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PubMed1994

Conserved spatial learning in cooled rats in spite of slowing of dentate field potentials.

Behaviorally induced brain temperature changes have significant effects on field potentials recorded in the hippocampal formation. All components of the field potential are slowed during cooling. Field excitatory postsynaptic potentials (f-EPSPs) are often reduced, while the population spike is increased in this state. To investigate whether such synaptic alterations affect hippocampus-dependent learning, we have compared the effects of reduced brain temperature on dentate field potentials and spatial learning in a Morris water maze. Rats were implanted with thermistors in the brain. A subset of the rats received electrodes for field potential recording in the perforant path-granule cell synapses of the dentate gyrus. After recovery, the rats were cooled by swimming in a pool of water. This invariably led to a brain temperature reduction of several degrees centigrade and a delay of the extracellular response. In addition, the field potential changed as described above. The effect of these changes on spatial learning in a second pool, the water maze, was determined by first cooling and then reheating each rat to a given level of brain temperature prior to each spatial training session. In spite of marked changes in dentate field potentials, all rats trained at brain temperatures above 30 degrees C learned to find the submerged platform similarly well. The speed of acquisition and the final precision of search behavior were also similar in these rats. Only rats that had been cooled below 30 degrees C failed to locate the hidden target. These animals also showed clear evidence of motor impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMedDate not supplied

Chronic, severe hypertension does not impair spatial learning and memory in Sprague-Dawley rats.

This study tested the hypothesis that long-term hypertension impairs spatial learning and memory in rats. In 6-wk-old Sprague-Dawley rats, chronic hypertension was induced by placing one of three sizes of stainless steel clips around the descending aorta (above the renal artery), resulting in a 20-80-mm Hg increase of arterial pressure in all arteries above the clip, that is, the upper trunk and head. Ten months later, the rats were tested for 5 d in a repeated-acquisition water maze task, and on the fifth day, they were tested in a probe trial; that is, there was no escape platform present. At the end of the testing period, the nonsurgical and sham control groups had similar final escape latencies (16 +/- 4 sec and 23 +/- 9 sec, respectively) that were not significantly different from those of the three hypertensive groups. Rats with mild hypertension (140-160 mm Hg) had a final escape latency of 25 +/- 6 sec, whereas severely hypertensive rats (170-199 mm Hg) had a final escape latency of 21 +/- 7 sec and extremely hypertensive rats (>200 Hg) had a final escape latency of 19 +/- 5 sec. All five groups also displayed a similar preference for the correct quadrant in the probe trial. Together, these data suggest that sustained, severe hypertension for over 10 mo is not sufficient to impair spatial learning and memory deficits in otherwise normal rats.

Animals↗

PubMed2004

Adolescent gamma-hydroxybutyric acid exposure decreases cortical N-methyl-D-aspartate receptor and impairs spatial learning.

gamma-hydroxybutyric acid (GHB), which belongs to the class of substances referred to as "club drugs", is abused for its euphoric, sedative and anabolic effects. GHB use and abuse is most prevalent among adolescents and young adults. In almost all cases of GHB abuse, subjects report of amnesia. Behavioral effects of GHB in animals, particularly on learning and memory are not known. In this study, effects of GHB exposure on spatial learning and memory in adolescent rats were tested using the Morris water maze (MWM). Adolescent male rats were treated with a single daily injection of one of three doses of GHB for 5 days; control rats received equivalent volumes of saline. GHB-treated rats took longer and swam greater distances to find the hidden platform than control rats. Swim speed in GHB-treated rats was no different from that in vehicle-treated rats. In the probe trial, adolescent rats exposed to GHB spent less time in the target quadrant than control rats. In the visual task, drug-treated rats did not perform any differently than control rats. Brain regions from GHB-exposed and saline-treated rats were examined for N-methyl-D-aspartate (NMDA) receptor changes using [3H]MK-801 binding as a biochemical marker for NMDA channel function. [3H]MK-801 binding in the frontal cortex was significantly reduced compared to saline-treated controls. Together, these data indicate that GHB exposure in adolescent rats negatively impacts spatial learning and this is associated with altered regulation of cortical NMDA receptor.

Age Factors↗

PubMed2006

Oral Accutane (13-cis-retinoic acid) has no effects on spatial learning and memory in male and female Sprague-Dawley rats.

Descriptions of psychiatric effects with Accutane (13-cis-retinoic acid (13-cis-RA)) use prompted a series of studies in a rodent model to ascertain its cognitive effects. Previously, we reported no effects on measures of anhedonia and depression in rats treated with 7.5, 22.5, or 30 mg/kg 13-cis-RA [S.A. Ferguson, F.J. Cisneros, B. Gough, J.P. Hanig, K.J. Berry, Chronic oral treatment with 13-cis-retinoic acid (isotretinoin) or all-trans-retinoic acid does not alter depression-like behaviors in rats, Toxicol. Sci. 87 (2005) 451-459 [16]; S.A. Ferguson, F.J., Cisneros, J.P. Hanig, K.J. Berry, Chronic oral treatment with Accutane (13-cis-retinoic acid) does not increase measures of anhedonia or depression in male and female Sprague-Dawley rats, (in preparation) [19]]. Here, we assessed spatial learning and memory in male and female Sprague-Dawley rats gavaged daily beginning on postnatal day (PND) 59 with vehicle control (soybean oil), 7.5 or 30 mg/kg of 13-cis-RA. We have reported that 7.5 mg/kg produces serum levels of 13-cis-RA comparable to those of humans prescribed Accutane [S.A. Ferguson, P.H. Siitonen, F.J. Cisneros, B. Gough, J.F. Young, Steady state pharmacokinetics of oral treatment with 13-cis-retinoic acid or all- trans-retinoic acid in male and female adult rats, Basic Clin. Pharmacol. Toxicol. 98 (2006) 582-587 [18]]. Three behavioral tasks assessed spatial learning and memory after chronic 13-cis-RA treatment: the escape-reinforced Morris water maze (PNDs 111-115), the food-reinforced 8-arm radial maze (PNDs 132-136), and the water-reinforced NCTR complex maze (PNDs 153-157). Behaviors were measured after a minimum of 52 and maximum of 94 days of 13-cis-RA treatment. 13-cis-RA treatment had no effects on performance of the 8-arm radial maze or the NCTR complex maze. Treatment effects on Morris water maze performance were negligible and neither dose-related nor consistent. Performances of the control group were quite similar to those previously described in this laboratory. These results indicate that chronic 13-cis-RA treatment in male and female rats has few effects on measures of spatial learning and memory.

Administration, Oral↗

PubMed1995

Spatial learning ability of rats following acute exposure to alcohol during early postnatal life.

Previous research has indicated that the developing brain is vulnerable to the effects of alcohol exposure. Most of this research has used an experimental design in which animals where chronically subjected to alcohol for a lengthy period of time during gestation and/or the preweaning period. Recent evidence has indicated that the morphology of the brain and the subsequent behaviour of the animal may also be susceptible to alcohol administered for a short duration during specified periods of development. Wistar rats were exposed to 7.5 g/kg body weight of ethanol administered as a 10% solution via an intragastric cannula over an 8 h period either on the 5th (PND5) or the 10th (PND10) postnatal day of age. Gastrostomy controls received a 5% sucrose solution substituted isocalorically for the ethanol. Another set of pups raised by their mother were used as 'suckle controls'. All surgical procedures were carried out under halothane vapour anaesthesia. After the artificial feeding regimes all pups were returned to lactating dams and weaned at 21 days of age. The spatial learning ability of these rats was tested in the Morris water maze when they were between 41-54 days of age. This task requires the rats to swim in a pool containing water made opaque and locate and climb onto a submerged platform. The time taken to accomplish this is known as the "escape latency." Each rat was subjected to 24 trials over three days and a further trial on each of days 4 and 11 of the test period. Statistical analysis of the escape latency data revealed that both the PND5 and PND10 ethanol treated groups had significant deficits in their spatial learning ability compared with the control groups. However, there was no significant difference in the degree of impairment between the PND5 and PND10 rats. It is concluded that even short periods of alcohol exposure during brain development can cause lasting impairment of spatial learning behaviour in rats.

Animals↗

PubMed1991

Acute phorbol ester treatment improves spatial learning performance in rats.

Recent findings have lead researchers to speculate that hippocampal protein kinase C (PKC) in rodents is involved in spatial learning and memory. The purpose of this study was to determine if treating rats with a compound known to increase PKC activity would improve performance in a task that requires spatial learning processes. Rats were treated with a single intracerebroventricular injection of a phorbol ester, phorbol 12,13-dibutyrate (PDBu) that is known to increase PKC activity and then tested on the hidden-platform version of the Morris water taks. Results showed that PDBu-treated subjects' ability to learn to locate the escape platform was better than controls. In addition, PDBu-treated subjects showed signs of having remembered the location of the platform better than controls when tested 24 h later. These results support a role of brain PKC in processes required to learn the Morris water task.

Animals↗

PubMed1995

Reduced spatial learning in mice infected with the nematode, Heligmosomoides polygyrus.

Parasite modification of host behaviour influences a number of critical responses, but little is known about the effects on host spatial abilities. This study examined the effects of infection with the intestinal trichostrongylid nematode, Heligmosomoides polygyrus, on spatial water maze learning by male laboratory mice, Mus musculus. In this task individual mice had to learn the spatial location of a submerged hidden platform using extramaze visual cues. Determinations of spatial performance were made on day 19 post-infection with mice that had been administered either 50 or 200 infective larvae of H. polygyrus. The infected mice displayed over 1 day of testing (6 blocks of 4 trials) significantly poorer acquisition and retention of the water maze task than either sham-infected or control mice, with mice that had received 200 infective larvae displaying significantly poorer spatial performance than individuals receiving 50 larvae. The decrease in spatial learning occurred in the absence of either any symptoms of illness and malaise, or any evident motor, visual and motivational impairments. It is suggested that in this single host system the parasitic infection-induced decrease in spatial learning arises as a side-effect of the host's immunological and neuromodulatory responses and represents a fitness cost of response to infection.

Analysis of Variance↗

PubMed1992

Quantitative effects of cerebral infarction on spatial learning in rats.

Outcome following stroke is difficult to measure because the behavioral response to infarction is variable. We hypothesized that cognitive function, such as spatial learning, may be a reproducible and sensitive outcome variable. We developed an animal model of multifocal cerebral ischemia in order to study the effects of infarction on learning. To cause ischemia, several hundred microspheres were injected into the internal carotid arteries of rats. After ischemia, behavior was measured using a global rating and a Morris water maze. Postmortem serial brain sections were stained and the size of the infarctions was measured. We found that intracerebral microspheres caused cortical infarction and an impairment of spatial learning. This impairment was not due to occlusion of the internal carotid artery and was not found in animals who received a sham injection of saline. The degree of learning impairment was not correlated with the volume density of the infarctions or with the volume density of the remaining cerebral hemisphere. The learning impairment clearly differentiated normal from lesioned animals, and the impairment was probably due to a delay in acquisition of spatial information rather than a defect in retention or retrieval. Measurement of learning deficit after cerebral ischemia is an efficient and sensitive method for evaluating new stroke treatments and possibly for exploring structure function relationships.

Animals↗

PubMed2002

[Role of melatonin in spatial learning and memory in rats and its mechanism].

It has been suggested that melatonin is involved in learning and memory. In the present study, we investigated the effects of melatonin on spatial learning and memory in rats, using Morris water maze and electrophysiological methods. The results are as follows. (1) During a six-day water maze training, the mean escape latency of melatonin group in the last 4 days was 30.02+/-3.6 s, and that of control group was 18.44+/-2.7 s (P<0.01). The crossing annulus coefficient of melatonin group was 25.68+/-2.32%, and that of control group was 43.33+/-2.85% (P<0.01). (2) Microinjection of melatonin into CA1 area inhibited long-term potentiation (LTP). Sixty minutes after tetanus, the field excitory postsynaptic potentials (fEPSP) slope of group C (n=7 0.5 microliter saline) was 169.71+/-6.48 % of the baseline, and that of group M2 (n=6, 2 microgram melatonin) was 114.28+/-1.80% of the baseline. The difference is significant (P<0.01). (3) We also investigated the effects of melatonin on LTP after administration of scopolamine. Sixty minutes after tetanus, the fEPSP slope of group SM (n=6, 2 microgram scopolamine before 2 microgram melatonin) was 113.70+/-5.55% of the baseline. It showed a significant decrease compared with group C (P<0.01). However, there was no difference between groups SM and M2 (P>0.05, i.v.). The results obtained by applying melatonin after bicuculline were different from those after scopolamine. Sixty minutes after tetanus, the fEPSP slope of group BM (n=7, 1 microgram bicuculline before 2 microgram melatonin) was 162.29+/>10.52% of the baseline. Compared with group C, there is no significant difference (P>0.05); but compared with group M2, the difference is significant (P<0.01). Our results showed that application of melatonin in rats significantly inhibited not only spatial learning and memory, but also LTP in CA1 area. Furthermore, the results indicate that the inhibition of LTP by melatonin may not be mediated by cholinergic system, but may be through the modulation of GABAergic system.

Animals↗

PubMed1998

The effects of MK-801 on spatial working memory and within-session spatial learning.

The present study investigated the effects of the NMDA channel blocker MK-801 (0.05, 0.10, and 0.15 mg/kg) on a task that allows for the assessment of both spatial working memory and within-session spatial learning. During the first trial of each day, subjects were shown the spatial location of a food reward on a six-arm radial-arm maze. During nine subsequent free-choice trials, subjects were reinforced for returning to that same spatial location. The location of the food reward varied across days. Thus, choosing correctly on any given trial required subjects to remember where food had been received during the previous trials of that day. The effects of MK-801 on working memory were assessed by analyzing the overall number of errors committed during the nine free-choice trials of each day. The effects of MK-801 on within-session learning were assessed by comparing the number of errors committed during the first three trials of each day to the number of errors committed during the last three trials of each day. Only the highest dose of MK-801 tested (0.15 mg/kg) impaired spatial working memory. No dose of MK-801 impaired the ability of subjects to acquire spatial information within a given session. The failure of MK-801 to impair within-session spatial learning stands in contrast to the well-known effects of MK-801 on spatial learning measured across days. Thus, when coupled with previous research, the findings of the present study further suggest that the NMDA receptor plays a role in the long-term, but not short-term, storage of spatial information.

Adaptation, Psychological↗

PubMed1999

Differential modulation of lateral septal vasopressin receptor blockade in spatial learning, social recognition, and anxiety-related behaviors in rats.

The role of lateral septal vasopressin (VP) in the modulation of spatial memory, social memory, and anxiety-related behavior was studied in adult, male Wistar rats. Animals were equipped with osmotic minipumps delivering the VP-antagonist d(CH2)5-D-Tyr(Et)VAVP (1 ng/0.5 microl per h) bilaterally into the lateral septum (LS). Subsequently, all rats were subjected to four behavioral tests. First, animals were tested in a spatial learning paradigm (Morris water maze; 12 trials), followed by the social recognition test. A possible role for VP in anxiety-related behavior was then studied in the shock-probe burying test and the elevated plus-maze, respectively. The results showed that VP receptor antagonism impaired social recognition and reduced open-arm activity in the plus-maze, while it had no effect on spatial learning (Morris maze) and shock-probe burying behavior. The results indicate a strong task-dependent specificity of lateral septal VP functioning.

Animals↗

PubMed1988

The effect of pirenzepine on spatial learning in the Morris Water Maze.

The effects of the selective M1-muscarinic antagonist, pirenzepine, were studied on the Morris Water Maze, a test of spatial learning in the rat. Pirenzepine (0, 10 or 30 micrograms) was administered into lateral ventricle during acquisition of this task. Although 30 micrograms of pirenzepine impaired acquisition of the spatial aspects of the task, treated animals still appeared to be able to acquire a taxon strategy. A low dose of pirenzepine (10 micrograms) produced a slight deficit but this was only visible in a "spatial probe" trial. Although these results are consistent with the belief that muscarinic M1-receptors are involved in spatial learning, it cannot be excluded that the effects recorded were mediated by muscarinic M2-receptors, due to the low selectivity of pirenzepine.

Animals↗

PubMed1999

Contributions of the brain angiotensin IV-AT4 receptor subtype system to spatial learning.

The development of navigational strategies to solve spatial problems appears to be dependent on an intact hippocampal formation. The circular water maze task requires the animal to use extramaze spatial cues to locate a pedestal positioned just below the surface of the water. Presently, we investigated the role of a recently discovered brain angiotensin receptor subtype (AT4) in the acquisition of this spatial learning task. The AT4 receptor subtype is activated by angiotensin IV (AngIV) rather than angiotensins II or III, as documented for the AT1 and AT2 receptor subtypes, and is heavily distributed in the CA1-CA3 fields of the hippocampus. Chronic intracerebroventricular infusion of a newly synthesized AT4 agonist (Norleucine1-AngIV) via osmotic pump facilitated the rate of acquisition to solve this task, whereas treatment with an AT4 receptor antagonist (Divalinal) significantly interfered with the acquisition of successful search strategies. Animals prepared with bilateral knife cuts of the perforant path, a major afferent hippocampal fiber bundle originating in the entorhinal cortex, displayed deficits in solving this task. This performance deficit could be reversed with acute intracerebroventricular infusion of a second AT4 receptor agonist (Norleucinal). These results suggest that the brain AngIV-AT4 system plays a role in the formation of spatial search strategies and memories. Further, application of an AT4 receptor agonist compensated for spatial memory deficits in performance accompanying perforant path knife cuts. Possible mechanisms underlying this compensatory effect are discussed.

Animals↗

PubMed1992

Spatial learning ability of rats undernourished during early postnatal life.

Experiments to determine whether undernutrition during early life results in deficits in spatial learning behavior has produced conflicting results. It was hypothesized that this may be due to the differing degrees of undernutrition used in the various studies, and/or to the timing of the testing procedures with respect to the period of food deprivation. These possibilities were tested by undernourishing rats between birth and 30 days of age to two different levels (i.e., level-1 and level-2). The degree of undernutrition was greater at level-2 than level-1. Behavioral testing of these rats and well-fed controls was carried out in the Morris water maze when they were between either 35 and 65 or 170 and 200 days of age. Statistical analyses of the escape latency data from these experiments revealed that rats tested almost immediately after the period of undernutrition have alterations in their spatial learning behavior compared with controls. However, even a short period of nutritional rehabilitation removed any differences between control and previously undernourished groups, irrespective of the level of undernutrition.

Animals↗

PubMed2006

Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency.

Thyroid hormones are critical for the development and maturation of the central nervous system. Although somatic and neurological effects are well documented following severe thyroid hormone deprivation, much less is known of the functional consequences of moderate levels of hormone insufficiency. We have previously demonstrated that severe thyroid hormone reductions in the postnatal period are associated with impairments in synaptic transmission in the dentate gyrus. The present study was performed to examine the dose-response relationships of moderate levels of hormone disruption on synaptic function in the dentate gyrus in an in vivo preparation and to determine the effects on spatial learning. Pre- and postnatal thyroid hormone insufficiency was induced by administration of 3 or 10 ppm propylthiouracil (PTU) to pregnant and lactating dams via the drinking water from gestation day (GD) 6 until postnatal day (PN) 30. This regimen produced a 47% and 65% reduction in serum T4, in the dams of the low and high-dose groups, respectively. At the time of testing of adult offspring, hormone status had returned to control levels. In littermates, field potentials evoked in the dentate gyrus in response to stimulation of the perforant path were assessed under urethane anesthesia. The data reveal dose-dependent reductions in synaptic transmission and impairments in long-term potentiation (LTP) of the EPSP component of the compound field potential. In contrast, LTP of the population spike measure was paradoxically enhanced. Spatial learning in the Morris water maze was profoundly impaired in high-dose animals. Although the majority of subjects in the low-dose group eventually acquired the task, their acquisition rate lagged behind control values. Reversal learning was assessed in all animals reaching criterion performance and found to be impaired in PTU-exposed animals relative to controls. These data support previous findings in area CA1 in vitro, extend observations associated with dentate gyrus synaptic function to a lower dose range, and provide correlative evidence of behavioral disruption in a hippocampal-dependent learning task following developmental thyroid hormone insufficiency.

Age Factors↗

PubMed1994

(R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) blocks spatial learning in rats and long-term potentiation in the dentate gyrus in vivo.

Recently, it was demonstrated by the use of the competitive and selective antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) that metabotropic glutamate receptor (mGluR) activation is required to induce long-term potentiation (LTP) in the hippocampus. Accordingly, we investigated whether MCPG also inhibits spatial learning. Rats were trained on a spatial alternation task in a Y-maze with footshock reinforcement, and MCPG (0.0208 mg) was injected intracerebroventricularly prior to training and/or retention test. Animals injected pre-training are clearly impaired in retention, whereas preretention application was without effect. A state dependency could be excluded. Additionally, MCPG at the same concentration completely blocks a potentiation at perforant path/dentate gyrus synapses in vivo. These results strongly implicate a role of mGluRs in spatial learning and LTP.

Animals↗

PubMedDate not supplied

Cholinergic modulation of spatial learning in mice in a Morris-type water maze.

Injection of the centrally active muscarinic antagonist scopolamine i.p. 20 min pre-test at 3 mg/kg but not at 1 mg/kg, impaired spatial learning of a Morris-type water maze adapted for mice. Both doses caused hyperactivity. D-amphetamine (3 mg/kg, i.p.), which also caused hyperactivity, did not impair spatial learning nor did methylscopolamine (3 mg/kg, i.p.). In a cued version of the water maze, apart from a temporary disturbance on day 1, scopolamine (3 mg/kg) and control groups behaved similarly, indicating that scopolamine-induced place learning deficits are not due to changes in swimming ability, motivation or ability to use proximal cues. Physostigmine (0.1 and 0.2 mg/kg, i.p.) and oxotremorine (0.02 mg/kg but not 0.01 mg/kg, i.p.) antagonized the deficits in the swimming maze. Neither drug affected the scopolamine hyperactivity despite causing hypoactivity per se. In contrast, the peripherally acting cholinergic drug neostigmine was inactive against scopolamine in either test at 0.1 mg/kg. THA (2-8 mg/kg, i.p.), RS86 (0.25-1 mg/kg, i.p.) and nicotine (1 and 3 mg/kg, i.p.) were also unable to antagonize the scopolamine effect. These studies show that scopolamine disrupts acquisition of spatial rather than cued learning in mice in a Morris-type water maze and that this effect appears to be mediated centrally and can be dissociated from drug-induced hyperactivity. Moreover, this deficit can be reversed with certain cholinergic agents.

Animals↗

PubMed2006

The effects of cytotoxic perirhinal cortex lesions on spatial learning by rats: a comparison of the dark agouti and Sprague-Dawley strains.

The effects of perirhinal cortex lesions in rats on spatial memory might depend on the choice of strain. The present study, therefore, compared perirhinal lesions in Sprague-Dawley rats (associated with deficits) with Dark Agouti rats (associated with null effects). Tests of reference memory and working memory in the water maze failed to provide evidence that perirhinal lesions disrupt overall levels of performance (irrespective of strain) or that these lesions have differential effects on the rates of spatial learning in these 2 strains. Strain differences were, however, found, as the Dark Agouti strain was often superior. Furthermore, the perirhinal lesions did have differential effects in the 2 strains, but these did not appear to relate directly to changes in spatial learning.

Animals↗