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PubMed2004

Place cells of aged rats in two visually identical compartments.

Aged rats perform poorly on spatial learning tasks, a cognitive impairment which has been linked to the failure of hippocampal networks to fully encode changes in the external environment [Barnes CA, Suster MS, Shen J, McNaughton BL. Multistability of cognitive maps in the hippocampus of old rats. Nature 1997;388(6639):272-5; Wilson IA, Ikonen S, Gureviciene I, McMahan RW, Gallagher M, Eichenbaum H, et al. Cognitive aging and the hippocampus: how old rats represent new environments. J Neurosci 2004;24(15):3870-8]. To examine whether the impairment in hippocampal processing extends to conditions in which self-motion provides the cues for environmental change, we have analyzed spatial firing patterns of hippocampal pyramidal neurons in young and aged rats, as well as in young rats with selective cholinergic lesions, another model of cognitive aging. The rats walked between two visually identical environments, pitting self-motion cues that indicated environmental change against visual inputs that indicated no differences between environments. Our results indicated that place cells in both aged and cholinergic-lesioned rats were equally likely as those of young rats to create new spatial representations in the second compartment. These findings suggest that the hippocampal network of aged rats is able to process changes in internally generated cues without rigidity, but that incomplete processing of external landmark cues may lead to impaired spatial learning.

Action Potentials↗
PubMedDate not supplied

Intrahippocampal administration of lead (Pb) impairs performance of rats in the Morris water maze.

We examined spatial learning in the Morris water maze after daily acute bilateral micro-injection of 13.9 ng sodium acetate (NaAc) or 37.9 ng lead acetate (PbAc) in 1 microliter volumes into the dorsal hippocampus of normal adult rats. After six days of injections and water maze training, rats injected with NaAc were able to find a hidden platform in 8.3 s, and those injected with PbAc were significantly slower (15.2 s; p < 0.02). In a second experiment, rats were trained to find a hidden platform before injections began and then tested in order to determine if intrahippocampal injections of Pb affected the recall of a previously learned task. The escape latency on the first day after injections began was increased slightly when compared to the last day of training before injections, however the NaAc and PbAc groups were not significantly different over three days of injections. Both treatment groups performed as well as they did before injections began by the second day of injections. These results suggest that the direct injection of Pb into the hippocampus impairs the acquisition but not the recall of the spatial learning task in the Morris water maze.

Analysis of Variance↗
PubMed1996

Pretreatment but not posttreatment with GYKI 52466 reduces functional deficits and neuronal damage after global ischemia in rats.

Glutamate antagonists have been shown to be neuroprotective in animal models of cerebral ischemia. Global cerebral ischemia in rats leads to selective neuronal damage in the hippocampus and striatum. Following ischemia a deficit in spatial learning and memory occurs. The aim of the present study was to investigate the potential neuroprotective effect of GYKI 52466, an antagonist at the non-N-methyl-D-aspartate receptor, with behavioural and histological measures of global ischemia in rats. Global ischemia was induced by four-vessel-occlusion (4VO) for 20 min in rats. GYKI 52466 (30 mg/kg i.p.) was administered either 20 min before induction of ischemia or immediately after onset of reperfusion. One week after surgery spatial learning was tested in the Morris water maze. After behavioural testing the animals were sacrificed and the neuronal damaged was assessed. GYKI 52466 reduced the increase in escape latency and in swim distance induced by 4VO when given before ischemia but not when applied after ischemia. Neuronal damage in the CA1 sector of the hippocampus produced by 4VO was significantly attenuated by pretreatment but not by posttreatment with GYKI 52466. Striatal neuronal damage was not affected by either treatment with GYKI 52466. GYKI 52466 had neuroprotective effects in a rat model of global cerebral ischemia. Pretreatment with GYKI 52466 protected rats against behavioural deficits and hippocampal neuronal damage induced by 4VO.

Animals↗
PubMed1996

Landmark stability: studies exploring whether the perceived stability of the environment influences spatial representation.

To investigate whether spatial learning complies with associative learning theories or with theories of cognitive mapping, rats were trained in three experiments exploring the effect of variations in spatial predictive relationships. In experiment 1, it was found that making one of two landmarks the sole spatial predictor of reward, by varying the spatial relationship between reward and other cues, reduced the control over search exerted by that landmark compared with that observed when the landmark and context cues were both reliable predictors of reward location. This requirement for landmark stability rather than predictive power appears to contradict results obtained in conventional conditioning paradigms. Discrimination learning was unaffected, suggesting a dissociation between discrimination and spatial learning with respect to the influence of geometric stability. Further experiments used arrays of both single and multiple landmarks. Experiment 2 revealed that the stability of a single landmark improved accuracy of search, but also showed that local stability between a pair of landmarks that moved around the arena together was sufficient to support spatial learning. Experiment 3 examined landmark stability using fixed directional cues in the absence of vestibular disorientation. This also revealed a relative advantage of stable landmarks, but animals presented with a landmark that moved from trial to trial did show some evidence of learning. Parametric manipulation of landmark stability offers an intriguing way of influencing the process of spatial representation and thus understanding better the processes through which egocentric representations of perceived space are transformed into allocentric representations of the real world.

Journal Article↗
PubMed1996

The regulation of hippocampal dynorphin by neural/neuroendocrine pathways: models for effects of aging on an opioid peptide system.

Previous research has demonstrated increased messenger RNA expression and peptide content in an opioid system localized to hippocampal dentate granule cells in aged rats. This altered regulation of dynorphin was correlated with the emergence of an age-related impairment in spatial learning. Considerable evidence exists for additional effects of aging on systems that provide input to the dynorphin-containing dentate granule cells. Such changes have been well documented for loss of perforant path innervation from entorhinal cortex, deterioration in septohippocampal cholinergic neurons, and high amounts of glucocorticoids that have, among their targets, receptors located in the dentate gyrus. Similar to the effects of aging on hippocampal dynorphin, age-related changes in each of these systems correlate with the severity of spatial learning impairment in aged rats. This raises the possibility that dysregulation of dynorphin in the aged brain is a reactive response to antecedant change(s) in this circuitry, a hypothesis that was examined by separately manipulating in young rats the three neural/neuroendocrine systems identified above. Of the three models examined only removal of the perforant path reproduced the effect of aging on dynorphin in the hippocampal formation. An immunotoxin was used in Experiment 1 to selectively remove septo-hippocampal cholinergic neurons in young rats. No alteration in hippocampal opioid peptides was produced by this treatment. Experiment 2 examined effects of exposure to excess corticosterone. Adrenalectomized rats exhibited a significant decrease in hippocampal dynorphin-A (1-8) content, which was reversed by corticosterone replacement at a concentration approximating normal basal levels. Dynorphin-A (1-8) content, however, was not reliably increased by exposure to excess corticosterone. In contrast, perforant path removal was found to reproduce the effect of aging on dynorphin content; either aspiration of the entorhinal cortex or knife-cut transections of the perforant path reliably increased hippocampal dynorphin content. These results support the conclusion that age-related deterioration in the septohippocampal cholinergic system and evaluated exposure to corticosterone are not sufficient to induce an elevation in hippocampal dynorphin content. Only removal of the perforant path innervation was found to reproduce the elevation in hippocampal dynorphin content observed in aged rats with hippocampal-dependent learning impairment.

Adrenalectomy↗
PubMed1996

Repetitive and transient increases in hippocampal neural cell adhesion molecule polysialylation state following multitrial spatial training.

Polysialylated neurons, located at the inner border of the dentate granule cell layer, have been demonstrated to exhibit time-dependent change in their frequency at 10-12 h following training in the Morris water maze, a spatial learning paradigm. Such a change was not observed in animals required to locate a visible platform or in those rendered amnesic with scopolamine. This frequency response was capable of rapid reactivation following further training stimuli in a manner that was independent of circadian influence. These learning-associated modulations in neural cell adhesion molecule (NCAM) polysialylation state did not increase in magnitude despite improved performance, suggesting their activation is required for processing information rather than contributing to previously stored, task-associated memory. An increase in NCAM polysialylation appears to be a universal learning response to both spatial and nonspatial paradigms as similar time-dependent changes occurred following training in a one-trial, step-through, passive avoidance response subsequent to water maze training.

Animals↗
PubMed2002

Androgens protect against apolipoprotein E4-induced cognitive deficits.

Compared with apolipoprotein (apo) E2 and E3, apoE4 increases the risk of Alzheimer's disease (AD), but it remains unknown how apoE4 affects neuronal function. ApoE4 interacts with female gender, further increasing the risk of AD and decreasing treatment response. Female mice are also more susceptible to apoE4-induced impairments of spatial learning and memory than male mice. To assess the role of sex steroids in this process, we studied mice deficient in mouse apoE (Apoe(-/-)) and expressing human apoE4 or apoE3 in the brain at comparable levels. Even brief periods of androgen treatment improved the memory deficits of female apoE4 mice. Female apoE3 mice had no memory deficits and did not benefit from the treatment. ApoE4 male mice, which performed normally in a water-maze test at baseline, developed prominent deficits in spatial learning and memory after blockade of androgen receptors (ARs), whereas apoE3 male mice did not. Untreated apoE4 mice had significantly lower cytosolic AR levels in the neocortex than wild-type, Apoe(-/-), and apoE3 mice. Improved memory in androgen-treated female apoE4 mice was associated with increased cytosolic AR levels. Our findings suggest that apoE4 contributes to cognitive decline by reducing AR levels in the brain, and that stimulating AR-dependent pathways can reverse apoE4-induced cognitive deficits.

Androgen Antagonists↗
PubMed2001

Chronic elevation of brain GABA levels beginning two days after status epilepticus does not prevent epileptogenesis in rats.

Vigabatrin (VGB) treatment is neuroprotective in various models of status epilepticus (SE) and delays the development of kindling via mechanisms that are assumed to relate to the elevation of GABA levels in the brain. Here, we tested the hypothesis that a chronic elevation of brain GABA levels obtained by VGB treatment prevents the development of spontaneous seizures (i.e. epilepsy) following SE in rats. Self-sustained SE (SSSE) was induced by stimulating the lateral nucleus of the amygdala. Two days later, chronic VGB (75 mg/kg/day) or saline treatment was started via subcutaneous osmotic minipumps. The development of spontaneous seizures was monitored once a week (24 h at a time) using video-EEG recording. Rats were perfused for histology either at the end of the 10-week drug treatment, or later at the end of an 8-week drug-free follow-up period. Before perfusion for histology, spatial learning and memory perform was tested in the Morris water-maze. Spontaneous seizures were observed in 55% (6/11) of the saline-treated and 73% (8/11) of the VGB-treated rats during the 10-week treatment period. Seizure frequency, severity, and duration were similar in VGB-treated rats and controls during and after the drug-treatment period. VGB treatment did not decrease neuronal damage in various temporal lobe regions or mossy fiber sprouting. VGB treatment also did not attenuate spatial learning or memory impairments. These findings indicate that the augmentation of GABAergic neurotransmission by VGB does not prevent the development of epilepsy when treatment is started 2 days after SE.

Animals↗
PubMed2000

Timing of ketogenic diet initiation in an experimental epilepsy model.

Following kainic acid (KA)-induced status epilepticus (SE), the ketogenic diet (KD) retards the development of epileptogenesis, with fewer spontaneous recurrent seizures (SRS) and less mossy fiber sprouting than rats on a normal diet. In this study, we investigated whether there is a critical period for initiation of the KD, in terms of the diet's effectiveness in reducing SRS. In addition, we investigated whether early treatment with the KD prevents the deficits in spatial learning and memory that ordinarily follow KA-induced SE. Young rats (P30) underwent KA-induced SE, followed by assignment to one of three treatment groups: control diet ('KA'), KD begun 2 days after SE ('KD2'), and KD begun fourteen days after SE ('KD14'). For 12 weeks following SE, rats were monitored by closed circuit video recording (12 h/wk) to detect SRS. KD2 rats had significantly fewer SRS than rats in the control or KD14 groups. On water maze testing to assess spatial learning and memory, KD2 rats had significantly poorer acquisition of place learning than control (KA alone) or KD14 rats. KD2 rats also failed to gain weight well. There was no difference between groups on routine histologic examination of the hippocampus. In summary, P30 rats placed on the KD 2 days after SE were relatively protected from recurrent seizures, but showed behavioral and physical impairment. Rats placed on the KD 14 days after KA-induced SE did not differ from controls with regard to spontaneous seizure rate.

Animals↗
PubMed1995

Striatal met-enkephalin and substance P levels are decreased in mice infected with the LP-BM5 murine leukemia virus.

Mice infected with the LP-BM5 murine leukemia virus mixture develop severe immunosuppression and an encephalopathy characterized by spatial learning deficits. Twelve weeks after infection of C57BL/6J mice with LP-BM5, significant (50-60%) reductions in Met-enkephalin and substance P levels were observed in the striatum, whereas somatostatin levels were unchanged. In addition, a 39% decrease in hypothalamic substance P concentrations was observed, with no alteration in Metenkephalin levels. The apparent selectivity of the decrease in neuropeptide concentrations indicates that a functional alteration of the primary striatal efferent neurons occurs in this infection, which may contribute to the impairment of spatial learning observed in these mice. Moreover, this decrease in striatal neuropeptide levels is similar to the neuropathological changes in basal ganglia observed in HIV-infected individuals and is consistent with previous studies suggesting that the LP-BM5-infected mouse may serve as a useful model of AIDS dementia.

Animals↗
PubMed2000

Functional consequences of reduction in NMDA receptor glycine affinity in mice carrying targeted point mutations in the glycine binding site.

We have used site-directed mutagenesis in conjunction with homologous recombination to generate two mouse lines carrying point mutations in the glycine binding site of the NMDAR1 subunit (Grin1). Glycine concentration-response curves from acutely dissociated hippocampal neurons revealed a 5- and 86-fold reduction in receptor glycine affinity in mice carrying Grin1(D481N) and Grin1(K483Q) mutations, respectively, whereas receptor glutamate affinity remained unaffected. Homozygous mutant Grin1(D481N) animals are viable and fertile and appear to develop normally. However, homozygous mutant Grin1(K483Q) animals are significantly lighter at birth, do not feed, and die within a few days. No gross abnormalities in CNS anatomy were detected in either Grin1(D481N) or Grin1(K483Q) mice. Interestingly, in situ hybridization and Western blot analysis revealed changes in the expression levels of NMDA receptor subunits in Grin1(D481N) mice relative to wild type that may represent a compensatory response to the reduction in receptor glycine affinity. Grin1(D481N) mice exhibited deficits in hippocampal theta burst-induced long-term potentiation (LTP) and spatial learning and also a reduction in sensitivity to NMDA-induced seizures relative to wild-type controls, consistent with a reduced activation of NMDA receptors. Mutant mice exhibited normal prepulse inhibition but showed increased startle reactivity. Preliminary analysis indicated that the mice exhibit a decreased natural aversion to an exposed environment. The lethal phenotype of Grin1(K483Q) animals confirms the critical role of NMDA receptor activation in neonatal survival. A milder reduction in receptor glycine affinity results in an impairment of LTP and spatial learning and alterations in anxiety-related behavior, providing further evidence for the role of NMDA receptor activation in these processes.

Animals↗
PubMed1997

Spatial disorientation blocks reliable goal location on a plus maze but does not prevent goal location in the Morris maze.

Cue control in spatial learning was investigated in a plus maze and a Morris maze. Rats transported in opaque containers with prior rotation to a plus maze, but not a Morris maze, could not find a goal defined by external cues. Rats transported in clear containers without rotation found the goal in both mazes. In the Morris maze, goal location was readily relearned following cue removal by rats in clear containers but not by rats in the opaque/rotation group. B. L. McNaughton et al.'s (1996) theory that during spatial learning sensory information is bound to preconfigured internal maps in the hippocampus, whose metric is self-motion and whose orientation depends on input from an inertial based head direction system, may explain this study's findings.

Animals↗
PubMed1996

Failure of carbamazepine to prevent behavioural and histopathological sequels of experimentally induced status epilepticus.

Sustained electrical stimulation of the perforant pathway was used to induce long-lasting hippocampal seizures in conscious rats. One hour prior to stimulation, rats were given i.p. injections of either saline or a commonly used antiepileptic drug, carbamazepine (5H-dibenz[b, f]azepine-5-carboxamide; CBZ; 20 mg/kg). When tested 2 weeks later in a water maze, both the saline- and the carbamazepine-pretreated rats showed similarly a severe impairment in spatial learning compared to non-stimulated controls. Histological evaluation revealed that the pyramidal cell damage was (P < 0.05) milder in the carbamazepine-pretreated group in the CA1, but not the CA3c subfield. However, the number of somatostatin-immunoreactive neurons in both stimulated groups was reduced equally. Thus, at the dose of 20 mg/kg, which is a usual anticonvulsive dose in humans, carbamazepine seems to offer only partial protection against pyramidal cell damage, but no protection against the hilar somatostatin-immunoreactive neuron loss or the spatial learning deficit after perforant pathway stimulation in rats. The result clearly differs from that obtained either with a GABA (gamma-aminobutyric acid)-enhancing drug and a novel antiepileptic, vigabatrin (4-amino-hex-5-enoic acid) or with a competitive NMDA (N-methyl-D-aspartate) receptor antagonist, CGP 39551 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid carboxyethylester) in the same test situation.

Animals↗
PubMed1997

Prenatal exposure to methylmercury alters locomotor activity of male but not female rats.

In the present study the neurotoxic effects of a low dosage (0.5 mg/kg per day) of methylmercury (MeHg) on the developing nervous system were investigated. Pregnant rats were treated with MeHg from day 7 of pregnancy to day 7 of lactation. Locomotor activity (locomotion, rearing, and motility) and spatial learning ability were tested in the offspring at 6 months of age. The expression of tyrosine hydroxylase (TH) was examined by immunohistochemistry and in situ hybridization. A significant decrease in spontaneous motility and rearing was observed only in the MeHg-treated male rats. After administration of a low dose of d-amphetamine (0.5 mg/kg) no differences could be observed between control and MeHg-treated male rats, suggesting that changes in dopaminergic transmission were involved. However, no change in TH messenger RNA expression was observed. No changes in spatial learning acquisition or memory were shown in MeHg-treated rats. Taken together, these findings show that during development a very low dosage of MeHg exerts neurotoxic effects detectable in adulthood, and that susceptibility is gender-dependent.

Animals↗
PubMed2000

Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement.

We recently demonstrated that stress-induced cognitive deficits in rats do not correlate with hippocampal neuronal loss. Working on the premise that subtle structural changes may however be involved, we here evaluated the effects of chronic stress on hippocampal dendrite morphology, the volume of the mossy fiber system, and number and morphology of synapses between mossy fibers and CA3 dendritic excrescences. To better understand the mechanisms by which stress exerts its structural effects, we also studied these parameters in rats given exogenous corticosterone. Further, to search for signs of structural reorganization following the termination of the stress and corticosterone treatments, we analysed groups of rats returned to treatment-free conditions. All animals were assessed for spatial learning and memory performance in the Morris water maze. Consistent with previous findings, dendritic atrophy was observed in the CA3 hippocampal region of chronically stressed and corticosterone-treated rats; in addition, we observed atrophy in granule and CA1 pyramidal cells following these treatments. Additionally, profound changes in the morphology of the mossy fiber terminals and significant loss of synapses were detected in both conditions. These alterations were partially reversible following rehabilitation from stress or corticosterone treatments. The fine structural changes, which resulted from prolonged hypercortisolism, were accompanied by impairments in spatial learning and memory; the latter were undetectable following rehabilitation. We conclude that there is an intimate relationship between corticosteroid levels, hippocampal neuritic structure and hippocampal-dependent learning and memory.

Animals↗
PubMed1999

Attenuation of ischemia-induced cellular and behavioral deficits by X chromosome-linked inhibitor of apoptosis protein overexpression in the rat hippocampus.

Transient forebrain ischemia produced by four-vessel occlusion (4-VO) triggers the delayed death of CA1 neurons in the hippocampus, resulting in behavioral deficits of spatial learning performance. We demonstrate that CA1 neuronal loss induced by 4-VO (12 min) is preceded by a selective and marked elevation of catalytically active caspase-3 in these neurons, indicative of apoptosis. Virally mediated overexpression of the anti-apoptotic gene X chromosome-linked inhibitor of apoptosis protein (XIAP) prevented both the production of catalytically active caspase-3 and degeneration of CA1 neurons after transient forebrain ischemia. CA1 neurons protected in this manner appeared to function normally, as assessed by immunohistochemical detection of the neuronal activity marker nerve growth factor inducible-A and by spatial learning performance in the Morris water maze. These findings indicate that caspase-3 activation is a key event in ischemic neuronal death and that blockade of this event by XIAP overexpression permits CA1 neurons to survive and operate properly after an ischemic insult.

Animals↗
PubMed2006

Long-term effects of immunotoxic cholinergic lesions in the septum on acquisition of the cone-field task and noncognitive measures in rats.

In rats, nonspecific mechanical or neurotoxic lesions of the septum impair spatial memory in, e.g., Morris water- and radial-maze tasks. Unfortunately, the lack of specificity of such lesions limits inferences about the role of the cholinergic hippocampal projections in spatial cognition. We therefore tested the effects of septal lesions produced by 192 IgG-saporin in rats, which is highly selective for basal forebrain cholinergic neurons, on home cage activity, noncognitive tests (modified Irwin test, open field and forced swimming tests, and various sensorimotor tasks), and the cone-field spatial learning task. The immunotoxic lesion reduced acetylcholine (ACh) levels in the septum (-61%) and hippocampus (>-75%). Rats with lesions showed mild home-cage hyperactivity at 4 weeks postlesion, but no noncognitive deficits at 13 weeks postsurgery. In the cone-field task, rats with septal lesions made more working- and reference-memory errors than the controls, but acquisition curves were parallel in both groups. The speed of visiting cones was faster in the rats with lesions, indicative of disturbed attention or increased motivation. These data support the growing evidence that involvement of the septohippocampal cholinergic system in spatial learning and memory may have been overestimated in studies that used lesions with poor selectivity.

Acetylcholine↗
PubMed1997

Estrogen alleviates cognitive dysfunction following transient brain ischemia in ovariectomized gerbils.

Capability of estrogen to alleviate spatial-learning deficits due to brain ischemia was evaluated in ovariectomized gerbils. Thirty-nine ovariectomized gerbils were physically trained to swim in a 90 cm-diameter round pool. The half of the ovariectomized animals received subcutaneous implantation of a Silastic capsule of estrogen, 1 week before ischemic assault. Transient brain ischemia was accomplished on experimental day 1 by bilateral clipping of the common carotid artery for 15 min under pentobarbital and ketamine anesthesia. On day 3 and onwards, daily Morris water-maze task was imposed. Although estrogen-treated non-ischemic animals spent longer time in the water, their distances swam were not different from non-treated animals: estrogen had no effect on the spatial learning to take the shortest distance to get to the submerged table. In the ovariectomized non-treated gerbils, ischemia prolonged the time in the water and lengthened the distance swam. Among the ischemic gerbils, those given estrogen swam a significantly shorter distance than the non-treated animals. The results indicate that estrogen alleviates the ischemia-induced deficits in the acquisition of the water-maze task. The results also defy previous association of estrogen with decreased acquisition of the water-maze task, which was based principally on the prolonged time in the water.

Animals↗