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Amygdala kindling increased fear-response, but did not impair spatial memory in rats.

The behavioral effects of amygdala kindling, a model of experimental epilepsy in rats, are reported. The animals were stimulated twice a day until stage 5 (generalized clonic) seizures were obtained three times. Two weeks later the performance of the amygdala-kindled and sham-operated rats was tested in the open-field test, on the elevated plus maze, elevated bridges, and in the Morris water maze. The results show that amygdala kindling decreased exploratory and other motor activity in the open-field test, had anxiogenic effects on the elevated plus-maze, decreased boldness on the elevated bridges, but had a negligible affect in the spatial memory task. These results suggest that amygdala kindling affects the normal fear reaction of rats, a response that is known to be mediated through the amygdaloid pathways.

Amygdala↗

Impairment of hippocampal CA1 heterosynaptic transformation and spatial memory by beta-amyloid(25-35).

In Alzheimer's disease, the cholinergic damage (reduced neurotransmission) and cognitive impairment occur long before beta-amyloid (Abeta) plaque formation. It has not been established whether the link between soluble Abeta and cholinergic functions contributes to synaptic dysfunction that underlies the cognitive impairment. Here, we report that Abeta(25-35), an active form of Abeta, inhibited long-term synaptic modification that depends on the associative activation of cholinergic and GABAergic inputs when bilaterally injected intracerebroventricularly (icv; 200 microg/site). The Abeta microinjections did not affect single-pulse-evoked glutamatergic and GABAergic synaptic transmission onto the hippocampal CA1 pyramidal cells, while cholinergic intracellular theta; was dramatically reduced by the Abeta(25-35) injection. Spatial memory of the water maze task was also impaired by the bilateral icv Abeta(25-35) injections, while bilateral microinjections of the same dose of Abeta(35-25) was ineffective in affecting the long-term synaptic modification evoked by associative activation of cholinergic and GABAergic inputs, the cholinergic intracellular theta;, or producing memory impairments. Thus restoring the synaptic plasticity involved in this associative activation of cholinergic and GABAergic inputs may offer an important therapeutic target in the treatment of early Abeta-induced memory decline.

Amyloid beta-Peptides↗

Selective immunolesions of CH4 cholinergic neurons do not disrupt spatial memory in rats.

Adult male Long-Evans rats were subjected to bilateral lesions of the cholinergic neurons in the nucleus basalis magnocellularis (NBM) by injection of 0.2 or 0.4 microg 192-IgG-saporin in 0.4 microl phosphate-buffered saline. Control rats received an equivalent amount of phosphate-buffered saline. Starting 2 weeks after surgery, all rats were tested for locomotor activity in their home cage, beam-walking performance, T-maze alternation rates (working memory), reference and working memory performance in a water-maze task, and memory capabilities in the eight-arm radial maze task using uninterrupted and interrupted (delay of 2 min, 2 h and 6 h after four arms had been visited) testing procedures. Histochemical analysis showed a significant decrease of acetylcholinesterase (AChE)-positive reaction products (30-66%) in various cortical regions at the 0.2-microg dose. At the dose of 0.4 microg, there was an additional, although weak, damage to the hippocampus (17-30%) and the cingulate cortex (34%). The behavioral results showed only minor impairments in spatial memory tasks, and only during initial phases of the tests (reference memory in the water maze, working memory in the radial maze). The behavioral effects of the dramatic cholinergic lesions do not support the idea of a substantial implication of cholinergic projections from the NBM to the cortex in the memory processes assessed in this study, but they remain congruent with an involvement of these projections in attentional functions.

Acetylcholinesterase↗

The effect of steroid sulfatase inhibition on learning and spatial memory.

Steroid sulfatase inhibitors can enhance the concentration of the neurosteroid DHEAS in rat brain. Previous studies have demonstrated that the steroid sulfatase inhibitor (p-O-sulfamoyl)-N-tetradecanoyl tyramine (DU-14) could reverse scopolamine induced amnesia in rats in a passive avoidance memory paradigm. The intent of this study was to determine whether chronic pretreatment with DU-14 could reverse scopolamine amnesia and/or enhance spacial memory in the place, probe and cued versions of the Morris water maze (MWM). Rats were divided into four groups and administered IP for 15 days either DU-14 (30.0 mg/Kg) or corn oil (1.0 ml/Kg) vehicle. On training days animals were administered either scopolamine (1.0 mg/Kg) or saline (1.0 ml/Kg). The groups administered DU-14 displayed a significant enhancement in learning and spacial memory in the place version of the MWM, when compared to respective vehicle-scopolamine and vehicle-saline groups. In the probe version, the DU-14-saline group remained in the target quadrant of the maze significantly longer than any of the other groups indicating enhanced retention. In the cued version of the MWM, treatment with DU-14 did not significantly change escape latency suggesting that the steroid sulfatase inhibitor did not alter motivation or locomotion. These results suggest that the chronic administration of steroid sulfatase inhibitors enhance learning and spatial memory in rats.

Amnesia↗

Retroactive interference effects of surprising reward omission on serial spatial memory.

Reward omission was used to produce retroactive interference in a serial delayed-alternation task. Rats were given forced choices in 3 T mazes presented in succession followed by free choices in which the alternate arm in each maze was rewarded. Nonreward during the delay between forced- and free-choice runs produced a decrement in performance (i.e., retroactive interference) in comparison to reward during the delay. Interference in retention of the first maze in a list occurred when the second maze contained surprising reward or omission (i.e., an outcome contrary to previous training in that maze) in comparison to expected reward or omission. In addition to producing retroactive interference, omission sometimes increased alternation in the maze in which it occurred. These results support a differential rehearsal hypothesis of spatial memory.

Animals↗

The effect of hypothermia on the rat's spatial memory in the water tank task.

The effect of hypothermia on the retention of the water tank navigation task has been examined in 21 male hooded rats. After a 3-min swimming test on Day 1 the animals were trained on Days 2 and 3 (2 X 12 trials) to find a small submerged platform 1 cm below the surface of a large pool (120 cm in diameter) of opaque water. On Day 4, the rats were divided into three groups (n = 7) which were cooled to colonic temperatures of 22-24 degrees C (H1), 25-27 degrees C (H2), and 28-31 degrees C (H3), respectively, and given 12 retrieval trials in the water tank. Average escape latencies increased from 6 s in normothermic rats on Day 3 to 33, 19, and 12 s on Day 4 in the H1, H2, and H3 groups, respectively. Under the same testing conditions the performance of groups H1, H2, and H3 improved on Day 5 to 20, 8 and 6 s, respectively. It is concluded that spatial memory retrieval is resistant to mild hypothermia (30 degrees C), but that it is severely impaired at body temperatures below 25 degrees C. Reacquisition of the task is slowed down but not fully prevented in deep hypothermia.

Animals↗

Evidence from a partial report task for forgetting in dynamic spatial memory.

G. Sperling (1960) and others have investigated memory for briefly presented stimuli by using a partial versus whole report technique in which participants sometimes reported part of a stimulus array and sometimes reported all of it. For simple, static stimulus displays, the partial report technique showed that participants could recall most of the information in the stimulus array but that this information faded quickly when participants engaged in whole report recall. An experiment was conducted that applied the partial report method to a task involving complex displays of moving objects. In the experiment, 26 participants viewed cars in a low-fidelity driving simulator and then reported the locations of some or all of the cars in each scene. A statistically significant advantage was found for the partial report trials. This finding suggests that detailed spatial location information was forgotten from dynamic spatial memory over the 14 s that it took participants to recall whole report trials. The experiment results suggest better ways of measuring situation awareness. Partial report recall techniques may give a more accurate measure of people's momentary situation awareness than whole report techniques. Potential applications of this research include simulator-based measures of situation awareness ability that can be part of inexpensive test batteries to select people for real-time tasks (e.g., in a driver licensing battery) and to identify people who need additional training.

Adolescent↗

Tianeptine and its enantiomers: effects on spatial memory in rats with medial septum lesions.

Tianeptine, an atypical antidepressant that exhibits clinical efficacy in measures of depression and anxiety, has been reported to enhance learning and memory in rats under certain conditions, an effect not observed with other tricyclic antidepressants. The present study explores further the possibility that tianeptine or its enantiomers (S 16190 and S 16191) can enhance either learning or retention in animals in which the hippocampus has been made partially dysfunctional. The effects of tianeptine and its enantiomers were tested using an open field watermaze test, in rats with partial lesions of the medial septum/diagonal band of Broca (MSDB). When given to normal rats, tianeptine (10 mg/kg, i.p.) did not significantly affect learning as compared to animals injected with saline. We therefore created, in other animals, partial ibotenic acid lesions of MSDB and showed histochemically that these lesions reduced but did not abolish the density of acetylcholinesterase staining in the hippocampus. They impaired both the acquisition of place-navigation and the long-term retention of spatial information over 7 days. Against the baseline of impaired performance in animals with these lesions, neither tianeptine (10 mg/kg) nor its enantiomers (5 mg/kg) affected the rate of acquisition of place navigation. However, tianeptine did enhance the retention of spatial memory over 7 days. These results are discussed in relation to different effects that tianeptine may have on learning including its ability to block stress-induced dendritic re-modelling of the hippocampus.

Animals↗

The effects of selective lesions within the anterior thalamic nuclei on spatial memory in the rat.

Groups of rats received cytotoxic lesions centred in either the anterior thalamic nucleus (AM), the anterior ventral and anterior dorsal thalamic nuclei (AV/AD), or all three nuclei combined (ANT.T). These lesions were made by injecting N-methyl-D-aspartate acid (NMDA). These rats, and a group of surgical controls (SHAM), were trained on a rewarded forced-alternation task in a T-maze. While the selective AM and AV/AD lesions produced an initial acquisition impairment, only the animals with combined lesions (ANT.T) showed a persistent deficit throughout the 16 acquisition sessions. Subsequent testing with a cross-maze confirmed that the SHAM, AV/AD, and AM groups were able to use allocentric cues, while the ANT.T group were impaired. In contrast none of the three anterior groups were impaired on a subsequent egocentric discrimination and reversal task run in the same apparatus. A final test using the eight arm radial-maze, revealed marked deficits in the ANT.T group as well as milder deficits in the AV/AD group. The results from these experiments help to confirm the importance of the anterior thalamic nuclei for allocentric tasks, but suggest that no region is pre-eminently important. The findings also help to account for other studies which have reported that anterior thalamic lesions have seemingly mild effects on tests of spatial memory.

Animals↗

Altered activity, social behavior, and spatial memory in mice lacking the NTAN1p amidase and the asparagine branch of the N-end rule pathway.

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. N-terminal asparagine and glutamine are tertiary destabilizing residues, in that they are enzymatically deamidated to yield secondary destabilizing residues aspartate and glutamate, which are conjugated to arginine, a primary destabilizing residue. N-terminal arginine of a substrate protein is bound by the Ubr1-encoded E3alpha, the E3 component of the ubiquitin-proteasome-dependent N-end rule pathway. We describe the construction and analysis of mouse strains lacking the asparagine-specific N-terminal amidase (Nt(N)-amidase), encoded by the Ntan1 gene. In wild-type embryos, Ntan1 was strongly expressed in the branchial arches and in the tail and limb buds. The Ntan1(-/-) mouse strains lacked the Nt(N)-amidase activity but retained glutamine-specific Nt(Q)-amidase, indicating that the two enzymes are encoded by different genes. Among the normally short-lived N-end rule substrates, only those bearing N-terminal asparagine became long-lived in Ntan1(-/-) fibroblasts. The Ntan1(-/-) mice were fertile and outwardly normal but differed from their congenic wild-type counterparts in spontaneous activity, spatial memory, and a socially conditioned exploratory phenotype that has not been previously described with other mouse strains.

Amidohydrolases↗

Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory.

The fetal and even the young brain possesses a considerable degree of plasticity. The plasticity and rate of neurogenesis in the adult brain is much less pronounced. The present study was conducted to investigate whether housing conditions affect neurogenesis, learning, and memory in adult rats. Three-month-old rats housed either in isolation or in an enriched environment were injected intraperitoneally with bromodeoxyuridine (BrdU) to detect proliferation among progenitor cells and to follow their fate in the dentate gyrus. The rats were sacrificed either 1 day or 4 weeks after BrdU injections. This experimental paradigm allows for discrimination between proliferative effects and survival effects on the newborn progenitors elicited by different housing conditions. The number of newborn cells in the dentate gyrus was not altered 1 day after BrdU injections. In contrast, the number of surviving progenitors 1 month after BrdU injections was markedly increased in animals housed in an enriched environment. The relative ratio of neurogenesis and gliogenesis was not affected by environmental conditions, as estimated by double-labeling immunofluorescence staining with antibodies against BrdU and either the neuronal marker calbindin D28k or the glial marker GFAp, resulting in a net increase in neurogenesis in animals housed in an enriched environment. Furthermore, we show that adult rats housed in an enriched environment show improved performance in a spatial learning test. The results suggest that environmental cues can enhance neurogenesis in the adult hippocampal region, which is associated with improved spatial memory.

Aging↗

Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor.

In aged rodents, impairments in learning and memory have been associated with an age-dependent decline in forebrain of cholinergic function, and recent evidence indicates that the cholinergic neurons in the nucleus basalis magnocellularis, the septal-diagonal band area and the striatum undergo age-dependent atrophy. Thus, as in Alzheimer-type dementia in man, degenerative changes in the forebrain cholinergic system may contribute to age-related cognitive impairments in rodents. The cause of these degenerative changes is not known. Recent studies have shown that the central cholinergic neurons in the septal-diagonal band area, nucleus basalis and striatum are sensitive to the neurotrophic protein nerve growth factor (NGF). In particular, intraventricular injections or infusions of NGF in young adult rats have been shown to prevent retrograde neuronal cell death and promote behavioural recovery after damage to the septo-hippocampal connections. It is so far not known, however, whether the atrophic cholinergic neurons in aged animals are responsive to NGF treatment. We report here that continuous intracerebral infusion of NGF over a period of four weeks can partly reverse the cholinergic cell body atrophy and improve retention of a spatial memory task in behaviourally impaired aged rats.

Acetylcholinesterase↗

Ameliorative effect of tacrine on spatial memory deficit in chronic two-vessel occluded rats is reversible and mediated by muscarinic M1 receptor stimulation.

Our previous study demonstrated that permanent two-vessel occlusion (2VO)-induced working memory deficit was improved by daily administration of tacrine, a cholinesterase inhibitor. In this study, we investigated the mechanism underlying the effects of tacrine in 2VO rats using the eight-arm radial maze task. Daily administration of tacrine (0.1 or 0.3 mg/kg i.p.) started 5 weeks after the 2VO operation significantly improved the maze performance. In the delay-interposition task, a significant impairment of maze performance was observed in the tacrine (0.3 mg/kg, i.p.)-treated rats at a delay of 90 min but not delays of 5 or 30 min. Sham-operated rats were not affected by delay. After leaving animals with no further treatment for 4 weeks, the tacrine-pretreated 2VO rats showed significantly impaired performance compared to the sham-operated control animals. However, the performance of the tacrine-pretreated 2VO rats was significantly improved by restarting the daily administration of tacrine (0.3 mg/kg, i.p.). The effect of tacrine was reversed by the muscarinic antagonist scopolamine and the selective M1 antagonist pirenzepine. Moreover, a microdialysis study revealed that tacrine (1 or 3 mg/kg, i.p.) increased the extracellular acetylcholine (ACh) level for a period of over 3 h in the cerebral cortex of 2VO rats. These findings suggest that the ameliorative effect of tacrine on the spatial memory deficit in 2VO rats is reversible and may be mediated by stimulating the muscarinic M1 receptor via elevation of the extracellular ACh level in the brain.

Acetylcholine↗

Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone.

Oxygen free radicals and oxidative events have been implicated as playing a role in bringing about the changes in cellular function that occur during aging. Brain readily undergoes oxidative damage, so it is important to determine if aging-induced changes in brain may be associated with oxidative events. Previously we demonstrated that brain damage caused by an ischemia/reperfusion insult involved oxidative events. In addition, pretreatment with the spin-trapping compound N-tert-butyl-alpha-phenylnitrone (PBN) diminished the increase in oxidized protein and the loss of glutamine synthetase (GS) activity that accompanied ischemia/reperfusion injury in brain. We report here that aged gerbils had a significantly higher level of oxidized protein as assessed by carbonyl residues and decreased GS and neutral protease activities as compared to young adult gerbils. We also found that chronic treatment with the spin-trapping compound PBN caused a decrease in the level of oxidized protein and an increase in both GS and neutral protease activity in aged Mongolian gerbil brain. In contrast to aged gerbils, PBN treatment of young adult gerbils had no significant effect on brain oxidized protein content or GS activity. Male gerbils, young adults (3 months of age) and retired breeders (15-18 months of age), were treated with PBN for 14 days with twice daily dosages of 32 mg/kg. If PBN administration was ceased after 2 weeks, the significantly decreased level of oxidized protein and increased GS and neutral protease activities in old gerbils changed in a monotonic fashion back to the levels observed in aged gerbils prior to PBN administration. We also report that old gerbils make more errors than young animals and that older gerbils treated with PBN made fewer errors in a radial arm maze test for temporal and spatial memory than the untreated aged controls. These data can be interpreted to indicate that oxidation of cellular proteins may be a critical determinant of brain function. Moreover, it also implies that there is an age-related increase in vulnerability of tissue to oxidation that can be modified by free radical trapping compounds.

Aging↗

Distinctions between hippocampus of mouse and rat: protein F1/GAP-43 gene expression, promoter activity, and spatial memory.

We began these experiments as an attempt to replicate in the mouse the induction by kainate (KA) of F1/GAP-43 mRNA we observed in adult rat hippocampal granule cells [Mol. Brain Res., 33 (1995) 22-28]. However, even though KA induced behavioral seizures in the mouse similar to those in the rat, neither induction of F1/GAP-43 mRNA nor subsequent mossy fiber sprouting observed in the rat was detected in three different mouse strains. It was also surprising that the distribution of constitutive levels of F1/GAP-43 mRNA in mouse and rat hippocampus was qualitatively different. Indeed, F1/GAP-43 expression in CA3 pyramidal cells was significantly greater in rat than mouse, while F1/GAP-43 expression in CA1 cells of rat and mouse was equivalent using densitometric analysis. Thus, F1/GAP-43 expression in rat is quantitatively higher in CA3 and CA1 pyramidal cells. In mouse, expression was equivalent in these two subfields. In a transgenic mouse bearing a rat F1/GAP-43 promoter-reporter (lacZ) construct (line 252), in-vivo promoter activity of F1/GAP-43 was studied in hippocampal cells. Transgene expression in hippocampal pyramidal subfields, high in CA3, low in CA1 pyramidal cells, paralleled the distribution of rat F1/GAP-43 mRNA levels, not mouse. Differences in the constitutive F1/GAP-43 expression pattern in hippocampus between rat and mouse may therefore be determined by different recognition elements present on the F1/GAP-43 promoter. KA injected into the line 252 transgenic mouse did not activate the rat F1/GAP-43 promoter in mouse hippocampal granule cells. The absence of both F1/GAP-43 mRNA expression induction and promoter activation in mouse granule cells after KA is likely related to genera differences in transcriptional regulatory mechanisms, though post-transcriptional mechanisms cannot be excluded. Since the different hippocampal chemistry of F1/GAP-43 in rat and mouse likely extends to other molecular species, behaviors in rat and mouse that depend on hippocampal function might be different as well. We therefore evaluated spatial memory ability in a delayed matching-to-sample task. In contrast to rat, we were surprised to find no evidence of the ability to learn this task in three different mouse strains. Since interest in mouse genetics in relation to behavior and memory functions of hippocampus is growing, generalizations concerning hippocampal function from studies carried out on the mouse need to be made with caution considering the specific behavioral, pharmacological, and general molecular differences observed here. One can also be opportunistic and exploit the natural variations between these two genera to gain insight into the molecular mechanisms underlying information storage.

Animals↗

Estrogen replacement enhances acquisition of a spatial memory task and reduces deficits associated with hippocampal muscarinic receptor inhibition.

A delayed matching-to-position (DMP) T-maze task was used to examine the effects of estrogen replacement on spatial learning and memory, as well as the ability of estrogen replacement to reduce performance deficits produced by acute systemic and intrahippocampal muscarinic cholinergic inhibition. Two experiments were performed. In Experiment 1, ovariectomized animals were trained to criterion on the DMP task and then tested with increased intertrial delays and following systemic scopolamine administration. The animals then received either continuous estrogen replacement or sham surgery and were retested beginning 10 days later. In Experiment 2, ovariectomized animals received guide cannulae implanted bilaterally into the hippocampus. Half of these animals also began receiving continuous estrogen replacement. Two months later, the animals were trained on the DMP task and then tested with increased intertrial delays and following systemic as well as intrahippocampal scopolamine administration. Animals received the same test battery 8 months later and were then immediately trained on a reversal task. The results indicate that estrogen-treated animals acquired the DMP task at a significantly faster rate than the ovariectomized, non-estrogen-treated controls. In addition, estrogen replacement significantly reduced deficits in DMP performance produced by intrahippocampal, but not systemic, scopolamine administration. This occurred when animals were tested after 3.5 months, as well as after 12 months, of continuous estrogen replacement. No evidence for an effect of estrogen replacement on spatial working memory or reversal learning was detected. These findings demonstrate that estrogen replacement can enhance acquisition of a spatial memory task and reduce performance deficits associated with hippocampal cholinergic impairment.

Analysis of Variance↗

Spatial memory is related to hippocampal subcellular concentrations of calcium-dependent protein kinase C isoforms in young and aged rats.

Relationships were examined between spatial learning and hippocampal concentrations of the alpha, beta2, and gamma isoforms of protein kinase C (PKC), an enzyme implicated in neuronal plasticity and memory formation. Concentrations of PKC were determined for individual 6-month-old (n = 13) and 24-month-old (n = 27) male Long-Evans rats trained in the water maze on a standard place-learning task and a transfer task designed for rapid acquisition. The results showed significant relationships between spatial learning and the amount of PKC among individual subjects, and those relationships differed according to age, isoform, and subcellular fraction. Among 6-month-old rats, those with the best spatial memory were those with the highest concentrations of PKCgamma in the particulate fraction and of PKCbeta2 in the soluble fraction. Aged rats had increased hippocampal PKCgamma concentrations in both subcellular fractions in comparison with young rats, and memory impairment was correlated with higher PKCgamma concentrations in the soluble fraction. No age difference or correlations with behavior were found for concentrations of PKCgamma in a comparison structure, the neostriatum, or for PKCalpha in the hippocampus. Relationships between spatial learning and hippocampal concentrations of calcium-dependent PKC are isoform-specific. Moreover, age-related spatial memory impairment is associated with altered subcellular concentrations of PKCgamma and may be indicative of deficient signal transduction and neuronal plasticity in the hippocampal formation.

Aging↗

Remote spatial memory in an amnesic person with extensive bilateral hippocampal lesions.

The hippocampus may have a time-limited role in memory, being needed only until information is permanently stored elsewhere, or this region may permanently represent long-term allocentric spatial information or cognitive maps in memory. To test these ideas, we investigated remote spatial memory in K.C., a patient with bilateral hippocampal lesions and amnesia for autobiographical events. In his spatial knowledge, general aspects were preserved, but details were lost, a pattern that resembled his memory loss in other domains. K.C. performed normally on allocentric spatial tests of his neighborhood and the world. He had difficulty, however, in recognizing and identifying non-salient neighborhood landmarks, and in recognizing city locations on world maps. This suggests that the hippocampus is not crucial for maintenance and retrieval of remotely formed spatial representations of major landmarks, routes, distances and directions, but is necessary for specifying location details, regardless of when they were acquired.

Amnesia↗