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PubMed2000

Spatial learning and memory deficits induced by exposure to iron-56-particle radiation.

It has previously been shown that exposing rats to particles of high energy and charge (HZE) disrupts the functioning of the dopaminergic system and behaviors mediated by this system, such as motor performance and an amphetamine-induced conditioned taste aversion; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, spatial learning and memory were assessed in the Morris water maze 1 month after whole-body irradiation with 1.5 Gy of 1 GeV/nucleon high-energy (56)Fe particles, to test the cognitive behavioral consequences of radiation exposure. Irradiated rats demonstrated cognitive impairment compared to the control group as seen in their increased latencies to find the hidden platform, particularly on the reversal day when the platform was moved to the opposite quadrant. Also, the irradiated group used nonspatial strategies during the probe trials (swim with no platform), i.e. less time spent in the platform quadrant, fewer crossings of and less time spent in the previous platform location, and longer latencies to the previous platform location. These findings are similar to those seen in aged rats, suggesting that an increased release of reactive oxygen species may be responsible for the induction of radiation- and age-related cognitive deficits. If these decrements in behavior also occur in humans, they may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere.

Analysis of Variance↗

PubMed2002

Improvement of spatial learning and memory after adenovirus-mediated transfer of the nerve growth factor gene to aged rat brain.

Adenovirus-mediated transfer of the nerve growth factor gene promotes significant recovery of age-related cholinergic neuronal deficits in aged rats, but the effects of such treatment on cognitive dysfunction remain unclear. Herein we report a beneficial effect of first-generation adenovirus-mediated nerve growth factor gene transfer (AdNGF) on the spatial learning and memory of aged rats. The NGF protein was detected by enzyme-linked immunosorbent assay in cerebrospinal fluid as early as 3 days after gene transfer and was expressed for at least 30 days. Escape latency in the Morris water maze hidden-platform test was significantly improved on day 8 postinoculation in memory-impaired rats treated with AdNGF as well as at later testing intervals. Ultimately, the escape latency values for the AdNGF group become indistinguishable from those for aged rats with normal learning capacity. Immunohistochemical analysis of septal cholinergic neurons for choline acetyltransferase (ChAT) showed significant increases in both the number and somal distribution of ChAT-positive cells after inoculation of memory-impaired rats with AdNGF. Improvement in memory performance was positively correlated with increases in both NGF concentration in cerebrospinal fluid (r = 0.73, p = 0.005) and the number of ChAT-staining cells (r = 0.77, p = 0.0022). We conclude that AdNGF can improve cognitive function in memory-impaired aged rats and, with refinements in vector-driven expression of the transgene, may prove suitable for use in humans.

Animals↗

PubMed2005

Calcium chelation improves spatial learning and synaptic plasticity in aged rats.

Impaired regulation of intracellular calcium is thought to adversely affect synaptic plasticity and cognition in the aged brain. Comparing young (2-3 months) and aged (23-26 months) Fisher 344 rats, stratum radiatum-evoked CA1 field EPSPs were smaller and long-term potentiation (LTP) was diminished in aged hippocampal slices. Resting calcium, in presynaptic axonal terminals in the CA1 stratum radiatum area, was elevated in aged slices. Loading the slice with the calcium chelator, BAPTA-AM, depressed LTP in young slices, but enhanced this plasticity in old slices. Forty-five minutes following LTP-inducing high frequency stimulation, resting calcium levels were significantly increased in both young and old presynaptic terminals, and significantly reduced by pretreatment with BAPTA-AM. In vivo, intraperitoneal administration of BAPTA-AM prior to training in the reference memory version of the Morris water maze test, significantly improved the acquisition of spatial learning in aged animals, without a significant effect in young rats. These results support the hypothesis that increasing intracellular neuronal buffering power for calcium in aged rats ameliorates age-related impaired synaptic plasticity and learning.

Aging↗

PubMed2006

Early maternal deprivation reduces prepulse inhibition and impairs spatial learning ability in adulthood: no further effect of post-pubertal chronic corticosterone treatment.

Prolonged maternal deprivation leads to long-term alterations in hypothalamic-pituitary-adrenal (HPA) axis activity, disturbances of auditory information processing and neurochemical changes in the adult brain, some of which are similar to that observed in schizophrenia. Here we report the adult behavioural effects of maternal deprivation (12h on postnatal days 9 and 11) in Wistar rats on paradigms of auditory information processing (prepulse inhibition), sensitivity to dopamimetics (amphetamine-induced hyper-locomotion) and cognition (T-maze delayed alternation and Morris water-maze). In addition, we examined the long-lasting effect of chronic 21-day corticosterone treatment during the post-pubertal period (i.e., postnatal days 56-76) on each of these behavioural paradigms in maternally deprived and control rats. Behavioural testing commenced 2 weeks after the termination of corticosterone treatment. Maternal deprivation led to a significant reduction in PPI and impaired spatial learning ability in adulthood, but did not affect the behavioural response to amphetamine. Post-pubertal chronic corticosterone treatment did not have any major long-lasting effects on any of the behavioural measures in either maternally deprived or control rats. Our findings further support maternal deprivation as an animal model of specific aspects of schizophrenia.

Acoustic Stimulation↗

PubMedDate not supplied

Effects of prenatal cocaine on Morris and Barnes maze tests of spatial learning and memory in the offspring of C57BL/6J mice.

Cocaine was administered to gravid C57BL/6J mice on embryonic days E8-18 at doses of either 17.5 or 20 mg/kg x 2 per day; controls received equal volumes of vehicle. The two cocaine dose groups were indistinguishable in their effects on maternal weight gain, offspring survival or body weight; therefore, the two groups were combined. Offspring were assessed as adults in straight channel swimming, cued and spatial reference-memory and working memory versions of the Morris water maze (MWM), and in the Barnes spatial maze to escape from a light, tone and fan. Cocaine offspring had shorter latencies in the straight channel and increased cumulative distance from the platform and path length in the spatial version of the Morris maze, but only when the platform size was reduced, not under standard platform conditions. In the working memory test, cocaine offspring showed deficits in acquisition and, following random trials, on relearning during a final test phase. In the Barnes maze, cocaine offspring were delayed in utilizing more efficient search strategies and took longer to find the goal. Taken together, the data suggest that prenatal cocaine induces modest but significant long-term alterations in both reference and working memory-based spatial learning and memory.

Animals↗

PubMed1998

Spatial learning and memory induce up-regulation of nitric oxide-producing neurons in rat brain.

Changes of nitric oxide (NO)-producing neurons in the brain following learning is not yet clear. In present study, nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and neuronal NO synthase (nNOS) immunohistochemistry were used to detect NOS neurons in rat brain. Results demonstrated that expression of NOS neurons in dentate gyrus and frontal cortex was significantly increased after a water-rewarded spatial alternation task when compared with that after sham training. The elevated expression of NOS neurons occurred not only in the earlier memory stage, but also in the later memory stage. In addition, the expression location and cell counts of NOS neurons in dentate gyrus and frontal cortex with NADPH-d staining or nNOS immunoreactivity resembled each other, but the cell counts of NADPH-d positive neurons were a little more than those of nNOS immunoreactive neurons. The involvement of NO in the processes of spatial learning and memory is further suggested.

Animals↗

PubMed1997

Long-term effects of developmental exposure to 2,2',3,5',6-pentachlorobiphenyl (PCB 95) on locomotor activity, spatial learning and memory and brain ryanodine binding.

There is mounting evidence that perinatal exposure to ortho-substituted PCB congeners causes neurobehavioral and neurochemical alterations. The molecular mechanism for these effects is not understood, but certain ortho-substituted PCBs have been found to interact specifically with ryanodine-sensitive Ca2+ channels in vitro. These channels are widely expressed in brain and are thought to be responsible for Ca(2+)-induced Ca2+ release. Thus, the ryanodine receptor may represent a selective molecular target through which ortho-substituted PCBs disrupt calcium signaling in neurons, and produce neurochemical and neurobehavioral alterations. Of the PCBs evaluated, 2,2',3,5',6-pentachlorobiphenyl (PCB 95) exhibits the highest potency and efficacy towards the ryanodine receptor in vitro. Therefore, we conducted an in vivo study to investigate the effects of developmental exposure to PCB 95 on neurobehavioral functional and regional brain ryanodine binding. Time-mated Sprague-Dawley rats were dosed with PCB 95 (8 or 32 mg/kg/day) or corn oil vehicle via gavage on gestation days 10-16. One male and one female from each litter were evaluated for neurobehavioral effects. Locomotor activity was evaluated in an automated open field at 35 and 100 days of age. Spatial learning and memory was assessed using an eight arm radial maze working memory task at 60 days of age and a T-maze delayed spatial alternation task at 140 days of age. The animals were then euthanized and [3H] ryanodine binding was assayed in homogenates of cerebral cortex, hippocampus and cerebellum. Rats exposed to PCB 95 showed normal levels of activity as juveniles, but were hypoactive in adulthood. They also showed a faster acquisition of the working memory task on the radial arm maze, but did not differ from controls on the T-maze delayed spatial alteration task. Region-specific changes in ryanodine binding to Ca2+ channels were also observed, with decreased binding in the hippocampus, increased binding in the cerebral cortex and a biphasic effect in the cerebellum. How these changes in ryanodine receptor function are related to the alterations in behavior will be a challenging problem to elucidate.

Animals↗

PubMed1998

Posterior parietal cortex lesions severely disrupt spatial learning in DBA mice characterized by a genetic hippocampal dysfunction.

C57BL/6 (C57) and DBA/2 (DBA) inbred mice with posterior parietal cortex or sham lesions were tested in a radial eight-arm maze task with all the paths baited. In the high learner C57 strain, parietal lesions produced a limited impairment of performance without affecting maze-running strategies while the same lesions were found to affect more severely performance in the poor learner DBA strain. Because (1) the processing of spatial information has been found to depend on the conjunctive participation of the hippocampus and the posterior parietal cortex, and (2) DBA mice represent a genetic model of hippocampal dysfunction, the fact that parietal lesions impair spatial performance more severely in the DBA strain suggests that the contribution of the posterior parietal cortex to spatial learning depends on the degree of functionality of the hippocampus.

Animals↗

PubMed2004

Effects of hypothermia and hyperthermia on attentional and spatial learning deficits following neonatal hypoxia-ischemic insult in rats.

We previously reported that rats exposed to neonatal hypoxic-ischemic (HI) insult showed selective and long-lasting learning and memory impairments in the plus maze, 8-arm radial maze, choice reaction time (CRT) task, and water maze, and that they showed severe brain injury to areas such as parietal cortex, hippocampus, striatum and thalamus. In this study, we examined the effects of hypothermia and hyperthermia on learning and memory deficits following neonatal HI insult. Seven-day-old Wistar rats were subjected to left carotid artery ligation followed by 2 h of hypoxia (8% O2/92% N2) under three different temperature conditions: 27 degrees C (hypothermia), 33 degrees C (normothermia) and 37 degrees C (hyperthermia) in temperature-controlled chambers. Hypothermia significantly reduced attentional deficits in the CRT task and spatial learning deficits in the water maze, and protected against severe brain injury in comparison with the control temperature. On the other hand, hyperthermia aggravated the behavioral deficits and brain injury. These outcomes clearly show that temperature regulation during HI insult plays an important role in the induction of behavioral and histological changes following neonatal HI insult in rats.

Analysis of Variance↗

PubMed2002

Transgenic mice expressing the human C99 terminal fragment of betaAPP: effects on spatial learning, exploration, anxiety, and motor coordination.

The functional consequence of beta-amyloid precursor protein (betaAPP) manipulation on behavior was assessed in Tg13592 mice, characterized by transgene expression of the 99 amino acid C-terminal sequence of human betaAPP in brain and skeletal muscle but with plaque formation only in muscle. By comparison to the C57BL/6 background strain controlled for age and gender, Tg13592 transgenic mice had fewer movements in an automated chamber and fewer enclosed arm entries in the elevated plus-maze. This hypoactivity was probably due to a loss in the motivation to explore novel environmental stimuli rather than motor weakness or anxiety. In addition, the acquisition of place learning in the Morris water maze task was impaired in Tg13592 mice. The transgenic mice were not impaired in a probe trial or while swimming toward a visible platform. These results are concordant with the hypothesis that transgene expression of the C-terminal sequence of human betaAPP in brain is sufficient for causing behavioral abnormalities. The hypoactivity and the spatial learning deficit were associated with higher cytochrome oxidase activity seen in thalamic nuclei, indicating that altered regional brain metabolism caused by betaAPP transgene expression may be responsible for the behavioral changes.

Amyloid beta-Protein Precursor↗

PubMed2004

Chronic prenatal ethanol exposure alters hippocampal GABA(A) receptors and impairs spatial learning in the guinea pig.

Chronic prenatal ethanol exposure (CPEE) can injure the developing brain, and may lead to the fetal alcohol syndrome (FAS). Previous studies have demonstrated that CPEE upregulates gamma-aminobutyric acid type A (GABA(A)) receptor expression in the cerebral cortex, and decreases functional synaptic plasticity in the hippocampus, in the adult guinea pig. This study tested the hypothesis that CPEE increases GABA(A) receptor expression in the hippocampus of guinea pig offspring that exhibit cognitive deficits in a hippocampal-dependent spatial learning task. Timed, pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight per day), isocaloric-sucrose/pair-feeding, or water throughout gestation. GABA(A) receptor subunit protein expression in the hippocampus was measured at two development ages: near-term fetus and young adult. In young adult guinea pig offspring, CPEE increased spontaneous locomotor activity in the open-field and impaired task acquisition in the Morris water maze. CPEE did not change GABA(A) receptor subunit protein expression in the near-term fetal hippocampus, but increased expression of the beta2/3-subunit of the GABA(A) receptor in the hippocampus of young adult offspring. CPEE did not change either [(3)H]flunitrazepam binding or GABA potentiation of [(3)H]flunitrazepam binding, but decreased the efficacy of allopregnanolone potentiation of [(3)H]flunitrazepam binding, to hippocampal GABA(A) receptors in adult offspring. Correlational analysis revealed a relationship between increased spontaneous locomotor activity and growth restriction in the hippocampus induced by CPEE. Similarly, an inverse relationship was found between performance in the water maze and the efficacy of allopregnanolone potentiation of [(3)H]flunitrazepam binding in the hippocampus. These data suggest that alterations in hippocampal GABA(A) receptor expression and pharmacological properties contribute to hippocampal-related behavioral and cognitive deficits associated with CPEE.

Animals↗

PubMed2004

Impaired SynGAP expression and long-term spatial learning and memory in hippocampal CA1 area from rats previously exposed to perinatal hypoxia-induced insults: beneficial effects of A68930.

Hypoxic encephalopathy is a common cause of neonatal seizures and long-term neurological cognitive deficits. In rats at postnatal days 10-12 (P10-P12), global hypoxia induced spontaneous seizures and chronic brain injury, mimicking clinical aspects of neonatal hypoxia. Synaptic Ras-GTPase activating protein (SynGAP) has important roles in RAS/MAPK-dependent synaptic plasticity and mammalian learning. We investigated possible alterations of SynGAP expression occurring in memory-impaired animals previously exposed to perinatal hypoxia insults. We also evaluated the therapeutic efficacy of A68930, a selective agonist of dopamine D1/D5 receptors, on perinatal hypoxia insults. In the hippocampal CA1 region, perinatal hypoxia insults (P10) led to a reduction in SynGAP expression associated with impairment in long-term spatial learning and memory performance at P45. The use of A68930 (at a dose of 1, 2, 3mg/kg, P17-P23) effectively attenuated the deleterious effects as described above. Our results may indicate the involvement of SynGAP in certain forms of brain injury, leading to long-term learning and memory deficits. A68930 may have clinical potential as a therapeutic agent for alleviation of long-term cognitive deficits in rats and other animal models.

Animals↗

PubMedDate not supplied

Influence of the shape of the experimental room on spatial learning in rats.

Rats and other mammals can orient themselves in their habitat and locate various goals using different learning strategies. When a cartographic or local strategy is used, the animals construct and store in their long-term memories a complex representation of the extramaze space. However, exactly what constitutes the behaviorally key components of the extramaze space is still little known. The purpose of this study was to investigate whether the shape of the environment that surrounds the animal is an informative factor when a cartographic strategy is used. Two experiments were performed in which the rats were trained to find food in the goal arm of a four-arm, plus-shaped maze. Experiment 1 shows that lesions to the hippocampus impair the acquisition of this task, which suggests that in fact, a cartographic strategy is necessary to solve it. In Experiment 2, in which only one group of neurologically intact rats was used, we directly manipulated the shape of the space around the maze. The results showed that once the animals have learned the task, the hiding of all the extramaze single landmarks while keeping intact the general shape of the experimental room does not affect performance. Only when the shape of the surrounding space was modified did the performance deteriorate significantly. These results are discussed in relation to the different components of the extramaze environment and the contribution of each of them to the spatial learning.

Animals↗

PubMed1993

Elevated seizure threshold and impaired spatial learning in transgenic mice with putrescine overproduction in the brain.

We have studied the role of putrescine by using transgenic mouse lines overexpressing the human ornithine decarboxylase gene in most of their tissues. The aberrant expression of the transgene is most strikingly manifested in the brain, leading to an increase of up to 20-fold in putrescine content. We report that the transgenic mice with grossly elevated putrescine in all brain regions analysed (cortex, striatum, hippocampus and cerebellum) showed a significantly elevated seizure threshold to chemical and electrical stimuli, and impaired performance in spatial learning and memory tests. The view that putrescine may be primarily responsible for these changes was supported by the fact that the concentrations of the major neurotransmitter amino acids, glutamate and GABA in the brain, were not changed in the transgenic animals, and by the finding that a further increase in brain putrescine, achieved by inhibition of the catabolism of L-ornithine, appeared to provide additional protection against electroshock-induced seizures. These results suggest that the commonly observed increase in ornithine decarboxylase activity and the massive increase in brain putrescine in connection with neuron damage is a neuroprotective measure rather than a cause of the damage.

Animals↗

PubMed2004

Bromocriptine reduces lipid peroxidation and enhances spatial learning and hippocampal neuron survival in a rodent model of focal brain trauma.

Oxidative stress is a significant contributor to the secondary sequelae of traumatic brain injury (TBI), and may mediate subsequent neurobehavioral deficits and histopathology. The present study examined the neuroprotective effects of bromocriptine (BRO), a dopamine D2 receptor agonist with significant antioxidant properties, on cognition, histopathology, and lipid peroxidation in a rodent model of focal brain trauma. BRO (5 mg/kg) or a comparable volume of vehicle (VEH) was administered intraperitoneally 15 min prior to cortical impact or sham injury. In experiment 1, spatial learning was assessed in an established water maze task on post-surgery days 14-18, followed by quantification of hippocampal cell survival and cortical lesion volume at 4 weeks. In experiment 2, rats were sacrificed 1 hr post-surgery, and malondialdehyde (MDA), the end product of lipid peroxidation, was measured in the frontal cortex, striatum, and substantia nigra using a thiobarbituric acid reactive substances assay. The TBI+BRO group was significantly more adept at locating a hidden platform in the water maze compared to the TBI+VEH group and also exhibited a greater percentage of surviving CA3 hippocampal neurons. TBI increased MDA in all examined regions of the VEH-treated, but not BRO-treated group versus SHAMs. MDA was significantly decreased in both the striatum (4.22 +/- 0.52 versus 5.60 +/- 0.44 nmol per mg/tissue +/- SEM) and substantia nigra (4.18 +/- 0.35 versus 7.76 +/- 2.05) of the TBI+BRO versus TBI+VEH groups, respectively, while only a trend toward decreased MDA was observed in the frontal cortex (5.44 +/- 0.44 versus 6.96 +/- 0.77). These findings suggest that TBI-induced oxidative stress is attenuated by acute BRO treatment, which may, in part, explain the benefit in cognitive and histological outcome.

Animals↗

PubMed2003

Repeated exposures to subthreshold doses of chlorpyrifos in rats: hippocampal damage, impaired axonal transport, and deficits in spatial learning.

Organophosphorus (OP) compounds are detectable in the environment for years after use and endanger many populations. Although the effects of acutely toxic doses of many OP compounds are well described, much less is known about repeated low-level exposures. The purpose of these studies was to further evaluate potential toxicological effects of the extensively used OP pesticide chlorpyrifos (CPF) in rats. CPF, across a range of subthreshold doses (i.e., for acute toxicity), reduced rearing and sniffing activity and the magnitude of weight gain over 14 days of repeated exposure. Performance in a spatial learning task was impaired after 14 days of exposure to CPF (18.0 and 25.0 mg/kg) when testing was initiated 24 h after the last injection but not after a 14-day washout. However, inhibition of both fast anterograde and retrograde axonal transport was observed for up to 20 days after exposure to 25.0 mg/kg CPF. Studies using hippocampal cultures indicated that 8 days of continuous exposure to the parent compound, CPF (> or =100 micro M), resulted in cell toxicity and death. Furthermore, a dose (2.5 mg/kg) of CPF that had no effects on weight gain or memory performance when administered 5 days per week over 38 days impaired forelimb grip strength in the later days of testing. Collectively, these results indicate that repeated exposures to subthreshold doses of CPF may lead to growth retardation, behavioral abnormalities, and muscle weakness. Some of these symptoms may be attributed to effects of the OP on axonal transport.

Animals↗

PubMed2005

[Chronic pain impairs spatial learning and memory ability and down-regulates Bcl-2 and BDNF mRNA expression in hippocampus of neonatal rats].

OBJECTIVE: To investigate the effect and possible mechanism of complete Freund's adjuvant induced chronic pain on later function of learning and memory in neonatal rats. METHODS: Sixty Sprague-Dewley rat pups (10 litters of 6 pups) were randomly divided into control group and chronic pain group (n = 30 in each group). In the chronic pain group, left hind paws of the rats were treated with subcutaneous injection of 20 microl of CFA on postnatal day-2. The control rat pups received normal saline. The hippocampus of rats were separated on postnatal days 10 and 21 (one rat in each group from every litter, n = 10). The expression of Bcl-2 and BDNF mRNA were investigated by RT-PCR. Morris water maze tests were performed on day 21 (one rat in each group from every litter, n = 10). RESULTS: In hidden-platform training of Morris water maze, the mean escape latency of rats in the chronic pain group were longer than that of the control rats. In spatial probe tests, the average percentages of the swimming time and distances in the platform quadrant in the pain group rats were less than those in the control group. There was no significant difference in visible-platform training between the two groups. The Bcl-2 and BDNF mRNA expressions in hippocampus of the pain group rats were lower than those in the control at day 10, but no significant difference at day 21. CONCLUSION: Chronic pain stress induced by CFA impairs the spatial learning and memory function in neonatal rats. These effects might exert through down-regulating Bcl-2 and BDNF mRNA expression in the hippocampus.

Animals↗

PubMed1999

Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning.

Deletion of the ryanodine receptor type 3 (RyR3) results in specific changes in hippocampal synaptic plasticity, without affecting hippocampal morphology, basal synaptic transmission or presynaptic function. Robust long-term potentiation (LTP) induced by repeated, strong tetanization in the CA1 region and in the dentate gyrus was unaltered in hippocampal slices in vitro, whereas weak forms of plasticity generated by either a single weak tetanization or depotentiation of a robust LTP were impaired. These distinct physiological deficits were paralleled by a reduced flexibility in re-learning a new target in the water-maze. In contrast, learning performance in the acquisition phase and during probe trial did not differ between the mutants and their wild-type littermates. In the open-field, RyR3(-/-) mice displayed a normal exploration and habituation, but had an increased speed of locomotion and a mild tendency to circular running. The observed physiological and behavioral effects implicate RyR3-mediated Ca(2+) release in the intracellular processes underlying spatial learning and hippocampal synaptic plasticity.

Animals↗