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Hippocampal acetylcholine release correlates with spatial learning performance in freely moving rats.

To assess the activity of septohippocampal cholinergic neurons during the learning of a radial-arm maze task we measured changes in extracellular acetylcholine levels in the hippocampus by means of the vertical microdialysis technique. During the 12 days spent learning the spatial task the extracellular concentration of acetylcholine in the hippocampus was monitored while rats performed the test. One week before radial-arm maze training a guide cannula was implanted unilaterally in the hippocampus. On each day of testing a removable microdialysis probe was inserted through the guide cannula and the dialysate was collected during the test performance. The concentration of acetylcholine in the dialysate was detected by means of a high-performance liquid chromatograph coupled to an electrochemical detector. We found that hippocampal acetylcholine release progressively increased from 139% to 245% during the 12 days of radial-maze learning and the magnitude of change in acetylcholine output was positively correlated with spatial memory performance, thus suggesting that changes in the functioning of these neurons are involved in learning.

Acetylcholine↗

Behavioral performance of tfm mice supports the beneficial role of androgen receptors in spatial learning and memory.

In adulthood, androgens and androgen receptors might contribute to the sexually dimorphic performance in spatial learning and memory, but their roles seem complex. To study the potential role of androgen receptors in spatial learning and memory, we tested adult 6-8-month-old mutant mice with a naturally occurring defect in the androgen receptor gene (testicular feminization mutant or tfm) and C57Bl/6J wild-type mice. Because the trait is X-linked, only tfm males are completely androgen insensitive while female tfm mice are heterozygous, carrying one wild-type and one tfm copy of the androgen receptor. Here we show that female tfm carrier mice outperform tfm male mice in the water maze, while there are no gender differences in water maze performance in wild-type mice. In tfm mice, there were no gender differences in measures of anxiety in the open field or plus maze or sensorimotor function, indicating that potential differences in these measures did not contribute to the differences observed in the water maze. There were no differences in tfm and wild-type female and male mice in emotional learning and memory in the passive avoidance test. These findings support a beneficial role for androgen receptors in spatial learning and memory.

Androgen-Insensitivity Syndrome↗

Markers for biogenic amines in the aged rat brain: relationship to decline in spatial learning ability.

The major goal of the study was to evaluate the relationship of brain aging to individual differences in functional decline in rats. Forebrain choline-acetyltransferase (ChAT) and monoamines, including their metabolites, were examined in young and aged male Long-Evans rats in relation to their spatial learning ability. Aged rats that were unimpaired on a spatial learning task exhibited few changes in neurochemistry relative to the young group: each change in this subgroup was also evident in the remaining aged animals that were behaviorally impaired. Additional changes in neurochemical measures only found in the behaviorally impaired aged animals included decreased ChAT in the basal forebrain, striatum, and frontal cortex. A cluster analysis using the 15 neurochemical measures that were sensitive to aging yielded groupings of aged animals that differed with respect to their spatial learning ability, but not in their cue learning latencies. In this analysis the activity of ChAT in the basal forebrain and striatum appeared to be the best predictors of spatial learning impairment.

Aging↗

Long-lasting effects of neonatal dexamethasone treatment on spatial learning and hippocampal synaptic plasticity: involvement of the NMDA receptor complex.

The effects of neonatal dexamethasone (DEX) treatment on spatial learning and hippocampal synaptic plasticity were investigated in adult rats. Spatial learning in reference and working memory versions of the Morris maze was impaired in DEX-treated rats. In hippocampal slices of DEX rats, long-term depression was facilitated and potentiation was impaired. Paired-pulse facilitation was normal, suggesting a postsynaptic defect as cause of the learning and plasticity deficits. Western blot analysis of hippocampal postsynaptic densities (PSD) revealed a reduction in NR2B subunit protein, whereas the abundance of the other major N-methyl-D-aspartate (NMDA) receptor subunits (NR1, NR2A), AMPA receptor subunits (GluR2/3), scaffolding proteins, and Ca2+/calmodulin-dependent protein kinase II (alphaCaMKII) were unaltered. This selective reduction in NR2B likely resulted from altered receptor assembly rather than subunit expression, because the abundance of NR2B in the homogenate and crude synaptosomal fractions was unaltered. In addition, the activity of alphaCaMKII, an NMDA receptor complex associated protein kinase, was increased in PSD of DEX rats. The results indicate that neonatal treatment with DEX causes alterations in composition and function of the hippocampal NMDA receptor complex that persist into adulthood. These alterations likely explain the deficits in hippocampal synaptic plasticity and spatial learning induced by neonatal DEX treatment.

Animals↗

HIV-1 Tat inhibits long-term potentiation and attenuates spatial learning [corrected].

Although memory deficits have been clearly documented in patients with human immunodeficiency virus type-1 (HIV-1) infection, the physiological basis of this dysfunction is poorly understood. We focused on Tat, a viral protein released from HIV-1-infected cells and investigated its effect on spatial learning in adult mice. An intracerebroventricular injection of Tat leads to attenuation of spatial learning accompanied by suppression of long-term potentiation (LTP), the cellular basis of spatial learning, in hippocampal cornu ammonis 1 pyramidal neurons. Tat facilitates extrasynaptic but not synaptic N-methyl-D-aspartate (NMDA) receptor activity. Taken together, these data provide strong evidence that the Tat pathway underlies the development of memory dysfunction in patients with HIV-1 infection and suggest a causal relationship between Tat, the facilitation of extrasynaptic NMDA receptor activity, inhibition of LTP, and attenuation of spatial learning.

Animals↗

Nociceptin/orphanin FQ modulates spatial learning via ORL-1 receptors in the dorsal hippocampus of the rat.

The endogenous peptide nociceptin (orphanin FQ) plays a role in several important physiological functions in the CNS such as pain, anxiety and locomotion. It has previously been found that injection of 10 nmol nociceptin into the CA3 region of the hippocampus markedly impairs spatial learning and memory in the rat. The present study examined the effects of lower doses of nociceptin (3.3, 1, 0.33 and 0.1 nmol/rat) on spatial learning. The 3.3 nmol dose impaired spatial learning over the 5 days of training although the effect was not as strong as with 10 nmol. In contrast, the two lower doses, 1 and 0.33 nmol/rat, improved spatial learning whereas the lowest dose, 0.1 nmol/rat, had no significant effect. Both the impairing and facilitating effect of nociceptin could be blocked by an ORL-1 receptor antagonist, [Phe1Psi(CH(2)-NH)Gly2]NC(1-13)NH2 (10 nmol/rat), indicating that both effects are ORL-1 receptor-mediated. The 3.3 nmol dose of nociceptin did not impair the performance in the visual platform task and did not alter swim speed or motor activity indicating no effects on motivation or motor performance. Taken together, these results show that nociceptin has a biphasic dose-effect curve and provide further evidence for a role of this neuropeptide in cognitive processes in the hippocampus.

Animals↗

Ibotenate Lesions of Hippocampus and/or Subiculum: Dissociating Components of Allocentric Spatial Learning.

This study examined the effects of ibotenic acid-induced lesions of the hippocampus, subiculum and hippocampus +/- subiculum upon the capacity of rats to learn and perform a series of allocentric spatial learning tasks in an open-field water maze. The lesions were made by infusing small volumes of the neurotoxin at a total of 26 (hippocampus) or 20 (subiculum) sites intended to achieve complete target cell loss but minimal extratarget damage. The regional extent and axon-sparing nature of these lesions was evaluated using both cresyl violet and Fink - Heimer stained sections. The behavioural findings indicated that both the hippocampus and subiculum lesions caused impairment to the initial postoperative acquisition of place navigation but did not prevent eventual learning to levels of performance almost as effective as those of controls. However, overtraining of the hippocampus + subiculum lesioned rats did not result in significant place learning. Qualitative observations of the paths taken to find a hidden escape platform indicated that different strategies were deployed by hippocampal and subiculum lesioned groups. Subsequent training on a delayed matching to place task revealed a deficit in all lesioned groups across a range of sample choice intervals, but the subiculum lesioned group was less impaired than the group with the hippocampal lesion. Finally, unoperated control rats given both the initial training and overtraining were later given either a hippocampal lesion or sham surgery. The hippocampal lesioned rats were impaired during a subsequent retention/relearning phase. Together, these findings suggest that total hippocampal cell loss may cause a dual deficit: a slower rate of place learning and a separate navigational impairment. The prospect of unravelling dissociable components of allocentric spatial learning is discussed.

Journal Article↗

Long-term effects of seizures in neonatal rats on spatial learning ability and N-methyl-D-aspartate receptor expression in the brain.

For the purpose of investigating the long-term effects of seizures in neonatal rats on spatial learning ability and N-methyl-D-aspartate (NMDA) receptor expression in adult rat brain, a seizure was induced by inhalant flurothyl daily in neonatal Wistar rats from postnatal day 6 (P6). The authors assigned six rats each averagely into the single-seizure group, the recurrent-seizure group (seizures induced in six consecutive days), and the control group. During P60 to P65, the rats were tested for spatial learning ability with the Morris water maze task. On P75, the authors examined protein expression of the NMDA receptor (NR) subunits, NR1, 2A, 2B, 2C, and 2D, in the cerebral cortex and hippocampus by Western blotting analysis. On P65, the escape latencies from the water maze of the rats in the recurrent-seizure group were significantly longer than those of the control rats, but there was no difference between the single-seizure group and the control group. NR subunit expression in the cerebral cortex and hippocampus of the rats with single seizure was similar to those in the control rats. Compared with the control rats, the protein expressions of NR1, NR2A and NR2B in the cerebral cortex and NR2A in the hippocampus of the recurrent-seizure group was significantly decreased, but NR2C protein expression in the cerebral cortex and hippocampus significantly increased. Recurrent seizures induced in neonatal rats might cause long-term spatial learning ability deficit and modify NR expression in the cerebral cortex and hippocampus of adult rats. The results suggest that abnormal NR expression might play an important role in long-term spatial learning ability deficit induced by recurrent seizures in early life.

Animals↗

Interaction of microwaves and a temporally incoherent magnetic field on spatial learning in the rat.

The effect of a temporally incoherent magnetic field ('noise') on microwave-induced spatial learning deficit in the rat was investigated. Rats were trained in six sessions to locate a submerged platform in a circular water maze. Four treatment groups of rats were studied: microwave-exposure (2450-MHz continuous-wave microwaves, power density 2 mW/cm(2), average whole-body specific absorption rate 1.2 W/kg), 'noise' exposure (60 mG), 'microwave+noise' exposure, and sham exposure. Animals were exposed to these conditions for 1 h immediately before each training session. One hour after the last training session, animals were tested in a 2-min probe trial in the maze during which the platform was removed. The time spent during the 2 min in the quadrant of the maze in which the platform had been located was scored. Results show that microwave-exposed rats had significant deficit in learning to locate the submerged platform when compared with the performance of the sham-exposed animals. Exposure to 'noise' alone did not significantly affect the performance of the animals (i.e., it was similar to that of the sham-exposed rats). However, simultaneous exposure to 'noise' significantly attenuated the microwave-induced spatial learning deficit (i.e. 'microwave+noise'-exposed rats learned significantly better than the microwave-exposed rats). During the probe trial, microwave-exposed animals spent significantly less time in the quadrant where the platform was located. However, response of the 'microwave+noise'-exposed animals was similar to that of the sham-exposed animals during the probe trial. Thus, simultaneous exposure to a temporally incoherent magnetic field blocks microwave-induced spatial learning and memory deficits in the rat.

Analysis of Variance↗

Block of spatial learning by mGluR agonist tADA in rats.

As demonstrated recently, mGluRs are involved in some forms of learning. We thus investigated the effect of tADA (trans-azetidine-2,4-dicarboxylic acid) applied intracerebroventricularly prior to learning a spatial alternation paradigm. Compared to controls, tADA treated animals were amnesic when tested for retention 24 hr after training. Effects of state-dependency were excluded. These data and our earlier work indicate that both mGluR agonists and antagonists can have memory-disrupting effects.

Animals↗

Approaches to learning spatial relationships in gross anatomy: perspective from wider principles of learning.

When students learn spatial relationships in gross anatomy, as in other areas of study, fundamentals should be learned first; otherwise confusion results. The fundamentals in gross anatomy are defined not in conceptual terms but by principles of visual perception. In particular, they derive from Gestalt principles such as collinearity and symmetry, which generally make learning and recognition of visual patterns easier. The collinearity (straight line formations) and symmetry in the body cavities are obvious when one studies the empty cavities, or body cavities with only a few symmetrical structures in place. These principles are, however, totally obscured if one starts one's study, as in traditional dissection, with the body cavities crammed full of a complex mass of interlocking organs. and their ducts, vessels, etc. Therefore, it is recommended that learning gross anatomy (especially of the body cavities) would be an easier exercise if it started with empty body cavities, then building up, with a careful sequence of prosections, to the more complex and realistic anatomy of the full cavities. This system of learning is perceptually preferable to traditional dissection. However, it needs to be enlivened in several ways, e.g., with respect to design principles evident in anatomical structure (especially for the musculoskeletal system), developmental processes, and sometimes by explicit reference to clinical relevance.

Anatomy↗

Facilitation of acquisition and performance of operant and spatial learning tasks in self-stimulation experienced rats.

Adult male Wistar rats were implanted bilateraly with bipolar electrodes in substantia nigra-ventral tegmental area (SN-VTA) to experience intracranial self-stimulation (ICSS) for 15 min per day over a period of 10 days. These rats were then assessed for the acquisition and performance of the operant and the spatial learning tasks. ICSS experienced rats showed rapid acquisition of both the operant and the spatial learning tasks. Both the lever press performance for 7 sessions in the operant learning task and mean number of alternations per session in the spatial learning task were significantly higher (p < .001) in ICSS experienced rats compared with controls. The results suggest that prior ICSS experience facilitates the acquisition and performance in both the operant and the spatial learning tasks, which may be due to the structural and neurochemical alterations in the hippocampus induced by ICSS experience.

Analysis of Variance↗

Enrichment enhances the expression of sgk, a glucocorticoid-induced gene, and facilitates spatial learning through glutamate AMPA receptor mediation.

We have previously demonstrated that the serum and glucocorticoid-inducible kinase (sgk) gene plays a causal role in facilitating memory performance in rats. Environment enrichment is known to facilitate spatial learning. We therefore examined the effect of enrichment on sgk expression. We also examined the role of sgk in spatial and nonspatial learning and the regulation of sgk expression by activation of different glutamate receptors. Both real-time polymerase chain reaction and Western blot analyses revealed that enrichment training preferentially increased sgk mRNA and protein levels in the hippocampus. Transfection of sgk mutant DNA to the hippocampal CA1 area markedly impaired spatial learning, fear-conditioning learning and novel object-recognition learning in rats, but enrichment training effectively reversed these learning deficits. Meanwhile, S422A mutant DNA transfection prevented enrichment-induced spatial learning facilitation. In studying glutamate receptor regulation of sgk expression, we found that blockade of N-methyl-d-aspartate (NMDA) receptors in general, and the NR2B subunit in particular both effectively blocked enrichment-induced spatial learning facilitation, but they did not block enrichment-induced sgk expression. Upon various glutamate agonist infusions, only alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) increased sgk mRNA levels significantly in the hippocampus. Furthermore, blockade of AMPA receptors effectively blocked both enrichment-induced spatial learning facilitation and sgk expression. These results indicate that there is a dissociation between NMDA receptor activation and sgk expression. Enrichment enhanced spatial learning through both NMDA and AMPA receptor activation, whereas enrichment-induced sgk expression is specifically mediated through AMPA receptors. These results suggest that sgk could serve as a novel molecular mechanism, in addition to the NMDA receptor NR2B, underlying enrichment-induced learning facilitation.

Age Factors↗

Hippocampal long-term potentiation and spatial learning in the rat: effects of GABAB receptor blockade.

This series of experiments assessed the role of GABAB receptors in the induction of long-term potentiation in the dentate gyrus in vivo, and spatial learning and memory in three different tasks. In urethane-anesthetized rats, the GABAB receptor antagonist CGP 46381 was injected intraperitoneally at a dose which effectively suppressed GABAB-mediated paired pulse disinhibition. Theta-burst stimulation reliably produced long-term potentiation in control rats. However, GABAB receptor blockade significantly suppressed the induction of long-term potentiation in the dentate gyrus. To compare the results of the long-term potentiation experiments with behavior, we assessed the performance of rats on several spatial learning and memory tasks in the presence of CGP 46381. We found that the working memory performance of highly trained rats on the eight-arm radial maze was unaffected by CGP 46381. There was also no effect of GABAB receptor blockade on learning in the eight-arm maze using a five-trial repeated acquisition paradigm. However, when we tested spatial learning in naive rats using a mildly stressful water maze task, we found that CGP 46381 substantially impaired both the latency to find the platform and the path-length travelled in the maze during acquisition. CGP 46381-treated rats took longer to learn the location of the escape platform and travelled a greater distance over the acquisition trials. These data demonstrate that GABAB receptor blockade results in a suppression of hippocampal long-term potentiation in vivo and impairs spatial learning in a task where stress may be a component of performance.

Animals↗

Effect of age on the radial arm water maze-a test of spatial learning and memory.

Aged rats show decrements in performance on cognitive tasks that require the use of spatial learning and memory. We used the 8-arm radial water maze (RAWM) to measure spatial learning as a function of age in young (6 months) and old (21 months) male F344 rats. Rats were placed in the RAWM in different start arms with the same goal arm for 3 days (five trials/day); the goal arm was changed on day 4. Old rats demonstrated spatial impairment as evidenced by increased latencies to find the hidden platform on day 4. Old rats made significantly more errors, both reference and working memory errors, than young rats on all days. It is likely that the old rats utilized non-spatial strategies to solve the task, and therefore were impaired in learning a new platform location. The RAWM is a reliable, sensitive, and powerful additional test to assess age-related spatial learning and memory deficits, combining the advantages of the Morris water maze and the radial arm maze while minimizing the disadvantages.

Aging↗

Preservation of spatial learning in fyn tyrosine kinase knockout mice.

Previous work has shown that knockout mice lacking the fyn tyrosine kinase gene (fyn-/-) are impaired in spatial learning. Here, we have re-examined the spatial learning of fyn-/- mutants in an open field water maze. Unlike wild-type mice, fyn-/- knockouts often floated without moving when placed in the water but could swim adequately when their hind feet were mechanically stimulated. Under these conditions, fyn-/- mice showed significant improvement over trials in locating a hidden platform. On a transfer trial, at the end of training, they spent a disproportionate amount of time swimming in the location of the previously hidden platform. These findings suggest that fyn-/- knockouts are capable of spatial learning, but suffer an impairment that compromises their ability to swim normally.

Animals↗

Endomorphin-2 but not Leu-enkephalin modulates spatial learning when microinjected in the CA3 region of the rat hippocampus.

The recently discovered endogenous mu-selective opioid peptide, endomorphin-2, and the endogenous delta-selective opioid peptide, Leu-enkephalin, were tested for their ability to affect spatial learning in the Morris water task. It was found that microinjection of 10 nmol endomorphin-2 into the CA3 region of the rat hippocampus significantly impaired spatial learning. However, the two lower doses tested, 3.3 and 1 nmol, had no effect in this test. Leu-enkephalin did not have any effect on spatial learning at the two doses tested (10 and 3.3 nmol). Neither peptide had any effect on motor performance as measured by swim speed. The results indicate that mu-receptors in the CA3 region of the rat hippocampus are more relevant than delta-receptors for spatial learning.

Animals↗

Aging, spatial learning, and total synapse number in the rat CA1 stratum radiatum.

The aim of this study was to determine whether spatial learning deficits in aged rats are associated with a loss of hippocampal synapses. The Morris water maze task was used to assess the spatial learning capacity of young and aged rats and to attribute aged animals to learning-impaired and learning-unimpaired groups. The number of axospinous synapses in the entire volume of the CA1 stratum radiatum was estimated with unbiased stereological techniques. The results show that the total number of all axospinous synapses and of their perforated and nonperforated subtypes remains constant in the CA1 stratum radiatum of aged learning-impaired rats as compared to aged learning-unimpaired rats and to young adults. Thus, neither age-related deficits in spatial learning nor advanced chronological age are associated with a loss of axospinous synapses from the rat CA1 stratum radiatum.

Aging↗