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PubMed1989

The effects of chronic oxotremorine treatment on spatial learning and tolerance development in mice.

C57BL mice were treated with 0.5 mg/kg/hr oxotremorine through an implanted subcutaneous cannula for 6 days. Tolerance to oxotremorine was evaluated after treatment by constructing cumulative dose-response curves and measuring body temperature and rotarod performance. At 2 hr after removal, mice exhibited a 15-fold tolerance as measured by body temperature and a 4-fold tolerance as measured by rotarod performance. This tolerance as measured by body temperature was lost by two days after removal from treatment. Immediately after treatment, 3H-QNB binding was reduced in cortex, hippocampus, midbrain, hindbrain, and hypothalamus. Receptors returned to normal within 4 to 8 days after cessation of treatment depending on the brain region. Spatial learning was examined using the Morris water task. Mice that began their training in this task 1 day after they were removed from oxotremorine treatment were impaired in their spatial ability as evidenced by a lack of preference for the trained site during a probe trial. Mice that began their training 2 days after cessation of oxotremorine treatment showed no evidence of impairment in spatial learning. These results suggest that a loss of muscarinic receptors after oxotremorine treatment can be dissociated from tolerance loss and spatial learning deficits.

Animals↗

PubMed1993

Effects of intracranial infusions of chlordiazepoxide on spatial learning in the Morris water maze. I. Neuroanatomical specificity.

The present investigation sought to determine the neuroanatomical locus through which the amnesic and anxiolytic effects of the benzodiazepine agonist chlordiazepoxide are mediated. Rats were infused with either chlordiazepoxide (60 nmol/microliters) or artificial CSF (1 microliter) into either the frontal cortex, nucleus basalis magnocellularis/substantia innominata, amygdala, medial septum, hippocampus, or cerebellum and run in the open field to assess anxiety as thigmotaxia and in the Morris water maze to assess spatial learning. Other rats were given chlordiazepoxide (5 mg/kg) or saline (1 ml/kg) systemically and run in the open field and water maze. When chlordiazepoxide was administered systemically, rats showed significantly less thigmotaxia, but not overall activity, than controls in the open field, and were deficit in spatial learning, but not cue learning or swim speed, in the water maze. Intracranial infusions revealed a neuroanatomical specificity for the amnesic and anxiolytic actions of chlordiazepoxide. Infusions of chlordiazepoxide into the amygdala, but none of the other structures, reduced thigmotaxia without affecting overall activity levels whereas infusions into the medial septum, but none of the other structures, prevented spatial learning, but not cue learning, and reduced swim speed in the water maze. Together, these finding suggest that the medial septum and the amygdala mediate the amnesic and anxiolytic actions of chlordiazepoxide, respectively. Moreover, these results provide direct evidence that the amnesic and anxiolytic actions of chlordiazepoxide are independent.

Amnesia↗

PubMed2002

Spatial learning is unimpaired in mice containing a deletion of the alpha-synuclein locus.

Alpha-synuclein belongs to a family of structurally related proteins expressed highly in the brain and is the major component of filamentous deposits present in a range of neurodegenerative diseases (synucleinopathies). It has been implicated in learning and memory, yet the physiological role of this protein is still unclear. It was recently found that a subpopulation of C57BL/6J mice carries a chromosomal deletion of the alpha-synuclein locus, often unknown to the experimenter. As genetically engineered mice are often backcrossed with C57BL/6J animals for learning and memory experiments, we studied the importance of alpha-synuclein in spatial learning tasks by examining the performance of alpha-synuclein-/- mice in the hidden platform reference memory version of the watermaze. Our data show that alpha-synuclein-/- mice had no significant impairment in performance during training or probe trials, compared with wild-type littermates. Therefore, we conclude that alpha-synuclein is not essential for this type of spatial learning.

Animals↗

PubMed1992

Effects of vinconate, a novel vinca alkaloid, on spatial learning deficits induced by the basal forebrain lesion in rats.

We investigated the effects of vinconate, a novel vinca alkaloid, on spatial learning deficits induced by the basal forebrain (BF) lesion in rats. Bilateral BF lesions were produced by injecting ibotenic acid (6 micrograms/0.5 microliter/side). In BF-lesioned rats, impairment of spatial learning in escaping onto the platform during training and decrease in spatial bias during the spatial probe trial in Morris's water maze task were both observed. Vinconate (5 and 10 mg/kg) treatment shortened the increase of escape latency to the platform in BF-lesioned rats and significantly reversed the decrease in spatial bias induced by the BF lesion. Vinconate (10 mg/kg) attenuated the decrease in choline acetyltransferase activity in the frontoparietal cortex caused by the BF lesion. The present study suggests that vinconate has an antiamnesic effect on the BF-lesion-induced amnesia by ameliorating the dysfunction in cholinergic neurons.

Animals↗

PubMed2003

Exercise during pregnancy increases hippocampal brain-derived neurotrophic factor mRNA expression and spatial learning in neonatal rat pup.

Physical activities for a few days can increase brain-derived neurotrophic factor (BDNF) mRNA in rat hippocampus. To investigate the influence of maternal exercise during pregnancy on rat pup hippocampal BDNF mRNA, we studied its expression by a semi-quantitative RT-PCR method after young pregnant rats were exercised on a motor driven treadmill. Pups of exercised mothers had significantly increased hippocampal BDNF mRNA expression compared to the control rat pups at birth (on postnatal day 0) (P<0.001). In contrast, hippocampal BDNF mRNA expression in pups of exercised mothers decreased significantly on postnatal day 28 (P<0.002). Spatial learning of rat pups was examined by multiple T maze training for 7 consecutive days between postnatal days 40 and 47. Pups of exercised mothers showed a significant increase in spatial learning ability as demonstrated by significant decreases in total time from starting to target and total number of errors as compared to age-matched control pups during the first 4 days of 7 consecutive days on multiple T maze training (P<0.05). Thus, physical exercise during gestation in pregnant mothers can increase hippocampal BDNF mRNA expression of postnatal pups and result in an improvement in spatial learning in pups from exercised dams.

Animals↗

PubMed1997

A dose of MK801 previously shown to impair spatial learning in the radial maze attenuates primed burst potentiation in the dentate gyrus of freely moving rats.

Spatial learning but not memory performance in the radial maze is disrupted by low doses of MK801 (0.0625 mg/kg ip), a noncompetitive N-methyl-D-aspartate receptor channel blocker (M. L. Shapiro & C. O'Connor, 1992). The effect of this low dose of MK801 on hippocampal physiology and synaptic plasticity was assessed in 16 behaving female Sprague-Dawley rats. The drug increased the frequency (0.5 Hz), marginally reduced the amplitude of hippocampal rhythmical slow wave activity (RSA), did not alter non-RSA slow wave activity, and reduced normal synaptic transmission from the entorhinal cortex to the dentate gyrus by approximately 8%. Independent of these effects on normal physiology. MK-801 also reduced primed burst potentiation, a form of synaptic plasticity produced by physiologically patterned stimulation, by approximately 20% in the same pathway. Thus, low doses of MK801 may impair spatial learning by reducing, directly or indirectly, the likelihood of synaptic plasticity in the hippocampus.

Animals↗

PubMed2004

Spatial learning in rats is impaired by microinfusions of protein kinase C-gamma antisense oligodeoxynucleotide within the nucleus accumbens.

The nucleus accumbens (NAcc) has been shown to play a role in motor and spatial learning. Protein kinase C (PKC) has been implicated in the mechanisms of initiation and maintenance of long-term potentiation that is thought to be involved in the storage of long-term memory. In the present study, the importance of de novo synthesis of PKC-gamma within the NAcc in the acquisition and retention of spatial discrimination learning was assessed using an antisense knockdown approach. Separate groups of Long-Evans rats were exposed to acute microinfusions (6microg/microl) of PKC-gamma antisense oligodeoxynucleotide (AS-ODN), control oligodeoxynucleotide (C-ODN) or vehicle into the NAcc at 24 and 3h before each training session. Behavioral findings showed that the blockade of NAcc-PKC-gamma translation caused impairments in the early phase of learning and retention of spatial information. Biochemical experiments showed that PKC-gamma expression was reduced and Ca(2+)/phospholipid-dependent protein kinase C (PKC) activity was blocked significantly in the AS-ODN-treated rats in comparison with control rats. The present findings suggest that NAcc-PKC-gamma plays a role during the early acquisition of spatial learning. Also, retention test results suggest that NAcc-PKC-gamma may be working as an intermediate factor involved in the onset of molecular mechanisms necessary for spatial memory consolidation within the NAcc.

Animals↗

PubMed1992

Effects of vinconate on spatial learning impairments induced by medial septal lesion in rats.

We investigated the effects of vinconate, a novel vinca alkaloid, on spatial learning deficits induced by medial septal (MS) lesion in rats. MS lesion was produced by passing an anodal DC current. In vehicle-treated MS-lesioned rats impairment of spatial learning was observed, shown by a decrease in correct choices and an increase in total errors during training in a radial arm maze task. Vinconate (10 mg/kg) treatment alleviated the decrease in correct choices and the increase in total errors induced by MS lesion. Vinconate (5 and 10 mg/kg) treatment showed a tendency to reverse the decrease in choline acetyltransferase activity in the hippocampus caused by MS lesion. The present study suggests that vinconate has an anti-amnesic effect on MS lesion-induced amnesia by ameliorating the dysfunction in cholinergic (ACh) neurons.

Animals↗

PubMed2006

Impairment of spatial learning by estradiol treatment in female mice is attenuated by estradiol exposure during development.

High doses of estradiol (E(2)) can impair spatial learning in the Morris water maze, in ovariectomized mice, but the same dose has no effect on adult castrated males. Here, we test the hypothesis that this sex difference is caused by neonatal actions of E(2). In Experiment 1, C57BL/6J pups were given daily estradiol benzoate (EB) or oil injections from the day of birth until postnatal Day 3. Adults were gonadectomized and received EB (s.c.) or oil 28 h before the first day of training, and 4 h before each of four daily training sessions on the Morris water maze. Females given oil as neonates, and EB prior to training displayed the poorest performance. Females that received EB as neonates and EB prior to training were insensitive to the deleterious effects of adult EB and performed better than males given the same hormone treatments. We conducted a second experiment using aromatase enzyme knockout (ArKO) mice. Adult male and female ArKO and wild-type (WT) littermates were gonadectomized and received either injections of oil or EB prior to and during water maze training (as described above). Hormone treatment failed to affect performance, yet, female but not male ArKO mice showed impaired learning compared to WT littermates. Thus, exposure to estradiol during neonatal development can counteract the deleterious effects of EB on adult spatial learning.

Animals↗

PubMed1988

Constraints on water maze spatial learning in rats: implications for behavioral studies of brain damage and recovery of function.

In an effort to develop spatial learning tasks not requiring food or water deprivation for use in studies of recovery of function after brain damage, T-maze spatial alternation learning was examined in intact rats using water maze swim-escape procedures. Consistent with previous studies, rewarded spatial alternation involving food or water deprivation was readily learned by intact rats. However, none of the groups of rats trained in the swim-escape tasks learned to alternate goal arm choices in the water maze at reliable rates. This was true regardless of whether non-correction or correction procedures were used, and regardless of intertrial delay intervals. Although average alternation rates over sessions did increase from chance levels, the majority of the rats did not reach criterion levels, even with as many as 38 consecutive days of testing. In contrast, a conditional spatial alternation task in the water maze, using a win-shift procedure, was readily learned. Surprisingly, a win-stay version of this conditional spatial task was not learned over 21 days of testing. These unexpected constraints on spatial learning and memory processes in rats cannot be attributed simply to failure of spatial information processing, nor to strict limitations on working memory in swim-escape tasks, since excellent spatial navigation abilities have been documented, and mastery of at least some working-memory tasks have now been demonstrated in swim-escape tasks.

Animals↗

PubMed1998

Attenuation of scopolamine-induced spatial learning impairments by an angiotensin IV analog.

Recently, a receptor for the angiotensin II(3-8) (Ang IV) hexapeptide, was discovered in the hippocampus, suggesting a possible role in learning. The present study utilized intracerebroventricularly (icv) infused scopolamine hydrobromide (scop) to disrupt spatial learning in the circular water maze, followed by the Ang IV analog norleucine1-Ang IV (Nle1-Ang IV), to restore normal performance. Rats were icv pretreated with either scop or artificial cerebrospinal fluid (aCSF) followed by either icv injected Nle1-Ang IV or aCSF, and then behaviourally tested. During acquisition training, each animal's latency to locate the platform, path distance, speed, and efficiency ratios were measured. A probe trial was conducted on the final day of training and the time spent in the target quadrant and the number of crossings over the former location of the platform (annulus crossings) were observed. The results indicate that those animals treated with scop followed by aCSF performed poorly during acquisition training as compared with controls. In contrast, those animals that received scop followed by Nle1-Ang IV attained equivalent latencies, distances, and efficiency ratios to find the platform as those achieved by controls. There were no observed differences in swimming speed, thus arguing against drug-induced motor impairment. During the probe trial, animals treated with scop followed by aCSF spent less time in the target quadrant and made fewer annulus crossings as compared to controls, while the scop, Nle'-Ang IV treated animals performed equivalently to controls. These results suggest that Nle1-Ang IV acts to counteract the disruption of spatial learning induced by scopolamine.

Angiotensin II↗

PubMed1993

Mechanical deafferentation of basal forebrain-cortical pathways and neurotoxic lesions of the nucleus basalis magnocellularis: comparative effect on spatial learning and cortical acetylcholine release in vivo.

Rats were assigned to one of the following treatments: bilateral cut of basal forebrain-cortical fibers (DEAFF), ibotenic (IBO) or quisqualic (QUIS) acid lesions of the NBM and sham operations (SHAM). They were trained to perform a radial eight-arm maze task with all the paths or only four paths baited. Cortical cholinergic release measured by microdialysis in vivo and choline acetyltransferase activity were also assessed in the four lesion conditions. The results show that, in the full baited maze task, only the DEAFF group showed a severe spatial learning impairment. In the four-baited path task, the DEAFF group was still more impaired than the other groups but a performance deficit also emerged in rats with IBO lesions. Neurochemical data indicated that cortical choline acetyltransferase activity was reduced by 25% after IBO lesions, by 52% after DEAFF and by 46% after Quis lesions. However, cortical cholinergic release, which dropped in the same fashion after DEAFF or QUIS lesions, was unaffected by IBO lesions. Thus, in spite of the distinctive patterns of behaviour exhibited by the three lesioned groups, no correlation between cortical cholinergic deficiencies and spatial learning impairment was found. The similar behavioural effects produced by DEAFF and fornix sections suggests that, among the basal forebrain-cortical pathways, descending fibers projecting onto the septo-hippocampal system could exert a strong control on spatial learning performance.

Acetylcholine↗

PubMed2005

N-3 fatty acid deficiency induced by a modified artificial rearing method leads to poorer performance in spatial learning tasks.

Docosahexaenoic acid (DHA) is a major structural component of the nervous system, and depletion may lead to losses in neural function. Our objective was to demonstrate a deficit in spatial task performance in rats with low brain DHA due to a low n-3 fatty acid intake using a first-generational artificial rearing technique. Newborn rat pups were separated on d 2 and assigned to two artificial rearing groups or a dam-reared control group. Pups were hand fed artificial milk via custom-designed nursing bottles containing either 0.02% (n-3 Def) or 3.1% (n-3 Adq) of total fatty acids as LNA. At d 21, rats were weaned to either n-3 Def or n-3 Adq pelleted diets and several behavioral tasks were evaluated at 9 wk of age. Brain DHA was lower (58% and 61%, p < 0.001) in n-3 Def in comparison to n-3 Adq and dam-reared rats, respectively. At adulthood, the n-3 fatty acid-deficient rats had a significantly greater moving time than the dam-reared group (p < 0.05), but there were no differences among the three groups in the elevated plus maze test. The n-3 fatty acid deficient rats exhibited a longer escape latency (p < 0.05) and poorer memory retention in the Morris water maze compared with n-3 fatty acid adequate and dam-reared rats. We concluded that artificial rearing can be used to produce n-3 fatty acid deficiency in the first generation. This deficiency was associated with significantly reduced spatial learning. Adequate brain DHA levels are required for optimal spatial learning.

Animal Nutritional Physiological Phenomena↗

PubMed2001

The selective 5-HT(1A) receptor agonist repinotan HCl attenuates histopathology and spatial learning deficits following traumatic brain injury in rats.

The selective 5-HT(1A) receptor agonist Repinotan HCl (BAY x3702) has been reported to attenuate cortical damage and improve functional performance in experimental models of cerebral ischemia and acute subdural hematoma. Using a clinically relevant contusion model of traumatic brain injury, we tested the hypothesis that a 4-h continuous infusion of Repinotan HCl (10 microg/kg/h i.v.) commencing 5 min post-injury would ameliorate functional outcome and attenuate histopathology. Forty isoflurane-anesthetized male adult rats were randomly assigned to receive either a controlled cortical impact (2.7 mm tissue deformation, 4 m/s) or sham injury (Injury/Vehicle=10, Injury/MK-801=10, Injury/Repinotan HCl=10, Sham/Vehicle=10), then tested for vestibulomotor function on post-operative days 1-5 and for spatial learning on days 14-18. Neither Repinotan HCl nor the non-competitive N-methyl-D-aspartate receptor antagonist MK-801, which served as a positive control, improved vestibulomotor function on beam balance and beam walk tasks relative to the Injury/Vehicle group, but both did significantly attenuate spatial learning and memory deficits on a water maze task. Repinotan HCl also reduced hippocampal CA(1) and CA(3) neuronal loss, as well as cortical tissue damage, compared to the Injury/Vehicle group at 4 weeks post-trauma. No significant difference in histological outcome was revealed between the Repinotan HCl- and MK-801-treated groups.These findings extend the therapeutic efficacy of Repinotan HCl to a contusion model of experimental brain injury and demonstrate for the first time that 5-HT(1A) receptor agonists confer neuroprotection and attenuate spatial learning deficits following controlled cortical impact injury. This treatment strategy may be beneficial in a clinical context where memory impairments are common following human traumatic brain injury.

Animals↗

PubMed2005

Effect of Morris water maze diameter on visual-spatial learning in different mouse strains.

The Morris water maze task is a widely used tool to assess hippocampus-dependent learning and memory in rodents. Performance depends upon several factors including not only the traits of the experimental animals, but also apparatus and protocol characteristics. The present study aimed at investigating the effect of maze diameter on acquisition and probe trial performance in three commonly used strains: C57Bl/6, BALB/c, and 129/SvEvBrd mice. Three maze diameters (150, 120, and 75 cm) were used under identical protocol and testing conditions. Downscaling maze dimensions, hence reducing difficulty and stress levels, did not allow BALB/c mice, commonly known as poor learners, to acquire this visual-spatial learning task. C57Bl/6 mice performed satisfactory in all three maze settings, with superior probe trial performance in the 120-cm-diameter setting. Further downscaling of maze dimensions might even render this task too simple for this strain. If the 129S5/SvEvBrd background strain is preferred, testing of visual-spatial learning abilities should be performed in a small sized MWM pool, as this strain performed only adequately in the smallest maze setting. Attention is drawn to the importance of supplying a detailed description 129 substrain nomenclature in future studies. Generalization of observations from one strain to another and from data obtained with a specific strain and maze diameter to other maze dimensions should be dealt with very carefully. The present study emphasizes the importance of a well-substantiated choice of background strain and water maze characteristics when researchers plan to investigate visual-spatial learning and memory in a chemically/lesion-induced or targeted mutagenesis model.

Animals↗

PubMed1995

Spatial learning with a minislab in the dorsal hippocampus.

We have determined the volume and location of hippocampal tissue required for normal acquisition of a spatial memory task. Ibotenic acid was used to make bilateral symmetric lesions of 20-100% of hippocampal volume. Even a small transverse block (minislab) of the hippocampus (down to 26% of the total) could support spatial learning in a water maze, provided it was at the septal (dorsal) pole of the hippocampus. Lesions of the septal pole, leaving 60% of the hippocampi intact, caused a learning deficit, although normal electrophysiological responses, synaptic plasticity, and preserved acetylcholinesterase staining argue for adequate function of the remaining tissue. Thus, with an otherwise normal brain, hippocampal-dependent spatial learning only requires a minislab of dorsal hippocampal tissue.

Acetylcholinesterase↗

PubMed2005

Involvement of delta1-opioid receptors in the spatial learning impairment in streptozotocin-induced diabetic mice.

It is well accepted that diabetes leads to learning and memory impairment in humans and rodents. Because central delta-opioid receptors have important roles in learning processes, we investigated the involvement of delta-opioid receptors in the spatial learning impairment in streptozotocin (STZ)-induced diabetic mice by the Morris water maze test. The escape latencies to the platform were significantly increased in diabetic mice without changes in the ability to swim. The delta1/delta2-opioid receptor antagonist naltrindole (1 mg/kg/day, s.c.) slightly, but not significantly, reduced the escape latencies in diabetic mice. The selective delta1-opioid receptor antagonist 7-benzylidenenaltrexone (0.3 and 1 mg/kg/day, s.c.), but not the selective delta2-opioid receptor antagonist naltriben (0.3 and 1 mg/kg/day, s.c.), significantly reduced the escape latencies in diabetic mice. These antagonists had no effect on the escape latencies in non-diabetic mice. The selective delta1-opioid receptor agonist [D-Pen2, D-Pen5]-enkephalin (10 nmol/mouse/day, i.c.v.) significantly increased the escape latencies in both non-diabetic and diabetic mice. Based on these results, we suggest that the enhanced response to central delta1-opioid receptors in diabetic mice is involved, at least in part, in the spatial learning impairment in the Morris water maze test.

Animals↗

PubMed2006

[Effect of chronic Toxoplasma infection on the spatial learning and memory capability in mice].

OBJECTIVE: To investigate the effect of chronic infection of Toxoplasma gondii on the spatial learning and memory capability in mice. METHODS: Toxoplasma tachyzoites (RH strain) were reanimated at 37 degrees C after 15 days' storage at -20 degrees C, and injected intraperitoneally to mice of the experimental group each with 7.7 x 10(5). Normal saline was given to the control group, 0.5 ml per mouse. Two months later, all mice were tested in the Morris Water Maze. Smears of the mice brain homogenate and pathological sections were examined. RESULTS: (1) The density of cysts in the brain homogenate was 15/HP, and there was no evident pathological change in the hippocampus and adjacent areas of mice in the brain in the experimental mice. (2) Latency to platform, cumulative distance to the platform, total distance traveled in both experimental and control groups decreased significantly with the increase of training days (P < 0.01). The latency and cumulative distance in experimental group were significantly longer than that of the control group (P < 0.01). (3) The searching strategy of mice in the experimental group was significantly different from that of the control group. CONCLUSION: Toxoplasma tachyzoites can induce chronic infection in mice and the infection can damage at some extent the spatial learning and memory capability of mice.

Animals↗