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PubMed2002

The sliding window correlation procedure for detecting hidden correlations: existence of behavioral subgroups illustrated with aged rats.

We developed the sliding window correlation procedure in order to examine populations for possible heterogeneity in the ways two variables are related with each other. This procedure involves computing correlation coefficients (R) for overlapping successive segments of the covariate scores. The distribution of resulting Rs reveals fluctuations in the degree and direction of R over the sample of ranked scores. This procedure is applied to behavioral data of aged rats, which were rank-ordered according to water maze performance, and correlated with open field exploration and conflict behavior in a light/dark chamber. Results revealed correlation coefficients of varying magnitudes and opposing directions for different segments of the population, which were obscured by overall correlation analysis. E.g. for the superior learners, the Rs were highest between maze learning ability, increased open field exploration and reduced anxiety in the conflict test, whereas for the intermediate learners the Rs were highest for maze learning ability related with reduced exploration and increased anxiety. Thus, the sliding window correlation distribution can be applied in conjunction with overall correlation analysis to provide information about the potential presence and locations of subgroups within a population, especially if overall correlation analysis does not yield significant results.

Aging↗
PubMed1995

Assessment of offspring development and behavior following gestational exposure to inhaled methanol in the rat.

The prospect of widespread human exposure associated with its use as an alternative fuel has sparked concern about the toxic potential of inhaled methanol (MeOH). Previous studies have revealed congenital malformations in rats following inhaled MeOH (Nelson et al. (1985). Fundam. Appl. Toxicol. 5, 727-736) but these studies did not include postnatal behavioral assessment. In the present study, pregnant Long-Evans rats were placed in exposure chambers containing 15,000 ppm MeOH or air for 7 hr/day on Gestational Days (GD) 7-19. The total alveolar dose of methanol was estimated at about 6.1 g/kg/day, for a total dose of about 42.7 g/kg for the entire study. Maternal body weights were recorded daily and blood methanol concentrations were determined at the end of exposure on GD 7, 10, 14, and 18. Following birth (Postnatal Day 0 [PND 0]), a number of tests were performed at various points in development, including: offspring mortality and body wt (PND 1,3), motor activity (PND 13-21, 30, 60), olfactory learning (PND 18), behavioral thermoregulation (PND 20-21), T-maze learning (PND 23-24), acoustic startle response (PND 24, 60), reflex modification audiometry (PND 60), pubertal landmarks (PND 31-56), passive avoidance (PND 72), and visual-evoked potentials (PND 160). Maternal blood MeOH levels, measured from samples taken within 15 min after removal from the exposure chamber, declined from about 3.8 mg/ml on the first day of exposure to 3.1 mg/ml on the 12th day of exposure. MeOH transiently reduced maternal body wt (4-7%) on GD 8-10, and offspring BW (5%) on PND 1. No other test revealed significant effects of MeOH. Prenatal exposure to high levels of inhaled MeOH appears to have little effect on this broad battery of tests beyond PND 1 in the rat.

Administration, Inhalation↗
PubMed1997

Anosognosia and procedural learning in Alzheimer's disease.

Awareness of cognitive deficits may rely on the implicit learning of intellectual limitations, and anosognosia in Alzheimer's disease (AD) may result from deficits in implicit learning. To examine this hypothesis, a consecutive series of 55 patients with probable AD were divided into groups with mild (n = 13), severe (n = 12), or no anosognosia (n = 30) and were assessed with a neuropsychological battery that included tests of declarative and procedural learning. Whereas there were no significant between-group differences in tests of declarative learning (the Buschke Selective Reminding Test and the Benton Visual Retention Test), patients with severe anosognosia showed a significantly worse performance on procedural learning (as measured with the Maze Learning Test) and a test assessing set shifting abilities (the Wisconsin Card Sorting Test) than AD patients without anosognosia. The authors' results suggest that deficits in procedural learning and anosognosia in AD may result from dysfunction in habit-learning systems.

Aged↗
PubMed2006

Retrosplenial cortex lesions impair water maze strategies learning or spatial place learning depending on prior experience of the rat.

There has been debate whether lesions strictly limited to retrosplenial (RS) cortex impair spatial navigation, and how robust and reliable any such impairment is. The present study used a detailed behavioral analysis with naive or strategies-pretrained rats given RS lesions and trained in a water maze (WM). Naive RS lesioned rats failed to acquire the required WM strategies throughout training. Strategies-pretrained RS lesioned rats were specifically impaired in spatial place memory without a WM strategies impairment. Additional training overcame the spatial memory impairment. Thus the behavioral consequences of the lesion depend on the specific previous experience of the animal. The use of appropriate training and testing techniques has revealed experience-dependant dissociable impairments in WM strategies learning and in spatial memory, indicating that RS cortex is involved in both forms of learning.

Animals↗
PubMed1992

Functional changes implicating dopaminergic systems following perinatal treatments.

A series of experiments, involving diverse perinatal treatments of either rats or mice, have been performed in order to investigate the effects of these treatments upon certain selected spontaneous and learned behaviors in the laboratory. Rat dams were administered either metallic mercury, organic tin or neuroleptic compounds, and the offspring of these dams was studied with behavioral tests at adult ages, prenatal studies. Newborn rat pups were administered either 6-hydroxydopamine (6-OHDA) (at various doses), or metallic mercury and then tested at adult ages. Newborn mice were administered either metaclopramide, an antiemetic compound, or haloperidol, a neuroleptic compound, and tested for spontaneous and d-amphetamine induced activity as adults. The behavioral battery the rats were tested with consisted of measures of spontaneous motor activity, including locomotion/ambulation, rearing, and head dipping behaviors, and a parameter under which diverse behaviors were collected, total activity. Alterations to instrumental maze learning performance were studied through application of the spatial learning tasks: the radial arm maze and the circular swim maze. Possible changes in dopaminergic pathways were assessed by measuring the effects of perinatal treatments upon d-amphetamine-induced activity. It was shown that prenatal metallic mercury, organic tin and the neuroleptic compounds, haloperidol and remoxipride altered various parameters of spontaneous motor activity, retarded maze learning in the radial arm maze and potentiated d-amphetamine-induced activity. Metallic mercury rats were not subjected to the amphetamine test and remoxipride rats were not retarded according to the learning task. Postnatal metallic mercury, 6-OHDA, haloperidol and the antiemetic compound, metaclopramide, also altered spontaneous and d-amphetamine-induced activity as well as radial arm maze performance, excluding in this case haloperidol and metaclopramide. None of these treatments altered performance in the circular swim maze, except for 6-OHDA where doses inflicting severe depletions (greater than 85% depletion compared to control values) caused notable impairments. One tentative conclusion from the pattern of behavioral changes, generally in the absence of any measurable neurochemical changes, observed after these treatments is that the functional development of dopaminergic systems had, to a greater or lesser degree, been altered.

Animals↗
PubMed1993

Behavioural retardation in the neuropathology of mental retardation.

A series of experiments, involving diverse perinatal treatments of either rats or mice, have been performed in order to investigate the effects of these treatments upon certain selected spontaneous and learned behaviours in the laboratory in order to derive animal models of behavioural retardation. Rat dams were administered either methylazoxymethanol, metallic mercury, organic tin or neuroleptic compounds, and the offspring of these dams were studied on the behavioural tests at adult ages, prenatal studies. Newborn rat pups were administered either 6-OHDA (at various doses), or metallic mercury and then tested at adult ages. Newborn mice were administered either metaclopramide, an antiemetic compound or haloperidol, a neuroleptic compound, and tested for spontaneous and d-amphetamine induced activity as adult. The behavioural battery that the rats were tested with consisted of measures of spontaneous motor activity, including locomotion/ambulation, rearing, and head dipping behaviours, and a parameter under which diverse behaviours were collected, total activity. Alterations to instrumental maze learning performance were studied through application of the spacial learning tasks: the radial arm maze and the circular swim maze. Possible changes in dopaminergic pathways were assessed by measuring the effects of perinatal treatments upon d-amphetamine induced activity. It was shown that prenatal methylazoxymethanol, metallic mercury, organic tin and the neuroleptic compounds, haloperidol and remoxipride, altered various parameters of spontaneous motor activity, retarded maze learning in the radial arm maze and potentiated d-amphetamine induced activity. Metallic mercury rats were not subjected to the amphetamine test and remoxipride rats were not retarded on the learning task. Postnatal metallic mercury, 6-OHDA, haloperidol and the antiemetic compound, metaclopramide, also altered spontaneous and d-amphetamine induced activity as well as radial arm maze performance, excluding in this case haloperidol and metaclopramide. None of these treatments altered performance in the circular swim maze, except for 6-OHDA where doses inflicting severe depletions (greater than 85% depletion compared to control values) caused notable impairments. These diverse findings seem to implicate dopaminergic processes in brain development.

Animals↗
PubMed1997

Studies on the influence of enriched-environment housing combined with systemic administration of an alpha2-adrenergic antagonist on spatial learning and hyperactivity after global ischemia in rats.

BACKGROUND AND PURPOSE: The purpose of this study was to determine whether an enriched housing environment and/or systemic administration of the alpha2-adrenergic receptor antagonist atipamezole facilitate the rate of spatial learning after global ischemia in rats. METHODS: Carotid arteries were closed for 20 minutes after permanent cauterization of vertebral arteries on the previous day. Enriched-environment housing and drug/saline treatment were begun 3 days after ischemia. For rehabilitation, housing in an enriched environment was combined with exploration in a labyrinth. Behavioral tests (the open-arena test and water-maze learning set task) were performed after 1-week periods of drug/saline treatment three times. In addition, the open-arena test was performed to evaluate the baseline level of animals 2 days after the induction of ischemia and at the end of the experiment, when the water-maze task was assessed in another room. RESULTS: Rats housed in an enriched environment after ischemia showed better acquisition of the water-maze learning set task after 1 week of housing. The influence of atipamezole treatment on this parameter did not reach statistical significance. In the open-arena test, ischemic animals were slightly hyperactive; however, this symptom was eliminated by housing in an enriched environment. CONCLUSIONS: The present data suggest that housing in an enriched environment facilitates the rate of spatial learning in rats with global ischemia. Rehabilitation also alleviated the hyperactivity observed in ischemic animals.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2002

Enriched early experiences of mice underexpressing the beta-amyloid precursor protein restore spatial learning capabilities but not normal openfield behavior of adult animals.

We have previously reported severely impaired spatial learning in mutant mice underexpressing a shortened variant of the beta-amyloid precursor protein (beta-APPtheta/theta). This targeted mutation is functionally equivalent to a null mutation. It also disturbs behavioral and neurological maturation with deficits emerging mainly between postnatal day (pd) 11 and 19. Such early tested mice exhibited almost no genotype-related difference in Morris water maze learning, raising the possibility that early handling might have compensated for genetic deficits. To verify this effect, we compared watermaze learning and open field behavior of 66 adult mutant and wildtype mice having been handled during pd 3-27 with that of 70 non-handled mutant and wildtype mice. Neurological testing during pd 3-27 markedly reduced time near wall and improved spatial retention of adult mutants, restoring their learning capabilities to wildtype levels. Early handling did not cure the mutation associated activity deficit in the open field, but mainly increased center field exploration in both mutants and wildtypes. In a follow-up experiment we analyzed whether an early (pd 3-10, n = 22) or middle (pd 11-19, n = 24) period of handling in form of neurological testing had differential effects on adult behavior. Mice handled during pd 11-19 had slightly shorter escape times than mice handled during pd 3-10 but were not significantly different in other behavioral measures. There were no sex related differences. Correlational and factor analysis showed that both the mutation and early handling had pleiotropic behavioral effects, resulting in differentially impaired mutants depending on the test situation. Likewise, early handling affected not only thigmotactic tendencies but also, more subtly, other behavioral components underlying water maze learning. We conclude that early postnatal stimulation can prevent mutation induced learning deficits in adult mice, but probably through other developmental mechanisms than those affected by the mutation. This implies that some behavioral impairments related to beta-APP malfunction may be corrected through simple treatments.

Amyloid beta-Protein Precursor↗
PubMed1999

Time course for recovery of water maze performance and central cholinergic innervation after fluid percussion injury.

This study further investigates the possible connection between postconcussive cognitive impairment and damage to forebrain cholinergic innervation. Moderate parasagittal fluid percussion injury was delivered to adult male rats. Water maze performance and synaptosomal choline uptake was measured at various times following injury. Water maze learning was severely impaired between 1 and 5 weeks, but recovered to normal by 10 weeks. Synaptosomal choline uptake was significantly decreased by 15-27% in the ipsilateral hippocampus and parietal cortex 3 and 7 days following injury, but not by 3 weeks or thereafter. Choline acetyltransferase was also significantly decreased in the ipsilateral cortex at 3 and 7 days with subsequent recovery. This study shows that parasagittal fluid percussion injury causes significant impairment in water maze learning and ipsilateral forebrain cholinergic innervation. Both of these parameters recover spontaneously, but with different time courses.

Animals↗
PubMed2000

Hippocampal mossy fibers and swimming navigation learning in two vole species occupying different habitats.

We showed previously for mice that size differences of the infrapyramidal hippocampal mossy fiber projection (IIP-MF) correlate with spatial learning abilities. In order to clarify the role of the IIP-MF in a natural environment, we studied the bank vole (Clethrionomys glareolus), adapted to a wide range of different habitats, and the root vole (Microtus oeconomus), living in homogenous grassland habitats with small home ranges. Morphometry on Timm-stained horizontal brain sections of six C. glareolus and six M. oeconomus revealed that the size of the entire mossy fiber projection was 42% larger in C. glareolus than M. oeconomus. C. glareolus had also an IIP-MF projection about 230% larger than that of the root vole. A sample of captured animals was then transferred to the laboratory (C. glareolus, n = 23; M. oeconomus, n = 15) and underwent testing for swimming navigation according to a standardized protocol used to assess water maze learning in about 2,000 normal and transgenic mice. Both species learned faster than laboratory mice. Overall escape times showed no differences, but path length was significantly reduced in C. glareolus, which also showed superior performance in a variety of scores assessing spatial search patterns. On the other hand, M. oeconomus showed faster swimming speed, and strong thigmotaxis combined with circular swimming. M. oeconomus also scored at chance levels during the probe trial, about as poorly as mutant knockout mice considered to be deficient in spatial memory. These differences probably reflect differential styles of water maze learning rather than spatial memory deficits: C. glareolus appears to be superior in inhibiting behavior interfering with proper spatial search behavior, while M. oeconomus succeeds in escaping by using rapid circular swimming. We assume that size variations of the IIP-MF correspond to a mechanism stabilizing hippocampal processing during spatial learning or complex activities. This corresponds to the ecological lifestyle of the two species and is in line with previous observations on the role of the IIP-MF.

Animals↗
PubMed1987

Exploration and spatial learning in staggerer mutant mice.

Staggerer mutant mice, that lose cerebellar Purkinje cells and granule cells and inferior olive neurons, were evaluated in tests of spontaneous alternation and maze learning. It was found that, contrary to normal mice, the staggerer mutants did not alternate spontaneously and had deficits in the acquisition of maze learning. It is hypothesized that the olivocerebellar system has a role in visuo-spatial organization.

Animals↗
PubMed1998

Activity and passive-avoidance learning in cobalt-injected rats.

A wide range of cognitive-behavioral sequelae, including memory deficits, results from hard metal disease in humans. Cobalt is a common component in the manufacture of hard metals and is a biologically active, toxic substance. This study examined the effects of cobalt exposure in rats. Results showed decreased exploratory behavior and a trend for higher-dose subjects to show decreased passive avoidance learning. No significant differences in active maze learning were found. These results indicate the value of further explorations of the cognitive-behavioral effects of cobalt exposure and suggest a number of methodological cautions.

Animals↗
PubMed1996

Effects of social isolation rearing on learning in the Morris water maze.

Impaired learning has been shown as a consequence of isolation-rearing in a variety of paradigms. However, there are situations in which learning in isolation-reared rats is enhanced or unimpaired compared to socially reared rats. The present experiments investigated the effects of isolation rearing on place navigation in the Morris water maze. Two complementary paradigms were studied: isolation and socially reared rats were exposed to the water maze either without drug pretreatment or following systemic administration of scopolamine. Two conditions were examined: place learning and reversal learning. Male Lister hooded rats were either housed singly (isolation reared) or in groups of four (social reared) from weaning at 21 days of age. Six weeks later place learning and reversal learning were determined using the Morris water maze. The time taken to locate the submerged island (escape latency) was used as the measure of learning ability. The results showed that place learning, and reversal learning were enhanced in isolation reared rats compared to socially reared controls. Pretreatment with scopolamine (0.3 and 0.5 mg/kg, i.p.) produced a dose-related cognitive deficit as shown by an increase in the escape latency. Scopolamine (0.3 mg/kg) impaired both place and reversal learning but this was less pronounced in isolation compared to socially-reared rats. These results suggest that rearing in isolation may enhance spatial learning though central cholinergic mechanisms.

Animals↗
PubMed1998

Effect of the long-term feeding of dietary lipids on the learning ability, fatty acid composition of brain stem phospholipids and synaptic membrane fluidity in adult mice: a comparison of sardine oil diet with palm oil diet.

The effect of 12 month feeding of 5% palm oil or sardine oil diet on the maze-learning ability, fatty acid composition of brain stem phospholipids and synaptic membrane fluidity in mice was studied. The time required to reach the maze exit and the number of times that a mouse strayed into blind alleys in the maze were measured three times every 4 days. The time and number of mice fed on the sardine oil diet were less than those of animals fed on the palm oil diet in the first and second trials. The results of fatty acid composition analysis of brain stem phosphatidylethanolamine showed that the percentage of docosahexaenoic acid (22:6, n-3; DHA) was higher, but the arachidonic acid (20:4, n-6; AA) and docosatetraenoic acid (22:4, n-6; DTA) were lower in the sardine oil diet fed-mice than in the palm oil diet fed-animals. Moreover, the microviscosity of the synaptic plasma membrane in the sardine oil diet group was lower than that in the palm oil diet group. These results suggest that the adult mice fed on the sardine oil diet for a long period maintain higher levels of docosahe xaenoic acid in brain phospholipids, synaptic membrane fluidity and maze-learning ability than animals fed on the palm oil diet.

Animals↗
PubMed1997

Mildly impaired water maze performance in male Fmr1 knockout mice.

Fmr1 knockout mice constitute a putative model of fragile X syndrome, the most common form of heritable mental disability in humans. We have compared the performance of transgenic mice with an Fmr1 knockout with that of normal littermates in hidden- and visible-platform water maze learning, and showed that knockouts exhibit subnormal spatial learning abilities and marginal motor performance deficits. During 12 training trials of the hidden-platform task, escape latency and path length decreased significantly in knockouts and control littermates, and no effect of genotype was found. During four ensuing reversal trials, however, significant differences were found between knockouts and control littermates both in escape latency and path length. During the visible-platform condition, the reversal trials also revealed a difference between knockouts and normal littermates in escape latency, but not in path length. Possibly due to marginal motor incapacity, knockouts swam significantly slower than controls during these latter trials. During both probe trials of the hidden-platform task, knockouts as well as normal littermates spent more time in the target quadrant than in the other quadrants, and percent of time spent in the target quadrant was the same in both groups; swimming velocity was not significantly different between knockouts and normal littermates during these trials. Entries in the target area during the probe trials did show a significant effect of genotype on number of entries. The present results largely confirm and extend our previous findings. Impaired spatial abilities in Fmr1 knockouts might have been due to relatively low response flexibility or high memory interference in Fmr1 knockouts. It remains unclear, however, which brain region or neurochemical system might be involved in these disabilities. We conclude that Fmr1 knockout mice might be a valid model of fragile X mental retardation.

Animals↗
PubMed2001

Learning about the context in genetically-defined mice.

Defective utilisation of background stimuli may result in a large range of cognitive impairments. We describe here three experimental paradigms taxing the processing of contextual information, (i) radial maze learning under distinct cueing conditions and successive context shifts; (ii) reactivity to spatial and object change; (iii) contextual versus cue fear conditioning with pre-test exposure to the experimental context. These paradigms have then been used to characterise the behaviour of null mutant and transgenic mice. In a first series of experiments, we assessed the effect of the null mutation of the gene encoding for Tissue Plasminogen Activator (tPA). Initial investigations pointed to a reduction of the late phase of long-term potentiation in tPA-knock out relative to wild type mice without any consistent performance impairment in several hippocampal-dependent tasks. When tested following our protocols, we found tPA knock out impaired in habituation of object exploration, reactivity to spatial change and contextual fear conditioning. The second example concerns mice overexpressing the mutant human Cu,Zn superoxide dismutase (SOD1) gene, that provide a murine model of amyotrophic lateral sclerosis. We found these mice exhibiting a paradoxical selective enhancement of reactivity to spatial change in comparison with mice overexpressing either the endogeneous murine Cu,Zn SOD1 or the wild type human Cu,Zn SOD1 genes. Our conclusion emphasises the view that experimental protocols involving contextual manipulations may be suitable for differentiating behavioural phenotypes.

Animals↗
PubMed1976

Environmental stimulation reduces learning deficits in experimental cretinism.

Behavioral deficits in adult rats exposed perinatally to thiouracil were substantially reduced or elimated by a 5-week period of "superenriched" postweaning rearing conditions before testing. This treatment resulted in remediation of hypothyroid rats' deficits in maze learning, maze retention, and resistance to extinction of bar-pressing; the facilitative effect persisted for more than 4 months. These behavioral results were consistent with neurohistological findings from studies of early thyroid deficiency and postweaning environmental stimulation in rats.

Age Factors↗
PubMed2003

Impairment of reward-related learning by cholinergic cell ablation in the striatum.

The striatum in the basal ganglia-thalamocortical circuitry is a key neural substrate that is implicated in motor balance and procedural learning. The projection neurons in the striatum are dynamically modulated by nigrostriatal dopaminergic input and intrastriatal cholinergic input. The role of intrastriatal acetylcholine (ACh) in learning behaviors, however, remains to be fully clarified. In this investigation, we examine the involvement of intrastriatal ACh in different categories of learning by selectively ablating the striatal cholinergic neurons with use of immunotoxin-mediated cell targeting. We show that selective ablation of cholinergic neurons in the striatum impairs procedural learning in the tone-cued T-maze memory task. Spatial delayed alternation in the T-maze learning test is also impaired by cholinergic cell elimination. In contrast, the deficit in striatal ACh transmission has no effect on motor learning in the rota-rod test or spatial learning in the Morris water-maze test or on contextual- and tone-cued conditioning fear responses. We also report that cholinergic cell elimination adaptively up-regulates nicotinic ACh receptors not only within the striatum but also in the cerebral cortex and substantia nigra. The present investigation indicates that cholinergic modulation in the local striatal circuit plays a pivotal role in regulation of neural circuitry involving reward-related procedural learning and working memory.

Acetylcholine↗