Maze Learning Deficits Research Articles

Pfiesteria Toxin and Learning Performance

Pfiesteria piscicida is an estuarine dinoflagellate involved with fish kills along the east coast of the United States. We previously documented a radial-arm maze learning deficit in rats exposed to Pfiesteria that may be related to cognitive deficits seen in humans after accidental Pfiesteria exposure. The current study elucidated important behavioral parameters of this deficit. There were six dose groups. Forty (10/group) adult female Sprague–Dawley rats were injected (SC) with a single dose of Pfiesteria taken from aquarium-cultured Pfiesteria (35,600, 106,800, or 320,400 Pfiesteria cells/kg of rat body weight or a cell-free filtrate of the 106,800 cells/kg dose). One control group (N = 10) was injected with saline and one (N = 10) with aquarium water not containing Pfiesteria. Half of the rats in each group were tested on an 8-arm radial maze in a standard test room, and the other half were tested on the radial maze in a sound-attenuating chamber. In the standard maze room, there was a significant effect of Pfiesteria (p < 0.05) impairing choice accuracy improvement over the first six sessions of training among rats administered 106,800, 320,400, and the 106,800 cells/kg filtered sample. In contrast, there was no indication of an effect of Pfiesteria when the rats were tested on the same configuration radial maze in the sound-attenuating chamber. After 18 sessions of training in one room, the rats were switched for six sessions of testing in the other room and finally were switched back to their original room for three sessions. There was a significant Pfiesteria-induced deficit when the rats were tested in the standard test room but not when they were tested in the sound-attenuating chamber. When the Pfiesteria-exposed rats were initially switched from the sound-attenuating chamber to the standard test room they performed significantly worse than controls, whereas Pfiesteria-treated rats switched from the standard test room to the sound-attenuating chamber did not perform differently from controls. These results suggest that the Pfiesteria-induced learning impairment may result from the negative impact of distracting stimuli. At the time of the learning impairment, no overt Pfiesteria-related effects were seen using a functional observational battery and no overall response latency effects were seen, indicating that the Pfiesteria-induced choice accuracy deficit was not due to generalized debilitation. In the initial use of the figure-8 maze in this line of research, the rats in the same Pfiesteria treatment groups that showed significant deficits in the radial-arm maze showed greater declines in activity rates in a 1-h figure-8 locomotor activity test. Both the 106,800 and 320,400 Pfiesteria cells/kg groups showed significantly greater linear trends of activity decline relative to tank water-treated controls. This reflected an initial slight hyperactivity in the Pfiesteria-treated animals followed by a decrease to control levels. Pfiesteria effects in the figure-8 maze and in early radial-arm maze training may be useful in a rapid screen for identifying the critical toxin(s) of Pfiesteria in future studies. Published by Elsevier Science Inc.

Age-associated memory impairment. Assessing the role of nitric oxide.

Several neurotransmitter systems have been investigated to assess hypothesized mechanisms underlying the decline in recent memory abilities in normal aging and in Alzheimer's disease. Examining the performance of F344 rats in a 14-unit T-maze (Stone maze), we have focused on the muscarinic cholinergic (mACh) and the N-methyl-D-aspartate (NMDA) glutamate (Glu) systems and their interactions. Maze learning is impaired by antagonists to mACh or NMDA receptors. We have also shown that stimulation of mACh receptors can overcome a maze learning deficit induced by NMDA blockade, and stimulation of the NMDA receptor can overcome a similar blockade of mACh receptors. No consistent evidence in rats has been produced from our laboratory to reveal significant age-related declines in mACh or NMDA receptor binding in the hippocampus (HC), a brain region that is greatly involved in processing of recent memory. Thus, we have directed attention to the possibility of a common signal transduction pathway, the nitric oxide (NO) system. Activated by calcium influx through the NMDA receptor, NO is hypothesized to be a retrograde messenger that enhances presynaptic Glu release. Maze learning can be impaired by inhibiting the synthetic enzyme for NO, nitric oxide synthase (NOS), or enhanced by stimulating NO release. However, we have found no age-related loss of NOS-containing HC neurons or fibers in rats. Additionally, other laboratories have reported no evidence of an age-related loss of HC NOS activity. In a microdialysis study we have found preliminary evidence of reduced NO production following NMDA stimulation. We are currently working to identify the parameters of this phenomenon as well as testing various strategies for safely stimulating the NO system to improve memory function in aged rats.

Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment

Streptozotocin-diabetic rats express deficits in water maze learning and hippocampal synaptic plasticity. The present study examined whether these deficits could be prevented and/or reversed with insulin treatment. In addition, the water maze learning deficit in diabetic rats was further characterized. Insulin treatment was commenced at the onset of diabetes in a prevention experiment, and 10 weeks after diabetes induction in a reversal experiment. After 10 weeks of treatment, insulin-treated diabetic rats, untreated diabetic rats and non-diabetic controls were tested in a spatial version of the Morris water maze. Next, hippocampal long-term potentiation (LTP) was measured in vitro. To further characterize the effects of diabetes on water maze learning, a separate group of rats was pre-trained in a non-spatial version of the maze, prior to exposure to the spatial version. Both water maze learning and hippocampal LTP were impaired in diabetic rats. Insulin treatment commenced at the onset of diabetes prevented these impairments. In the reversal experiment, insulin treatment failed to reverse established deficits in maze learning and restored LTP only partially. Non-spatial pre-training abolished the performance deficit of diabetic rats in the spatial version of the maze. It is concluded that insulin treatment may prevent but not reverse deficits in water maze learning and LTP in streptozotocin-diabetic rats. The pre-training experiment suggests that the performance deficit of diabetic rats in the spatial version of the water maze is related to difficulties in learning the procedures of the maze rather than to impairments of spatial learning.

Brain lesions and delayed water maze learning deficits after intracerebroventricular spermine

The effects of spermine on the acquisition and retention of spatial learning in the Morris water maze were studied. Spermine 25 and 125 nmol i.c.v. did not alter the ability of rats to find a hidden platform in the water maze when administered before training over 5 days. However, the inhibitory effect of the benzodiazepine, diazepam (3 mg/kg i.p., 30 min prior to training), on path length to target was markedly potentiated by the higher dose of spermine, consistent with spermine acting as a functional antagonist at the NMDA receptor. This drug combination did not affect performance on visible platform trials. Administration of doses of 125 and 250 nmol (but not 62.5 nmol) of spermine i.c.v. in the week prior to training (daily for 5 days) dose-dependently inhibited subsequent learning of a platform position in the absence of drug. These higher doses of spermine produced neuronal loss and increased [ 3 H] PK11195 binding indicating microglial activation predominantly in the hippocampus and to a lesser extent in the striatum, septum, thalamus and amygdala. Spermine 125 nmol i.c.v. (daily for 7 days) also abolished retention of a previously learned platform position when administered in an interval between training and retention testing. The inhibitory effects of spermine 125 nmol i.c.v. (daily for 7 days) on subsequent spatial learning were not antagonised by concomitant administration of 30 nmol dizocilpine. These results demonstrate that spermine produces a delayed neurotoxic effect in particular neuronal populations in the brain that selectively impair spatial learning and recall.

Radial maze learning deficits in striatal kainic acid-lesioned rats and effects of GABA receptor agonists

Cholecystokinin (CCK) is deeply involved in the control of learning and emotional behaviors. The authors characterize the behavioral properties of Otsuka Long Evans Tokushima Fatty (OLETF) rats, which lack the CCK-A receptor because of a genetic abnormality. In the Morris water-maze task, the OLETF rats showed an impaired spatial memory. In the inhibitory avoidance test, they showed facilitating response 24 h after training. Hypoalgesia was observed in a hot-plate test. In the elevated plus-maze and food neophobia test, OLETF rats showed an anxiety-like response. In addition, OLETF rats were hypoactive in the Morris water-maze and the elevated plus-maze. The results suggest that the OLETF rats showed a spatial memory deficit, hypoactivity and anxiety due, at least in part, to the lack of CCK-A receptors.

Reciprocal changes in expression of mRNA for nerve growth factor and its receptors TrkA and LNGFR in brain of aged rats in relation to maze learning deficits.

Quantitative in situ hybridization was used to examine the expression of mRNA for nerve growth factor (NGF) and its receptors, p140Trk (TrkA) and p75LNGFR (LNGFR), in different brain regions of adult (3-month-old) and aged (27-month-old) Wistar rats. The brain regions studied were hippocampus (dentate gyrus, CA3 region), basal forebrain (medial septum, diagonal band) and caudate-putamen. Prior to hybridization histochemistry behaviorally impaired as well as severely impaired animals were selected from a large group of old rats according to their performance in the Morris water maze. The impaired rats showed longer escape latencies and, thus, implicitly impaired performance in the place version of the task, but did not differ from adult controls on the platform crossing measure registered during the spatial probe trial. The severely impaired rats were significantly impaired on both measures, both in comparison with the adult animals and in comparison with the impaired aged rats. Inspection of the hippocampus revealed no age- or performance-related changes in NGF mRNA levels. The overall expression of TrkA mRNA in basal forebrain and caudate was found to be decreased in the impaired (-20%) as well as the severely impaired aged rats (-17%). A significant increase in p75LNGFR mRNA was found in the basal forebrain of the impaired rats in comparison with the severely impaired aged rats (+35%) and adult animals (+33%). These findings show that age-related maze performance deficits are accompanied by a decrease in basal forebrain and striatal TrkA mRNA expression. The increase in basal forebrain LNGFR mRNA levels observed in impaired, but not severely impaired, aged rats may reflect an early manifestation of processes underlying age-related cognitive deficits and may constitute a restorative and/or compensatory mechanism, since these rats displayed fewer deficits in navigation of the maze.

Holeboard maze-learning deficits and brain monoaminergic neurotransmitter concentrations in rats after intracerebroventricular injection of 3-bromopyruvate

3-Bromopyruvate is a suicide inhibitor of pyruvate dehydrogenase complex in brain homogenates, and after intracerebral injection reduces acetylcholine tissue content and muscarinic cholinergic receptors in brain cortex and hippocampus for extended periods of time. A stereotaxic injection of 0.2 μmol 3-bromopyruvate was given twice into the cerebral ventricles of male Wistar rats. Ten weeks later, the animals were tested for learning deficits in a food-motivated complex holeboard test. 3-Bromopyruvate-treated rats showed an increased number of visits to nonfood-baited holes over a 5-day testing period (four trials per day) compared to sham-operated control rats, an increased number of visits to food-baited holes over the first 2 days of the testing period and an increased time for completing the task. There were no changes in brain monoaminergic neurotransmitter concentrations compared to controls. The results indicate that long-term learning deficits in a spatial discrimination paradigm are caused by 3-bromopyruvate, which might be related to a cholinergic deficit induced by a primary inhibition of brain glucose metabolism at the step of pyruvate dehydrogenase complex. This animal model may be useful for behavioral studies in relation to neurodegenerative diseases like dementia of Alzheimer type.

Elegant studies of transplant-derived repair of cognitive performance

AbstractCholinergic-rich grafts have been shown to be effective in restoring maze-learning deficits in rats with lesions of the forebrain cholinergic projection system. However, the relevance of those studies to developing novel therapies for Alzheimer's disease is questioned.

Lashley maze learning deficits in NZB mice

In a prior study we found excellent Lashley III maze learning in BXSB mice and poor learning in NZB mice, despite the fact that both strains are autoimmune and develop cortical ectopias. This prompted us to examine NZB Lashley maze performance in detail, including comparisons to other strains and attempts to improve performance by giving additional trials with or without additional intramaze visual cues. In conventional Lashley testing (10 trials), RF mice (non-autoimmune and nonectopic) and BXSBs performed well in the Lashley maze. They had high learning indices and few errors. NZB mice performed poorly, with low learning indices and many errors. Even with additional trials or additional trials plus intramaze cues, NZB performance remained poor. The number of backward and forward errors stayed high; learning indices were low. Since both BXSB and NZB mice develop autoimmune disorders and cortical ectopias, it is unlikely that differential Lashley performance is the result of the presence of these phenomena. NZB mice are known to have alterations in their hippocampal morphology, and this is a possible mediator of the Lashley deficit.

Effects of noradrenergic DSP4 lesion on the effectiveness of pilocarpine in reversing scopolamine-induced amnesia

We studied the effectiveness of pilocarpine in reversing the scopolamine-induced water maze learning deficit (increase in escape latencies, decrease in spatial bias) in control and DSP4- (a noradrenergic neurotoxin) lesioned rats. The water maze acquisition deficit (escape latency, first spatial bias) induced by scopolamine 0.8 mg/kg was augmented by DSP4 treatment. The water maze performance deficit induced by scopolamine was reversed by pilocarpine 4 mg/kg in both DSP4-lesioned and control rats. A smaller dose of pilocarpine (1 mg/kg) did not reverse scopolamine-induced acquisition deficit in either control or DSP4-lesioned rats. Analysis of the second spatial bias test measured 2 weeks after training revealed that pilocarpine 4 mg/kg reversed scopolamine-induced retention deficit in control and DSP4-lesioned rats. Pilocarpine 1 mg/kg reversed scopolamine-induced retention performance deficit during the second spatial bias test in control but not in DSP4-lesioned rats. The present results suggest that 1) noradrenergic and cholinergic systems may interact in the regulation of spatial acquisition and retention and 2) the effectiveness of cholinergic drugs in reversing scopolamine-induced spatial retention deficit may be affected by noradrenergic lesioning.

The effects of prenatal nicotine on radial-arm maze performance in rats

Studies have revealed lasting cognitive impairments, including deficits in attention and learning, in the offspring of women who smoke. Animal models have shown that prenatal nicotine can induce behavioral impairments, including deficits in learning and memory, and one study showed that only females were impaired on a maze task. The purpose of the present experiment was two-fold: 1) to attempt to replicate the reported sex difference in maze learning and 2) to assess the ability of nicotine-treated subjects to learn a maze that placed particularly heavy demands on their attentional capabilities. Pregnant mothers were given 6.0 mg/kg/day of nicotine in their drinking water. Offspring of both sexes were tested following weaning in an 8-arm-radial maze using a confinement procedure. Results showed that prenatal nicotine treatment produced significant impairments in performance in the radial-arm maze. These impairments were seen in animals of both sexes, a finding which challenges the view that only females prenatally treated with nicotine show deficits in maze learning.

Radial maze learning deficits and mediodorsal thalamic damage in context of multifocal seizure-induced brain lesions.

Radial maze learning deficits and mediodorsal thalamic damage in context of multifocal seizure-induced brain lesions.

Radial maze learning deficits and mediodorsal thalamic damage in context of multifocal seizure-induced brain lesions.

Rats were either trained 21 days after seizure induction or trained before seizure induction and tested 21 days later. The seizures, which induce insidious brain damage within a multitude of diencephalic and subcortical telencephalic structures, were induced by a single injection of lithium (3 mEq/kg sc) followed 24 hr later by pilocarpine (30 mg/kg sc). Compared with controls, the treated rats displayed significant deficits in the acquisition and recall of a radial maze task. Although there was multifocal brain damage, only the amount of damage within the mediodorsal thalamic group was significantly and strongly correlated (rho = .79) with numbers of errors.

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Deficits in radial-arm maze learning in aged rats

The present study was designed to investigate the possible deficits in the place learning on the 8-arm radial maze in aged rats. In this task, reward was given in the 4 predetermined arms. Aged rats (27 months old, N = 7) acquired this task more slowly than young rats (12 months old, N = 11), and didn't reach to the performance level of the young rats within 80 training trials. Analysis of error choices revealed that the aged animals first entered in the unbaited arms more often than the young rats, whereas there was no difference in the number of re-entered choices to the baited and unbaited arms between the aged and young animals. Therefore, it was concluded that learning deficits in aged rats were attributed to deficits in the reference memory but not in the working memory.

Basal forebrain infusion of HC-3 in rats: Maze learning deficits and neuropathology

Ten adult male Sprague-Dawley rats were infused with hemicholinium (HC-3) using mini-osmotic pumps over a 14 day period through bilateral, chronically implanted cannulae in the nucleus basalis magnocellularis (nbm). Ten matched controls were infused in the same fashion with saline. HC-3 rats receiving implants demonstrated a significant deficit in maze-learning ability compared with individual and group performances before receiving the implants. In saline rats there was no significant difference in maze-learning ability before and after receiving implants. The HC-3 group receiving implants demonstrated a significant deficit in maze-learning ability compared with the saline control group. Serial sections through nbm from control and HC-3 rats indicated that all cannulae were located within infusion range of nbm. In HC-3 subjects, cholinergic cell bodies were destroyed with concurrent degeneration of terminal fields in cortex. Except for cannula insertion damage, the cholinergic neurotransmitter system appeared unharmed in controls. Stains for neuritic plaques and neurofibrillary damage were negative in both groups. The memory deficit in experimental subjects supported by the demonstrated destruction of nbm cholinergic neurons suggests that HC-3 may be useful in the development of an animal model for Alzheimer's Disease.

Long-term effects of nerve growth factor and neural transplants on behavior of rats with medial septal lesions

The present experiment investigated the interaction between exogenous nerve growth factor (NGF) and intrahippocampal septal grafts on the behavior of rats after a medial septum lesion. Young female rats received a bilateral injection of a fetal septal cell suspension into the dorsal hippocampus either immediately (immediate grafts) or 8 days after the lesion (delayed grafts). For delayed grafts, a higher concentration of endogenous neurotrophic factors can be assumed to be present in the deafferentated host tissue at the time of transplantation. One group of rats with lesions received NGF with the immediate grafts, another group received NGF alone. A sham-operated group and 3 groups with lesions (and given either immediate or delayed intrahippocampal saline injections, or no other treatment) constituted controls. The animals were tested for spontaneous alternation and for performance in a radial 8-arm maze, 1, 5 and 9 months postoperatively. Medial septal lesions reduced spontaneous alternation but, 9 months after surgery, recovery was observed in both lesion-control rats and in rats with delayed grafts (but not with immediate grafts). In the radial maze task, lesions produced a persistent impairment, although both immediate and delayed grafts reduced this deficit several months after surgery (more markedly and rapidly in the case of delayed grafts). NGF, however, increased the maze learning deficit especially 5 months postoperatively. These latter results are in contrast to findings of earlier studies showing transient beneficial effects of NGF administration. It is suggested that the effects of NGF in the present study might be due to an enhanced sprouting of sympathetic fibers into the hippocampal formation.

Environmental enrichment and restriction: Effects on reactivity, exploration and maze learning in mice with septal lesions

Following weaning, male, Heterogeneous mice were maintained either in socially/environmentally enriched conditions or in restricted conditions. Behavioral testing began when the mice were 60 days of age. The day after an initial handling-reactivity test, the mice were given either septal lesions or control surgery, and returned to their respective housing conditions. Following surgery, the mice underwent a successive battery of behavioral tests, consisting of the following: (1) handling reactivity; (2) open field exploration, as affected by the stress of a water swim; and, (3) performance on a water-maze spatial discrimination task. Restricted mice were more reactive than enriched mice before surgery, but with daily postsurgical handling, the reactivity of the restricted control group approached that of their enriched counter-parts. Also, there were no differences between enriched and restricted controls on acquisition or reversal of the spatial discrimination, or in exploration of a novel open field. The two intact groups did differ, however, in their open field behavior following the stress of a water swim. In contrast to the behavior of the control animals, the environmental housing conditions altered the behavior of the mice with septal lesions on each of the tests. The restricted mice with lesions were extremely reactive to handling, and displayed spatial reversal deficits; the enriched mice with lesions were much less reactive than the restricted septals, and showed no maze learning deficits. The open field tests, especially those following the water swim, revealed surgery by housing interactions as well, though not necessarily consistent with a “normalizing” effect of environmental enrichment for mice with septal lesions. The task-specific nature of this continuously maintained environmental manipulation, and the relative value of environmental stimulation in alleviating effects of septal damage are considered.

Deficits in discrimination and maze learning resulting from maternal histidinemia in rats.

Deficits in discrimination and maze learning resulting from maternal histidinemia in rats.

Persistent spatial maze-learning deficits in hippocampal-lesioned rats across a 7-week postoperative period

Rats with bilateral dorsal hippocampal lesions were tested on a series of three Rabinovitch-Rosvold maze patterns at either 1 week (Days 6, 7, and 8) or 7 weeks (Days 48, 49, and 50) following surgery. All rats in both groups were significantly impaired in the acquisition of these complex spatial maze patterns, regardless of the postoperative delay prior to testing. This lack of improvement stands in sharp contrast to earlier findings from our laboratory, in which it was determined that the decrease in levels of spontaneous alternation and the alterations in open-field activity produced by hippocampal lesions did return to normal levels within 6 weeks following surgery. The present results indicate that spatial maze learning may be classified as a persistent (although perhaps not permanent) deficit produced by hippocampal damage.