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Forgetting, reminding, and remembering: the retrieval of lost spatial memory.

Retrograde amnesia can occur after brain damage because this disrupts sites of storage, interrupts memory consolidation, or interferes with memory retrieval. While the retrieval failure account has been considered in several animal studies, recent work has focused mainly on memory consolidation, and the neural mechanisms responsible for reactivating memory from stored traces remain poorly understood. We now describe a new retrieval phenomenon in which rats' memory for a spatial location in a watermaze was first weakened by partial lesions of the hippocampus to a level at which it could not be detected. The animals were then reminded by the provision of incomplete and potentially misleading information-an escape platform in a novel location. Paradoxically, both incorrect and correct place information reactivated dormant memory traces equally, such that the previously trained spatial memory was now expressed. It was also established that the reminding procedure could not itself generate new learning in either the original environment, or in a new training situation. The key finding is the development of a protocol that definitively distinguishes reminding from new place learning and thereby reveals that a failure of memory during watermaze testing can arise, at least in part, from a disruption of memory retrieval.

Amnesia, Retrograde↗

Memory and long-term potentiation (LTP) dissociated: normal spatial memory despite CA1 LTP elimination with Kv1.4 antisense.

Long-term potentiation (LTP) in the hippocampal slice preparation has been proposed as an in vitro model for long-term memory. However, correlation of LTP with memory in living animals has been difficult to demonstrate. Furthermore, in the last few years evidence has accumulated that dissociate the two. Because potassium channels might determine the weight of synapses in networks, we studied the role of Kv1.4, a presynaptic A-type voltage-dependent K+ channel, in both memory and LTP. Reverse transcription-PCR and Western blot analysis with specific antibodies showed that antisense oligodeoxyribonucleotide to Kv1.4 microinjected intraventricularly into rat brains obstructed hippocampal Kv1.4 mRNA, "knocking down" the protein in the hippocampus. This antisense knockdown had no effect on rat spatial maze learning, memory, or exploratory behavior, but eliminated both early- and late-phase LTP and reduced paired-pulse facilitation (a presynaptic effect) in CA1 pyramidal neurons without affecting dentate gyrus LTP. This presynaptic Kv1.4 knockdown together with previous postsynaptic Kv1.1 knockdown demonstrates that CA1 LTP is neither necessary nor sufficient for rat spatial memory.

Animals↗

A detailed analysis of rats' spatial memory in a probe trial of a Morris task.

In the present study, we evaluated the search behavior of rats during a probe trial of a Morris water escape task. More specifically, the spatial memory during different stages of a 2 min probe trial in different zones was examined. After rats were trained for 4 days with four trials per day, their spatial memory was tested in a first probe trial. The rats showed a preference for the target quadrant during each of four 30-s intervals. The time in the annulus decreased across the four 30-s intervals. The preference for the previous target quadrant was also observed in a second probe trial, when the rats had received additional training for 4 days with four trials per day. However, the time spent in the annulus was highest during the first 30-s of the probe trial, and was lower and similar during the next three 30-s intervals. Therefore, probe trials of 60s seem to underestimate the spatial ability of rats. It appears that using a quadrant for assessing the performance may overestimate the spatial ability of a rat. Our findings suggest that the evaluation of the spatial memory of rats in a probe trial in the Morris water escape task requires a more detailed analysis.

Animals↗

Sleep deprivation impairs spatial memory and decreases extracellular signal-regulated kinase phosphorylation in the hippocampus.

Loss of sleep may result in memory impairment. However, little is known about the biochemical basis for memory deficits induced by sleep deprivation. Extracellular signal-regulated kinase (ERK) is involved in memory consolidation in different tasks. Phosphorylation of ERK is necessary for its activation and is an important step in mediating neuronal responses to synaptic activities. The aim of the present study was to determine the effects of total sleep deprivation (TSD) on memory and ERK phosphorylation in the brain. Rats were trained in Morris water maze to find a hidden platform (a spatial task) or a visible platform (a nonspatial task) after 6 h TSD or spontaneous sleep. TSD had no effect on spatial learning, but significantly impaired spatial memory tested 24 h after training. Nonspatial learning and memory were not impaired by TSD. Phospho-ERK levels in the hippocampus were significantly reduced after 6 h TSD compared to the controls and returned to the control levels after 2 h recovery sleep. Total ERK1 and ERK2 were slightly increased after 6 h TSD and returned to the control levels after 2 h recovery sleep. These alterations were not observed in the cortex after TSD. Protein phosphotase-1 and mitogen-activated protein kinase phosphatase-2, which dephosphorylates phospho-ERK, were also measured, but they were not altered by TSD. The impairments of both spatial memory and ERK phosphorylation indicate that the hippocampus is vulnerable to sleep loss. These results are consistent with the idea that decreased ERK activation in the hippocampus is involved in sleep deprivation-induced spatial memory impairment.

Animals↗

Histamine ameliorates spatial memory deficits induced by MK-801 infusion into ventral hippocampus as evaluated by radial maze task in rats.

AIM: To investigate the role of histamine in memory deficits induced by MK-801 infusion into the ventral hippocampus in rats. METHODS: An 8-arm radial maze (4 arms baited) was used to assess spatial memory. RESULTS: Bilateral ventral intrahippocampal (ih) infusion of MK-801 (0.3 microg/site), an N-methyl-D-aspartate (NMDA) antagonist, impaired the retrieval process in both working memory and reference memory. Intrahippocampal injection of histamine (25 or 50 ng/site) or intraperitoneal (ip) injection of histidine (25, 50 or 100 mg/kg) markedly ameliorated the spatial memory deficits induced by MK-801. Both the histamine H1 antagonist pyrilamine (0.5 or 1.0 microg/site, ih) and the H2 antagonist cimetidine (2.5 microg/site, ih) abolished the ameliorating effect of histidine (100 mg/kg, ip) on reference memory deficits, but not that on working memory deficits induced by MK-801. CONCLUSION: The results indicate that histamine in the ventral hippocampus can ameliorate MK-801-induced spatial memory deficits, and that histamine's effect on reference memory is mediated by postsynaptic histamine H1 and H2 receptors.

Animals↗

Reversal of scopolamine-induced spatial memory deficits in rats by TAK-147.

AIM: To evaluate effect of TAK-147 on spatial memory deficit induced by scopolamine. METHODS: Morris water maze was used to measure spatial memory in rats and open field test was used to analyse locomotor activity. RESULTS: In the acquisition memory process, scopolamine (0.4 mg/kg, ip) markedly increased the escape latency to the platform. Ip injection of both TAK-147 and donepezil ameliorated scopolamine-induced deficit, dose-related and significant effect was obtained at doses of 0.1-1.0 mg/kg. In the memory retrieval process, increased latency induced by scopolamine (1.5 mg/kg, ip) was also significantly reversed by treatment with TAK-147 (0.1, 0.3, and 1.0 mg/kg), donepezil (0.3 and 1.0 mg/kg), and tacrine (3 and 5 mg/kg), respectively. TAK-147 has a little potent efficacy to donepezil, and was more potent than tacrine. In the locomotor test, both TAK-147 and donepizil created no appreciable change of locomotor activities, compared with scopolamine or saline. CONCLUSION: TAK-147 plays an important role in spatial cognition, and this result provides additional evidence that TAK-147 is an ideal AChE inhibitor and is useful for the treatment of Alzheimer's disease.

Animals↗

Post-training intrahippocampal infusion of the COX-2 inhibitor celecoxib impaired spatial memory retention in rats.

In this study, we investigated the effects of intrahippocampal infusion of indomethacin as a non-selective cyclooxygenase inhibitor and celecoxib as a selective cyclooxygenase-2 inhibitor on spatial memory in the Morris water maze. Rats were trained for 3 days; each day included two blocks, and each block contained 4 trials. Tests were performed 48 h after surgery. Bilateral intrahippocampal infusion of indomethacin (0.01, 0.1, or 1 M) did not show any significant effect on spatial memory retention at these concentrations in rats. We also examined effects of infusion of celecoxib (0.02, 0.06, or 0.1 M) on memory retention. Bilateral infusion of 0.1 M celecoxib significantly altered escape latency and traveled distance in rats. These results strongly suggest that cyclooxygenase-2 is involved in spatial memory retention.

Analysis of Variance↗

Nicotine blocks stress-induced impairment of spatial memory and long-term potentiation of the hippocampal CA1 region.

The effect of chronic nicotine treatment on chronic psychosocial stress-induced impairment of short-term memory and long-term potentiation (LTP) was determined. An "intruder" stress model was used to induce psychosocial stress for 4-6 wk, during which rats were injected with saline or nicotine (1 mg/kg s.c.) twice a day. The radial arm water maze memory task was used to test hippocampus-dependent spatial memory. Chronic psychosocial stress impaired short-term memory without affecting the learning phase or long-term memory. Concurrent chronic nicotine treatment prevented stress-induced short-term memory impairment. In normal rats chronic nicotine treatment had no effect on learning and memory. Extracellular recordings from the CA1 region of anaesthetized rats showed severe reduction of LTP magnitude in stressed rats, which was normalized in nicotine-treated stressed rats. Nicotine had no effect on LTP in control animals. These results showed that chronic nicotine treatment improved hippocampus-dependent spatial memory and LTP only when impaired by stress.

Animals↗

Repetitive post-training exposure to enflurane modifies spatial memory in mice.

BACKGROUND: Previously the authors found that a single post-training exposure to enflurane or isoflurane, but not halothane, enhanced memory storage in an active avoidance task, which is a behavior with underlying mechanisms that are poorly understood and still debated. In contrast, spatial tasks are known to depend on hippocampal functions. This study investigated the effects of repetitive post-training exposure to enflurane on spatial memory in mice. METHODS: Using an eight-arm radial maze, 80 mice were trained to eat a pellet placed on the end of each of the eight arms. Training occurred on four consecutive days with one trial per day. The number of errors in the first eight choices was recorded to determine performances for each day of training. Immediately after each training session, mice in the enflurane group received 1 h exposure to 0.5%, 1%, or 2% enflurane in air through a calibrated vaporizer. The performance ratios (the ratio of errors on each day compared with the first day of the 4 days) in the control and the enflurane groups were compared. RESULTS: The performance ratios (which equals the mean of the error in the fourth day/the error in the first day) in the control, and 0.5%, 1%, and 2% enflurane groups were 0.66, 0.65, and 0.32 (P < 0.01, vs. control), and 0.46 (P < 0.05, vs. control), respectively. CONCLUSIONS: Repetitive post-training exposure to 1% and 2% enflurane significantly enhanced spatial memory in the eight-arm radial maze task. Enflurane enhances consolidation of spatial memory, possibly by affecting hippocampal activity.

Anesthetics, Inhalation↗

Spatial memory in the rat requires the dorsolateral band of the entorhinal cortex.

The extensive connections of the entorhinal cortex with the hippocampus and the neocortex point to this region as a major interface in the hippocampal-neocortical interactions underlying memory. We asked whether hippocampal-dependent recall of spatial memory depends on the entorhinal cortex, and, if so, which parts are critical. After training in a Morris water maze, rats received fiber-sparing lesions in the dorsolateral band of the entorhinal cortex, which mediates much of the visuospatial input to the dorsal hippocampus. These lesions entirely disrupted retention and retarded new learning. Spatial memory was spared by lesions in the ventromedial band, which connects primarily with ventral hippocampus, but these lesions reduced defensive behavior on an elevated plus maze, mirroring the effects of damage to ventral hippocampus. The results suggest that the functional differences between dorsal and ventral hippocampus reflect their connectivity with modules of the entorhinal cortex that are differently linked to the rest of the cortex.

Animals↗

Spatial memory deficits in patients with chronic bilateral vestibular failure.

The role of the vestibular system for navigation and spatial memory has been demonstrated in animals but not in humans. Vestibular signals are necessary for location-specific "place cell" activity in the hippocampus which provides a putative neural substrate for the spatial representation involved in navigation. To investigate the spatial memory in patients with bilateral vestibular failure due to NF2 with bilateral neurectomy, a virtual variant (on a PC) of the Morris water task adapted to humans was used. Significant spatial learning and memory deficits were shown in 12 patients as compared to 10 healthy controls. These data suggest that functional hippocampal deficits manifest due to a chronic lack of vestibular input in these patients. These deficits can even be demonstrated with the subjects stationary, i.e., without any actual vestibular or somatosensory stimulation.

Adult↗

Extensive cytotoxic lesions of the rat retrosplenial cortex reveal consistent deficits on tasks that tax allocentric spatial memory.

Despite the connections of the retrosplenial cortex strongly suggesting a role in spatial memory, the lesion data to date have been equivocal. Whether subjects are impaired after retrosplenial lesions seems to depend on whether the lesions were aspirative or excitotoxic, with the latter failing to produce an impairment. A shortcoming of previous excitotoxic lesion studies is that they spared the most caudal part of the retrosplenial cortex. The present study thus used rats with extensive neurotoxic lesions of the retrosplenial cortex that encompassed the entire rostrocaudal extent of this region. These rats were consistently impaired on several tests that tax allocentric memory. In contrast, they were unimpaired on an egocentric discrimination task. Although the lesions did not appear to affect object recognition, clear deficits were found for an object-in-place discrimination. The present study not only demonstrates a role for the retrosplenial cortex in allocentric spatial memory, but also explains why previous excitotoxic lesions have failed to detect any deficits.

Animals↗

Involvement of hippocampal NMDA and AMPA receptors in acquisition, formation and retrieval of spatial memory in the Morris water maze.

This study investigated the roles of hippocampal N-methyl-D-aspartate (NMDA) receptors and alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA) receptors in acquisition, consolidation and retrieval processes of spatial memory. Male Wistar rats with indwelling cannulae in the dorsal hippocampus received 4 training trials on the Morris water maze for consecutively 6 days. Rats received infusion of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5) or the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) into the hippocampus under one of the three schedules: 5 min prior to each daily training session, immediately after each daily training session or 5 min prior to the final testing trial. Pretraining intra-hippocampal infusion of 5.0 micrograms AP5 retarded acquisition. The same dose of AP5 given after training had little effect but a higher dose (10.0 micrograms) did slow down progress in the acquisition curve. Pretest infusion AP5 failed to affect memory retrieval. Pretraining intra-hippocampal infusion of 1.0 micrograms CNQX also impaired acquisition, but posttraining infusion of CNQX at 1.0 or 2.0 micrograms had no effect. However, pretest infusion of 1.0 micrograms CNQX markedly impaired retrieval of the already-formed spatial memory. These findings taken together suggest that acquisition in a spatial task involves hippocampal NMDA and AMPA receptors, consolidation of spatial memory involves NMDA receptors and retrieving such memory involves AMPA receptors.

2-Amino-5-phosphonovalerate↗

Topography of Arc/Arg3.1 mRNA expression in the dorsal and ventral hippocampus induced by recent and remote spatial memory recall: dissociation of CA3 and CA1 activation.

The understanding of the mechanisms of memory retrieval and its deficits, and the detection of memory underlying neuronal plasticity, is greatly impeded by a lack of precise knowledge of the brain circuitry that underlies the functions of memory. The specific roles of anatomically distinct hippocampal subdivisions in recent and long-term memory retention and recall are essentially unknown. To address these questions, we mapped the expression of Arc/Arg 3.1 mRNA, a neuronal activity marker, in memory retention at multiple rostrocaudal levels of the dentate gyrus, CA3, CA1, subiculum, and lateral and medial entorhinal cortices after a platform search in a water-maze spatial task at 24 h and 1 month compared with swim and naive controls. We found that the entorhinohippocampal neuronal activity underlying the recall of recent and remote spatial memory has an anatomically distributed and time-dependent organization throughout both the dorsal and ventral hippocampus that is subdivision specific. We found a dissociation in the activity of the entorhinal cortex, CA3, and CA1 over a period of memory consolidation. Although CA3, the dorsal hippocampus, and the entorhinal cortex demonstrated the most persistent learning-specific signal during both recent and long-term memory recall, CA1 and the ventral hippocampus displayed the most dramatic signal decline. We determined the coordinates of activity clusters in the hippocampal subdivisions during the platform search and their dynamics over time. Our mapping data suggest that although the level of corticohippocampal interaction is similar during the retrieval of recent and remote spatial memories, the mnemonic function of the hippocampus may have changed, and the activity underlying remote spatial memory could be anatomically segregated within hippocampal subdivisions in small segments.

Animals↗

Deprenyl and the relationship between its effects on spatial memory, oxidant stress and hippocampal neurons in aged male rats.

Oxidative stress may play a major role in the aging process and associated cognitive decline. Therefore, antioxidant treatment may alleviate age-related impairment in spatial memory. Cognitive impairment could also involve the age-related morphological alterations of the hippocampal formation. The aim of this study was to examine the relationship between the effects of deprenyl, an irreversible monoamine-oxidase B inhibitor, on spatial memory by oxidant stress and on the total number of neurons in the hippocampus CA1 region of aged male rats. In this study, 24-month-old male rats were used. Rats were divided into control and experimental groups which received an injection of deprenyl for 21 days. Learning experiments were performed for six days in the Morris water maze. Spatial learning was significantly better in deprenyl-treated rats compared to saline-treated rats. Deprenyl treatment elicited a significant decrease of lipid peroxidation in the prefrontal cortex, striatum and hippocampus regions and a significant increase of glutathione peroxidase activity in the prefrontal cortex and hippocampus. It was observed that deprenyl had no effect on superoxide dismutase activity. The total number of neurons in the hippocampus CA1 region was significantly higher in the deprenyl group than in the control group. In conclusion, we demonstrated that deprenyl increases spatial memory performance in aged male rats and this increase may be related to suppression of lipid peroxidation and alleviation of the age-related decrease of the number of neurons in the hippocampus. The results of such studies may be useful in pharmacological alleviation of the aging process.

Aging↗

Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment.

Chronic restraint stress causes significant dendritic atrophy of CA3 pyramidal neurons that reverts to baseline within a week. Therefore, the authors assessed the functional consequences of this atrophy quickly (within hours) using the Y maze. Experiments 1-3 demonstrated that rats relied on extrinsic, spatial cues located outside of the Y maze to determine arm location and that rats with hippocampal damage (through kainic acid, colchicine, or trimethyltin) had spatial memory impairments. After the Y maze was validated as a hippocampally relevant spatial task, Experiment 4 showed that chronic restraint stress impaired spatial memory performance on the Y maze when rats were tested the day after the last stress session and that tianeptine prevented the stress-induced spatial memory impairment. These data are consistent with the previously demonstrated ability of tianeptine to prevent chronic stress-induced atrophy of the CA3 dendrites.

Animals↗

Role of the parahippocampal region in spatial and non-spatial memory: effects of parahippocampal lesions on rewarded alternation and concurrent object discrimination learning in the rat.

Rats with aspiration or excitotoxic (NMDA) lesions of the parahippocampal region were trained on a series of behavioral tasks which consisted of: (1) a test of spatial memory (discrete trial rewarded alternation), (2) a black-white discrimination, and (3) a test of non-spatial memory commonly used in primate models of amnesia (visual concurrent object discrimination). Rats in both lesion groups were severely impaired on the concurrent discrimination, even though they were able to learn the black-white discrimination normally. Animals with aspiration lesions were also impaired on the spatial memory task, whereas those with NMDA lesions did not differ from controls. The results indicate that concurrent object discrimination is a particularly sensitive measure of hippocampal/parahippocampal functions and suggest that these structures in the rat may serve mnemonic functions which are qualitatively similar to those of human and non-human primates.

Animals↗

Passive and active processes in visuo-spatial memory: double dissociation in developmental learning disabilities.

The distinction between passive and active visuo-spatial memory has been useful to interpret various pattern of deficits reported in individual differences studies. However, this interpretation raises the issue of task difficulty, since active tasks could be failed simply because more complex and the corresponding deficit could reflect a reduced capacity of the system. We describe two children with Nonverbal Learning Disability whose performance provides evidence of a dissociation between passive and active memory processes. One of the children showed a selective impairment in passive tasks and performed flawlessly in active tasks, whereas the second child displayed the opposite pattern. These data suggest that a qualitative difference between passive and active processes does exist and that differences in performance do not reflect a lower/higher level of task difficulty. Further, these data underlie the importance of formulating theoretical models of visuo-spatial memory including both material-related (i.e., visual vs spatial) and process-related (i.e., passive vs active) distinctions.

Adolescent↗