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PubMed2004

Isoform-specific knockout of FE65 leads to impaired learning and memory.

FE65 is a multimodular adapter protein that is expressed predominantly in brain. Its C-terminal phosphotyrosine interaction domain (PID) binds to the intracellular tail of the beta-amyloid precursor protein (betaPP), a protein of central importance to the pathogenesis of dementias of the Alzheimer type. To study the physiological functions of FE65, we generated a line of FE65 knockout mice via gene targeting. By Western analysis with a panel of FE65-specific antibodies, we demonstrate that the 97-kDa full-length FE65 (p97) was ablated in the mutant mice, and that a previously undescribed FE65 isoform with apparent molecular mass of 60 kDa (p60) was expressed in both wild-type and mutant mice. p60 had a truncated N-terminus and was likely to be generated through alternative translation. Expressions of the two isoforms appeared to be brain region distinct and age dependent. The p97FE65(-/-) mice were viable and showed no obvious physical impairments or histopathological abnormalities. However, p97FE65(-/-) and p97FE65(+/-) mice exhibited poorer performances than wild-type mice on a passive avoidance task when tested at 14 months (P <.05). p97FE65(-/-) mice at 14 months also exhibited impaired hidden-platform acquisition (P <.05) and a severe reversal-learning deficit (P <.002) but normal visual-platform acquisition in the Morris water maze tests. Probe trials confirmed impairments in p97FE65(-/-) mice in relearning of new spatial information, suggesting a hippocampus-dependent memory-extinction deficit. Reduced secretion of Abeta peptides was observed in primary neuronal cultures of hybrids of p97FE65(-/-)/betaPP transgenic (Tg2576) mice. These studies suggest an important and novel function of FE65 in learning and memory.

Aging↗
PubMed2006

The connection between the hippocampal and the striatal memory systems of the brain: a review of recent findings.

Two major memory systems have been recognized over the years (Squire, in Memory and Brain, 1987): the declarative memory system, which is under the control of the hippocampus and related temporal lobe structures, and the procedural or habit memory system, which is under the control of the striatum and its connections (Mishkin et al., in Neurobiology of Learning by G Lynch et al., 1984; Knowlton et al., Science 273:1399, 1996). Most if not all learning tasks studied in animals, however, involve either the performance or the suppression of movement. Animals acquire connections between environmental or discrete sensory cues (conditioned stimuli, CSs) and emotionally or otherwise significant stimuli (unconditioned stimuli, USs). As a result, they learn to perform or to inhibit the performance of certain motor responses to the CS which, when learned well, become what can only be called habits (Mishkin et al., 1984): to regularly walk or swim to a place or away from a place, or to inhibit one or several forms of movement. These responses can be viewed as conditioned responses (CRs) and may sometimes be very complex. This is of course also seen in humans: people learn how to play on a keyboard in response to a mental or written script and perform the piano or write a text; with practice, the performance improves and eventually reaches a high criterion and becomes a habit, performed almost if not completely without awareness. Commuting to school in a big city in the shortest possible time and eschewing the dangers is a complex learning that children acquire to the point of near-perfection. It is agreed that the rules that connect the perception of the CS and the expression of the CR change from their first association to those that take place when the task is mastered. Does this change of rules involve a switch from one memory system to another? Are different brain systems used the first time one plays a sonata or goes to school as compared with the 100th time? Here we will comment on: 1) reversal learning in the Morris water maze (MWM), in which the declarative or spatial component of a task is changed but the procedural component (to swim) persists and needs to be re-linked with a different set of spatial cues; and 2) a series of observations on an inhibitory avoidance task that indicate that the brain systems involved change with further learning.

Animals↗
PubMed2006

Simvastatin enhances learning and memory independent of amyloid load in mice.

OBJECTIVE: Normal aging is often associated with a decline in learning and memory functions. This decline is manifested to a much greater extent in Alzheimer's disease. Recent studies have indicated statins, a class of cholesterol-lowering drugs, as a potential therapy for Alzheimer's disease. Our objective was to determine whether administering a statin drug (simvastatin) would protect against the development of behavioral deficits in an established mouse model of Alzheimer's disease. METHODS: Tg2576 mice and their nontransgenic littermates were treated with simvastatin and assessed by behavioral tests and biochemical analyses. RESULTS: Simvastatin treatment not only reversed learning and memory deficits in the Tg2576 mice, but also enhanced learning and memory in the nontransgenic mice. Moreover, levels of amyloid beta protein in the brains of treated mice did not differ from those of untreated mice. Simvastatin treatment was associated with increased expression levels of protein kinase B (Akt) and endothelial nitric oxide synthase in the mouse brain. INTERPRETATION: Our findings demonstrate that the effects of simvastatin on learning and memory are independent of amyloid beta protein levels. The mechanisms by which simvastatin exerts its beneficial effects may be related to modulation of signaling pathways in memory formation.

Alzheimer Disease↗
PubMed2004

Administration of eliprodil during ethanol withdrawal in the neonatal rat attenuates ethanol-induced learning deficits.

RATIONALE: Prenatal exposure to alcohol can disrupt brain development, leading to a variety of behavioral alterations, including learning deficits. We have postulated that some central nervous system damage may be due to N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity that occurs during ethanol withdrawal. Consistent with this hypothesis, we previously demonstrated that administration of MK-801, an NMDA receptor antagonist, during ethanol withdrawal attenuates ethanol-related learning deficits using an animal model of fetal alcohol effects. However, MK-801 binds to the phencyclidine site, which affects all NMDA receptor subtypes and can cause adverse side effects and toxicity. Eliprodil is a more selective NMDA receptor antagonist that acts at the polyamine modulatory site of NMDA receptors. OBJECTIVES: The purpose of this study was to determine if administration of eliprodil during ethanol withdrawal would reduce the severity of learning deficits associated with developmental alcohol exposure. METHODS: Male rat pups were randomly assigned to ethanol-exposed or control treatments. On postnatal day (PD) 6, during a period of brain development similar to that of the mid-third trimester in humans, subjects were exposed to 6.0 g/kg ethanol or isocaloric maltose solutions via oral gavage. Twenty-four hours after the end of the ethanol treatment, during ethanol withdrawal, all subjects received an intraperitoneal injection of one of three doses of eliprodil (5, 10, or 25 mg/kg) or vehicle. On PD 40, all subjects were tested on a serial spatial discrimination reversal learning task. RESULTS: Ethanol-exposed subjects treated with vehicle committed a significantly greater number of errors compared to controls. Administration of eliprodil during ethanol withdrawal significantly decreased the number of errors in the ethanol-exposed groups, but had no significant effect on the performance of controls. CONCLUSION: These data support the hypothesis that NMDA receptor-mediated excitotoxicity during ethanol withdrawal contributes to fetal alcohol effects.

Animals↗
PubMed2006

A neuropsychological comparison of obsessive-compulsive disorder and trichotillomania.

BACKGROUND: Obsessive-compulsive disorder (OCD) and trichotillomania (compulsive hair-pulling) share overlapping co-morbidity, familial transmission, and phenomenology. However, the extent to which these disorders share a common cognitive phenotype has yet to be elucidated using patients without confounding co-morbidities. AIM: To compare neurocognitive functioning in co-morbidity-free patients with OCD and trichotillomania, focusing on domains of learning and memory, executive function, affective processing, reflection-impulsivity and decision-making. METHOD: Twenty patients with OCD, 20 patients with trichotillomania, and 20 matched controls undertook neuropsychological assessment after meeting stringent inclusion criteria. RESULTS: Groups were matched for age, education, verbal IQ, and gender. The OCD and trichotillomania groups were impaired on spatial working memory. Only OCD patients showed additional impairments on executive planning and visual pattern recognition memory, and missed more responses to sad target words than other groups on an affective go/no-go task. Furthermore, OCD patients failed to modulate their behaviour between conditions on the reflection-impulsivity test, suggestive of cognitive inflexibility. Both clinical groups showed intact decision-making and probabilistic reversal learning. CONCLUSIONS: OCD and trichotillomania shared overlapping spatial working memory problems, but neuropsychological dysfunction in OCD spanned additional domains that were intact in trichotillomania. Findings are discussed in relation to likely fronto-striatal neural substrates and future research directions.

Adult↗
PubMed1999

The effects of NMDA-induced retrohippocampal lesions on performance of four spatial memory tasks known to be sensitive to hippocampal damage in the rat.

Four separate cohorts of rats were employed to examine the effects of cytotoxic retrohippocampal lesions in four spatial memory tasks which are known to be sensitive to direct hippocampal damage and/or fornix-fimbria lesions in the rat. Selective retrohippocampal lesions were made by means of multiple intracerebral infusions of NMDA centred on the entorhinal cortex bilaterally. Cell damage typically extended from the lateral entorhinal area to the distal ventral subiculum. Experiment 1 demonstrated that retrohippocampal lesions spared the acquisition of a reference memory task in the Morris water maze, in which the animals learned to escape from the water by swimming to a submerged platform in a fixed location. In the subsequent transfer test, when the escape platform was removed, rats with retrohippocampal lesions tended to spend less time searching in the appropriate quadrant compared to controls. Experiment 2 demonstrated that the lesions also spared the acquisition of a working memory version of the water maze task in which the location of the escape platform was varied between days. In experiment 3, both reference and working memory were assessed using an eight-arm radial maze in which the same four arms were constantly baited between trials. In the initial acquisition, reference memory but not working memory was affected by the lesions. During subsequent reversal learning in which previously baited arms were now no longer baited and vice versa, lesioned animals made significantly more reference memory errors as well as working memory errors. In experiment 4, spatial working memory was assessed in a delayed matching-to-position task conducted in a two-lever operant chamber. There was no evidence for any impairment in rats with retrohippocampal lesions in this task. The present study demonstrated that unlike direct hippocampal damage, retrohippocampal cell loss did not lead to a general impairment in spatial learning, implying that the integrity of the retrohippocampus and/or its interconnection with the hippocampal formation is not critical for normal hippocampal-dependent spatial learning and memory. This outcome is surprising for a number of current hippocampal theories, and suggests that other cortical as well as subcortical inputs to the hippocampus might be of more importance, and further raises the question regarding the functional significance of the retrohippocampal region.

Animals↗
PubMed1995

Forms of inhibition in animal and human learning.

Forms of inhibition were identified in human predictive learning that are qualitatively similar to those identified by P.C. Holland (1984) in rats. When P (positive) signaled the outcome and PN (N = negative) signaled the absence of the outcome, participants learned the discrimination, but the negative cue did not suppress responding to a transfer cue. Post-learning reversal training, in which N was followed by the outcome, did not abolish the original discrimination. These 2 results imply a configural form of inhibition. Negative transfer, which indicated a 2nd, elemental form of inhibition, was observed when neither PN nor N were reinforced during the discrimination stage. Under these conditions, negative transfer and the original discrimination were both abolished by individually pairing N with the outcome. Empirical parallels and differences with the animal conditioning literature are discussed.

Adult↗
PubMed2006

Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32-dependent pathways: evidence from PDE1B-DARPP32 double-knockout mice.

Mice lacking phosphodiesterase 1B (PDE1B) exhibit an exaggerated locomotor response to D-methamphetamine and increased in vitro phosphorylation of DARPP32 (dopamine- and cAMP-regulated phosphoprotein, M r 32 kDa) at Thr34 in striatal brain slices treated with the D1 receptor agonist, SKF81297. These results indicated a possible regulatory role for PDE1B in pathways involving DARPP32. Here, we generated PDE1B x DARPP32 double-knockout (double-KO) mice to test the role of PDE1B in DARPP32-dependent pathways in vivo. Analysis of the response to d-methamphetamine on locomotor activity showed that the hyperactivity experienced by PDE1B mutant mice was blocked in PDE1B-/- x DARPP32-/- double-KO mice, consistent with participation of PDE1B and DARPP32 in the same pathway. Further behavioral testing in the elevated zero-maze revealed that DARPP32-/- mice showed a less anxious phenotype that was nullified in double-mutant mice. In contrast, in the Morris water maze, double-KO mice showed deficits in spatial reversal learning not observed in either single mutant compared with wild-type mice. The data suggest a role for PDE1B in locomotor responses to psychostimulants through modulation of DARPP32-dependent pathways; however, this modulation does not necessarily impact other behaviors, such as anxiety or learning. Instead, the phenotype of double-KOs observed in these latter tasks may be mediated through independent pathways.

Analysis of Variance↗
PubMed1988

Postnatal application of p-chloroamphetamine or fenfluramine reduces response selection during early ontogenetic development of rat avoidance behaviour.

The influence of one single intraperitoneal application of 50 mumol/kg fenfluramine (FF) or 50 mumol/kg parachloroamphetamine (PCA), respectively, on the 8th postnatal day upon avoidance learning in the early ontogenesis was compared with vehicle-injected controls (NaCl solution). The intoxicated groups were unable to learn a self-shaped avoidance behaviour in a peripheral field avoidance test. They did not find out during the third postnatal week that only central fields of an open field remained unpunished; escape responses along walls were not inhibited in favour of escape into central fields as in controls. The passive avoidance component which is expressed by increasing stay duration in central fields was not developed in FF and PCA rats. The active avoidance component expressed by CS-induced escape before UCS did also not increase in the intoxicated rats. There were no differences of passive avoidance between groups, however, in the fourth week. In the W-maze test after weaning differences between intoxicated groups and controls were evident in the first session and when the schedule was changed. In the reversal learning session the intoxicated groups made more errors. The results support the view that serotoninergic neuron groups participate in the inhibition of incorrect responses and differentiation learning. This early postnatal deficiency may be partly compensated in further development.

Aging↗
PubMed1999

Estrogen replacement enhances acquisition of a spatial memory task and reduces deficits associated with hippocampal muscarinic receptor inhibition.

A delayed matching-to-position (DMP) T-maze task was used to examine the effects of estrogen replacement on spatial learning and memory, as well as the ability of estrogen replacement to reduce performance deficits produced by acute systemic and intrahippocampal muscarinic cholinergic inhibition. Two experiments were performed. In Experiment 1, ovariectomized animals were trained to criterion on the DMP task and then tested with increased intertrial delays and following systemic scopolamine administration. The animals then received either continuous estrogen replacement or sham surgery and were retested beginning 10 days later. In Experiment 2, ovariectomized animals received guide cannulae implanted bilaterally into the hippocampus. Half of these animals also began receiving continuous estrogen replacement. Two months later, the animals were trained on the DMP task and then tested with increased intertrial delays and following systemic as well as intrahippocampal scopolamine administration. Animals received the same test battery 8 months later and were then immediately trained on a reversal task. The results indicate that estrogen-treated animals acquired the DMP task at a significantly faster rate than the ovariectomized, non-estrogen-treated controls. In addition, estrogen replacement significantly reduced deficits in DMP performance produced by intrahippocampal, but not systemic, scopolamine administration. This occurred when animals were tested after 3.5 months, as well as after 12 months, of continuous estrogen replacement. No evidence for an effect of estrogen replacement on spatial working memory or reversal learning was detected. These findings demonstrate that estrogen replacement can enhance acquisition of a spatial memory task and reduce performance deficits associated with hippocampal cholinergic impairment.

Analysis of Variance↗
PubMed2006

Effects of prenatal exposure to alcohol on activity, anxiety, motor coordination, and memory in young adult Wistar rats.

The objective of the present study was to examine the effects of prenatal exposure to ethanol on motor performance, emotionality, learning and memory in young-adult, male Wistar rats. Alcohol was delivered to the pregnant dams intragastrically, throughout gestation days (GD) 7-20, at the dose of 6 g/kg/day resulting in the peak blood alcohol concentration (BAC) of 350 mg/dl as assessed on GD 20. Isocaloric intubation and untreated control groups were included. Alcohol exposed rats were not impaired in the rotarod/accelerod tests. Their behavior in the open field and plus maze suggested increased neophobia. Hyperactivity was not observed. In the spatial-navigation task in the water maze, by the middle of the training, fetal alcohol rats showed a tendency towards a slower place acquisition compared to controls, but statistical analysis of the data did not yield between-group differences significant. Towards the end of the training, all rats reached a similar performance level. No detectable between-group differences were noted either in memory retention after a delay, in reversal learning, or in working memory task. Our findings demonstrate that the adverse behavioral effects of a binge-like alcohol administration during half of the first and throughout the second trimester equivalent are difficult to be disclosed in young-adult male Wistar rats. The possible reasons of the lack of significant behavioral deficits in the fetal-alcohol rats observed in the present study are discussed.

Analysis of Variance↗
PubMed1988

Ontogenetic development of avoidance learning in rats after eye opening.

Five male and one female group of 8 pups were selected from 8 liters on the second postnatal day and returned to 6 dams. The animals were investigated in two subsequent tests; first, in a peripheral field avoidance test using a 60 x 75 x 22 cm open field subdivided into 20 equal squares of 15 x 15 cm with separate floor grids for electrical punishment and, second, in a W-like maze with a start arm falling into a common alley from which left and right each two goal arms branched off. Four qualities were measured in the first test: finding out that only central fields remained unpunished; the stay duration in central fields indicating passive avoidance; the response to a conditioned stimulus, when they entered peripheral fields indicating active avoidance; the quality of extinction. The differences of these qualities changed significantly from week to week as the acquisition speed and the consolidation increased, the extinction was rapid in the third week, very slow in the fourth week and adult-like in the fifth week. The self-chosen strategy of pups showed dominance of escape with subsequent motor inhibition in the third week, dominance of trials and active avoidance in the fourth week, dominance of passive avoidance in the fifth week. We found no difference between males and females, or between blind and control rats. The W-maze test revealed additionally that reversal learning from left goal to right goal was still difficult in the fourth week and that brightness-cued alteration of goals in which wrong choices were punished when a time limit was overcome could not be learned before the sixth week and not consolidated before the end of the seventh week. The results suggest that various brain processes are involved in the development of avoidance and learning strategies which mature unevenly and reach their peaks at different ages.

Aging↗
PubMed1983

Intermittent thiamine deficiency in the rhesus monkey. II. Evidence for memory loss.

Thiamine-deprived rhesus monkeys exhibited a pattern of impairments in spatial-reversal learning and in recognition of highly familiar items reminiscent of certain memory deficits shown by Wernicke-Korsakoff patients. Postmortem examination in these experimental animals showed neuronal degeneration in the basal ganglia, the parafascicular nucleus of the thalamus, and discrete nuclei of the brainstem and cerebellum. No abnormalities were found in the mammillary bodies and mediodorsal nucleus of the thalamus, structures that have been incriminated in the genesis of the memory impairment of the Wernicke-Korsakoff syndrome of man.

Animals↗
PubMed2005

Chemistry of the mind: neurochemical modulation of prefrontal cortical function.

The neurochemical modulation of prefrontal cortical function is reviewed with special reference to the ascending dopaminergic and serotoninergic projections. Evidence is surveyed from studies of rats, nonhuman primates, and humans to suggest that prefrontal dopamine has specific functions in attentional control and working memory, mediated mainly through the D1 receptor, whereas manipulations of serotonin are shown by contrast to affect reversal learning in monkeys and human volunteers and measures of impulsivity in rats. These findings are discussed in the context of these as well as other neurotransmitter systems (including noradrenaline and acetylcholine) having distinct roles in the neuromodulation of prefrontal cortical function. The capacity of the prefrontal cortex itself to exert top-down regulation of these ascending neurochemical systems is also discussed.

Animals↗
PubMed2006

Neonatal behavior and infant cognitive development in rhesus macaques produced by assisted reproductive technologies.

Assisted reproductive technologies (ART) used in fertility clinics include in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), followed by embryo transfer into the biological or a surrogate mother. Over 1,000,000 liveborn offspring--an estimated 1 in 150 United States newborns--have been produced worldwide by ART since 1978. IVF appears to produce healthy children in singleton pregnancies, though concerns remain regarding preterm deliveries, multiple pregnancies, as well as the longer-term consequences of all ART procedures. Clinical studies remain difficult to interpret and subject to confounding variables, as developmental problems may be due to a parent's reproductive conditions rather than, or in addition to, an ART procedure. Also, because of expense and time commitments, the United States ART clinical population is not fully representative of society diversities. This socio-economic skewing might compensate for negative effects, masking small, or modest developmental deficits. Embryo splitting (ES), an ART procedure used only with animals, can produce genetically identical offspring. ES involves dividing four- to eight-cell embryos into separate blastomeres and implanting them into empty zona pellucida, followed by embryo transfer. Although these ART techniques have produced nonhuman primate offspring, there has been no research on behavioral safety. Here, we report the first study of behavioral development by rhesus macaques infants produced through ES, ICSI, and IVF. We assessed neonatal reflexes, self-feeding ability, recognition memory, object concept attainment, simple discrimination learning and reversal, and learning set (LS) acquisition. Although the sample sizes are small, we found no overall ART group delayed development. Surprisingly, the ES and ICSI monkeys appeared to be accelerated in attaining age milestones involving sensory-motor behaviors and a difficult Well Hiding object concept task. We conclude that macaque monkeys may provide an excellent model for the study of early human development by offspring of parents with conditions requiring ART pregnancies, as well as a model for the behavioral study of genetic-environment interactions using identical twins produced by ES.

Analysis of Variance↗
PubMed2006

Myristoylated alanine rich C kinase substrate (MARCKS) heterozygous mutant mice exhibit deficits in hippocampal mossy fiber-CA3 long-term potentiation.

The myristoylated alanine-rich C kinase substrate (MARCKS) is a primary protein kinase C (PKC) substrate in brain thought to transduce PKC signaling into alterations in the filamentous (F) actin cytoskeleton. Within the adult hippocampus, MARCKS is highly expressed in the dentate gyrus (DG)-CA3 mossy fiber pathway, but is expressed at low levels in the CA3-CA1 Schaffer collateral-CA1 pathway. We have previously demonstrated that 50% reductions in MARCKS expression in heterozygous Marcks mutant mice produce robust deficits in spatial reversal learning, but not contextual fear conditioning, suggesting that only specific aspects of hippocampal function are impaired by reduction in MARCKS expression. To further elucidate the role of MARCKS in hippocampal synaptic plasticity, in the present study we examined basal synaptic transmission, paired-pulse facilitation, post-tetanic potentiation, and long-term potentiation (LTP) in the hippocampal mossy fiber-CA3 and Schaffer collateral-CA1 pathways of heterozygous Marcks mutant and wild-type mice. We found that LTP is significantly impaired in the mossy fiber-CA3 pathway, but not in the Schaffer collateral-CA1 pathway, in heterozygous Marcks mutant mice, whereas basal synaptic transmission, paired-pulse facilitation, and post-tetanic potentiation are unaffected in both pathways. These findings indicate that a 50% reduction in MARCKS expression impairs processes required for long-term, but not short-term, synaptic plasticity in the mossy fiber-CA3 pathway. The implications of these findings for the role of the mossy fiber-CA3 pathway in hippocampus-dependent learning processes are discussed.

Animals↗
PubMed2001

Resting regional cerebral glucose metabolism in advanced Parkinson's disease studied in the off and on conditions with [(18)F]FDG-PET.

Studies of resting regional cerebral glucose consumption (rCMRGlc) in nondemented patients with Parkinson's disease (PD) have produced conflicting results, reporting both reduced and normal metabolism in advanced disease and reduced or normal metabolism after dopaminergic therapy. To investigate these issues, [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) was performed in 11 nondemented PD patients with advanced disease and 10 age-matched controls. PD patients were studied after withdrawal of all dopaminergic medication to produce a practically defined off condition, and a second time 1 hour after levodopa, resulting in a clinical on state. Dynamic PET scans and simultaneous arterialised venous blood samples of [(18)F] activity were obtained. A graphical approach was used to generate parametric images of rCMRGlc and statistical parametric mapping to localise significant metabolic changes in PD. Compared with controls, global rCMRGlc was reduced in the on but not in the off condition in PD. In both states, significant regional reductions of glucose uptake were found in the parietal, frontal, temporal cortex, and caudate nucleus. Reductions correlated with the severity of disability in frontal and temporal cortex. Direct comparison between on and off conditions revealed relatively greater reductions of uptake in the ventral/orbital frontal cortex and the thalamus during on. Results suggest that cortical and caudate hypometabolism are common in advanced PD and that caution is mandatory if [(18)F]FDG PET is being used to differentiate advanced PD from dementia and progressive supranuclear palsy where similar reductions are seen. Furthermore, in PD, administration of levodopa is associated with further hypometabolism in orbitofrontal cortex; an area known to be relevant for reversal learning where performance is typically impaired after dopaminergic treatment.

Adult↗
PubMed2001

Prolonged exposure to low doses of ozone: short- and long-term changes in behavioral performance in mice.

Two separate experiments were designed to assess the effects of ozone exposure on outbred CD-1 mice. In the first experiment, adult males were exposed continuously to O3 at 0, 0.3, or 0.6 ppm for 30 days and their behavior was assessed in a 5-min open-field test on exposure days 4 and 19 and on day 3 after the end of the exposure phase. In addition, mice performed a Morris water maze task from exposure day 24 to 28. In the second experiment, adult females were exposed from 30 days prior to the formation of breeding pairs until gestational day 17 to the same doses used in the first experiment. Litters were fostered at birth to untreated dams and neurobehavioral development of the offspring was investigated until adulthood. Specifically, somatic and sensorimotor development [postnatal day (PND) 2-20], homing performance (PND 12), motor activity (PND 21), passive avoidance (PND 22-23), water maze performances (PND 70-74), and response to a nociceptive stimulus (PND 100) were assessed. Results from both experiments confirm that exposure to O3 slightly but selectively affected neurobehavioral performance in rodents. Exposure to O3 did not grossly affect neurobehavioral development, whereas it consistently impaired reversal learning in the Morris water maze test in both prenatally and adult exposed mice. Moreover, longer latency to step-through in the first trial of the passive avoidance test and a decrease in wall rearing in the hot-plate test were recorded in O3 prenatally exposed mice. Except for the first open-field test, altered responses were observed only in animals exposed at the intermediate concentration of the gas. Adaptation and/or onset of compensatory mechanisms might be responsible for the lack of linear dose-response relationships.

Adaptation, Physiological↗