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At least 919 records · Page 51Linked to original sources
PubMed2002

Selective nicotinic receptor consequences in APP(SWE) transgenic mice.

The nicotinic (nAChRs) and muscarinic (mAChRs) acetylcholine receptors and acetylcholinesterase (AChE) activity were studied in the brains of APP(SWE) transgenic mice (Tg+) and age-matched nontransgenic controls (Tg-) that were between 4 and 19 months of age. A significant increase in the binding of 125I-labeled alpha-bungarotoxin (alpha7 nAChRs) was observed in most brain regions analyzed in 4-month-old Tg+ mice, preceding learning and memory impairments and amyloid-beta (Abeta) pathology. The enhanced alpha7 receptor binding was still detectable at 17-19 months of age. Increase in [3H]cytisine binding (alpha4beta2 nAChRs) was measured at 17-19 months of age in Tg+ mice, at the same age when the animals showed heavy Abeta pathology. No significant changes in [3H]pirenzepine (M1 mAChRs) or [3H]AFDX 384 (M2 mAChRs) binding sites were found at any age studied. The upregulation of the nAChRs probably reflects compensatory mechanisms in response to Abeta burden in the brains of Tg+ mice.

Acetylcholinesterase↗
PubMed1994

Psychometric testing in rats during normal ageing. Procedures and results.

Examples are given for assessing parameters for motor activity learning and memory. By using the method of the open field the authors could verify that motor activity decreases with age and that it underlies obviously endogenous rhythms which undergo age dependent alterations (e.g. diminution of the amplitude). From the results of an investigation on the influence of ageing and stress on learning ability and memory of the rat the authors draw the following conclusions: Learning ability declines with advancing age. The effect of ageing on memory could not be clearly shown. The effect of the stressors used (crowding and noise) seems to depend on the season of the year (circannual biorhythm).

Aging↗
PubMed2005

Psychoemotional manifestations in hippocampectomized rats.

The effects of lesioning of the dorsal hippocampus on the psychoemotional state of Wistar rats were studied. Hippocampal lesions did not affect the learning process, but affected mainly the pattern of psychoemotional manifestations in all animals regardless of the typology of higher nervous activity. All animals showed reductions in the extremes of types of passive and active stress reactions. Individual effects depended on the behavioral phenotypes of the animals. Hippocampal lesions in rapidly learning rats (10%) led to sharp decreases in irritability (active/passive = 0.35/0.5 instead of 1.0/0.4), while passive-defensive manifestations were not altered. In slowly learning animals (30%), hippocampal lesions were not accompanied by qualitative changes in the patterns of psychoemotional manifestations, while non-learning rats (60%) showed decreases in passive and increases in active manifestations (active/passive = 0.45/1.4 instead of 0.3/1.9). It is suggested that the hippocampus is involved in producing psychoemotional reactions, individual patterns of which depend on the morphofunctional characteristics of the system responsible for organizing the psychoemotional state.

Animals↗
PubMed2005

Effect of cholinergic medication, before and after focal photothrombotic ischemic cortical injury, on histological and functional outcome in aged and young adult rats.

The present study evaluated the effect of galanthamine, a selective competitive cholinesterase inhibitor, on histological and functional outcome after experimental stroke in rats. Cholinesterase inhibitors are commonly used as cognitive enhancers for dementia in aged people, including those who may sustain ischemic attacks. Young adult (5 months) and aged (24 months) rats were treated with saline or galanthamine at a dose of 2.5 mg/kg (i.p., once a day). Drug treatment started 4 days before focal cortical photothrombosis (Rose Bengal, 20 mg/kg) and continued for 21 days thereafter. Sensorimotor recovery was assessed by a new beam-walking test and spatial learning by the Morris water-maze over a 3-week follow-up period. Infarct volumes were measured from nitroblue tetrazolium-stained sections at the end of follow-up. Infarct volumes in the cortex were similar in ischemic controls and ischemic rats treated with galanthamine. In the beam-walking test, there was a transient impairment forelimb function and a permanent impairment in hindlimb after cortical infarct both in young adult and aged rats. Galanthamine treatment did not affect the sensorimotor recovery rate. Analysis of water-maze data did not reveal significant differences in length of path, escape latency, or swim speed between sham-operated, ischemic controls and ischemic rats treated with galanthamine. In conclusion, present findings suggest that the aging brain has considerable plastic capacity to maintain functioning after focal cerebral insults restricted to the motor cortex. Galanthamine is not beneficial with respect to the histological or functional outcome in rats subjected to cortical photothrombosis.

Age Factors↗
PubMed2005

Behavioral and histological effects of chronic antipsychotic and antidepressant drug treatment in aged rats with focal ischemic brain injury.

Psychotropic drugs are commonly used in the elderly, including those who may sustain ischemic attacks. Concomitant CNS medication may interfere with functional recovery. The present study evaluated the effect of risperidone, an atypical neuroleptic, and fluoxetine, a selective serotonin reuptake inhibitor, on histological and functional outcome after experimental stroke in aged rats, which might be more vulnerable to brain insults. Aged Wistar rats were treated with risperidone at a dose of 1 mg/kg (i.p., once a day), fluoxetine at a dose of 5 mg/kg (i.p., once a day), or their combination. Drug treatment was started 7 days before focal cortical photothrombosis (Rose Bengal, 20 mg/kg) and continued for 28 days thereafter. Sensorimotor recovery was assessed by a new beam-walking test and spatial learning by the Morris water-maze before cortical stroke, immediately after stroke, and at the end of follow-up. Infarct volumes were measured from nitroblue tetrazolium-stained sections at the end of follow-up. The high slip ratio for the contralateral hindlimb in ischemic rats treated with risperidone indicated sensorimotor impairment when tested 2 h after drug administration. Sensorimotor impairment was not observed, however, when the rats were tested 24 h after risperidone administration. Similarly, water-maze performance was impaired 2 h after risperidone. Fluoxetine did not affect sensorimotor or water-maze performance. Cortical infarct volumes were not different in ischemic controls and ischemic rats treated with antipsychotic drugs. The present study showed that an atypical neuroleptic, risperidone, acutely impairs behavioral performance, but does not affect histological or functional outcome in aged rats subjected to cortical photothrombosis.

Affect↗
PubMed2005

Behavioral effects of photothrombotic ischemic cortical injury in aged rats treated with the sedative-hypnotic GABAergic drug zopiclone.

Sedative-hypnotic drugs commonly used in the elderly may affect functional recovery following cerebrovascular events. Previous research has shown that prolonged exposure to diazepam can interfere with recovery of function and exaggerate tissue loss after brain injury. The present study evaluated the effect of zopiclone, a widely used hypnotic drug, on functional and histological outcome after cortical photothrombosis in aged rats, which might be particularly vulnerable to brain insults and inhibitory sedative-hypnotic drugs. Aged Wistar rats were treated with zopiclone at a dose of 3 mg/kg (i.p., once a day) beginning 4 days before ischemia induction and continuing for 23 days. Sensorimotor recovery was assessed by a new ledged beam-walking test and spatial learning by the Morris water-maze. After a 7-day washout period all rats were administered a single dose of zopiclone (3 mg/kg, i.p.) and retested. Infarct volumes were measured from nitroblue tetrazolium-stained sections at the end of the experiment. Beam-walking data showed that ischemic rats treated with zopiclone were not more impaired than untreated rats. Indeed, they showed fewer faults with the impaired hindlimb than ischemic controls on post-operative day 16. Water-maze performance was not affected by zopiclone. After the washout period a single dose of zopiclone did not worsen forelimb or hindlimb function, but seemed to improve performance in the water-maze test. Cortical infarct volumes were similar in ischemic controls and ischemic rats treated with zopiclone. In conclusion, zopiclone was not detrimental and even seemed to improve behavioral outcome without affecting ischemic damage in aged rats subjected to cortical photothrombosis.

Aging↗
PubMed2006

Rapid auditory processing and learning deficits in rats with P1 versus P7 neonatal hypoxic-ischemic injury.

Hypoxia-ischemia (HI) is associated with premature birth, and injury during term birth. Many infants experiencing HI later show disruptions of language, with research suggesting that rapid auditory processing (RAP) deficits (i.e., impairment in the ability to discriminate rapidly changing acoustic signals), play a causal role in language problems. We recently bridged these lines of research by showing RAP deficits in rats with unilateral-HI injury induced on postnatal days 1, 7, or 10 (P1, P7, or P10. While robust RAP deficits were found in HI animals, it was suggested that our within-age sample size did not provide sufficient power to detect age-at-injury differences within the pooled HI group. The current study sought to examine differences in neuropathology and behavior following unilateral-HI injury on P1 versus P7 in rats. Ages chosen for HI induction reflect differential stages of neurodevelopmental maturity, and subsequent regional differences in vulnerability to reduced blood flow/oxygen (modeling age-related differences in premature/term HI injury). Results showed that during the juvenile period, both P1 and P7 HI groups exhibited significant RAP deficits, but deficits in the P1 HI group resolved with repeated testing (compared to shams), while P7 HI animals showed lasting deficits in RAP and spatial learning/memory through adulthood. The current findings are in accord with evidence that HI injury during different stages of developmental maturity (age-at-injury) leads to differential neuropathologies, and provide the novel observation that in rats, P1 versus P7 induced pathologies are associated with different patterns of auditory processing and learning/memory deficits across the lifespan.

Acoustic Stimulation↗
PubMed2004

Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formation.

Biochemical and genetic studies indicate that the inflammatory proteins, apolipoprotein E (ApoE) and alpha(1)-antichymotrypsin (ACT) are important in the pathogenesis of Alzheimer's disease (AD). Using several lines of multiply transgenic/knockout mice we show here that murine ApoE and human ACT separately and synergistically facilitate both diffuse A beta immunoreactive and fibrillar amyloid deposition and thus also promote cognitive impairment in aged PDAPP(V717F) mice. The degree of cognitive impairment is highly correlated with the ApoE- and ACT-dependent hippocampal amyloid burden, with PDAPP mice lacking ApoE and ACT having little amyloid and little learning disability. A analysis of young mice before the onset of amyloid formation shows that steady-state levels of monomeric A beta peptide are unchanged by ApoE or ACT. These data suggest that the process or product of amyloid formation is more critical than monomeric A beta for the neurological decline in AD, and that the risk factors ApoE and ACT participate primarily in disease processes downstream of APP processing.

Aging↗
PubMed2005

Uncertainty, neuromodulation, and attention.

Uncertainty in various forms plagues our interactions with the environment. In a Bayesian statistical framework, optimal inference and prediction, based on unreliable observations in changing contexts, require the representation and manipulation of different forms of uncertainty. We propose that the neuromodulators acetylcholine and norepinephrine play a major role in the brain's implementation of these uncertainty computations. Acetylcholine signals expected uncertainty, coming from known unreliability of predictive cues within a context. Norepinephrine signals unexpected uncertainty, as when unsignaled context switches produce strongly unexpected observations. These uncertainty signals interact to enable optimal inference and learning in noisy and changeable environments. This formulation is consistent with a wealth of physiological, pharmacological, and behavioral data implicating acetylcholine and norepinephrine in specific aspects of a range of cognitive processes. Moreover, the model suggests a class of attentional cueing tasks that involve both neuromodulators and shows how their interactions may be part-antagonistic, part-synergistic.

Acetylcholine↗
PubMed2005

Variations in working memory capacity predict individual differences in general learning abilities among genetically diverse mice.

Up to 50% of an individuals' performance across a wide variety of distinct cognitive tests can be accounted for by a single factor (i.e., "general intelligence"). Despite its ubiquity, the processes or mechanisms regulating this factor are a matter of considerable debate. Although it has been hypothesized that working memory may impact cognitive performance across various domains, tests have been inconclusive due to the difficulty in isolating working memory from its overlapping operations, such as verbal ability. We address this problem using genetically diverse mice, which exhibit a trait analogous to general intelligence. The general cognitive abilities of CD-1 mice were found to covary with individuals' working memory capacity, but not with variations in long-term retention. These results provide evidence that independent of verbal abilities, variations in working memory are associated with general cognitive abilities, and further, suggest a conservation across species of mechanisms and/or processes that regulate cognitive abilities.

Animals↗
PubMed2005

Choto-san, a Kampo formula, improves chronic cerebral hypoperfusion-induced spatial learning deficit via stimulation of muscarinic M1 receptor.

A recent double-blind and placebo-controlled study demonstrated a beneficial effect of Choto-san, a Kampo (traditional medicine of Japan) formula, on cognitive impairment in patients with vascular dementia. However, the neuronal mechanism underlying the therapeutic effects of this formula remains to be clarified. Using a chronic cerebral hypoperfusion model, we investigated the effect of Choto-san on cognitive dysfunction in mice to clarify its mechanism of actions. Chronic cerebral hypoperfusion was induced by permanent occlusion of both the common carotid arteries (2VO). Choto-san and Uncaria, a major constituent of Choto-san, caused an improvement in 2VO-induced learning deficits, whereas Uncaria-free Choto-san did not. The effects of Choto-san and Uncaria were blocked by pirenzepine, a selective muscarinic M1 antagonist. In a tube-dominance test, 2VO induced increased rates of assertive behavior in mice. 2VO mice administered Choto-san showed significantly reduced rates of assertive behavior compared to vehicle-treated controls, whereas Uncaria-free Choto-san and Uncaria had little effect on 2VO-induced assertive behavior. 2VO caused a significant decrease in the level of acetylcholine (ACh) contents in the brain, and the daily administration of Choto-san or Uncaria raised the ACh level to that in the sham-operated controls. These results suggest that Choto-san has an ameliorating effect on the spatial memory deficit caused by chronic hypoperfusion, and that the effect is mainly attributable to Uncaria. Moreover, it was suggested that the effects of Choto-san and Uncaria are at least partly mediated by stimulation of the muscarinic M1 receptor.

Acetylcholine↗
PubMed2006

Two months makes a difference in spatial orientation learning in very old FBNF1 rats.

Age-related changes in cognitive performance may be more pronounced in the period near or exceeding the median life span. Therefore, we compared the acquisition of a Morris water escape task by two groups of very old Fischer344 x Brown Norway hybrid rats. The mean age difference between the two groups of rats (a 33- to 34-month-old group versus a 35- to 36-month-old group) was about 2 months. Both groups of rats initially had the same level of performance, but then the younger group learned to escape onto the submerged platform faster, swimming a shorter distance, than the older group. By the fifth acquisition session, the younger rats needed only half the time and swam a shorter distance before they reached the platform than the older rats. These differences in learning were not due to different locomotor abilities as both groups had a similar swimming speed. These results suggest that age-related changes in cognitive performance are indeed more pronounced in the period around the median life span. We also discussed different set-ups to perform cross-sectional age-comparison studies. If there are not sufficient animals from one batch, it may be worthwhile to combine animals from different batches per age group, provided that breeding, rearing, housing, and testing conditions are highly standardized.

Aging↗
PubMed2001

The anti-amnesic effects of sigma1 (sigma1) receptor agonists confirmed by in vivo antisense strategy in the mouse.

The sigma1 (sigma1) receptor cDNA was recently cloned in several animal species, including the mouse. In order to firmly establish the implication of sigma1 receptors in memory, a phosphorothioate-modified antisense oligodeoxynucleotide (aODN) targeting the sigma1 receptor mRNA and a mismatched analog (mODN) were administered intracerebroventricularly for 3 days in mice. Scatchard analyses of in vitro (+)-[3H]SKF-10,047 binding to sigma1 sites showed that Bmax values were significantly decreased in the hippocampus (-58.5%) and cortex (-38.1%), but not in the cerebellum, of aODN treated mice, as compared to saline- or mODN-treated animals. In vivo binding levels were also significantly decreased after aODN treatment in the hippocampus and cortex but not in the cerebellum. The anti-amnesic effects of the selective sigma1 agonists PRE-084 or SA4503 were evaluated against the learning impairments induced by dizocilpine or scopolamine, respectively, using spontaneous alternation behavior and passive avoidance task. The anti-amnesic effects of PRE-084 or SA4503, observed after saline- or mODN-treatment, were blocked after aODN administration. These observations bring a molecular basis to the modulatory role of sigma1 receptors in memory processes.

Amnesia↗
PubMed1997

WAY 100635, a 5-HT1A receptor antagonist, prevents the impairment of spatial learning caused by intrahippocampal administration of scopolamine or 7-chloro-kynurenic acid.

The effect of WAY 100635, a 5-HT1A receptor antagonist, on the impairment of spatial learning caused by intrahippocampal administration of scopolamine, a cholinergic muscarinic receptor antagonist, or 7-chloro-kynurenic acid, an antagonist at the glycine site associated with the NMDA receptor complex, was studied in a two-platform spatial discrimination task. Scopolamine (4 microg/microl) or 7-chloro-kynurenic acid (3 microg/microl), administered bilaterally into the CA1 region of the dorsal hippocampus 10 min before each training session, impaired choice accuracy with no effect on choice latency and errors of omission. Administered subcutaneously at 1 (but not at 0.3) mg/kg 30 min before each training session, WAY 100635 did not modify the acquisition of spatial learning, but prevented the impairment of choice accuracy caused by intrahippocampal scopolamine or 7-chloro-kynurenic acid. These findings suggest that blockade of 5-HT1A receptors can compensate the loss of cholinergic or NMDA-mediated excitatory input to pyramidal cells in the hippocampus. The mechanisms involved and the importance of these findings for the symptomatic treatment of memory disorders in man are discussed.

Animals↗
PubMed1998

Effects of neocortical ectopias upon the acquisition and retention of a non-spatial reference memory task in BXSB mice.

BXSB mice have a 40-60% incidence of small, focal, neocortical dysplasias called ectopias. Ectopics and non-ectopics were compared on horizontal-vertical discrimination learning, a non-spatial cognitive task. No differences were found during acquisition. Ectopic mice, however, were superior when retested 8 weeks later. The results support prior findings that ectopic mice have better long-term spatial memory and extend this conclusion to the non-spatial domain.

Animals↗
PubMed2003

Children with Fetal Alcohol Syndrome are impaired at place learning but not cued-navigation in a virtual Morris water task.

We employed a computerized (virtual) Morris water task (VMWT) to measure place learning and cued-navigation in eight adolescent males (9.5-16.5 years old) diagnosed with Fetal Alcohol Syndrome (FAS). Eight adolescent males matched for age and ethnicity with no history of prenatal alcohol exposure served as controls. Participants were trained to navigate to a hidden platform in a fixed location relative to a set of four conspicuous extramaze cues. After 20 hidden platform trials, a single no-platform probe trial was conducted, followed by 8 trials during which the platform was visible (cued-navigation). The FAS group traveled further than controls to navigate to the hidden platform during training. During the probe trial, controls navigated more directly to the platform region and persisted in searching where the platform had been more than the FAS group. Cued-navigation was comparable in both groups, suggesting that group differences in place learning were not attributable to visual-motor or motivational deficits in the FAS subjects. This pattern of impaired place learning and spared cued-navigation is similar to that reported in rats exposed to ethanol during periods of prenatal or early postnatal brain growth, as well as in animals with hippocampal damage.

Adolescent↗
PubMed1997

Effects of nefiracetam on amnesia animal models with neuronal dysfunctions.

The effects of N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide (nefiracetam; DM-9384), on learning and memory in several amnesia animal models with neuronal dysfunctions were investigated. Nefiracetam improved scopolamine-, bicuculline-, picrotoxin-, ethanol-, chlordiazepoxide- and cycloheximide-induced amnesia. Anti-amnesic action of nefiracetam on scopolamine model was antagonized by nifedipine and flunarizine, but not by diltiazem. Repeated administration of nefiracetam to AF64A-treated animals improved impairment of learning and memory as well as the alterations in cholinergic and monoaminergic neurotransmitters in the hippocampus. Basal forebrain (BF) lesioned rats induced by excitotoxin or by thermal coagulation showed impairment of learning accompanied by a marked reduction in choline acetyltransferase (ChAT) and acetylcholine esterase activities. Nefiracetam improved the learning deficit of the BF-lesioned rats. Nefiracetam also improved the carbon monoxide-induced delayed and acute amnesia. Nefiracetam stimulated acetylcholine release in the frontal cortex. Repeated administration of nefiracetam increased ChAT activity, gamma-aminobutyric acid (GABA) turnover and glutamic acid decarboxylase activity, and facilitated the Na(+)-dependent high-affinity GABA uptake. Nefiracetam activated the high voltage-activated (N/L-type) Ca2+ channel. The dose-response curves of nefiracetam were bell-shaped in both behavioral and biochemical studies. Therefore, it is suggested that nefiracetam improves the dysfunction of cholinergic, GABAergic and/or monoaminergic neuronal function by acting at Ca2+ channel and enhancing the release of neurotransmitters, and modifies impairment of memory processes induced by drugs and hypoxia.

Amnesia↗
PubMed2001

Bromodeoxyuridine and methylazoxymethanol exposure during brain development affects behavior in rats: consideration for a role of nerve growth factor and brain derived neurotrophic factor.

Rats prenatally exposed to the neurotoxins methylazoxymethanol (MAM) or 5-Bromo-2'-deoxyuridine (BrdU) are used as animal models of brain maldevelopment. We administered in rats MAM (20 mg/kg), or BrdU (100 mg/kg) or both at gestational day 11. Locomotion was not affected by any prenatal treatment whereas learning was delayed in the Morris maze in MAM animals. BrdU induced decreased NGF and BDNF levels in the hippocampus. In the parietal cortex prenatal BrdU administration induced NGF potentation associated with decreased BDNF. Animals treated with both MAM and BrdU showed also an increased immunopositivity for choline acetyltransferase (ChAT) and low affinity neurotrophins' receptor (p75) in the septum and Meynert's nuclei. These findings suggest that embryonic exposure to MAM and/or BrdU may be useful for studying mechanisms associated with neurodegenerative diseases affecting brain morphology and behavior.

Animals↗