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Testosterone fails to reverse spatial memory decline in aged rats and impairs retention in young and middle-aged animals.

Recently, the vasopressin (AVP) innervation in the rat brain was shown to be restored in senescent rats following long-term testosterone administration. In order to investigate whether this restoration is accompanied by an improvement in learning and memory, both sham- and testosterone-treated young (4.5 months), middle-aged (20 months), and aged (31 months) male Brown-Norway rats were tested in a Morris water maze. All animals learned to localize a cued platform equally well, indicating that the ability to learn this task was not affected by sensory, motoric, or motivational changes with aging or testosterone treatment. There were no significant differences in retention following cue training. Subsequent training with a hidden platform in the opposite quadrant of the pool (place training) revealed impaired spatial learning in middle-aged and aged animals. Retention following place training was significantly impaired in the sham-treated aged rats as compared with sham-treated young rats. Testosterone treatment did not improve spatial learning nor retention of spatial information, but, on the contrary, impaired retention in young and middle-aged animals. The present results confirm earlier reports on an impairment of spatial learning and memory in senescent rats but fail to support a role of decreased plasma testosterone levels and central AVP innervation in this respect.

Aging

Scopolamine degrades spatial working memory but spares spatial reference memory: dissimilarity of anticholinergic effect and restriction of distal visual cues.

The influence of the centrally active anticholinergic, scopolamine hydrobromide, on working and reference memory was studied in rats tested in a 12-arm radial maze. Both 0.25 and 0.5 mg/kg doses of the drug increased the number of working memory (WM) errors but had no effect on reference memory (RM) errors. A lower dose (0.125 mg/kg) was ineffective, as was the peripherally active anticholinergic, scopolamine methylbromide (0.5 mg/kg). Some of the behavioral effects of anticholinergics on spatial memory are mimicked by blindness or eliminating distal visual cues. If distal visual cues were more important for maintaining accurate WM than for RM, the selective effect of scopolamine on WM could be easily explained. But surrounding the maze with a curtain to eliminate extramaze cues increased RM errors without significantly increasing WM errors. Thus, the selective effect of anticholinergies on spatial memory in the radial maze is qualitatively different from the effect of restricting distal visual cues and must arise from some other action of the drug.

Animals

Deficits in spatial memory performance induced by early undernutrition.

Recent studies have shown that rats have a remarkable ability to keep track of their spatial location. Explanations stress the involvement of a form of short-term (working) memory in which the hippocampus appears to play a major role. The hippocampus appears to be vulnerable to early undernutrition and preliminary investigations indicate that Areas CA3 and CA4 suffer the most. Ninety-day-old rats, previously undernourished prenatally and throughout lactation, were tested in an 8- and, then, a 16-arm radial maze. Significant differences were observed between the experimental and control groups on both tests, especially in the 16-arm maze. Error distributions were also significantly different with experimental animals tending to perseverate in 1 area of the maze. Differences were also observed in the time taken to make the choices and in exploratory behavior. We conclude that early undernutrition affected the spatial learning ability of the animals and that this may be due to the distortions observed in the normal growth pattern of the hippocampus.

Animals

Galanin impairs acquisition but not retrieval of spatial memory in rats studied in the Morris swim maze.

The effect of intraventricular administration of the neuropeptide galanin on acquisition and retrieval in a modified Morris swim maze was studied in rats. Galanin induced a significant deficit in the acquisition of the task while no effects on the retrieval were observed. No deficits were seen 24 h after the last treatment. Galanin did not increase the number of failures to reach the platform. It is suggested that endogenous galanin modulates learning possibly via the galanin-containing cholinergic neurons in the septum-basal forebrain area projecting to the hippocampus and cortex.

Animals

Transgenic mice for the amyloid precursor protein 695 isoform have impaired spatial memory.

Transgenic mice for the human amyloid precursor protein 695 (APP695) isoform may provide an animal model of Alzheimer's disease (AD). To evaluate this, the spatial learning abilities of transgenic and wild strain mice were compared in the Morris water maze task. The transgenic mice were significantly retarded in initial learning and in learning a new escape location, although in each case they eventually reached control levels. The transgenic mice also showed slower swimming speed and reduced nocturnal activity, which may contribute to their deficit in spatial learning. Preliminary neuropathological investigations failed to reveal amyloid depositions. Thus, a gene dosage effect of APP695 may account for the memory impairment but not the plaque formation associated with AD.

Amyloid beta-Peptides

Spatial memory and perception in stroke patients: the importance of order effects.

The performance of left and right CVA patients on two tasks, spatial matching and spatial recognition, was compared, using a design which also examined the effects of order of task presentation. All groups performed better on matching than on recognition trials, and the left CVA subjects obtained higher scores than right CVA subjects on both types of trial. A significant lesion X order interaction reflected the particularly poor performance of right CVA subjects who received the more difficult task (recognition) first. The clinical implications are discussed.

Adult

The relationship between intelligence and verbal and spatial memory.

Administered the Logical Memory Test (LM) and the Rey-Osterreith Test (RO), which have been assumed to pertain to verbal and spatial cognitive functioning, to 150 Ss referred for neuropsychological screening. Ss also were administered the short version of the WAIS, plus Digit Span. It was found that LM did relate more to verbal IQ than to spatial IQ and vice-versa for RO. It was not clear exactly what aspect of cognitive functioning Digit Span was tapping. The clinical implications of the study are that LM scores must be viewed in the light of verbal IQ level, and RO scores interpreted in relation to both spatial IQ and age. Data are presented that can be used for the statistical interpretation of an individual case test scores.

Adolescent

Loss of hippocampal theta rhythm results in spatial memory deficit in the rat.

Rats learned, using distal room cues, to run to a goal on an elevated, circular track starting from any position on the track. The goal was one of eight equidistant, recessed cups set around the track, the goal cup being distinguished from the others solely by its position in the room. After learning, electrolytic lesions were made in the medial septal nucleus eliminating hippocampal theta rhythm in some animals but not in others. Rats without theta rhythm were no longer able to perform the spatial task, whereas rats with undisturbed theta rhythm retrained normal performance. Although rats without theta rhythm could not find their way directly to the goal, they recognized its location when they came upon it by chance. This type of spatial deficit appears similar to that shown by hippocampally lesioned patient H.M. Subsequent tests demonstrated that rats deprived of theta rhythm before training could nevertheless learn the task.

Animals

Effects of nicotine on spatial memory deficits in rats with septal lesions.

Impaired septohippocampal function has been implicated in the memory deficits associated with Alzheimer's disease (AD), and septal lesions have been used to model the cognitive deficits associated with AD. In this study, we assessed the effects of systemic administration of nicotine on lesion-induced deficits in the acquisition of a spatial discrimination version of the Morris water maze. Rats with radiofrequency lesions of the medial septum were required to learn which of two visible platforms in a pool of water provided a means of escape. On each of the first 4 days of training, the rats received an injection of (-)nicotine (0, 0.1 or 0.3 mg/kg, i.p.) before training. Nicotine markedly improved the performance of septal rats. This enhanced performance was maintained in rats subsequently tested 1 and 15 days later without additional drug treatment. Septal rats initially trained under nicotine were impaired, however, when the platform locations were reversed and training was conducted under saline. Our findings suggest that nicotinic receptor stimulation might be useful in the treatment of cognitive deficits.

Alzheimer Disease

Post-trial flicker stimulation interferes with spatial memory in the Morris water maze.

Rats (n = 20) trained under monocular viewing conditions in the working memory version of Morris water maze task received daily a single acquisition trial with a new location of the invisible escape platform followed after 15 min by a single retrieval trial. Escape latency decreased by 50% during retrieval. Flash stimulation (20 Hz, 0.6 J) during the entire 15-min delay disrupted retention, but this effect was not observed when the flashes started 3 or 5 min after acquisition. It is concluded that successful place learning requires a brief interference-free post-acquisition interval.

Animals

Nerve growth factor levels and choline acetyltransferase activity in the brain of aged rats with spatial memory impairments.

Nerve growth factor (NGF) and choline acetyltransferase (ChAT) activity levels were measured in 7 different brain regions in young (3-month-old) and aged (2-years-old) female Sprague-Dawley rats. Prior to analysis the spatial learning ability of the aged rats was assessed in the Morris' water maze test. In the aged rats a significant, 15-30%, increase in NGF levels was observed in 4 regions (septum, cortex, olfactory bulb and cerebellum), whereas the levels in hippocampus, striatum and the brainstem were similar to those of the young rats. The NGF changes did not correlate with the behavioral performance within the aged group. Minor 15-30%, changes in ChAT activity were observed in striatum, brainstem and cerebellum, but these changes did not correlate with the changes in NGF levels in any region. The results indicate that brain NGF levels are maintained at normal or supranormal levels in rats with severe learning and memory impairments. The results, therefore, do not support the view that the marked atrophy and cell loss in the forebrain cholinergic system that is known to occur in the behaviorally impaired aged rats is caused by a reduced availability of NGF in the cholinergic target areas. The results also indicate that the slightly increased levels of NGF are not sufficient to prevent the age-dependent atrophy of cholinergic neurons, although they might be important for the stimulation of compensatory functional changes in a situation where the system is undergoing progressive degeneration.

Aging

Temporally graded, age-related impairments in spatial memory in the rat.

We report here on the analysis of data from 6-, 12-, and 24-month-old Long-Evans rats tested in the Morris water maze. The animals were given 18 trials over a 5-day period with the platform submerged (spatial condition); 3 trials on the first day, 4 trials on each of the subsequent 3 days, followed by 3 trials on the fifth day. On the sixth day, the animals were given five trials in which the platform was elevated above the water level (cued condition). Over the 18 trials in the spatial condition, the 24-month-old animals took significantly longer to find the platform than did the 6-month-old animals; the performance of the 12-month-day animals lay between the older and younger groups. We then analyzed the latency data depending on the position of the trial in that day of testing: The first trial of each day followed the preceding trial by 20-22 hours, whereas the last trial of each day followed the preceding trial by only 20 minutes. The performance of the 12-month-old animals on the first trial of the second, third, and fourth days of testing was indistinguishable from that of the 24-month-old animals. Whereas, the performance of the 12-month-old animals on the last trial of the second, third, and fourth days of testing was indistinguishable from that of the 6-month-old animals. An analysis of the distance data (distance covered before locating the platform) revealed the same pattern of results.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors

Prenatal irradiation and spatial memory in mice: investigation of critical period.

Pregnant CD1 mice were exposed on various gestational or postnatal days to 1 Gy of 250 kV X-rays. Ten adult, male offspring from each exposure condition were tested in a radial arm maze. Compared to sham-exposed control mice, acquisition of spatial information was unimpaired in animals exposed on gestational days 13 or 15, or on postnatal day 10, but animals exposed on gestational day 18 or postnatal day 1 showed sustained deficits in acquisition. These results appear consistent with the known time-course for the proliferation and migration of the dentate granule cells of the hippocampus in the mouse, and are discussed in relation to the dependence on hippocampal integrity of the acquisition and use of spatial information. The results suggest that comparable deficits in mental function might be expected in humans similarly exposed to ionizing radiation during periods of proliferation and migration of the dentate granule cells.

Animals

MK-801 impedes the acquisition of a spatial memory task in rats.

Several studies have reported that MK-801 impairs the acquisition of various learning and memory tasks, while others suggest that MK-801 may interfere with performance rather than having a specific effect on memory. To characterize further the effects of MK-801 on learning and memory, MK-801 (0.05 mg/kg, SC) was administered prior to or immediately after learning trials in a trial-independent water maze task. Since MK-801 may affect nonassociative variables that may influence learning and memory, motor activity and general reactivity measures were also determined for 0.0125, 0.025, or 0.05 mg/kg of MK-801 administered SC. Since MK-801 may also be used to treat children with epilepsy, we investigated the possible persistent cognitive effects on neonates. MK-801 (0.02 mg/kg, SC) was administered at postnatal days 9-15 and tested in the same task as above starting at day 36 of age. There were no persistent effects of neonatal treatment. However, in adult rats, MK-801 impaired the acquisition of the water maze task but did not affect performance during a recall task in the same apparatus. At doses affecting learning, there were no effects on motor activity or general reactivity in adult rats. These results are consistent with the conclusion that MK-801 interferes with acquisition of spatial learning in the rat.

Aging

Can age-related deficits in spatial memory be attenuated through the use of verbal coding?

In a sequential mental rotation task, women of three age groups (18-28, 50-60, and 70-80) viewed semi-abstract figures which were rotated in the picture plane. To investigate the effects of verbal mediation, each figure was presented under one of four labeling conditions. Errors increased as a function of age. Meaningful labels were beneficial in decreasing errors for the older subjects. Reaction time results generally replicated earlier studies, but there were indications that some women in the oldest group might have used strategies other than mental rotation. Results suggest that possible age related deficiencies in spatial abilities may be compensated for by greater use of verbal mediation.

Adolescent

Locomotion, active choice, and spatial memory in children.

In two studies, children between 4 and 6 years old were tested on a radial search task requiring nonredundant sampling of eight identically labeled positions in a room. In the training phase (5 days), children made free choices by walking between positions, were passively transported in a pushchair, actively directed their own route from a pushchair, or were led on foot to positions selected by the experimenter. When tested (whether walking or directing while seated in a pushchair), children who had either walked independently or directed the experimenter while being pushed performed competently; those led on foot without spatial choice performed almost as well. Only the children who had neither independent locomotor experience nor autonomous choice performed very poorly. The results are related to neurobiological models of spatial cognition and may have implications for the transportation of children with mobility problems.

Child, Preschool

Effects of systemic and intracerebroventricular administration of mecamylamine, a nicotinic cholinergic antagonist, on spatial memory in rats.

The effects of both systemic and intracerebroventricular administration of mecamylamine, a nicotinic antagonist, were tested on the Morris water maze performance of rats. In experiment 1, mecamylamine (0, 3, and 10 mg/kg, IP) was administered before daily training sessions on the Morris water maze, a task in which rats use environmental cues to learn the location of an invisible escape platform in a large pool of water. The escape latencies of rats given the higher dose of mecamylamine were significantly longer than the latencies of rats given either saline or the peripherally-acting nicotinic antagonist hexamethonium (10 mg/kg). Analysis of search patterns during a free swim trial conducted in the absence of an escape platform confirmed the disruptive effects of the higher dose of mecamylamine. Similar drug effects were not observed when these rats were trained to a visible platform, and mecamylamine did not affect the retrieval of spatial information in well-trained rats. In experiment 2, similar effects were observed with ICV administration of mecamylamine (0, 10, 30, and 100 micrograms). The two higher doses increased escape latencies during the last day of place training and all three doses significantly impaired performance on a free swim. No significant effects were noted on subsequent training to a visible platform, and only the highest dose marginally impaired the retrieval of spatial information in well-trained animals. Thus, mecamylamine appears to impair the acquisition of spatial information in the Morris water maze but does not affect retrieval of previously acquired spatial information at comparable doses.

Animals

Pigeons' spatial memory: III. Effect of distractors on delayed matching of key location.

The effect of distractors on pigeons' delayed matching of key location was investigated. Baseline trials began with a "ready" stimulus (brief operation of the grain feeder). Then one (randomly chosen) key from a three-by-three matrix was lit briefly as the sample. After a short delay (retention interval) the sample key was lit again along with one of the other eight keys. A peck at the key that had served as the sample (correct comparison) produced grain reinforcement, whereas a peck to the other key (incorrect comparison) produced only the intertrial interval. In Experiment 1, a houselight distractor, presented during either the sample, retention interval, or choice phases of the trial, had little if any effect on accuracy of matching key location. In Experiment 2, one of three types of spatial stimuli was interpolated during the retention interval, or the interval was blank as during baseline trials. The three stimuli were: the sample (correct comparison) location for that trial, the incorrect comparison location for that trial, or one of the seven unused locations for that trial. Relative to blank trials, accuracy improved slightly on sample-interpolated trials, decreased slightly on unused location-interpolated trials, and decreased considerably on incorrect comparison-interpolated trials. In Experiment 3, retention intervals were blank or had one of six types of interpolation: the sample, the incorrect comparison, two presentations of the sample, two presentations of the incorrect comparison, the sample followed by the incorrect comparison, or the incorrect comparison followed by the sample.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals