Memory Deficiency Research Articles

Impairment of hippocampal long‐term depression and defective spatial learning and memory in p35–/– mice

Cdk5 (cyclin-dependent kinase 5) activity is dependent upon association with one of two neuron-specific activators, p35 or p39. Genetic deletion of Cdk5 causes perinatal lethality with severe defects in corticogenesis and neuronal positioning. p35(-/-) mice are viable with milder histological abnormalities. Although substantial evidence implicates Cdk5 in synaptic plasticity, its role in learning and memory has not been evaluated using mutant mouse models. We report here that p35(-/-) mice have deficiencies in spatial learning and memory. Close examination of hippocampal circuitry revealed subtle histological defects in CA1 pyramidal cells. Furthermore, p35(-/-) mice exhibit impaired long-term depression and depotentiation of long-term potentiation in the Schaeffer collateral CA1 pathway. Moreover, the Cdk5-dependent phosphorylation state of protein phosphatase inhibitor-1 was increased in 4-week-old mice due to increased levels of p39, which co-localized with inhibitor-1 and Cdk5 in the cytoplasm. These results demonstrate that p35-dependent Cdk5 activity is important to learning and synaptic plasticity. Deletion of p35 may shift the substrate specificity of Cdk5 due to compensatory expression of p39.

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

Antagonists at serotonin type 6 (5-HT(6)) receptors show activity in models of learning and memory. Although the underlying mechanism(s) are not well understood, these effects may involve an increase in acetylcholine (ACh) levels. The present study sought to characterize the cognitive-enhancing effects of the 5-HT(6) antagonist Ro4368554 (3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)1H-indole) in a rat object recognition task employing a cholinergic (scopolamine pretreatment) and a serotonergic- (tryptophan (TRP) depletion) deficient model, and compared its pattern of action with that of the acetylcholinesterase inhibitor metrifonate. Initial testing in a time-dependent forgetting task employing a 24-h delay between training and testing showed that metrifonate improved object recognition (at 10 and 30 mg/kg, p.o.), whereas Ro4368554 was inactive. Both, Ro4368554 (3 and 10 mg/kg, intraperitoneally (i.p.)) and metrifonate (10 mg/kg, p.o., respectively) reversed memory deficits induced by scopolamine and TRP depletion (10 mg/kg, i.p., and 3 mg/kg, p.o., respectively). In conclusion, although Ro4368554 did not improve a time-related retention deficit, it reversed a cholinergic and a serotonergic memory deficit, suggesting that both mechanisms may be involved in the facilitation of object memory by Ro4368554 and, possibly, other 5-HT(6) receptor antagonists.

Prolonged Alzheimer-like Tau Hyperphosphorylation Induced by Simultaneous Inhibition of Phosphoinositol-3 Kinase and Protein Kinase C in N2a cells

Co-injection of wortmannin (inhibitor of phosphatidylinositol-3 kinase, PI3K) and GF109203X (inhibitor of protein kinase C, PKC) into the rat brain was found to induce spatial memory deficiency and enhance tau hyperphosphorylation in the hippocampus of rat brain. To establish a cell model with durative Alzheimer-like tau hyperphosphorylation in this study, we treated N2a neuroblastoma cells with wortmannin and GF109203X separately and simultaneously, and measured the glycogen synthase kinase 3 (GSK-3) activity by gamma-32P-labeling and the level of tau phosphorylation by Western blotting. It was found that the application of wortmannin alone only transitorily increased the activity of GSK-3 (about 1 h) and the level of tau hyperphosphorylation at Ser396/Ser404 and Ser199/Ser202 sites (no longer than 3 h); however, a prolonged and intense activation of GSK-3 (over 12 h) and enhanced tau hyperphosphorylation (about 24 h) were observed when these two selective kinase inhibitors were applied together. We conclude that the simultaneous inhibition of PI3K and PKC can induce GSK-3 overactivation, and further strengthen and prolong the Alzheimer-like tau hyperphosphorylation in N2a cells, suggesting the establishment of a cell model with early pathological events of Alzheimer's disease.

Interaction Between Emotion and Memory: Importance of Mammillary Bodies Damage in a Mouse Model of the Alcoholic Korsakoff Syndrome

Chronic alcohol consumption (CAC) can lead to the Korsakoff syndrome (KS), a memory deficiency attributed to diencephalie damage and/or to medial temporal or cortical related dysfunction. The etiology of KS remains unclear. Most animal models of KS involve thiaminedeficient diets associated with pyrithiamine treatment. Here we present a mouse model of CAC-induced KS. We demonstrate that CAC-generated retrieval memory deficits in working/ episodic memory tasks, together with a reduction of fear reactivity, result from damage to the mammillary bodies (MB). Experimental lesions of MB in non-alcoholic mice produced the same memory and emotional impairments. Drugs having anxiogenic-like properties counteract such impairments produced by CAC or by MB lesions. We suggest (a) that MB are the essential components of a brain network underlying emotional processes, which would be critically important in the retrieval processes involved in working/ episodic memory tasks, and (b) that failure to maintain emotional arousal due to MB damage can be a main factor of CAC-induced memory deficits. Overall, our animal model fits well with general neuropsychological and anatomic impairments observed in KS.

Dispersal of Therapeutic Donor Cells throughout the Brain of Mice with Lysosomal Storage Disease Occurs Following in Utero Transplantation of Fetal-Derived Neuronal Stem Cells.

Mucopolysaccharidosis Type VII (MPS VII) is one of many lysosomal storage diseases and is caused by a deficiency of beta-glucuronidase (GUS). Progressive accumulation of undegraded glycosaminoglycan (GAG) intermediates occurs in the lysosome diminishing intellect, mobility, organ function, and life span. Previously, the efficacy of enzyme replacement therapy (ERT), bone marrow transplantation, and gene therapy have been tested in MPS VII mice. GUS supplied to serum by ERT or released into extracellular spaces from transplanted (Tx) normal or gene transduced cells is taken up by receptor mediated endocytosis and transported to the lysosome. All these treatments reduce lysosomal storage in visceral organs, but poorly deliver sufficient enzyme to the central nervous system (CNS). We hypothesized that in utero intrathecal transplantation of primary neuronal stem cells (NSC) would remedy the GUS deficiency of MPS VII CNS. We isolated NSC from the cortical ventricular zone (CVZ) of E14 GUS+ eGFP+ fetuses. CVZ NSC incubated with EGF and bFGF formed neurospheres in 3–5 days. E14 MPS VII GUS- recipients were Tx intrathecally with NSC and examined for engraftment by histological staining for GUS and eGFP expressing cells. Successful engraftment occurred in 13 of 23 (56.5%) MPS VII recipients. Three animals Tx with 5–25,000 (K) had GUS+ cells in the rostral migratory stream (RMS). Two of seven animals Tx with 50-80K had donor cells in the RMS and five had donor cells in olfactory bulb, cerebrum (cortical layers, corpus callosum and striatum), midbrain, hippocampus (including dentate gyrus), and the cerebellum (Purkinje layers, peduncle, and lobular regions). This demonstrates “complete” dispersal. One mouse Tx with 90K had donor cells lining the lateral ventricle. Another Tx with 160K had donor cells lining ventricular spaces and throughout the cerebrum away from the RMS. An animal Tx with 180K NSC had “complete” donor engraftment like those above. Histological staining for GUS+ donor cells in mice with “complete” engraftment showed levels of staining greater than untreated heterozygous controls, both in numbers of cells positive and in intensity of staining. Biochemistry of tissue sections from these animals averaged 59.5 ±9.2% (mean ±SE) of normal (+/+) activity. The oldest animal detected with “complete” engraftment thus far was 7 months old at sacrifice, demonstrating long-term durability of engraftment. Using anti-eGFP, beta-tubulin III (neurons), and GFAP (astrocytes) antibodies, we confirmed the “complete” engraftment was due to widespread dispersal and integration of donor derived cells and not to diffusion of GUS enzyme from a few engrafted cells. The lineage markers confirmed normal differentiation of donor CVZ NSC. Further evaluations are underway to measure cognitive function in treated animals by the Repeated Acquisition and Performance Chamber (RAPC). Comparison of untreated MPS VII adult mice to normal controls by the RAPC indicates significant deficiencies in learning and memory in untreated MPS VII mice and confirms our ability to measure functional changes in treated animals. In summary, GUS+ eGFP+ fetal NSC primary isolates engraft brain of MPS VII fetal recipients and restore GUS activity ≥ phenotypically normal MPS VII heterozygotes.

Accelerated senescence prone mouse-8 shows early onset of deficits in spatial learning and memory in the radial six-arm water maze

Available data indicate that the senescence-accelerated prone mouse 8 (SAMP8) is an appropriate model of brain aging, with impairments in nonspatial learning and memory beginning as early as 2 months of age, and spatial learning and memory deficiencies not becoming apparent until after 4 months of age. However, with other strains (e.g., C57BL mice), the impairment in spatial memory was found earlier than that in nonspatial memory. We considered the possibility that the observed differences could be due to strain-specific differences in the training equipment. In the present study, a new optimized testing apparatus—the radial six-arm water maze (RAWM)—for detecting spatial learning and memory in mice, was employed, to determine whether there is impairment of spatial learning and memory in young SAMP8. The relationship between the spatial learning measures observed with the RAWM and the Morris maze, a classic spatial learning and memory testing apparatus, was also explored. It was found that, in the RAWM, rather than in the Morris maze, the impairment in spatial learning could be measured in SAMP8 mice as early as 3 months old, and the impairment in spatial memory in SAMP8 mice aged 5 months. These results suggested that the spatial learning and memory deficiencies could be found in early life of SAMP8 mice, and that RAWM and Morris maze each detect different aspects of spatial learning and memory.

Morphofunctional Changes in Neurons in the Temporal Cortex of the Brain in Relation to Spatial Memory in Bulbectomized Mice After Treatment with Mineral Ascorbates

The effects of an antioxidant mixture of mineral ascorbates (MA) on the state of neurons in the temporal area of the cortex and the behavior of mice subjected to bulbectomy (BE) were studied; these mice, as demonstrated previously, are characterized by deficiency of spatial memory and the development of a neurodegenerative process in brain structures showing pathological changes in Alzheimer's disease. One month after BE, there were abnormalities in the cytoarchitectonics of the temporal area of the cortex, with loss of clarity of the boundaries between its layers because of dystrophy of pyramidal neurons and foci of loss of these cells. There were sharp increases in the numbers of neurons showing pyknosis, karyolysis, and vacuolysis on the background of decreases in neuronal density. Three weeks of treatment by addition of MA to the diet prevented the degradation of spatial memory in mice after BE and protected neurons in the temporal area of the cortex from degenerative changes. These results provide evidence for the possibility of prophylaxis of neurodestructive changes of the Alzheimer's type.

Accelerated senescence prone mouse-8 shows early onset of deficits in spatial learning and memory in the radial six-arm water maze

Available data indicate that the senescence-accelerated prone mouse 8 (SAMP8) is an appropriate model of brain aging, with impairments in nonspatial learning and memory beginning as early as 2 months of age, and spatial learning and memory deficiencies not becoming apparent until after 4 months of age. However, with other strains (e.g., C57BL mice), the impairment in spatial memory was found earlier than that in nonspatial memory. We considered the possibility that the observed differences could be due to strain-specific differences in the training equipment. In the present study, a new optimized testing apparatus—the radial six-arm water maze (RAWM)—for detecting spatial learning and memory in mice, was employed, to determine whether there is impairment of spatial learning and memory in young SAMP8. The relationship between the spatial learning measures observed with the RAWM and the Morris maze, a classic spatial learning and memory testing apparatus, was also explored. It was found that, in the RAWM, rather than in the Morris maze, the impairment in spatial learning could be measured in SAMP8 mice as early as 3 months old, and the impairment in spatial memory in SAMP8 mice aged 5 months. These results suggested that the spatial learning and memory deficiencies could be found in early life of SAMP8 mice, and that RAWM and Morris maze each detect different aspects of spatial learning and memory.

P3-406 Bilateral strokes in the medical areas of putamens causing deficiency of memory and calculation

P3-406 Bilateral strokes in the medical areas of putamens causing deficiency of memory and calculation

Norleucine 1-Angiotensin IV alleviates mecamylamine-induced spatial memory deficits

The brain angiotensin AT 4 receptor subtype has been implicated in cognitive processing. We initially established that intracerebroventricular administration of the nAChR-antagonist mecamylamine (mec) interfered with spatial memory performance in male Sprague–Dawley rats. Next we demonstrated that mec-induced deficits in spatial memory were overcome by the AT 4 receptor-agonist Norleucine 1-Angiotensin IV (Nle 1-Ang IV). Nle 1-Ang IV could not, however, compensate for spatial learning impairments precipitated by both mec and the mAChR-antagonist scopolamine. These findings support the importance of the AT 4 receptor in cognitive processing and suggest that the ability of Nle 1-Ang IV to improve spatial memory deficiencies may be dependant upon the brain cholinergic system.

Working memory deficiencies in adults associated with low-level lead exposure: implications of neuropsychological test results

Background:Although lead exposure has steadily decreased in the last few years, some lead is still used in the metal processing industry, mostly for wall paints and plumbing. Recent studies on children showed neurobehavioral effects of low-level exposure, but little is known about the neurocognitive effects of lead concentrations in the upper reference range on adults. Methods:The neuropsychological effects of lead exposure were examined in 39 adult outpatients at the Unit of Environmental Medicine (UEM), University Hospital, Aachen, Germany. All patients underwent a comprehensive medical examination, including psychiatric. Venous blood and urine samples were collected and tested for heavy metals and selenium. Since the neuropsychological examination was not expected to reveal any severe abnormalities, only specific attentiveness functions were analyzed (alertness, working memory, flexibility, intermodal comparison) since these areas were the likeliest to show objectifiable effects. The tests were conducted using a standardized computerized battery.

Cambios morfológicos asociados a la memoria

It has been suggested that storing information in the brain takes place by means of changes in synaptic communication efficiency, which is known as neuronal plasticity. Plastic events include changes in the function, structure, distribution and number of synapses, and it has been suggested that these plastic events could be related to learning and memory. In this work we will review some studies that report structural changes in which experience and learning intervene. In particular, structural changes have been observed in a region of the brain called the hippocampus, which plays a crucial role in the learning and memory of spatial tasks. It has been claimed that the appearance of new synapses after learning a spatial task is linked to the formation of long-term memory and that the functioning of NMDA-type glutamate receptors is needed for both learning and the formation of new synapses to take place. Understanding the cellular mechanisms involved in the formation of memory is of utmost importance to be able to check the memory deficiencies that arise from injuries or as a consequence of old age and neurodegenerative diseases.

Neuropsychological performance in pediatric bipolar disorder

Background Growing awareness of childhood bipolar disorder necessitates further cognitive neuroscience research to determine unique developmental differences between pediatric and adult onset bipolar disorder. We sought to examine whether neuropsychological function in children with bipolar disorder resembles that in adults with the illness and to extend our knowledge about cognitive function in pediatric bipolar disorder. Methods We administered a computerized neuropsychological test battery known as the Cambridge Neuropsychological Test Automated Battery to a sample of 21 children and adolescents with bipolar disorder and compared them with 21 age- and gender-matched controls. Results In comparison to controls, children with bipolar disorder were impaired on measures of attentional set-shifting and visuospatial memory. Post hoc analyses in pediatric bipolar disorder subjects did not show significant associations between neuropsychological performance and manic symptomatology or attention-deficit/hyperactivity disorder comorbidity. Conclusions Cambridge Neuropsychological Test Automated Battery data presented here in pediatric bipolar disorder fit well within the broader framework of known neurocognitive deficits in adult bipolar disorder. Our pediatric bipolar disorder subjects demonstrated selective deficiencies in attentional set-shifting and visuospatial memory. Our work suggests altered ventrolateral prefrontal cortex function, especially when linked to other lesion and neuroimaging studies.

Vascular change of hippocampal capillary is associated with vascular change of retinal capillary in aging

Vascular deficiency, such as deleterious change of endothelial cells, becomes the prominent feature of hippocampal microvessels during the processes of aging in rodents and it seems to be associated with deficiency of intellectual behavior in aged subjects. The hippocampal microvessels and hippocampal pyramidal neurons form and accumulate intermediates of advanced Maillard reaction (glycation) end products, specifically N ε-carboxymethyl lysine (CML) and CML in rodents during the processes of aging. CML facilitates proliferation of endothelial cells in culture. However, further conjugation of CML with the substance(s) seems to occur in the microvessels and pyramidal neurons of hippocampus and it brings about deleterious change of endothelial cells and pyramidal neuron death. This would cause deficiency of recognition and reference memory in rodents during the processes of aging. In man in Alzheimer’s disease (AD), one might speculate that formation and accumulation of CML in the hippocampal microvessels initiate the accumulation of amyloid to produce cerebral amyloid angiopathy and it brings about hypoglycemia and hypoxia in the hippocampal pyramidal neurons. Furthermore, formation and accumulation of CML in the hippocampal pyramidal neurons initiate the deposition of neurofibrillary tangles and senile plaques which cause neuronal death. In this way, vascular deficiency of hippocampal microvessels seems to be associated with the demented disease, the atrophic process of the brain and accumulation of amyloid in the brain in man. In terms of vascular deficiency concerns, the vascular change of the retinal capillaries becomes also a prominent feature during the processes of aging and it has a positive correlation with the vascular change of hippocampal capillary. In man during senescence, one might also speculate that vascular change of eye capillaries would become the early market for diagnosis of dementia in AD.

Altered gene expression of Na +/Ca 2+ exchanger isoforms NCX1, NCX2 and NCX3 in chronic ischemic rat brain

To investigate the effect of chronic global cerebral ischemia on gene expression of Na +/Ca 2+ exchanger isoforms NCX1, NCX2 and NCX3 in rat brain. Chronic global cerebral ischemia was induced by bilateral common carotid artery ligation (BCAL) in rats for 1 week, 2 weeks and 4 weeks, respectively. Morris water maze was applied to demonstrate the credibility of BCAL models. After BCAL for 4 weeks, there was learning and memory deficiency that the latency and distance of BCAL group were longer than those of sham group from the second trial to tenth trial in hidden platform trials. Reverse transcription-polymerase chain reaction was used to assess the gene expression of Na +/Ca 2+ exchanger isoforms at mRNA level in cerebral cortex and hippocampus. For NCX1, its expression was decreased by 35%, 54% and 27% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively; For NCX2, its expression was decreased by 41%, 29% and 12% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively; For NCX3, its expression was decreased by 29%, 27% and 12% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively. However, in hippocampus, the expressions of NCX1 and NCX3 did not change significantly in different BCAL groups. NCX2 was increased by 60% in BCAL for 1 week only, but did not change significantly in BCAL for 2 weeks or 4 weeks. The study indicated that brain ischemia regulated gene expression levels of Na +/Ca 2+ exchanger isoforms especially in cerebral cortex.

Age-related deficits as working memory load increases: relationships with growth factors

Young and aged female rats were tested on a water radial-arm maze designed to measure performance as working memory load increased, followed by brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin 3 (NT3) protein assessments in hippocampus and frontal cortex. Aged rats showed deficiencies in both working and reference memory. There were also profound age-related working memory load effects. Aged rats made more errors as working memory load increased and showed learning only during early trials when memory load was low, while young rats exhibited learning over all trials. Neurotrophin assessment showed that frontal cortex NGF and BDNF levels were positively, and hippocampal NT3 negatively, correlated with number of errors made during specific trials in aged animals. Comparison to untested rats showed that testing increased NT3, but not BDNF or NGF, protein levels in both age groups. Findings suggest that young rats learn to handle a higher working memory load as testing progresses, while aged rats do not, and that frontal cortex and hippocampal neurotrophin levels may relate to working memory proficiency in aged female rats.

Pregnane-Type Steroidal Alkaloids ofSarcococca saligna: a New Class of Cholinesterase Inhibitors

Phytochemical investigation of Sarcococca saligna by extensive bioassay-guided fractionation resulted in the isolation of the pregnane-type steroidal alkaloids 1–15, i.e. of the five new compounds 1–5 and the ten known alkaloids 6–15. The structures of the new alkaloids salignenamide C (1), salignenamide D (2), 2β-hydroxyepipachysamine D (3), salignenamide E (4), and salignenamide F (5) were elucidated with the help of modern spectroscopic techniques, while the known alkaloids axillarine C (6), axillarine F (7), sarcorine (8), N3-demethylsaracodine (9), saligcinnamide (10), salignenamide A (11), vaganine A (12), axillaridine A (13), sarsalignone (14), and sarsalignenone (15) were identified by comparing their spectral data with those reported earlier. Inhibition of electric-eel acetylcholinesterase (EC 3.1.1.7) and horse-serum butyrylcholinesterase (EC 3.1.1.8) by alkaloids 1–15 were investigated. These new cholinesterase inhibitors may act as potential leads in the discovery of clinically useful inhibitors for nervous-system disorders, particularly by reducing memory deficiency in Alzheimer's disease patients by potentiating and effecting the cholinergic transmission process. These compounds were found to inhibit both enzymes in a concentration-dependent fashion with the IC50 values ranging from 5.21–227.92 μM against acetylcholinesterase and 2.18–38.36 μM against butyrylcholinesterase.

Novel memory mutants in Drosophila: Behavioral characteristics of the mutant nemyP153

BackgroundStarting from Benzer's initiative, the approach of forward genetics has been widely used to isolate mutations affecting learning and memory. For this aim, mainly the odor-shock conditioning was employed. We have isolated P insertional mutations affecting memory after courtship conditioning – another form of classical conditioning in Drosophila. Here we report the behavioral characteristics of one of these mutants, which we have called nemy (no extended memory).ResultsThe courtship activity of Drosophila males is reduced when a male has a previous experience of courting a fertilized female. In the wild-type strain C-S (K), this conditioned courtship inhibition lasts for 1–3 h in the test with a virgin female, and at least for 8 h in the test with a subsequent fertilized female. The mutant males nemyP153 display distinct memory deficiency in both tests already 0.5 h after training. The mutant males show an increased level of locomotor activity unrelated to courtship, and spend more time in such an element of courtship as pursuit. This, however, seems to be a pleiotropic effect of the mutation, independent from its influence on the courtship conditioning. The mutation reduces also memory performance after the odor-shock classical conditioning. At the same time, the sensory and motor functions involved in this type of learning seem to be normal.ConclusionsInsertion of P-lacW vector into 49B region of the second chromosome (mutation nemyP153) causes an increased level of locomotor activity, memory deficiency after the courtship conditioning and subnormal acquisition after the odor-shock conditioning.

Practical geriatrics: insomnia in late life.

Practical geriatrics: insomnia in late life.

Effect of chronic treatment of melatonin on learning, memory and oxidative deficiencies induced by intracerebroventricular streptozotocin in rats

Intracerebroventricular (ICV) streptozotocin (STZ) has been shown to cause cognitive impairment, which is associated with free radical generation in the brain of rats. Melatonin is a potent free radical scavenger and antioxidant. In the present study, the effect of melatonin was investigated against ICV STZ induced cognitive impairment and oxidative stress in rats. Adult male Wistar rats were injected with ICV STZ (3 mg/kg) bilaterally. The rats were treated with STZ twice, on days 1 and 3. The learning and memory behavior was assessed using passive avoidance paradigms, elevated plus maze and the closed field activity while the parameters of oxidative stress assessed were malondialdehyde (MDA) and glutathione. The rats were treated chronically with melatonin for 21 days starting from day 1 of STZ injection. The learning and memory behavior was evaluated on days 17, 18 and 19 and the rats were sacrificed on day 21 for estimation of MDA and glutathione. The rats treated with melatonin showed significantly less cognitive impairment. There was also insignificant increase in brain MDA and decrease in glutathione levels in melatonin-treated ICV STZ rats as compared to the vehicle-treated ICV STZ animals. The study demonstrates the effectiveness of melatonin in preventing the cognitive deficits as well as the oxidative stress caused by ICV STZ in rats and suggests it's potential in age and age-related neurodegenerative disorders where oxidative stress and cognitive impairment are involved.