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Aging of glutamate receptors: correlations between binding and spatial memory performance in mice.

C57B1/6 mice aged 3, 10, and 26 months were tested for spatial learning in the Morris water maze. Ten and 26 month old mice were ad libitum-fed or diet restricted (60% of ad libitum-fed calories). Diet restriction significantly improved memory performance among the 10 and 26 month olds. In age/diet group comparisons, aged ad libitum-fed mice had significantly higher average proximity scores, indicating poorer performance, in probe trials for place learning than the 3 month olds and diet restricted 10 month olds. Diet restricted 26 month olds did not differ significantly from 3 month olds or any other groups in probe trial measures. The group means for average proximity scores were significantly correlated with binding densities for the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in the frontal cortex and CA1 region of the hippocampus. Alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) binding correlated with group proximity scores in frontal and parietal cortices and within the CA1 and CA3 regions of the hippocampus. Kainate and metabotropic binding sites showed no significant correlations with behavior. These results suggest that there is a sparing of spatial memory with diet restriction in aging C57B1/6 mice and that the effects of aging on NMDA and AMPA receptors may be associated with age-related declines in spatial learning.

Aging

Effect of intraventricular injections of dihydro-beta-erythroidine (DH beta E) on spatial memory in the rat.

The analysis of the behavioral effect of the nicotinic acetylcholine receptor (nAChR) antagonists has been generally based on drugs which act at the associated ion channel. In contrast dihydro-beta-erythroidine (DH beta E) is a competitive antagonist at the nAChR. Using rats, DH beta E was injected intraventricularly prior to training in two spatial tests, the Morris Water Maze and a Win-Stay radial maze. In addition DH beta E 300 nmol was used to reverse the effect of (-)-nicotine on locomotor activity. In the Morris Water Maze DH beta E (300 nmol) disrupted memory of the platform location as measured by crosses of the area in a probe trial. At 300 nmol DH beta E showed no sensorimotor effects in a visible platform test. In the Win-Stay task there was a significant, dose dependent disruption of spatial memory. A dissociation of nicotine's effects on locomotor activity was observed, in that DH beta E 300 nmol was able to significantly attenuate (-)-nicotine enhancement of horizontal motor activity, but did not affect the initial reduction of vertical activity. Nicotinic processing of memory appears to be involved in these tests of spatial memory.

Animals

Spatial memory over long retention intervals: nonmemorial factors are not necessary for accurate performance on the radial-arm maze by rats.

A. Markowska, O. Buresová, and J. Bures (1983, Behavioral and Neural Biology, 38, 97-112) argued that the apparent persistence of accurate spatial working memory over delays of several hours arises from the formation of response strategies and the use of olfactory stimuli that develop with extended training at long delays. To test this explanation rats with extensive prior training at long delays were forced to enter the first four arms in a random order. On test days, the maze was rotated 180 degrees during the 2-h retention interval to determine whether the rats were using intramaze or extramaze (i.e., spatial) cues to guide their choices. On both rotation and control days, postdelay choices were spatially guided, averaging over 90% correct. Accurate spatial working memory at long delays is a reproducible phenomenon and does not appear to result from nonmemorial artifacts.

Animals

Dissociation of item and order spatial memory in rats following medial prefrontal cortex lesions.

In order to test whether there is a correspondence in function of prefrontal cortex in rats and humans, rats with medial prefrontal cortex lesions were tested for item and order memory for a list of items (spatial locations in a maze). Results indicate that for order memory rats with medial prefrontal cortex lesions cannot remember the order of presentation of four or eight specific spatial locations. This inability to remember order information can be seen even when animals with lesions have to remember only two spatial locations, can self-order the sequence of four or eight spatial locations, or have been presented with the same study phase on every trial. In contrast, for item memory animals with medial prefrontal cortex lesions retain the first item of the list in the variable study phase situation and remember all the items of the list in a constant study phase situation. However, there are also deficits for the last items within a list in the variable study phase situation for both win-stay and win-shift procedures. This deficit might be a function of an impairment in the utilization of appropriate temporal strategies, which normally would facilitate recognition memory in the win-stay and win-shift tasks. In general, the data suggest a partial, but not complete, dissociation of item-order memory. Furthermore, the data suggest that the medial prefrontal cortex is involved in temporal structuring of information.

Animals

Effects of MK-801 on spatial memory in homing and nonhoming pigeon breeds.

Homing pigeon breeds, the product of artificial selection on the basis of navigational and spatial ability, differ from nonhoming breeds in hippocampal size and distribution of N-methyl-D-aspartate (NMDA) dependent receptors. The effects of MK-801 (0.1 mg/kg administered intraperitoneally), a noncompetitive NMDA antagonist, on spatial reference memory (RM) were compared between the 2 breeds in a radial arm maze task. MK-801 disrupted the acquisition of RM in the nonhoming group but not the homing group, which was equivalent to the 2 saline-only control groups. As in previous findings with mammals, working memory was not affected by MK-801. This behavioral dissociation, coupled with differences in NMDA-dependent long-term potentiation between breeds, suggests an exceptional opportunity to investigate the role and function of the dorsomedial telencephalon region in spatial RM, through anatomical, neurochemical, and behavioral comparisons between homing and nonhoming pigeon breeds.

Animals

Verbal and spatial memory span in patients with extrapyramidal diseases.

Spatial span (Corsi's block-tapping test) and verbal span (Wechsler's Digits Forward test) were measured in 651 normal subjects and in three groups of extrapyramidal patients (Progressive supranuclear palsy, Parkinson, and Huntington's Chorea). Analysis showed Huntington's Chorea patients scored lower on both tests than did controls and other groups.

Adult

Effects of medetomidine, an alpha-2 adrenoceptor agonist, and atipamezole, an alpha-2 antagonist, on spatial memory performance in adult and aged rats.

The effects of a novel, highly selective alpha-2 agonist, medetomidine, and its antagonist, atipamezole, were studied on the working memory of rats performing a spatial delayed alternation task. Testing was performed in two stages, at the age of 8.3 months (mean) and again when the rats were 17.6 months (mean). A low dose (3 micrograms/kg) and a high dose (30 micrograms/kg) of medetomidine improved the performance of the old rats in the memory task but had no effect on the young rats. The dose-response curve of medetomidine resembles that of guanfacine, another alpha-2 agonist. At the low dose of medetomidine (3 micrograms/kg) the animals showed no signs of sedation. Since medetomidine even at a low dose has a beneficial effect on the memory performance of old rats, it could be a good candidate for the treatment of age-associated memory dysfunction.

Adrenergic alpha-Agonists

Spatial and temporal contributions to the structure of spatial memory.

Three experiments investigated the effects of spatial and temporal contiguity in item recognition, location judgment, and distance estimation tasks. Ss learned the locations of object names in spatial arrays, which were divided into 2 regions. The names of locations were presented during map learning so that critical pairs appeared close in space and close in time, close in space but far in time, far in space but close in time, and far in space and far in time. Names primed each other in recognition only when they were neighbors in both space and time. In contrast, the effects of spatial and temporal contiguity in priming in location judgments were additive. Finally, temporal contiguity affected estimates of Euclidean distance when locations were close together, but not when they were far apart.

Adult

Lesions of perirhinal cortex produce spatial memory deficits in the radial maze.

Rats with bilateral electrolytic lesions of perirhinal cortex (PRC) or sham control (SHAM) lesions were tested in spatial reference and working memory tasks in the radial arm maze. In experiment 1, one arm of the maze was baited and always located in a fixed position relative to the extra-maze environment. PRC lesioned animals made a significantly greater number of errors than did SHAM animals during initial training in this reference memory task and exhibited a delay-dependent impairment on trial 5 in a series when a delay period of 5, 60, 120, or 240 s was inserted between trials 4 and 5. In experiment 2, when a second group of the animals was tested on the standard radial arm maze working memory task, the performance of the PRC group was markedly impaired relative to controls. These data demonstrate that electrolytic PRC lesions result in a deficit in both spatial reference and spatial working memory tasks. These effects are interpreted as being consistent with the idea that PRC plays an important role in episodic memory processes. These processes may include the storage of information, which is required for the performance of spatial tasks.

Animals

Septo-hippocampal and nBM-cortical cholinergic neurones exhibit differential time-courses of activation as a function of both type and duration of spatial memory testing in mice.

We previously showed that the initial acquisition session of a spatial discrimination (mixed reference/working memory) test in an 8-arm radial maze induced differential activations in the ascending cholinergic septo-hippocampal and nBM-cortical pathways in mice. This data showed that the duration of post-test cholinergic activation was longer in the nBM-cortical pathway than in the septo-hippocampal projection. Moreover, the post-test durations but not the immediate post-test amplitudes of activation in each pathway decreased progressively as a function of repeated daily acquisition sessions. In the present study we have thus tested the hypotheses that the time-courses of post-test cholinergic activation in the septo-hippocampal and nBM-cortical pathways may vary both as a function of the type of memory used (working vs. reference) and according to the duration of repeated daily testing. Cholinergic activity in vivo in the hippocampus or frontal cortex of mice was quantified using measures of sodium-dependent high-affinity choline uptake at two different times (30 s and 15 min) following specific spatial working or reference memory testing in an 8-arm radial maze. The memory tests were administered daily over a 13-day period to attain high levels of performance in each type of task. In comparison to control groups both types of memory testing induced significant post-test cholinergic activations in each brain region on Day 15. However, cholinergic activity remained elevated in frontal cortex at 15 min post-test following reference memory testing, whereas significantly shorter durations of cortical and hippocampal cholinergic activation were observed following working memory testing using short (1 min) retention intervals. The possible significance of these differential modifications to the time-course of the post-test activations in these cholinergic pathways in working and reference memory processes and the putative transsynaptic mechanisms involved are discussed.

Animals

Preserved spatial memory in old rats survives 10 months without training.

Aged rats with extensive prior training on the radial maze retain the capacity for accurate spatial working memory (WM) for at least 3 months without practice. To investigate the temporal limits of this influence of prior experience we compared the reacquisition of spatial WM by a group of experienced 21.5-month-old rats to the original acquisition by naive 3-month-old rats. The aged rats had received 225 radial maze tests between 3 and 11 months of age. Despite 10 months without practice the old rats rapidly reacquired critical performance. Their reacquisition was markedly superior to original learning by the young rats, even when delays as long as 5 h were imposed between the rats' fourth and fifth choices during the daily tests in the eight-arm maze. Additional tests showed that neither young nor old rats employed a response strategy to maintain accurate spatial WM performance. Experience clearly confers long-lived protection against the otherwise deleterious effects of aging on spatial WM, but the mechanism by which this influence arises is unknown.

Aging

Loss of NGF receptor immunoreactivity in basal forebrain neurons of aged rats: correlation with spatial memory impairment.

Nerve growth factor (NGF) has recently been implicated as a trophic agent in the survival and maintenance of basal forebrain cholinergic neurons. To test the hypothesis that NGF may play a role in the age-related decline of cerebral cholinergic function and loss of cognitive ability, we investigated the possible correlation between the loss of basal forebrain neurons that stain for NGF receptor, and impairment of spatial reference memory performance in aged rats. Our results suggest that NGF receptor-positive basal forebrain neurons undergo marked cell atrophy and loss of neuropil staining in aged rats exhibiting impaired spatial learning and memory performance. Conversely, numerous, densely immunoreactive perikarya and a profuse neuritic plexus within the basal forebrain nuclei was consistently observed in behaviorally intact rats. Overall, the mean number of NGF receptor-positive basal forebrain neurons both in the nucleus of the diagonal band and nucleus basalis correlated with retention of the spatial task (r = 0.84 and r = 0.67, respectively; P less than 0.01). Our results support the view that progressive failure of retrograde trophic support due to the age-related loss of NGF receptors may promote degenerative changes in basal forebrain cholinergic neurons, and contribute to deterioration of cognitive ability in senescence.

Aging

Anatomical specificity and time-dependence of chlordiazepoxide-induced spatial memory impairments.

Injection of the benzodiazepine (BDZ) chlordiazepoxide (CDP) into the medial septum (MS) produced a dose-dependent retrograde working memory deficit in a delayed non-match-to-sample radial-arm maze task. CDP (30 nmol; 10 micrograms) decreased the number of correct choices and increased the number of errors without altering latency to make arm choices. The effects of CDP were site specific; injection into regions proximate to the MS, including the lateral septum, the anterior cingulate, and the nucleus basalis magnocellularis, did not affect any index of performance. The second experiment demonstrated that CDP impaired working memory only when rats were injected either 0 or 60 min, but not 15, 30, or 45 min, following training. The MS appears (a) to contribute to both early (encoding/ maintenance) and late (retrieval/utilization) phases of working memory and (b) to be a critical site of action for BDZ-induced deficits in spatial working memory.

Animals

N-methyl-D-aspartate receptor antagonist MK-801 and spatial memory representation: working memory is impaired in an unfamiliar environment but not in a familiar environment.

Female Sprague-Dawley rats were injected with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 or saline 30 min before daily testing in spatial working memory (WM) and reference memory (RM) procedures in an 8-arm radial maze. MK-801 impaired RM and WM acquisition but not performance when rats were trained to criterion before drug administration. Neither a 2-hr nor a 4-hr delay between the first and last 2 correct WM choices impaired long-term WM. MK-801 impaired WM performance in trained rats only when rats were tested in a new environment. Thus, 2 mechanisms may be required for relational memory: an NMDA-dependent mechanism for acquiring long-term spatial representations and an NMDA-insensitive mechanism for operating on these stored representations.

Animals

Both here and there: simultaneous expression of autonomous spatial memories in rats.

Foraging rats learned to avoid footshock that was present in a part of a circular arena that was either stable or rotating slowly in a lighted room. The rotation dissociated spatial information in the separate reference frames of the room and arena. After learning to avoid the shocked region in either condition, in the absence of shock, memory for this place was expressed by simultaneous avoidance of an area defined in the reference frame of the room as well as of an area defined in the reference frame of the rotating arena. Spatial memories in these distinct reference frames were acquired, retrieved, and extinguished autonomously.

Animals

Spatial memory in alcohol-dependent subjects: using a push-button maze to test the principle of equiavailability.

The principle of equiavailability states that once the locations in a spatial array are learned, then all locations in the array are simultaneously available in memory (Levine, Jankovic, & Palij, 1982). To test the application of this principle, 21 nonamnesic, alcohol-dependent, male subjects and 20 demographic and ability-matched male control subjects were required to learn a series of push-button maze paths and to perform shortcut or retrace movements on the paths. The results for the control subjects conformed to the principle of equiavailability. In contrast, the alcohol-dependent subjects did not show equiavailability. This pattern of results is interpreted as evidence of a spatial memory deficit in the alcohol-dependent subjects.

Adult

Spatial memory and N-methyl-D-aspartate receptor antagonists APV and MK-801: memory impairments depend on familiarity with the environment, drug dose, and training duration.

Rats given N-methyl-D-aspartate (NMDA) antagonists were tested in the radial maze in spatial working memory (WM) and reference memory (RM) tasks. Female rats given (+)-10,11-dihydro-5-methyl-5H-dibenzo [a,d] cycloheptene-5,10 imine (MK-801; 0.0625 mg/kg ip) before daily testing in an 8-arm WM task were impaired even after 70 days. Control rats learned quickly, were assigned to a group given MK-801 or saline, and were trained to avoid 4 of the 8 arms. MK-801 impaired this reversal learning but did not affect WM performance. Male rats were trained on an 8-arm WM task for 19 days and then given intracranial aminophosphonovaleric acid (APV; 33 mM), which impaired both WM and motor behavior. Male rats were trained for 65 days to enter 4 of 8 arms and then given intracranial APV (20 or 30 mM). WM and RM were normal in the familiar environment but were both impaired in an unfamiliar environment. Results suggest that the mnemonic effects of NMDA antagonists depend on environmental familiarity, dose, and training duration.

2-Amino-5-phosphonovalerate

Behavioral parameters of the spatial memory correlate with the potentiation of the population spike, but not with the population excitatory postsynaptic potential, of the CA1 region in rat hippocampal slices.

Rats were tested for spatial performance in a water maze with further in vitro investigation of short-term and long-term potentiation (STP and LTP) in the CA1 region of the hippocampus. Recordings of the population spike in stratum pyramidale and population excitatory postsynaptic potential (EPSP) in stratum radiatum were made with extracellular electrodes after stimulation of the radiatum and oriens inputs in the region. It was found that for both inputs, STP and LTP of the population spike amplitude correlated with behavioral parameters of memory: latency of reaching the hidden platform (escape latency) and percent of time which the animal spent inside the quadrant with the platform. Potentiation of the initial slope of EPSP, in contrast, did not correlate with these parameters. These data support the hypothesis that hippocampal LTP may underlie spatial performance and show that potentiation of the output characteristic of the hippocampus (population spike), but not of the EPSP, is a physiological correlate for spatial memory.

Action Potentials