Various degrees within a single drive as cues for spatial response learning in the white rat.
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Comparison of four spatial maze learning tests with methylnitrosourea-induced microcephaly rats.
The usefulness of four spatial maze learning test methods, single T-maze, Biel water maze, Morris water maze, and radial eight-arm maze, was compared using rats with different degrees of microcephaly, which were induced by single intraperitoneal injection with 3 and 5 mg/kg of methylnitrosourea (MNU) on day 13 of gestation. The single T-maze test did not detect a learning defect in either MNU group. In the Biel water maze test, the swimming time and number of errors were increased in the 5 mg/kg group, but these parameters were comparable to the control values in the retention and path B (reverse course) tests. On the Morris water maze task, the 5 mg/kg group required longer swimming time and distance to reach the goal. In the retest with the goal set on an opposite side, the swimming distance in the 5 mg/kg group was as long as the value in the original test. The radial eight-arm maze test detected fewer correct choices in both MNU groups, which showed different responses on this task. The brain weights in the 3 and 5 mg/kg groups were approximately 80 and 60% of the control value, respectively. The cerebral cortex weights were 77 and 50% of the control value, and the hippocampus weights were 78 and 51%. Among the four maze tests, only the radial eight-arm maze test could detect the effect of both doses of MNU. This shows that the method has the highest sensitivity to spatial learning defect in MNU-induced microcephalic rats.
Abnormalities, Drug-Induced↗
Interleukin-1 beta, but not interleukin-6, impairs spatial navigation learning.
The effects of the cytokines interleukin-1 and -6 (IL1 beta, IL6; 100 ng) on spatial learning were examined in the Morris water maze. Intracerebroventricular injection of IL1 or IL6 before the training on day 1 did not influence the acquisition of spatial navigation. However, IL1 administered at 60 min, but not immediately before the training, resulted in impaired performance of spatial navigation the following day. In contrast, IL6 administered at both times had no effect. In a second experiment the same doses of IL1 and IL6 increased the body temperature of rats in a time-related fashion. The temperature effect of IL1 developed after a delay of 120 min, while the IL-6-effect was immediate. Comparable behavioral changes might accompany infections or inflammatory diseases and therapeutic cytokine administration.
Animals↗
Exposure to chronic psychosocial stress and corticosterone in the rat: effects on spatial discrimination learning and hippocampal protein kinase Cgamma immunoreactivity.
Previous reports have demonstrated a striking increase of the immunoreactivity of the gamma-isoform of protein kinase C (PKCgamma-ir) in Ammon's horn and dentate gyrus (DG) of rodent hippocampus after training in a spatial orientation task. In the present study, we investigated how 8 days of psychosocial stress affects spatial discrimination learning in a hole board and influences PKCgamma-ir in the hippocampal formation. The acquisition of both reference memory and working memory was significantly delayed in the stressed animals during the entire training period. With respect to cellular plasticity, the training experience in both nonstressed and stressed groups yielded enhanced PKCgamma-ir in the CA1 and CA3 regions of the posterior hippocampus but not in subfields of the anterior hippocampus. Stress enhanced PKCgamma-ir in the DG and CA3 pyramidal cells of the anterior hippocampus. In stressed animals that were subsequently trained, the PKCgamma-ir was increased in the posterior CA1 region to the same level as that found in nonstressed trained animals. Stress apparently abrogated the PKCgamma-ir training response in the CA3 region. In a second experiment, the elevation of plasma corticosterone levels to values that are found during stress did not significantly influence reference memory scores but slightly and temporarily affected working memory. The training-induced enhancement of PKCgamma-ir in the CA1 region was similar in trained and corticosterone-treated trained animals, but the learning-induced PKCgamma-ir response in the posterior CA3 area was absent after corticosterone pretreatment. These results reveal that prolonged psychosocial stress causes spatial learning deficits, whereas artificial elevation of corticosterone levels to the levels that occur during stress only mildly affects spatial memory performance. The spatial learning deficits following stress are reflected only in part in the redistribution of hippocampal PKCgamma-ir following training.
Adrenal Glands↗
Differential involvement of anterior and posterior cingulate cortices in spatial discriminative learning in a T-maze in mice.
The contribution of the anterior and posterior cingulate cortical areas to spatial learning and memory was examined in mice using a behavioral paradigm based on a spatial discrimination task in a T-maze. Multiple injections of small amounts of ibotenic acid were used to produce fiber-sparing lesions of either the anterior (ACC) or the posterior (PCC) cingulate area. Mice with ACC lesions, though learning the initial acquisition and first reversal of the discrimination at about the normal rate, were impaired during the subsequent four reversal sessions. In contrast to control mice, they failed to improve their performance from the first to the last session. Nevertheless, when later required to repeatedly learn the same discrimination over several days (repetitive testing), animals with ACC lesions no longer exhibited any learning deficit. The converse pattern of results was found in mice with PCC lesions. These animals performed much more poorly than control animals during the acquisition and first reversal of the discrimination, but displayed remarkable improvement over the subsequent four reversal sessions, gradually overcoming their initial impairment. However, when later submitted to repetitive testing, these animals again showed a substantial learning deficit. Neither ACC nor PCC cingulate lesions significantly affected the animals' retention capacities as measured by single test-trials over a 24-h interval. Yet, mice with PCC lesions were retarded in reversal learning after a long intersession interval (10 days), indicating that PCC, but not ACC, lesions did interfere with some long-term retention processes. These results imply that the ACC, as a part of the medial frontal cortex, may play a crucial role in temporally ordering a series of spatial responses, whereas the PCC seems to contribute to the formation and retention of each individual spatial response, probably by transmitting information from limbic structures such as the anterior thalamus and hippocampal formation to posterior neocortical association areas.
Adaptation, Psychological↗
[Neuronal plasticity associated with learning and epileptic seizures: LTP and KIP].
Long-term synaptic potentiation (LTP) and kindling-induced potentiation (KIP) are hypothesized to play an important role in spatial learning and kindling development, respectively, and the possible roles of LTP in spatial learning and KIP in kindling development are reviewed in this paper. Blockage of NMDA receptors, protein synthesis inhibition and knockout of alpha-CaMKII gene markedly impaired both LTP-induction and spatial learning, and destruction of the dentate granule cells with colchicine has been reported to result in severe spatial learning deficits. These findings support the hypothesis that spatial learning may depend on the neuronal input from the entorhinal cortex to dentate granule cells via perforant path and LTP-induction at perforant path-dentate granule cell synapses. However, recent studies have revealed that MPC17742, a selective NMDA receptor antagonist, and 1S, 3S-ACPD, the group II metabotropic glutamate receptor agonist, block LTP-induction at perforant path-dentate granule cell synapses, but that those drugs did not prevent rats from spatial learning. Thus, adaptable changes in the dentate granule cell discharge caused by the neuronal information from the entorhinal cortex are necessary, but LTP at perforant path-dentate granule cell synapses is not necessarily requisite for spatial learning. It has been also hypothesized that kindling development might be based on the long-lasting synaptic potentiation (the KIP/kindling hypothesis). Destruction of the dentate granule cells with colchicine retarded kindling development of amygdala or entorhinal cortex has been reported, and repeated induction of LTP at perforant path-dentate granule cell synapses, furthermore, caused anomalous mossy fiber sprouting and facilitated the subsequent kindling development. These results are in accordance with the KIP/kindling hypothesis. However, even when LTP was induced once a day for 20 days, the repeated induction of LTP failed to induce epileptic discharge. We demonstrated that KIP observed in an interictal period faded away gradually during kindling stimulation before epileptic seizures began. Furthermore, rapid kindling at an interstimulus interval of 5 min blocked completely the development of KIP, whereas the afterdischarge prolonged gradually and generalized convulsions were often observed during the late stage of rapid kindling. Thus, LTP and KIP are not indispensable for kindling development, even if LTP facilitate the subsequent kindling development. It should be noted that instead of KIP, the abnormal plasticity essential for kindling development must appear during an transition period from interictal to ictal periods.
Animals↗
Hyperspecificity in visual implicit learning: learning of spatial layout is contingent on item identity.
Humans conduct visual search faster when the same display is presented for a 2nd time, showing implicit learning of repeated displays. This study examines whether learning of a spatial layout transfers to other layouts that are occupied by items of new shapes or colors. The authors show that spatial context learning is sometimes contingent on item identity. For example, when the training session included some trials with black items and other trials with white items, learning of the spatial layout became specific to the trained color--no transfer was seen when items were in a new color during testing. However, when the training session included only trials in black (or white), learning transferred to displays with a new color. Similar results held when items changed shapes after training. The authors conclude that implicit visual learning is sensitive to trial context and that spatial context learning can be identity contingent.
Adolescent↗
Spatial discrimination learning and CA1 hippocampal synaptic plasticity in mdx and mdx3cv mice lacking dystrophin gene products.
Duchenne muscular dystrophy is frequently associated with a non-progressive cognitive deficit attributed to the absence of 427,000 mol. wt brain dystrophin, or to altered expression of other C-terminal products of this protein, Dp71 and/or Dp140. To further explore the role of these membrane cytoskeleton-associated proteins in brain function, we studied spatial learning and ex vivo synaptic plasticity in the mdx mouse, which lacks 427,000 mol. wt dystrophin, and in the mdx3cv mutant, which shows a dramatically reduced expression of all the dystrophin gene products known so far. We show that reference and working memories are largely unimpaired in the two mutant mice performing a spatial discrimination task in a radial maze. However, mdx3cv mice showed enhanced emotional reactivity and developed different strategies in learning the task, as compared to control mice. We also showed that both mutants display apparently normal levels of long-term potentiation and paired-pulse facilitation in the CA1 field of the hippocampus. On the other hand, an increased post-tetanic potentiation was shown by mdx, but not mdx3cv mice, which might be linked to calcium-regulatory defects. Otherwise, immunoblot analyses suggested an increased expression of a 400,000 mol. wt protein in brain extracts from both mdx and mdx3cv mice, but not in those from control mice. This protein might correspond to the dystrophin-homologue utrophin. The present results suggest that altered expression of dystrophin or C-terminal dystrophin proteins in brain did not markedly affect hippocampus-dependent spatial learning and CA1 hippocampal long-term potentiation in mdx and mdx3cv mice. The role of these membrane cytoskeleton-associated proteins in normal brain function and pathology remains to be elucidated. Furthermore, the possibility that redundant mechanisms could partially compensate for dystrophins' deficiency in the mdx and mdx3cv models should be further considered.
Animals↗
Mice deficient for the synaptic vesicle protein Rab3a show impaired spatial reversal learning and increased explorative activity but none of the behavioral changes shown by mice deficient for the Rab3a regulator Gdi1.
Rab proteins are small GTPases involved in intracellular trafficking. Among the 60 different Rab proteins described in mammals, Rab3a is the most abundant in brain, where it is involved in synaptic vesicle fusion and neurotransmitter release. Rab3a constitutive knockout mice (Rab3a(-/-)) are characterized by deficient short- and long-term synaptic plasticity in the mossy fiber pathway and altered circadian motor activity, while no effects on spatial learning have been reported so far for these mice. The goals of this study were to analyse possible behavioral consequences of the lack of synaptic plasticity in the mossy fiber pathway using a broad battery of sensitive behavioral measures that has been used previously to analyse the behavior of Gdi1 mice lacking a protein thought to regulate Rab3a. Rab3a(-/-) mice showed normal acquisition but moderately impaired platform reversal learning in the water maze including reference memory and episodic-like memory tasks. A mild deficit in spatial working memory was also observed when tested in the radial maze. Analysis of explorative behavior revealed increased locomotor activity and enhanced exploratory activity in open field, O-maze, dark/light box and novel object tests. Spontaneous activity in normal home cage settings was unaffected but Rab3a(-/-) mice showed increased motor activity when the home cage was equipped with a wheel. No differences were found for delayed and trace fear conditioning or for conditioned taste aversion learning. Congruent with earlier data, these results suggest that Rab3a-dependent synaptic plasticity might play a specific role in the reactivity to novel stimuli and behavioral stability rather than being involved in memory processing. On the other hand, the phenotypic changes in the Rab3a(-/-) mice bore no relation to the behavioral changes as observed in the Gdi1 mice. Such divergence in phenotypes implies that the putative synaptic interaction between Gdi1 and Rab3a should be reconsidered and re-analysed.
Animals↗
Spatial relational learning persists following neonatal hippocampal lesions in macaque monkeys.
The hippocampus is important for the acquisition of spatial representations of the environment and consequently in contextual memory. This suggests that the neural substrates underlying spatial cognition might be essential for remembering specific life episodes. Indeed, hippocampal lesions prevent spatial relational learning in adult rodents and monkeys, and result in profound amnesia in adult humans. In contrast, we show here that monkeys with neonatal hippocampal lesions learned new spatial relational information. Our experiments suggest that early hippocampal damage leads to functional brain reorganization that enables spatial information to be acquired through the use of brain regions that normally do not subserve this function.
Adaptation, Physiological↗
Effect of chronic inhibition of calpains in the hippocampus on spatial discrimination learning and protein kinase C.
Several behavioral and electrophysiological studies have suggested that a sustained activation of protein kinase C would be required to underlie persistent changes associated with memory formation. Limited proteolysis of PKCs by calpains, calcium-activated proteases, cleaves the catalytic and the regulatory domains, generating a free catalytic fragment termed PKM, constitutively active. In order to investigate the potential physiological importance of this limited proteolysis as a mechanism of PKC activation, we have studied the effect of the calpastatin peptide, a specific calpain inhibitor, on the learning of a spatial discrimination task in a radial maze. Thus, using osmotic micro-pumps, the calpastatin peptide was infused bilaterally into the dorsal hippocampus during the six sessions of training and the probe test. The treatment was shown to facilitate the performance of the mice on the two last training sessions and on the probe test. This behavioral effect was shown to correspond to the reduced calpain activity observed in the hippocampus at the very end of the 7-day infusion of the calpastatin peptide, suggesting a relation between both events. In addition, PKC activity measured immediately after the probe test was notably decreased in the membrane fraction of the hippocampus. Although protein levels of PKCs and calpains quantified by western blot were not affected by calpastatin infusion, we found a noticeable correlation between mu-calpain and PKCgamma levels confirming the particular relationship between both proteins. These results suggest that calpains influence on PKCs activity may affect cellular mechanisms during memory processes.
Animals↗
Selective learning of spatial configuration and object identity in visual search.
To conduct an efficient visual search, visual attention must be guided to a target appropriately. Previous studies have suggested that attention can be quickly guided to a target when the spatial configurations of search objects or the object identities have been repeated. This phenomenon is termed contextual cuing. In this study, we investigated the effect of learning spatial configurations, object identities, and a combination of both configurations and identities on visual search. The results indicated that participants could learn the contexts of spatial configurations, but not of object identities, even when both configurations and identities were completely correlated (Experiment 1). On the other hand, when only object identities were repeated, an effect of identity learning could be observed (Experiment 2). Furthermore, an additive effect of configuration learning and identity learning was observed when, in some trials, each context was the relevant cue for predicting the target (Experiment 3). Participants could learn only the context that was associated with target location (Experiment 4). These findings indicate that when multiple contexts are redundant, contextual learning occurs selectively, depending on the predictability of the target location.
Adult↗
Spatial navigation learning in spontaneously hypertensive, renal hypertensive and normotensive Wistar rats.
The relation between blood pressure and cognitive performance was assessed in the spatial navigation task. Spatial learning by rats with spontaneous hypertension (SHR) and Goldblatt renal hypertension (RHR) was compared with that of normotensive Wistar rats (NR). The task required the rats to escape from water by finding a submerged and hidden platform. It was found that SHR rats showed improved learning capacity in the maze task in acquisition compared to the RHR and NR groups already on Day 1 and Day 2. The performances of all tested groups reached almost similar asymptotic level on Day 4 and in the probe trial on Day 5. After a reversal training the SHR rats did not show preference to swim in the new platform position quadrant. The present results confirm earlier reports on different behavioural characteristics associated with hypertension.
Animals↗
No evidence for overshadowing or facilitation of spatial pattern learning by visual cues.
Two experiments were conducted to examine the effects of redundant and relevant visual cues on spatial pattern learning. Rats searched for hidden food items on the tops of poles that formed a square (Experiment 1) or a checkerboard (Experiment 2) pattern. The experimental groups were trained with visual cues that specified the locations of the baited poles. All groups were tested without visual cues so that any overshadowing or facilitation of spatial pattern learning by visual cues could be detected. Spatial choices were controlled by the spatial pattern and by the visual cues in both experiments. However, there was no evidence of overshadowing or facilitation of spatial pattern learning by visual cues in either experiment. The results are consistent with the idea that the representation of the spatial pattern that guides choices is not controlled by the same learning processes as those that produce associations between visual cues and food locations.
Animals↗
Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats.
Hippocampal N-methyl-D-Aspartate (NMDA) receptors mediate mechanisms of cellular plasticity critical for spatial learning in rats. The present study examined the relationship between spatial learning and NMDA receptor expression in discrete neuronal populations, as well as the degree to which putative age-related changes in NMDA receptors are coupled to the effects of normal aging on spatial learning. Young and aged Long-Evans rats were tested in a Morris water maze task that depends on the integrity of the hippocampus. Levels of NR1, the obligatory subunit for a functional NMDA receptor, were subsequently quantified both biochemically by Western blot in whole homogenized hippocampus, and immunocytochemically by using a high-resolution confocal laser scanning microscopy method. The latter approach allowed comprehensive, regional analysis of discrete elements of excitatory hippocampal circuitry. Neither method revealed global changes, nor were there region-specific differences in hippocampal NR1 levels between young and aged animals. However, across all subjects, individual differences in spatial learning ability correlated with NR1 immunofluorescence levels selectively in CA3 neurons of the hippocampus. Parallel confocal microscopic analysis of the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor failed to reveal reliable differences as a function of age or spatial learning ability. This analysis linking age, performance, and NR1 levels demonstrates that although dendritic NR1 is generally preserved in the aged rat hippocampus, levels of this receptor subunit in selective elements of hippocampal circuitry are linked to spatial learning. These findings suggest that NMDA receptor abundance in CA3 bears a critical relationship to learning mediated by the hippocampus throughout the life span.
Age Factors↗
Cumulative long-term potentiation in the rat dentate gyrus correlates with, but does not modify, performance in the water maze.
The electrically induced increase in hippocampal synaptic strength known as long-term potentiation (LTP) is thought to involve some of the same mechanisms as those mediating information storage during spatial learning. Physiological saturation of synaptic weights might therefore be expected to occlude spatial learning. In support of this, Castro et al. (Castro CA, Silbert LH, McNaughton BL, Barnes CA, 1989, Nature 342:545-548) reported that repeated induction of LTP to asymptotic levels, over a 14-day period, blocked the ability of rats to learn the position of a hidden platform in a water maze shortly afterwards. The authors have attempted to replicate this finding in two experiments. In Experiment 1, rats were given either 400 Hz stimulation as 50 trains/day over a 5-day period, to induce LTP, or were given the same number of stimulus pulses at 1 Hz. Two hours after the last stimulation session they underwent eight spatial learning trials, occurring at 2-hour intervals. In Experiment 2, the procedure of Castro et al. was followed exactly, with LTP induced by 10 trains of 400 Hz stimulation daily for 14 days. Spatial learning trials began 10 minutes after the last stimulation session and consisted of 12 trials with alternating 30-second and 2-minute intervals. In neither experiment was a significant impairment of spatial learning observed. However, there was a strong positive correlation, in both experiments, between the final level of LTP and subsequent performance in the water maze.
Animals↗
Humans with traumatic brain injuries show place-learning deficits in computer-generated virtual space.
Spatial learning and memory has been linked to the hippocampus and temporal lobes and though these areas are often damaged in traumatic brain injury (TBI), spatial learning deficits after TBI have not received much attention. In the present study, a virtual environment was used to challenge people with TBI to solve a task comparable to the Morris water maze, which in turn has been shown to be highly sensitive to hippocampal and frontal lobe dysfunction in laboratory animals. A regular computer monitor was used to present 12 participants with TBI and 12 age- and sex-matched comparison participants with a computer-generated, three-dimensional "virtual arena maze," consisting of a large round arena within a very large square room. Participants were required to learn the place of an invisible target on the floor of the room based solely on distal cues on the walls of the room. Eight of the 12 participants with moderate to severe TBI showed substantial place-learning deficits in comparison to the uninjured participants. Performance in the virtual environment correlated with self-reported frequency of wayfinding problems in everyday life and with scores on a test of episodic memory, the Rivermead Behavioural Memory Task. These data confirm that deficits in spatial learning and memory follow TBI, and suggest that the virtual arena maze may provide a new method for objectively assessing them.
Adult↗
Enhanced learning in mice parallels vector-mediated nerve growth factor expression in hippocampus.
Spatial learning requires the integrity of the nerve growth factor (NGF)-responsive septohippocampal pathway. Loss of a single NGF allele at the mouse NGF locus (heterozygous null, ngf(+/-)) reduces septohippocampal NGF levels and NGF-regulated cholinergic neurotransmitter enzymes and results in spatial learning deficits in adult animals. A herpes simplex virus (HSV) amplicon vector was utilized to locally deliver NGF to the hippocampus of mice heterozygous and wild type (ngf(+/+)) at the NGF gene locus. NGF gene transfer produced transient increases in NGF protein levels and choline acetyltransferase activity in both ngf(+/-) and ngf(+/+) mice. However, spatial learning capability was improved only in ngf(+/-) mice. In aggregate, these findings suggest that amplicon-directed expression of NGF in subjects with baseline septohippocampal dysfunction can correct spatial learning deficits.
Animals↗