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F J van der Staay

Publications and source records attributed to F J van der Staay.

At least 19 recordsLinked to original sources
PubMed2005

Spatial discrimination deficits by excitotoxic lesions in the Morris water escape task.

The effects of the cholinesterase inhibitors (ChEI) metrifonate and donepezil were assessed on spatial performance of rats with bilateral lesions of the entorhinal cortex (EC), which is thought to model early changes in the brains of patients suffering from Alzheimer's disease. In the present study, we found that spatial discrimination deficits in rats, induced by bilateral ibotenic acid (IBO) lesions of the EC region can partially be antagonised by treatment with the cholinesterase inhibitors metrifonate (30 mg kg(-1)) and donepezil (0.3 and 3 mg kg(-1)). Performance was improved in the spatial discrimination task compared with that of the EC-lesioned control group. It is concluded that the rat with bilateral EC lesions is a suitable deficit model for the assessment of effects of putative Alzheimer therapeutics.

Analysis of Variance↗
PubMed2005

Absence of long-term behavioral effects after sub-chronic administration of low doses of methamidophos in male and female rats.

Putative long-term learning and memory effects of low-dose exposure to the cholinesterase inhibitor organophosphate methamidophos (Tamaron) early in life were studied in two parallel studies in middle-aged rats. Methamidophos was administered via the drinking water to female and male Wistar rats using nominal concentrations of 0 (control), 0.5, 1.5 and 4.5 ppm active ingredient for 16 weeks. Animals were then maintained for a recovery period of about 14 months without treatment. They were tested in the standard and repeated acquisition version of the Morris water escape task in two series of tests starting 33 and 55 weeks after termination of the methamidophos treatment. Functional observations and motor activity measurements preceded each series of testing. Exposure to methamidophos was confirmed by measurement of brain cholinesterase (ChE-B) at the end of the 16 weeks of treatment in satellite animals. At 4.5 ppm a biologically relevant reduction in ChE-B activity was observed without clinical signs of intoxication (males: 66%, females: 64% of control activity). Mid- and low-dose exposure to methamidophos revealed ChE-B activity of 90% and 100% in males and 88% and 97% in females, respectively. General examinations of the animals during treatment revealed no clinical signs suggesting cholinergic stimulation. Functional observations and motor activity measurements exhibited no relevant differences between treatment groups and controls. Neither the performance in the standard Morris water escape task that predominantly measures spatial reference memory, nor in the repeated acquisition task in the Morris tank, which predominantly measures spatial working memory, was affected by treatment with methamidophos. A small number of statistically significant differences were noted in the mean performance level between treatment groups, or between treatment by sex groups in both versions of the Morris task. However, these findings appeared to be idiosyncratic for a particular experiment and were not supported by findings from the other. They were consequently not considered as reflecting a consistent effect of methamidophos on learning and memory. In conclusion, administration of low doses of methamidophos to female and male Wistar rats for 16 weeks during early adulthood did not impair spatial working and reference memory in the Morris water escape task 33 and 55 weeks after cessation of treatment.

Analysis of Variance↗
PubMed2004

The T-maze continuous alternation task for assessing the effects of putative cognition enhancers in the mouse.

The T-maze continuous alternation task (T-CAT) assesses the spatial exploratory performance in mice. We performed a series of four experiments in order to establish the T-CAT in mice in our laboratory, to replicate published findings, and to investigate the effects of scopolamine and donepezil. In the first experiment, the task was found to be sensitive to differences between mouse strains, corroborating findings reported by Gerlai. HsdWin:CFW1 mice alternated below chance level, C57BL/6JIco and B6D2F1/JIco mice performed above chance level, and C57BL/6NTac and 129S6/SvEvTac mice performed at chance level. In the second experiment, donepezil (Aricept, E2020) at the dose of 3 mg/kg p.o. increased the rate of alternations above the level of the vehicle-treated control group in C57BL/6JIco mice, suggesting that this drug can act as cognition enhancer in normal animals. 1mg/kg scopolamine, administered intraperiteoneally (i.p.), impaired the spontaneous alternation behaviour of the mice. The slightly lower dose of 0.75 mg/kg did not affect alternation performance. The high dose of donepezil (3 mg/kg) was able to antagonise the scopolamine-induced performance deficit. With respect to time to complete a session, the results were inconclusive. In the third experiment, we found that scopolamine, administered i.p. at the dose of 1 mg/kg, or subcutaneously (s.c.) at the dose of 0.1 mg/kg, decreased the rate of spontaneous alternations in C57BL mice in the T-CAT and increased the time to complete a session. Most likely due to adverse side effects induced by the dose of 1mg/kg scopolamine, 4 out of 10 animals did not complete at least eight free-choice trials during the maximum session duration of 30min. No such adverse effects were seen after 0.1 mg/kg scopolamine, administered s.c. Finally, we evaluated whether the T-CAT yields replicable results. We conclude that the T-CAT provides a reliable tool for assessing the effects of cognition-modulating treatments in mice.

Analysis of Variance↗
PubMed2004

Chronic cognitive effects of bilateral subdural haematomas in the rat.

Humans suffering from subdural haematomas often show long-term cognitive dysfunctions. For identifying putative, recovery-enhancing therapeutics, animal models need to be developed in which recovery of function can be measured. For investigating whether and which type of recovery, i.e. spontaneous or training-induced recovery, or continuous partial retardation, is present in the rat model for bilateral subdural haematomas, spatial navigation abilities were assessed in the Morris water escape task in independent groups of rats at 1, 2, 4, 8, or 18 weeks after surgery. Complete spontaneous recovery seemed to occur at 8 weeks after injury. However, at 18 weeks after injury, the subdural haematoma caused a renewed deterioration of water maze performance, which was of a lesser degree than the impairments observed immediately after injury. This second phase performance deterioration was accompanied by an increase in generalised astrocyte reactivity. The rat subdural haematoma model provides an interesting tool for investigating spontaneous recovery processes of spatial navigation (8 weeks after injury), but also for progressive brain dysfunctions, considering the second phase of behavioural impairments seen at 18 weeks after injury.

Animals↗
PubMed2002

Effects of two selective phosphodiesterase type 5 inhibitors, sildenafil and vardenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat.

The present study investigated the effects of two cyclic GMP-specific phosphodiesterase enzyme type 5 inhibitors, sildenafil and vardenafil, on the memory performance in the object recognition task. Both compounds were given per orally (1, 3 and 10 mg/kg sildenafil; 0.1, 0.3, 1 and 3 mg/kg vardenafil) immediately after the exposure to two identical objects. The memory for the objects was tested 24 h later. Vehicle-treated rats spent equal times exploring a new and the familiar object demonstrating that they did not remember the familiar one. However, sildenafil improved the object discrimination performance of the rats with a high discrimination performance at a dose of 3 mg/kg. Rats treated with vardenafil also showed an improved object discrimination performance. Compared with sildenafil, vardenafil appeared to be even more potent in this respect since it already produced a high discrimination performance at a dose of 0.3 mg/kg. The effects of both compounds on cyclic GMP and cyclic AMP accumulation were studied in rat hippocampal slices incubated in vitro. Cyclic GMP levels were increased after incubation with the highest concentration of 100 microM vardenafil (together with 0.1 mM sodium nitroprusside), although no changes in cyclic GMP levels were detected after incubation with different concentrations of sildenafil. Both compounds had no effect on cyclic AMP levels. Additional cyclic GMP immunocytochemistry showed that incubation with vardenafil (in the presence of sodium nitroprusside) resulted in a concentration-dependent staining of cyclic GMP. Staining was predominantly found in neuronal fibres in the hippocampal CA2/CA3 region. It was already detected at a concentration of 0.1 microM vardenafil. Also positive fibres were detected after incubation with sildenafil but at a higher concentration of 10 microM. Taken together, these results suggest that inhibition of phosphodiesterase enzyme type 5 improves object recognition memory. This effect might be explained by increased levels of central cyclic GMP.

Animals↗
PubMed2002

The fallacy of behavioral phenotyping without standardisation.

Behavioral phenotyping of mutant mice is a new and challenging task for the behavioral neuroscientist. Therefore, standardisation of the experimental conditions is required to permit comparisons between the results of experiments within and between laboratories. Once mutation-induced behavioral changes have been identified, phenotyping of mouse mutants should be performed along a systematic trajectory, which allows for an in-depth characterisation of the mutant under investigation.

Animals↗
PubMed2001

Behavioural phenotyping of mouse mutants.

Behavioural phenotyping of mouse mutants is not a goal in itself but serves to characterise the behavioural effects of naturally occurring or experimentally induced mutations. Genetically engineered mouse mutants are valuable tools to elucidate the genetic control of behaviour and the interaction between genetic and environmental factors. However, a prerequisite for their use is the ability to assess different elements of behaviour. To this end, a battery of tests, which should be flexible enough to meet the needs of a particular study, should be used to characterise the behavioural phenotype. Detailed and extensive information about the effects of gene mutations is crucial for model building and model evaluation. Model building is an iterative process, switching between experimental data and theory formation. In order to facilitate this process and to allow comparison of results within and between laboratories, the standardisation of breeding, housing, and testing conditions is essential. The development and standardisation of sensitive, valid behavioural tests which are suited to phenotype mouse mutants is both a responsibility and a challenge to investigators of mouse behaviour.

Animals↗
PubMed2000

Effects of subdural haematoma on sensorimotor functioning and spatial learning in rats.

Twenty per cent of all strokes are haemorrhagic in character and are associated with severe disturbances in sensorimotor behaviour and cognition. Although spontaneous recovery of pre-stroke functioning occurs in some cases, the process is demanding, slow, and often incomplete. A first step in the preclinical testing of new putative, neuroprotective and recovery-supporting therapeutics is to validate animal models of brain injury. In a series of four experiments we evaluated the behavioural impairments and the time course of recovery of functional deficits in rats with an experimentally induced subdural haematoma. We found that unilateral subdural haematoma resulted in dysfunction in both simple reflexive (experiment 1) and skilled sensorimotor behaviour (experiment 2). Reflexive behaviour did not recover, or recovered only marginally, and neither did the deficits in skilled forepaw use. Bilateral subdural haematoma impaired the learning and memory performance of adult (experiment 3) and old rats (experiment 4) in the Morris water escape task. Considering the diversity of the deficits found in our experiments, we conclude that different models are needed to cover the broad range of deficits seen in stroke patients.

Age Factors↗
PubMed2000

Effects of the size of the morris water tank on spatial discrimination learning in the CFW1 mouse.

The spatial orientation of mice and rats in tasks such as the Morris water escape task is guided by extramaze cues. Using data from the control groups of mice used in two drug-finding experiments, we addressed the question whether the size of the Morris water tank affects spatial learning in mice. In these experiments, CFW1 mice had been tested in either a small or a large water tank. Reanalysis of the data revealed that pool size did not affect learning or bias for the previous training quadrant. The Morris water escape task appears to act as a severe stressor in particular mouse strains, and a high stress level may interfere with the learning ability or performance of mice, which may have serious consequences for the interpretation of data. This is of special relevance when assessing the Morris maze performance of strains of mice with a different sensitivity to stress. We conclude that mice can best be tested in a small pool, because the time and distance swam to find and escape onto the platform is decreased and the probability of success (that is, of encountering the platform) is increased. This will reduce stress and hence increase the comparability of data between different strains of mice.

Animals↗
PubMed2000

Modelling cognitive dysfunctions with bilateral injections of ibotenic acid into the rat entorhinal cortex.

Neurodegenerative diseases, traumatic brain injury and stroke are likely to result in cognitive dysfunctioning. Animal models are needed in which these deficits and recovery of the affected functions can be investigated. In the present study, the entorhinal area was chosen as the target for lesioning and for assessing the lesion-induced deficits in the Morris water maze. The entorhinal cortex is regarded as an interface between the hippocampus and neocortex. Deafferentiating the hippocampus through entorhinal lesions impairs spatial learning. The effects of lesions, induced by either electrocoagulation (experiment 1) or ibotenate excitotoxicity (experiment 2), on spatial orientation behaviour were investigated. Water maze performance after unilateral or bilateral ibotenate injections into the entorhinal cortex was studied in the third experiment. In an additional study, the replicability of the spatial learning deficit after lesions induced by bilateral injections of ibotenic acid into the entorhinal cortex was assessed by comparing the results of nine experiments. We found that spatial learning was impaired after bilateral lesions aimed at the entorhinal cortex. The electrolytic lesion technique produced a relatively large sham effect, whereas the excitotoxic lesioning method did not. Unilateral injections of ibotenic acid into the entorhinal cortex did not affect spatial navigation. The ibotenate-induced lesions replicably produced deficits in the Morris tasks. The degree of the induced spatial learning impairments and the effects on the rate of acquisition during training, however, differed between experiments. This result suggests that the fundamental biological diversity between shipments of rats can account for variation in the effects of parahippocampal damage on spatial learning even in highly standardized experimental set-ups. Rats lesioned by bilateral injections of ibotenic acid into the entorhinal cortex provide an interesting and reliable model for investigating cognitive dysfunctions in neurodegenerative diseases, stroke or traumatic brain injury.

Brain Injuries↗
PubMed1999

Spatial working memory and reference memory of Brown Norway and WAG rats in a holeboard discrimination task.

To determine whether working memory (WM) and reference memory (RM) represent different aspects of spatial memory, albino WAG rats and the pigmented Brown Norway rats were tested in the acquisition, retention, and reversal of spatial orientation tasks in the holeboard, which allows the simultaneous assessment of WM and RM. Putative nonmnemonic factors, such as the speed of visiting the holes or the development of a search strategy (preferred sequence of visiting the baited set of holes) were also evaluated because they might influence WM and RM performance. The WM performance of Brown Norway rats was generally worse than that of the WAG rats. The reverse was true for the RM performance. Correlation analysis supported the notion that these two measures are independent. Differences in the speed of visiting the holes and in the development of a preferred sequence of visiting the baited set of holes could not explain the strain differences in WM and RM performance. Because spatial WM and RM appear to be independent measures in the holeboard, this task could be used to investigate whether different neural substrate(s) underlie these two memory components.

Animals↗
PubMed1999

Behavioral effects of apamin, a selective inhibitor of the SK(Ca)-channel, in mice and rats.

Apamin, a highly selective and potent peptide that blocks the SK(Ca)-channels has been suggested to be a cognition enhancer. We tested apamin in the Morris water escape task, in shock motivated avoidance tasks, and in operant tasks in the Skinnerbox. We also used non-cognitive tests, such as the rat forced swimming test and cocaine-induced locomotor activity in the open field, and a test to assess the side effect profile. Mice and rats from different strains, and rats of different ages were used. The rat studies provided only weak support for the notion that apamin acts as a cognition enhancer. More convincing evidence was obtained from the mouse studies. Overt side effects of apamin were found at the dose of 0.3 mg kg(-1). This dose was close to, or even overlapped, the doses which improved cognition in mice. We conclude that apamin is a poor tool to assess the role of SK(Ca)-channels in learning and memory processes.

Aging↗
PubMed1999

The effects of subdural haematoma on spatial learning in the rat.

Although memory deficits are one of the most persistent consequences of human subdural haematoma, cognitive functioning has hardly been investigated in the rat subdural haematoma model. In the present study, the effects on spatial learning of right- and left-sided unilateral subdural haematoma and of bilateral subdural haematoma induced above the sensorimotor cortical areas were evaluated. Spatial learning was assessed by standard acquisition in the Morris water escape task (five sessions). Additional issues addressed were sensorimotor functioning (footprint analysis), recovery of cognitive functioning (tested by an overtraining and a reversal training) and replicability of induced cognitive deficits. Following unilateral subdural haematoma surgery, hardly any impairments in the Morris water escape task were observed: rats with a unilateral right-sided subdural haematoma showed very mild, transient deficits, whereas rats with left-sided subdural haematoma were indistinguishable from controls. Bilateral subdural haematoma surgery led to a clear, although transient, performance deficit. We conclude that animals with bilateral subdural haematoma may provide a promising cognitive deficit model for investigating recovery of function.

Animals↗
PubMed1998

Animal models in the development of symptomatic and preventive drug therapies for Alzheimer's disease.

Dementia of the Alzheimer type (AD) is clinically characterized by a progressive deterioration of intellect, memory, judgment, and abstract thinking. It is incurable, and causal therapy is not yet available. For the development of therapeutic drugs, valid animal models are needed that mimic the pathophysiological change in brain functions and the concomitant behavioural deterioration seen in AD patients. This article provides an overview of the animal models that are used most often to study the substrates and mechanisms of the pathological changes underlying AD and to identify, characterize and develop putative neuroprotective, antidegenerative, revalidation-supporting and/or cognition-enhancing compounds or treatments. The first generation of agents for the symptomatic treatment of the disease has been developed on the basis of results obtained with these models. These drugs are presently undergoing clinical testing or are already used therapeutically. There is, however, no single animal model that can mimic the full range of pathophysiological alterations and key symptoms of AD. New, genetically engineered mouse models that mimic at least some of the key pathological changes of AD are expected to provide tools that will facilitate the development of symptomatic and preventive drug therapies.

Aging↗
PubMed1997

Shift in the performance of 24-month-old Wistar rats in the Morris water escape task: a comparison across 36 experiments.

Spatial discrimination learning in aged rats serves as an animal model of cognitive aging. We assessed the replicability of spatial discrimination performance in the standard Morris water escape task. To this end the learning curves and the performance in a probe trial of 24-month-old outbred Wistar (HsdWin:Wu) control rats from 36 experiments were compared. These experiments had been performed at our laboratory under strictly controlled conditions over a period of 71 weeks. There was a very high variability in the learning curves between experiments. The initial performance level, i.e. the performance during the first session, did not change systematically across the 36 experiments. In contrast, the final performance level, i.e. the level reached in the fifth training session, decreased over the 71 week period, when the platform escape latency and the distance swam to reach the platform, measured as number of line crossings, were considered. In the last experiments of the series, learning curves were no longer seen: the rats did not improve their performance across the acquisition sessions. By contrast, the swimming speed and, in the probe trial, the bias for the quadrant where the platform had been positioned during training, did not change. This indicates that a decrease across experiments occurred predominantly with respect to spatial orientation performance, whereas the motor performance appeared to be unchanged. Explanations for this observation, such as differences in viability between shipments and the possible occurrence of genetic drift, are discussed.

Aging↗
PubMed1996

Sensorimotor impairments in rats with cerebral infarction, induced by unilateral occlusion of the left middle cerebral artery: strain differences and effects of the occlusion site.

Enormous differences exist between rat strains with respect to the infarct volume induced by unilateral middle cerebral artery (MCA) occlusion. We performed three experiments to address the following questions. Firstly, whether the pattern of MCA-occlusion (MCA-O) induced sensorimotor impairments in rats are strain dependent; secondly, whether proximal (i.e., close to its origin) and distal occlusions (above the lenticulostriate branch) of the MCA affect infarct volume and the behavioral impairments to a different extent; and thirdly, whether there is a relationship between the infarct volume and behavioral deficits. We found that the pattern of sensorimotor malfunctions induced by proximal unilateral MCA-O were highly strain dependent. Of the eight strains tested, Winkelmann-Wistar rats, Spontaneously Hypertensive Stroke-Prone rats, and Wistar-Kyoto rats were most severely affected. By contrast, Brown-Norway rats showed only mild behavioral deficits after the MCA-O. The second experiment confirmed that proximal occlusions induced slightly more behavioral malfunctions than distal occlusions did. Histological evaluation of the brain damage caused by proximal and distal MCA-O, confirmed that distal MCA-O damaged nearly exclusively cortical areas, and spared the caudate/putamen. An exploratory analysis of the relationship between infarct volume and behavioral deficits did not indicate that the severity of sensorimotor malfunctions can be predicted from the size of the infarct.

Animals↗
PubMed1996

Sensorimotor impairments in Wistar Kyoto rats with cerebral infarction, induced by unilateral occlusion of the middle cerebral artery: recovery of function.

Wistar Kyoto (WKY) rats with cerebral infarction induced by permanent unilateral occlusion of the middle cerebral artery (MCA) and sham-operated rats were tested in a series of simple behavioral test 2, 16 and 37 days after surgery. In addition, the motility of the animals was measured over a period of 62 h, after the third test series. A subset of the tests appeared to be suitable to assess the effects of cerebral infarction, namely, grasping reflex of contralateral hindpaw, circling behavior, forelimb flexion, hindlimb flexion, and latency to fall off a square bridge. Except for the impaired grasping reflex of the contralateral hindpaw, there was spontaneous complete recovery of function by the third test session, 37 days after surgery. Some of the other tests might not have been sensitive enough to detect the effects of the unilateral MCA-occlusion (MCA-O) on behavior. Moreover, the WKY rats were very inactive in some of the tests, so that reliable scoring of the effects was not always possible. A rat strain other than the WKY strain might be more suitable to study the behavioral consequences of MCA-O.

Animals↗