Memory Deficits In Rats Research Articles

A Peptide That Binds Specifically to the β-Amyloid of Alzheimer's Disease: Selection and Assessment of Anti-β-Amyloid Neurotoxic Effects

The accumulation of the amyloid-β peptide (Aβ) into amyloid plaques, an essential event in Alzheimer's disease (AD) pathogenesis, has caused researchers to seek compounds that physiologically bind Aβ and modulate its aggregation and neurotoxicity. In order to develop new Aβ-specific peptides for AD, a randomized 12-mer peptide library with Aβ1-10 as the target was used to identify peptides in the present study. After three rounds of selection, specific phages were screened, and their binding affinities to Aβ1-10 were found to be highly specific. Finally, a special peptide was synthesized according to the sequences of the selected phages. In addition, the effects of the special peptide on Aβ aggregation and Aβ-mediated neurotoxicity in vitro and in vivo were assessed. The results show that the special peptide not only inhibited the aggregation of Aβ into plaques, but it also alleviated Aβ-induced PC12 cell viability and apoptosis at appropriate concentrations as assessed by the cell counting kit-8 assay and propidium iodide staining. Moreover, the special peptide exhibited a protective effect against Aβ-induced learning and memory deficits in rats, as determined by the Morris water maze task. In conclusion, we selected a peptide that specifically binds Aβ1-10 and can modulate Aβ aggregation and Aβ-induced neuronal damage. This opens up possibilities for the development of a novel therapeutic approach for the treatment of AD.

Scutellarin protects against Aβ-induced learning and memory deficits in rats: involvement of nicotinic acetylcholine receptors and cholinesterase.

To examine the protective effects of scutellarin (Scu) on rats with learning and memory deficit induced by β-amyloid peptide (Aβ). Fifty male Wistar rats were randomly divided into 5 groups: control, sham operation, Aβ, Aβ+Scu, and Aβ+piracetam groups. Aβ(25-35) was injected into the lateral ventricle (10 μg each side). Scu (10 mg/2 mL) or piracetam (10 mg/2 mL was intragastrically administered per day for 20 consecutive days following Aβ treatment. Learning and memory was assessed with Morris water maze test. The protein and mRNA levels of nicotinic acetylcholine receptor (nAChR) α4, α7, and β2 subunits in the brain were examined using Western blotting and real-time PCR, respectively. The activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain and plasma were measured using Ellman's colorimetric method. In Aβ group, the escape latency period and first platform cross was significantly increased, and the total number of platform crossings was significantly decreased, as compared with the control and the sham operation groups. Both Scu and piracetam treatment significantly reduced the escape latency period and time to cross platform, and increased the number of platform crosses, but there were no significant differences between Aβ+Scu and Aβ+piracetam groups. In Aβ group, the protein levels of nAChR α4 and α7 subunits in the cerebral cortex were significantly decreased by 42%-47% and 58%-61%, respectively, as compared to the control and the sham operation groups. Scu treatment caused upregulation of α4 and α7 subunit proteins by around 24% and 30%, respectively, as compared to Aβ group, but there were no significant differences between Aβ+Scu and Aβ+piracetam groups. The protein level of nAChR β2 subunit had no significant difference among different groups. The mRNA levels of nAChR α4, α7, and β2 subunits were not significantly changed. In Aβ group, the activities of AChE and BuChE in the brain were significantly increased, but were significantly decreased in the plasma, as compared to the control and the sham operation groups. Scu or piracetam treatment restored the activities in brain and plasma nearly to the levels in the control group. The results suggest that Scu may rescue some of the deleterious effects of Aβ, possibly by stimulating nAChR protein translation and regulating cholinesterase activity.

Selective disconnection of the hippocampal formation projections to the mammillary bodies produces only mild deficits on spatial memory tasks: Implications for fornix function

It is now clear that the integrity of the fornix is important for normal mnemonic function. The fornix, however, is a major white matter tract, carrying numerous hippocampal formation afferents and efferents, and it is not known which specific components support memory processes. Established theories of extended hippocampal function emphasize the sequential pathway from the hippocampal formation (i.e., subicular complex) to the mammillary bodies and, thence, to the anterior thalamus, as pathology in each of these structures is implicated in anterograde amnesia in humans and spatial memory deficits in rats. The specific importance of the hippocampal formation projections that just innervate the mammillary bodies has, however, never been tested. This study isolated these specific projections in the rat by selectively cutting the descending component of the postcommissural fornix. Two successive, cohorts of rats with these tract lesions were tested on working memory tasks in the water-maze, T-maze, and radial-arm maze. Disconnecting the descending postcommissural fornix had only a mild effect or sometimes no apparent effect on the performance of these spatial memory tasks, even though tracing experiments confirmed the loss of hippocampal formation-mammillary projections. One implication is that the spatial deficits found in rats following standard fornix lesions are only partly attributable to the loss of projections from the hippocampal formation to the mammillary bodies. Perhaps more surprising, the behavioral impact of cutting the descending postcommissural fornix in rats appeared appreciably less than the effect of either mammillary body or mammillothalamic tract lesions. The present experiments show that the mammillary bodies can still effectively support spatial memory in the absence of their dense subicular complex inputs, so revealing the importance of the other afferents for sustaining mammillary body function. This new evidence for independent functions shows that the mammillary bodies are more than just a hippocampal relay.

S.04.06 Targeting the alpha7 nicotinic receptor subtype to restore working memory deficits in rats following sub-chronic ketamine exposure

To establish the model of human bronchial epithelial cells (16HBE) malignant transformation induced by glycidyl methacrylate (GMA) and define the different methylation genes at different stages.DNA was extracted at different 16HBE malignant phases and changes of genes DNA methylation at different stages were detected using Methylation chip of ‘NimbleGen HG18 CpG Promoter Microarray Methylation’. Methylation-specific PCR (MSP) was used to observe the methylation status of some genes, and then compared with the control groups.The result showed that GMA induced 16HBE morphorlogical transformation at the dose of 8 µg/mL, and cell exposed to GMA had 1 374 genes in protophase, 825 genes in metaphase, 1 149 genes in anaphase, respectively; 30 genes are all methylation in the 3 stages; 318 genes in protophase but not in metaphase and anaphase; 272 genes in metaphase but not in protophase and anaphase; 683 genes in anaphase but not in metaphase and protophase; 73 genes in protophase and metaphase but not in anaphase; 67 genes in protophase and anaphase but not in metaphase; 59 genes in metaphase and anaphase but not in protophase.The pattern of DNA methylation could change in the process of 16HBE induced by GMA.

Combination of novel α7 Nicotinic acetylcholine receptor agonists with existing alzheimer's treatments

Activation of α7 nicotinic acetylcholine receptors (α7 nAChRs) through selective, partial, or full agonists and/ormodulators, has been shown to improve cognitive function in both animal and human studies. The main cognitive improvement with these compounds relate to memory, in accordance with the high level of expression of α7 nAChRs in the frontal-cortex and hippocampus. Hence, α7 nAChR agonists/modulators may be attractive drug candidates to improve cognition in Alzheimer's disease (AD) andschizophrenia patients. The interaction of existing AD-medications was investigated in rats using combinations of subthreshold effective doses of both α7 nAChR agonists and acetylcholinesterase inhibitors (e.g. donepezil and/or rivastigmine) in the object recognition task. Memory deficits were induced by the muscarinic antagonist scopolamine. We found that low doses of α7 agonists in combination with subthreshold doses of donepezil, completely attenuated ascopolamine-induced memory deficit in rats in the object recognition task. These combinations hold promise for improved symptomatic AD treatment, because systemic exposures of acetylcholinesterase inhibitors can be kept below side effect-inducing levels in AD patients.

P03-173 - Effect of safranal, a constituent of crocus sativus, on MK-801-induced behavioral and memory deficits in rat

The psychotomimetic MK-801, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, induce behavioral and cognitive impairments similar to those seen in schizophrenia. Safranal, a constituent of Crocus sativus (saffron), was found to have anti-seizure and anti-ischemic effects. In the present study, we investigated the effect of safranal on behavioral changes and spatial memory deficits induced by MK-801 in adult male Wistar rats, using radial maze. Safranal (72.75, 145.5 and 291 mg/kg, i.p.) was administrated 30 min before MK-801 (5 mg/kg, i.p.). Single systemic injection of MK-801 significantly increased locomotion, stereotypic behavior (rearing, grooming, sniffing) and ataxia (p < 0.01) which became evident on day 1. Moreover, average reference and working memory errors were significantly increased within 10 days after MK-801 administration (p < 0.05).Pretreatment with safranal (291 mg/kg) significantly reduced locomotor hyperactivity and behavioral changes elicited by MK-801 (p < 0.001). Average reference errors were also significantly decreased in comparison with MK-801 treated animals (p < 0.01). These data indicated that treatment with safranal attenuated behavioral and spatial memory deficits in a rat model of an acute psychotic episode.

P.4.014 Targeting the alpha7 nicotinic receptor subtype to restore working memory deficits in rats following sub-chronic ketamine exposure

P.4.014 Targeting the alpha7 nicotinic receptor subtype to restore working memory deficits in rats following sub-chronic ketamine exposure

A comparison of scopolamine and biperiden as a rodent model for cholinergic cognitive impairment

RationaleThe nonselective muscarinic antagonist scopolamine hydrobromide (SCOP) is employed as the gold standard for inducing memory impairments in healthy humans and animals. However, its use remains controversial due to the wide spectrum of behavioral effects of this drug.ObjectiveThe present study investigated whether biperiden (BIP), a muscarinic m1 receptor antagonist, is to be preferred over SCOP as a pharmacological model for cholinergic memory deficits in rats. This was done by comparing the effects of SCOP and BIP using a battery of operant tasks: fixed ratio (FR5) and progressive ratio (PR10) schedules of reinforcement, an attention paradigm and delayed nonmatching to position task.ResultsSCOP induced diffuse behavioral disruption, which included sensorimotor responding (FR5, 0.3 and 1 mg/kg), food motivation (PR10, 1 mg/kg), attention (0.3 mg/kg, independent of stimulus duration), and short-term memory (delayed nonmatching to position (DNMTP), 0.1 and 0.3 mg/kg, delay-dependent but also impairment at the zero second delay). BIP induced relatively more selective deficits, as it slowed sensorimotor responding (FR5, 10 mg/kg) and disrupted short-term memory (DNMTP, 3 mg/kg, delay-dependent but no impairment at the zero second delay). BIP had no effect on food motivation (PR10) or attention.ConclusionMuscarinic m1 antagonists should be considered an interesting alternative for SCOP as a pharmacological model for cholinergic mnemonic deficits in animals.

Early hippocampal cell death, and late learning and memory deficits in rats exposed to the environmental toxin BMAA (β-N-methylamino- l-alanine) during the neonatal period

We have reported previously that exposure to the cyanobacterial neurotoxin β-N-methylamino- l-alanine (BMAA) during the neonatal period causes cognitive impairments in adult rats. The aim of this study was to investigate the long-term effects of neonatal BMAA exposure on learning and memory mechanisms and to identify early morphological changes in the neonatal brain. BMAA was injected subcutaneously in rat pups on postnatal days 9–10. BMAA (50 and 200 mg/kg) caused distinct deficits in spatial learning and memory in adult animals but no morphological changes. No impairment of recognition memory was detected, suggesting that neonatal exposure to BMAA preferentially affects neuronal systems that are important for spatial tasks. Histopathological examination revealed early neuronal cell death as determined by TUNEL staining in the hippocampus 24 h after a high dose (600 mg/kg) of BMAA whereas no changes were observed at lower doses (50 and 200 mg/kg). In addition, there was a low degree of neuronal cell death in the retrosplenial and cingulate cortices, areas that are also important for cognitive function. Taken together, these results indicate that BMAA is a developmental neurotoxin inducing long-term changes in cognitive function. The risk posed by BMAA as a potential human neurotoxin merits further consideration, particularly if the proposed biomagnifications in the food chain are confirmed.

Persistent spatial working memory deficits in rats following in utero RNAi of Dyx1c1

Disruptions in the development of the neocortex are associated with cognitive deficits in humans and other mammals. Several genes contribute to neocortical development, and research into the behavioral phenotype associated with specific gene manipulations is advancing rapidly. Findings include evidence that variants in the human gene DYX1C1 may be associated with an increased risk of developmental dyslexia. Concurrent research has shown that the rat homolog for this gene modulates critical parameters of early cortical development, including neuronal migration. Moreover, recent studies have shown auditory processing and spatial learning deficits in rats following in utero transfection of an RNA interference (RNAi) vector of the rat homolog Dyx1c1 gene. The current study examined the effects of in utero RNAi of Dyx1c1 on working memory performance in Sprague-Dawley rats. This task was chosen based on the evidence of short-term memory deficits in dyslexic populations, as well as more recent evidence of an association between memory deficits and DYX1C1 anomalies in humans. Working memory performance was assessed using a novel match-to-place radial water maze task that allows the evaluation of memory for a single brief (∼4-10 seconds) swim to a new goal location each day. A 10-min retention interval was used, followed by a test trial. Histology revealed migrational abnormalities and laminar disruption in Dyx1c1 RNAi-treated rats. Dyx1c1 RNAi-treated rats exhibited a subtle, but significant and persistent impairment in working memory as compared to Shams. These results provide further support for the role of Dyx1c1 in neuronal migration and working memory.

The effects of atorvastatin on memory deficit and seizure susceptibility in pentylentetrazole-kindled rats

Deficits in memory function have been observed in pentylentetrazole (PTZ)-kindled rats. In the present study we examined the effects of atorvastatin ((3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor) on PTZ kindling and related memory deficits in rats trained with the passive avoidance test. Subconvulsive PTZ doses rendered a gradual increase in seizure activity. PTZ kindling caused long-term memory to deteriorate. Atorvastatin per se and in PTZ-kindled rats improved learning and memory functions. It also prolonged latency (time to appearance of spike potentials) and diminished the amplitude and frequency of spike potentials, which indicate epileptic discharges. These novel findings suggest that the favorable effect of the atorvastatin on memory deficits provoked by PTZ kindling might be of clinical utility.

Acetyl-L-carnitine ameliorates GSK-3β–induced memory deficits in rats

Acetyl-L-carnitine ameliorates GSK-3β–induced memory deficits in rats

Chronic sodium nitrite intake induced spatial memory deficit in rats and the underlying mechanisms

Chronic sodium nitrite intake induced spatial memory deficit in rats and the underlying mechanisms

Dynamin 1 depletion and memory deficits in rats treated with Aβ and cerebral ischemia

Alzheimer's disease (AD) is progressive dementia with senile plaques composed of beta-amyloid (Abeta). Recent studies suggest that synaptic dysfunction is one of the earliest events in the pathogenesis of AD. Here we provide the first experimental evidence that a change in the level of dynamin 1 induced by Abeta correlates with memory impairment in vivo. We treated rats with transient cerebral ischemia with oligomeric forms of Abeta (Abeta oligomers), including dimers, trimers, and tetramers, intracerebroventricularly. The combination of Abeta oligomers and cerebral ischemia, but not cerebral ischemia alone, significantly impaired memory and decreased the level of dynamin 1, which plays a critical role in synaptic vesicle recycling, but did not affect the levels of other synaptic proteins, such as synaptophysin and synaptobrevin, in the hippocampus. Furthermore, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine prevented memory impairment and dynamin 1 degradation, suggesting that these changes might be mediated by NMDA receptors. These results suggest that Abeta oligomers induce memory impairment via dynamin 1 degradation, which may imply that dynamin 1 degradation is one of the causes of synaptic dysfunction in AD.

Iron Leads to Memory Impairment that is Associated with a Decrease in Acetylcholinesterase Pathways

Increasing evidence indicates that excessive iron in selective regions of the brain may be involved in the etiology of neurodegenerative disorders. Accordingly, increased levels of iron have been described in brain regions of patients in Parkinson's and Alzheimer's diseases. We have characterized neonatal iron loading in rodents as a novel experimental model that mimics the brain iron accumulation observed in patients with neurodegenerative diseases and produces severe cognitive impairment in the adulthood. In the present study we have investigated the involvement of the cholinergic system on iron-induced memory impairment. The effects of a single administration of the acetylcholinesterase (AChE) inhibitor galantamine or the muscarinic receptor agonist oxotremorine on iron-induced memory deficits in rats were examined. Male Wistar rats received vehicle or iron (10.0 mg/kg) orally at postnatal days 12 to 14. At the age of 2-3 months, animals were trained in a novel object recognition task. Iron-treated rats showed long-term impairments in recognition memory. The impairing effect was reversed by systemic administration of galantamine (1 mg/kg) immediately after training. In addition, iron-treated rats that received oxotremorine (0.5 mg/kg) showed enhanced memory retention. Rats given iron showed a decreased AChE activity in the striatum when compared to controls. The results suggest that, at least in part, iron-induced cognitive deficits are related to a dysfunction of cholinergic neural transmission in the brain. These findings might have implications for the development of novel therapeutic strategies aimed at ameliorating cognitive decline associated with neurodegenerative disorders.

Ameliorative Effect of a Hippocampal Metabotropic Glutamate– Receptor Agonist on Histamine H1 Receptor Antagonist–Induced Memory Deficit in Rats

This study was performed to investigate the ameliorative effects of metabotropic glutamate (mGlu)-receptor agonists on histamine H1 receptor antagonist–induced spatial memory deficit and the decrease in hippocampal theta activity in rats. Intraperitoneal injection of pyrilamine (35 mg/kg) resulted in impaired reference and working memory in the radial maze task and decreased hippocampal theta amplitude and power. The working memory deficit and decreased hippocampal theta power induced by pyrilamine were ameliorated by intrahippocampal injection of (RS)-3,5-dihydroxyphenylglycine (DHPG) (1 and 10 μg/side), a group I mGlu-receptor agonist; however, intrahippocampal injection of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC), a group II mGlu-receptor agonist, and l-(+)-2-amino-4-phosphonobutyric acid (l-AP4), a group III mGlu-receptor agonist, showed no significant effect on the pyrilamine-induced memory deficit and decreased hippocampal theta activity. These results indicate that the activation of hippocampal group ι mGlu receptors, but not group II and III mGlu receptors, improve the histamine H1 receptor antagonist–induced working memory deficit and decreased hippocampal theta activity.

AMELIORATIVE EFFECTS OF HISTAMINE ON SPATIAL MEMORY DEFICITS INDUCED BY SCOPOLAMINE INFUSION INTO BILATERAL DORSAL OR VENTRAL HIPPOCAMPUS AS EVALUATED BY THE RADIAL ARM MAZE TASK

1. The present study examined the role of the hippocampal histaminergic system in the regulation of spatial memory deficit in rats using the radial arm maze task after scopolamine injection into the bilateral dorsal (DH) or ventral (VH) hippocampus. 2. Bilateral injection of scopolamine (5 microg/site) into both the DH and VH impaired spatial memory in the retrieval memory process. Injection of histamine (50 or 100 ng/site) in the DH and intraperitoneal injection of histidine (100 mg/kg) markedly improved working memory and reference memory deficits induced by scopolamine injection into the DH. The histamine H(1) receptor antagonist pyrilamine (1 microg/site) abolished the ameliorative effects of histidine on working memory deficits, whereas both pyrilamine and the H(2) receptor antagonist cimetidine (0.5 microg/site) abolished the effect of histidine on reference memory. 3. Local injection of histamine (25 or 50 ng/site) into the VH and systemic injection of histidine (50 or 100 mg/kg) markedly improved working memory deficits induced by scopolamine injection into the VH, but did not improve the deficits in reference memory. Injection of both pyrilamine (0.2, 0.5 and 1 microg/site) and cimetidine (0.1 and 0.5 microg/site) into the VH reversed the effects of histidine. 4. The results of the present study indicate that histamine has different actions on cholinergic-related memory in the the DH and VH. Histamine in the DH ameliorates spatial working memory deficits by acting on histamine H(1) receptors and reference memory deficits through both H(1) and H(2) receptors. However, histamine in the VH ameliorates working memory deficits via an action on both H(1) and H(2) receptors.

Ethanol Attenuates Spatial Memory Deficits and Increases mGlu1a Receptor Expression in the Hippocampus of Rats Exposed to Prenatal Stress

Although it is generally believed that chronic ethanol consumption impairs learning and memory, results obtained in experimental animals are not univocal, and there are conditions in which ethanol paradoxically improves cognitive functions. In the present work, we investigated the effects of prenatal stress and of chronic ethanol exposure during adulthood on spatial memory in rats. Rats were subjected to a prenatal stress delivered as 3 daily 45-minute sections of restraint stress to the mothers during the last 10 days of pregnancy (PRS rats). After 7 months of ethanol exposure (ethanol 10%, oral intake), memory performances were evaluated in a spatial discrimination test in control and PRS male rats. Then, the oxidative damages and the expression of metabotropic glutamate (mGlu) receptors were assessed in their hippocampus. Chronic ethanol exposure resulted in a reduced performance in a spatial recognition task in control animals. Unexpectedly, however, the same treatment attenuated spatial memory deficits in rats that had been subjected to prenatal stress. This paradigm of ethanol administration did not produce detectable signs of oxidative damage in the hippocampus in either unstressed or PRS rats. Interestingly, ethanol intake resulted in differential effects in the expression of mGlu receptor subtypes implicated in mechanisms of learning and memory. In control rats, ethanol intake reduced mGlu2/3 and mGlu5 receptor levels in the hippocampus; in PRS rats, which exhibited a constitutive reduction in the levels of these mGlu receptor subtypes, ethanol increased the expression of mGlu1a receptors but did not change the expression of mGlu2/3 or mGlu5 receptors. Our findings support the idea that stress-related events occurring before birth have long-lasting effects on brain function and behavior, and suggest that the impact of ethanol on cognition is not only dose- and duration-dependent, but also critically influenced by early life experiences.

Ladostigil prevents age-related glial activation and spatial memory deficits in rats

Oxidative stress and glial activation occur in the aging brain. Ladostigil is a new monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitor designed for the treatment of Alzheimer's disease. It has neuroprotective and antioxidant activities in cellular models at much lower concentrations than those inhibiting MAO or AChE. When ladostigil (1mg/kg/day) was given for 6 months to 16-month-old rats it prevented the age-related increase in activated astrocytes and microglia in several hippocampal and white matter regions and increased proNGF immunoreactivity in the hippocampus towards the levels in young rats. Ladostigil also prevented the age-related reduction in cortical AChE activity and the increase in butyrylcholinesterase activity in the hippocampus, in association with the reduction in gliosis. The immunological and enzymatic changes in aged rats were associated with improved spatial memory. Ladostigil treatment had no effect on memory, glial or proNGF immunoreactivity in young rats. Early treatment with ladostigil could slow disease progression in conditions like Alzheimer's disease in which oxidative stress and inflammatory processes are present.

Gingkoselect alleviates chronic corticosterone-induced spatial memory deficits in rats

The preventive effects of Gingkoselect (100 mg/kg/day, orally, 21 days) on spatial memory deficits induced by a chronic restraint stress (2 h daily, 21 days) or chronic corticosterone treatment (5 mg/kg, subcutaneously, 21 days) were investigated using the Barnes maze. Chronic corticosterone, but not chronic stress, impaired spatial memory, as shown by increased latency to finding escape tunnel in the maze. Gingkoselect normalized cognitive deficits in rats chronically treated with corticosterone, and improved memory above the control levels in the chronically stressed rats.