72 h post-injury.ConclusionsOur work showed that, in the immature brain, the HI injury induced an early increased production of several proinflammatory mediators detectable in plasma and CSF, followed by tissue damage in the hypoxic hemisphere and short-term as well as long-lasting neurobehavioral deficits.

Theaflavin attenuates cerebral ischemia/reperfusion injury by abolishing miRNA‑128‑3p‑mediated Nrf2 inhibition and reducing oxidative stress.

Theaflavin has been proven to own strong antioxidative capacity; however, the molecular mechanism underlying its protective effect against cerebral ischemia-reperfusion (I/R) injury remains unclear. Therefore, the present study was designed to elucidate the neuroprotective effects of theaflavin on cerebral I/R injury and its underlying molecular mechanisms. To investigate the effects of theaflavin on neurological function, neurogenesis, and oxidative stress, experiments were performed using a cerebral I/R injury rat model, and neural stem cells (NSCs) were subjected to oxygen-glucose deprivation and reoxygenation (OGD/R). Further, the expression profiles of miRNA-128-3p and the regulatory function of nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) were evaluated in these models. We found that theaflavin treatment significantly reduced infarct volume and neuronal injury, and thus improved the impaired memory and learning ability. Furthermore, theaflavin treatment significantly enhanced the increase in NSC proliferation, reduction in the apoptotic rate and inhibition of oxidative stress. Mechanistically, theaflavin targeted miRNA-128-3p and further activated the Nrf2 pathway to reduce oxidative stress. In summary, theaflavin has a strong ability to attenuate cerebral I/R injury through miRNA-128-3p-mediated recovery of the impaired antioxidant defense system, which suggests that it could be a potential drug candidate for ischemic stroke.

Low-dose bisphenol A exposure impairs learning and memory ability with alterations of neuromorphology and neurotransmitters in rats

To investigate the developmental neurotoxicity of environmental bisphenol A (BPA) exposure for infants and children, postnatal rats were used as the animal model and were divided into four groups. Then, they were treated with different concentrations of BPA (i.e., 0, 0.5, 50, or 5000 μg/kg·bw/day of BPA as the control, low-, medium- and high-exposed group) from postnatal days 7 to 21. Y-maze tests, Golgi-Cox assays and liquid chromatography-tandem mass spectrometry (LC/MS/MS) were performed to test the changes of learning and memory ability, hippocampal neuromorphology and neurotransmitter levels, respectively. The results showed that the BPA-exposed rats, especially the low- and high-exposed rats, needed more trials and longer times to qualify for the learned criterion than the control rats. Additionally, rats after low- or high-exposure to BPA exhibited decreased DG dendritic complexity and reduced CA1 and DG dendritic spine densities in the hippocampus. Low-dosage BPA treatment could significantly alter the neurotransmitter contents in the hippocampus. In male rats, the levels of glutamic acid (Glu) and acetylcholine increased, while the 5-hydroxytryptamine (5-HT) and γ-aminobutyric acid (GABA) levels decreased, which lead to an unbalanced Glu/GABA ratio. However, in female rats, only 5-HT levels decreased. In conclusion, postnatal exposure to BPA could sex- and dose-dependently disrupt dendritic development and neurotransmitter homeostasis in the rat hippocampus. The impaired spatial learning and memory ability of rats induced by low-dose BPA is associated with both disrupted dendritic development and neurotransmitter homeostasis in the hippocampus.

Effect of Dietary Manipulation of B Vitamins During Pregnancy and Its Impact on Neurobehavior Development and Epigenetic Regulation of Imprinted Genes (P15-026-19)

ObjectivesTill date there have been studies to check the individual effect of maternal folate and vitamin B12 during pregnancy but less is known regarding the combined effect of both vitamins on growth and neuro-behaviour of the off-springs. So, the present study was designed with an aim to check the combined effect of both vitamins on: Neurobehaviour development of off-springs and epigenetic regulation of imprinted (H19, IGF2, IGF2R) genes. MethodsFour week old C57BL/6 female mice were randomized into nine groups BNFN, BNFO, BNFD, BDFN, BDFD, BDFO, BOFN, BOFO, BOFD and were fed diet for six weeks while male mice were on normal diet. Mating was performed and pregnant dams gave birth to the F1 off-springs. Both male and female fetuses in F1 generation were fed diets as per the dietary groups of their mothers. After six weeks males were used for neurobehavior studies and mating was carried out, on day 20 of gestation maternal and fetal tissues (F2 generation) were isolated. Folate, homocysteine and B12 levels were analyzed along with mRNA expression, promoter DNA methylation and histone modification of imprinted genes. ResultsFolate, vitamin B12 and homocysteine levels were altered in different folate and B12 dietary groups (P < 0.01). Adult mice exposed to folate and vitamin B12 conditions expressed delayed locomoter functions in BDFD (25.74%), BNFD (20.75%) and BOFD (20.16%) groups, impaired spatial learning and memory ability and increased GSH/GSSG levels in brain under deficient conditions. In maternal and fetal tissues, H19 was found to be over-expressed under deficient conditions which was co-related with decreased promoter methylation and decrease suppressive histone methylation marks H3K9me3 and H3K27me3 (P < 0.01) and increase in H3K4me2. Genomic imprinting patterns were found to be reversed in H19 in both male and female fetuses. IGF2 along with IGF2R showed loss of expression with increased methylation in promoter region (P < 0.05) and suppressive histone methylation marks in deficient conditions. AbbreviationsBN: B12 Normal FN: Folate Normal FD: Folate deficient FO: Folate over supplementation BD: B12 deficient BO: B12 over supplementation ConclusionsMaternal dietary ratio of folate and B12 during pregnancy influence neurobehaviour development and alters the establishment of proper imprints during development. Funding SourcesDepartment of Biotechnology.

Abnormal Amino Acid Profiles of Blood and Cerebrospinal Fluid from Cystathionine β-Synthase-Deficient Mice, an Animal Model of Homocystinuria.

Mental retardation is the most common feature among inborn errors of amino acid metabolism. Patients with homocystinuria/homocysteinemia caused by cystathionine β-synthase (CBS) deficiency suffer from thromboembolism and mental retardation from early ages; therefore, detection by newborn screening is performed. Furthermore, elevated levels of serum homocysteine during pregnancy are associated with the occurrence of neural tube defects (NTDs) in newborns. However, the causes of such central nervous system (CNS) defects are unknown. We found previously impaired learning abilities in Cbs-deficient (Cbs-/-) mice (but not NTD births). Here, we investigated the amino acid profiles of serum and cerebrospinal fluid (CSF) from Cbs-/- mice. Mice deficient in cystathionine γ-lyase (Cth), a downstream enzyme of CBS in transsulfuration, as well as wild-type mice, were analyzed as controls. Cbs-/- and Cth-/- mice were smaller than wild-type mice, and CSF yields in Cbs-/- mice were lower than the others. CSF amino acid levels were generally lower than those in serum, and compared with the dramatic amino acid level alterations in Cbs-/- mouse serum, alterations in CSF were less apparent. However, marked upregulation (versus wild-type) of aspartic acid/asparagine (Asp/Asn), glutamine (Gln), serine (Ser), threonine (Thr), phenylalanine (Phe), tyrosine (Tyr), methionine (Met), total homocysteine, and citrulline, and downregulation of lysine (Lys) were found in Cbs-/- mouse CSF. Because similar regulation of total homocysteine/citrulline/Lys was observed in the CSF of Cth-/- mice, which are free of CNS dysfunction, the reduced CSF volumes and the level changes of other amino acids could be relevant to Cbs-/--specific CNS defects.

Methamphetamine-associated cognitive decline is attenuated by neutralizing IL-1 signaling

Methamphetamine (METH) abusers are prone to develop a variety of comorbidities, including cognitive disabilities, and the immunological responses have been recognized as an important component involved in the toxicity of this drug. Cytokines are among the key mediators between systemic inflammatory status and tissue responses. One of these, interleukin 1 (IL-1), has been hypothesized to be involved in cognitive functions and also appears to play a pivotal role among inflammatory molecules. In the present study, we demonstrate that exposure of mice to METH markedly increased the protein level of IL-1β in hippocampal tissue. Additionally, METH administration induced a decline in spatial learning as determined by the Morris water maze test. We next evaluated the hypothesis that blocking IL-1β signaling can protect against METH-induced loss of cognitive functioning. The results indicated that METH-induced impaired spatial learning abilities were attenuated by co-administration of mouse IL-1 Trap, a dimeric fusion protein that incorporates the extracellular domains of both of the IL-1 receptor components required for IL-1 signaling (IL-1 receptor type 1 and IL-1 receptor accessory protein), linked to the Fc portion of murine IgG2a. This effect was associated with a decrease in hippocampal IL-1β level. The current study indicates for the first time that the loss of METH-related cognitive decline can be attenuated by neutralizing IL-1 signaling. Our findings suggest a potential new therapeutic pathway for treatment of altered cognitive abilities that occur in METH abusing individuals.

Deficiency but Not Supplementation of Selenium Impairs the Hippocampal Long-Term Potentiation and Hippocampus-Dependent Learning.

Among the chemical factors that have been implicated in the etiology of dementia, recent concern has focused on both increased and decreased exposure to the metalloid selenium (Se). This report describes the molecular, behavioral, and electrophysiological analysis of rats that were fed with Se-free chow and Se-enriched tap water for 21days. Three groups were produced, feeding them on a deficient diet with different Selenium content. Hippocampus-dependent spatial learning was measured using the water maze. Long-term potentiation (LTP) was recorded in the hippocampal dentate gyrus to assess how memory is formed at the cellular level. Hippocampal Se levels were measured in trained rats by using inductively coupled plasma mass spectrometry. Phosphorylated and total tau levels were measured in whole hippocampus by Western blot. An impairment of learning of rats feeding with Se-deficient diet was accompanied by attenuated LTP, and increased ratio of p231Tau-to- and decreased ratio of p416Tau-to-Tau in the non-stimulated hippocampus, despite no significant change was observed in Se levels of hippocampus and plasma. Se supplementation resulted in an increase in both tissues and an increase in the ratio of p231Tau-to-Tau in the non-stimulated hippocampus but did not change learning performance and LTP. Despite impaired learning and LTP, no group differed in probe trial and in the fraction of phosphorylated tau in LTP-induced hippocampus. Reduced level of selenium would probably result in reduced synaptic plasticity as well as impairment of learning ability, suggesting requirement of Se for normal synaptic function.

Dopamine D1 receptor agonist treatment alleviates morphine-exposure-induced learning and memory impairments

We investigated the mechanisms by which the dopamine D1 receptor alleviates morphine-exposure-induced cognitive impairments. Rats were intraperitoneally injected with morphine in a dose-escalating manner over 10 days, and 15 min before the morphine injection on days 1, 3, 5, 7, and 9, the rats were administered the D1 receptor agonist SKF81297 or the D1 receptor antagonist SCH38933 into the midbrain periaqueductal gray (PAG). The Morris water maze was used to examine learning- and memory-related behavioral changes. Midbrain PAG toll-like receptor 4 (TLR4) and protein kinase A (PKA) protein expression was examined using western blot analysis, and cellular expression and localization of TLR4 and PKA were investigated using immunohistochemistry. Chronic morphine exposure impaired spatial learning and memory ability, and resulted in longer latency to the platform, decreased number of platform crossings, and shortened time in the effective area and the target quadrant. Chronic morphine exposure also increased TLR4 and PKA expression in the PAG. However, D1 receptor agonist treatment improved learning and memory ability; in morphine-treated rats, administration of the D1 receptor agonist SKF81297 could shorten the latency to the platform, increase the number of platform crossings, and increase the time spent in the effective area and the target quadrant. In addition, TLR4 expression decreased and PKA expression significantly increased in the PAG in these animals. In summary, administration of the dopamine D1 receptor agonist SKF81297 into the PAG alleviated morphine-exposure-induced cognitive impairments.

Cognitive training improves the disturbed behavioral architecture of schizophrenia-like rats, “Wisket”

Translational schizophrenia research depends on the relevance of animal models supported by reliable tests. Human data suggest that the intensive cognitive training in schizophrenia improves the memory impairments and decreases the chance of acute psychiatric remission. Here we examined the effects of a 10-day long training session in the behavioral architecture of a new schizophrenia-like rat substrain (Wisket) in a narrow square corridor with food rewards (AMBITUS). The instrument was designed to model the natural environment of rats and enable the simultaneous recording of multiple behavioral parameters. For the compact visualization of differences between the Wisket and control animals in several parameters (behavioromics), color-coded grid plots were applied. The Wisket animals exhibited an altered pattern and/or amount of locomotion, exploratory and food collecting activity at the first few days, revealing impaired motivation, attention, anxiety and learning ability (face validity). Most of the parameters normalized with training, except for the decreased exploratory activity. This resembles the effects of cognitive behavioral therapy in human schizophrenics providing a significant support for the predictive validity of this substrain as an animal model of schizophrenia. This study also highlights the importance of behavior tests that investigate the egocentric learning ability during reward-based tasks.

ROCK2 regulates autophagy in the hippocampus of rats after subarachnoid hemorrhage.

The role of autophagy in subarachnoid hemorrhage (SAH) remains unclear. This study aimed to investigate the role of ROCK2 in the regulation of hippocampus autophagy after SAH. Thirty-six Sprague-Dawley rats were randomly divided into three groups - the sham group, the SAH group, and the SAH+ ROCK2 inhibitor group (or the drug group) - and analyzed through a behavior test. The hippocampus tissues were analyzed using immunochemistry and western blot analysis. We observed injured morphology in the hippocampus and impaired learning and memory ability in the rats in the SAH group, accompanied by upregulated ROCK2 expression and increased beclin-1 and LC3-II expression. Compared with the SAH group, we observed normal morphology in the hippocampus and better learning and memory ability in the rats in the drug group, accompanied by downregulated ROCK2 expression and increased beclin-1 and LC3-II expression. SAH activates autophagy in the hippocampus, but this could be inhibited by ROCK2. Inhibition of ROCK2 promotes autophagy and reduces the injury in the hippocampus, leading to the recovery of learning and memory ability following SAH. ROCK2 may represent a new target for the treatment of SAH.