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PubMed2006

Associative and spatial learning and memory deficits in transgenic mice overexpressing the RNA-binding protein HuD.

HuD is a neuronal specific RNA-binding protein associated with the stabilization of short-lived mRNAs during brain development, nerve regeneration and synaptic plasticity. To investigate the functional significance of this protein in the mature brain, we generated transgenic mice overexpressing HuD in forebrain neurons under the control of the alphaCaMKinII promoter. We have previously shown that one of the targets of HuD, GAP-43 mRNA, was stabilized in neurons in the hippocampus, amygdala and cortex of transgenic mice. Animals from two independent lines expressing different levels of the transgene were subjected to a battery of behavioral tests including contextual fear conditioning and the Morris water maze. Our results show that although HuD is increased after learning and memory, constitutive HuD overexpression impaired the acquisition and retention of both cued and contextual fear and the ability to remember the position of a hidden platform in the Morris water maze. No motor-sensory abnormalities were observed in HuD transgenic mice, suggesting that the poor performance of the mice in these tests reflect a true cognitive impairment. We conclude that posttranscriptional regulation of gene expression by stabilization of specific mRNAs may have to be restricted temporally and spatially for proper acquisition and storage of memories.

Analysis of Variance↗
PubMed2006

Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity.

Rats learning the Morris water maze exhibit hippocampal changes in synaptic morphology and physiology that manifest as altered synaptic efficacy. Learning requires structural changes in the synapse, and multiple cell adhesion molecules appear to participate. The activity of these cell adhesion molecules is, in large part, dependent on their interaction with the extracellular matrix (ECM). Given that matrix metalloproteinases (MMPs) are responsible for transient alterations in the ECM, we predicted that MMP function is critical for hippocampal-dependent learning. In support of this, it was observed that hippocampal MMP-3 and -9 increased transiently during water maze acquisition as assessed by western blotting and mRNA analysis. The ability of the NMDA receptor channel blocker MK801 to attenuate these changes indicated that the transient MMP changes were in large part dependent upon NMDA receptor activation. Furthermore, inhibition of MMP activity with MMP-3 and -9 antisense oligonucleotides and/or MMP inhibitor FN-439 altered long-term potentiation and prevented acquisition in the Morris water maze. The learning-dependent MMP alterations were shown to modify the stability of the actin-binding protein cortactin, which plays an essential role in regulating the dendritic cytoskeleton and synaptic efficiency. Together these results indicate that changes in MMP function are critical to synaptic plasticity and hippocampal-dependent learning.

Analysis of Variance↗
PubMedDate not supplied

Age-related psychomotor and spatial learning deficits in 129/SvJ mice.

The 129 mouse strain has been widely used to construct mutations that model behavioral aging in humans. The current study found significant age-related declines in both psychomotor and swim maze performance of 5-, 17-, and 27-month-old 129/SvJ mice. However, the age differences in swim maze acquisition were inconsistent with poor performance in the probe trial which assesses spatial memory. This inconsistency may result from the high degree of genetic polymorphisms and age-related visual pathology which afflicts this mouse strain. Therefore, we concluded that 129/SvJ mice present a problematic model of mammalian cognitive aging and involve a risk for behavioral contamination in studies involving mutant mice derived from this strain.

Aging↗
PubMed1995

Glucocorticoids, hippocampal corticosteroid receptor gene expression and antidepressant treatment: relationship with spatial learning in young and aged rats.

The emergence of cognitive deficits in a subgroup of aged rats is associated with increased hypothalamic-pituitary-adrenal axis activity, decreased hippocampal mineralocorticoid and/or glucocorticoid receptor gene expression and neuronal loss. Short-term treatment with antidepressant drugs in young rats increases hippocampal corticosteroid receptor gene expression. In this study, the effects of chronic antidepressant administration on hippocampal mineralocorticoid and glucocorticoid receptor gene expression and spatial memory in young and aged rats were investigated. Young (eight months) and old (22 +/- 1 months) Lister-hooded rats were ranked according to watermaze performance. Matched pairs of rats were treated with amitriptyline (10 mg/kg) or saline daily for nine weeks, then reassessed in the watermaze. Amitriptyline significantly improved spatial memory in the young rats (33% increase in transfer test time) and increased hippocampal mineralocorticoid, but not glucocorticoid receptor messenger RNA expression. By contrast, in aged rats, amitriptyline had no effect on spatial memory or hippocampal corticosteroid receptor gene expression, either in cognitively unimpaired or cognitively-impaired animals. In aged rats, basal plasma corticosterone levels, which were significantly higher than in young animals, correlated negatively with spatial memory, while hippocampal glucocorticoid receptor mRNA expression correlated negatively with plasma corticosterone levels and positively with spatial memory. Amitriptyline had no significant effect on basal morning plasma corticosterone levels in either young or aged rats, but significantly decreased evening corticosterone levels in aged rats. Our data support the notion that corticosterone exerts a concentration-dependent biphasic influence, via selective activation of hippocampal mineralocorticoid and glucocorticoid receptor, on spatial memory. Amitriptyline improves spatial memory in young rats and increases hippocampal mineralocorticoid receptor gene expression. The lack of amitriptyline effect on spatial memory in aged rats may reflect decreased plasticity of both the synaptic processes underlying spatial memory and the regulation of hippocampal mineralocorticoid/glucocorticoid receptor expression, with mineralocorticoid receptors fully occupied due to elevated basal plasma corticosterone levels (in part a consequence of inadequate glucocorticoid receptor function).

Aging↗
PubMed1989

Transplantation of septal cholinergic neurons to the hippocampus improves memory impairments of spatial learning in rats treated with AF64A.

Embryonic septal neurons were transplanted into damaged hippocampus in adult rats which had received lateral ventricular administration of AF64A, a cholinergic neurotoxin. About 3 months after transplantation, the rats with bilateral septal grafts showed significant improvement in the radial maze and T-maze tasks. Many ingrowths of acetylcholinesterase (AChE)-positive fibers originating from the grafts were observed in the hippocampus of the rats which showed good performance in these learning tasks. These results indicate that transplantation of septal cholinergic neurons into the AF64A-treated hippocampus may induce at least partial recovery in learning tasks believed to involve the hippocampus.

Animals↗
PubMed2002

Mice deficient in nervous system-specific carbohydrate epitope HNK-1 exhibit impaired synaptic plasticity and spatial learning.

The HNK-1 carbohydrate epitope, a sulfated glucuronic acid at the non-reducing terminus of glycans, is expressed characteristically on a series of cell adhesion molecules and is synthesized through a key enzyme, glucuronyltransferase (GlcAT-P). We generated mice with a targeted deletion of the GlcAT-P gene. The GlcAT-P -/- mice exhibited normal development of gross anatomical features, but the adult mutant mice exhibited reduced long term potentiation at the Schaffer collateral-CA1 synapses and a defect in spatial memory formation. This is the first evidence that the loss of a single non-reducing terminal carbohydrate residue attenuates brain higher functions.

Animals↗
PubMed2001

Lithium-pilocarpine-induced status epilepticus in immature rats result in long-term deficits in spatial learning and hippocampal cell loss.

Rat pups age of 14 postnatal day (P14) were subjected to lithium-pilocarpine (Li-PC) model of status epilepticus (SE). Control rats (n=6) were given an equivalent volume of saline intraperitoneally. Behavioral testing began on P60 including the Morris water maze, the radial arm maze, and the rotarod test. Brain were then analyzed with cresyl violet stain for histological lesions and evaluated for mossy fiber sprouting with the Timm stain. We observed spatial memory deficits both in the Morris water maze and radial arm maze in Li-PC-treated rat. There was no motor impairment in Li-PC-treated rat by the rotarod test. Two of six Li-PC-treated rats showed cell loss in hippocampal CA1 subfield. The Timm staining pattern was similar in both control and Li-PC-treated rats. Result of this study suggests that Li-PC-induced SE in immature rats cause long-term cognitive deficit and permanent cell loss in hippocampal CA1, but spare motor impairment.

Aging↗
PubMed1990

Spatial learning is affected by transient occlusion of common carotid arteries (2VO): comparison of behavioural and histopathological changes after '2VO' and 'four-vessel-occlusion' in rats.

Place learning in the Morris water maze following transient (24 min) occlusion of the common carotid arteries (2VO), and following permanent occlusion of both vertebral arteries plus transient (20 min) clamping of the carotids (4VO) was investigated in rats 6-9 days after occlusion. Both 2VO and 4VO treatment increased the latency to find the hidden platform during escape trials; spatial bias, tested in a probe trial, was decreased. Histological analysis revealed neural necrosis in the CA1 sector of the hippocampus in 4VO rats but not in 2VO animals. The data suggest that an experimentally induced reduction in cerebral blood flow of 50% (after 2VO) or 95% (after 4VO) produces persistent functional changes even in absence of actual neural damage.

Animals↗
PubMed1989

Spatial learning in rats: correlation with cortical choline acetyltransferase and improvement with NGF following NBM damage.

Rats display an acquisition deficit in a circular water maze following excitotoxic lesions of the nucleus basalis magnocellularis (NBM). Experiments were therefore performed to determine if acquisition behavior on this task could predict the degree of cortical cholinergic deafferentation and if the acquisition deficit could be pharmacologically reversed. Performance on acquisition was highly correlated with the lesion-induced reduction in cortical choline acetyltransferase (ChAT) activity. Accuracy of spatial behavior was highly correlated to percentage ChAT depletion (r = 0.75). Neither lesioned rats nor controls displayed a retention deficit after a 9-day interval, nor did either group display a passive-avoidance retention deficit. To test the causal relationship between cholinergic dysfunction and spatial behavior, the central nervous system cholinergic enhancer nerve growth factor (NGF) was intraventricularly infused for 4 weeks. NGF infusion resulted in improved acquisition of the water maze task compared to NBM-lesioned rats receiving vehicle infusion and untreated rats with NBM lesions. These studies indicate that the decrease in cortical ChAT activity is likely to be responsible for the observed acquisition deficit and that pharmacological manipulations can be successfully used to improve behavior following NBM lesions.

Animals↗
PubMed1999

Continuous blockade of brain mineralocorticoid receptors impairs spatial learning in rats.

Hippocampal mineralocorticoid receptors (MR) are proposed to mediate facilitation of cognition in the short-term. The acute central blockade of MR increases plasma corticosterone levels which itself can affect cognition thus complicating the interpretation of such studies. We therefore investigated the effects of chronic continuous central MR antagonism by spironolactone infused intracerebroventricularly (i.c.v.) (100 ng/h) via Alzet minipumps for 12 days. Rats given chronic i.c.v. infusion of spironolactone spent significantly less time (20% decrease, P < 0.05) within the platform quadrant during the watermaze probe test. Neither hippocampal MR nor glucocorticoid receptor mRNA expression were affected by spironolactone. Morning plasma corticosterone levels and adrenal and thymic weights were unchanged. Chronic central MR antagonism impairs spatial memory in the watermaze independent of changes in receptors or circulating glucocorticoid levels.

Animals↗
PubMed1985

Facilitation of spontaneous and learned spatial behaviours following 6-hydroxydopamine lesions of the lateral septum: a cholinergic hypothesis.

Mice received injections of 6-hydroxydopamine (6-OHDA) in the lateral septum; they were tested for spontaneous alternation, acquisition and reversal of a spatial discrimination in a T-maze. In each of these tasks, performance of 6-OHDA lesioned mice was improved relative to controls. Neurochemical analysis revealed that 6-OHDA lesioned mice exhibited a significant increase in the rate of sodium-dependent high affinity choline uptake in the hippocampus. These results are discussed in relation to current theories concerning the role of the septo-hippocampal complex and cholinergic system in the control of behaviour.

Animals↗
PubMed2004

Spatial learning enhances the expression of inositol 1,4,5-trisphosphate 3-kinase A in the hippocampal formation of rat.

Calcium-mediated signaling is crucial for the synaptic plasticity and long-term memory storage, which requires de novo protein synthesis. Inositol 1,4,5-trisphosphate 3-kinase A (IP(3)K-A) is an enzyme, which is involved in the maintenance of intracellular calcium homeostasis by converting inositol 1,4,5-trisphosphate (IP(3)) to inositol 1,3,4,5-tetrakisphosphate (IP(4)). Because IP(3)K-A is enriched in the dendritic spines of hippocampal neurons, it has been speculated that this enzyme is involved in the memory formation. In the present study, we demonstrated that the expression of IP(3)K-A is increased in the hippocampal formation of the rats during the Morris water maze training. Immunohistochemical analysis indicated the specific induction of IP(3)K-A protein in the hippocampal formation following 5-day water maze training. Furthermore, in situ hybridization histochemistry showed that the induction of IP(3)K-A mRNA in the hippocampal formation was observed on the first day of training, and the induced level of IP(3)K-A mRNA was maintained until the fifth day of training. These results suggest that IP(3)K-A plays a role in the processing of spatial memory, most likely by regulating the calcium signaling in the dendritic spines of hippocampal formation.

Analysis of Variance↗
PubMed2006

Deletion of the Coffin-Lowry syndrome gene Rsk2 in mice is associated with impaired spatial learning and reduced control of exploratory behavior.

Coffin-Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2 deficiency and skeletal abnormalities of CLS. Although analyses in mice have revealed prominent expression of Rsk2 in brain structures that are essential for learning and memory, evidence at the behavioral level for an involvement of Rsk2 in cognitive function is still lacking. Here, we have examined Rsk2-deficient mice in two extensive batteries of behavioral tests, which were conducted independently in two laboratories in Zurich (Switzerland) and Orsay (France). Despite the known reduction of bone mass, all parameters of motor function were normal, confirming the suitability of Rsk2-deficient mice for behavioral testing. Rsk2-deficient mice showed a mild impairment of spatial working memory, delayed acquisition of a spatial reference memory task and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. Our studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-deficient mice. The observed behavioral changes are in line with observations made in other mouse models of human mental retardation and support a role of Rsk2 in cognitive functions.

Abnormalities, Multiple↗
PubMed2002

Nerve growth factor improves spatial learning and restores hippocampal cholinergic fibers in rats withdrawn from chronic treatment with ethanol.

The cholinergic septohippocampal pathway has long been known to be important for learning and memory. Prolonged intake of ethanol causes enduring memory deficits, which are paralleled by partial depletion of hippocampal cholinergic afferents. We hypothesized that exogenous supply of nerve growth factor (NGF), known to serve as a trophic substance for septal cholinergic neurons, can revert the ethanol-induced changes in the septohippocampal cholinergic system. Adult rats were given a 20% ethanol solution as their only source of fluid for 6 months. During the first 4 weeks after the animals were withdrawn from ethanol, they were intraventricularly infused with either NGF or vehicle alone via implanted osmotic minipumps. The vehicle-infused withdrawn animals showed impaired performance on a spatial reference memory version of the Morris water maze task, both during the task acquisition and on the retention test. In contrast, NGF-treated withdrawn rats were able to learn the task as well as controls, and significantly outperformed the vehicle-infused withdrawn rats. The histological analysis revealed that, in the latter group, the length density of fibers immunoreactive to choline acetyltransferase was reduced relative to control values by approximately 25%, as measured in the dentate gyrus and regio superior of the hippocampal formation. However, in NGF-treated withdrawn rats, the length density of these fibers was identical to that of control rats. These data provide support to the notion that NGF is capable of ameliorating memory deficits and restoring septohippocampal cholinergic projections following chronic treatment with ethanol.

Afferent Pathways↗
PubMed1999

Influence of acute and repeated interleukin-2 administration on spatial learning, locomotor activity, exploratory behaviors, and anxiety.

Interleukin-2 (IL-2), released from activated T cells, influences central neurochemical functioning, and IL-2 immunotherapy in cancer patients may provoke neuropsychiatric and cognitive disturbances. In this study, acute, systemic IL-2 did not influence Morris water-maze performance in mice. In contrast, chronic IL-2 impaired performance when the position of the escape platform varied over days but was without effect when the platform position was fixed. These effects could not be attributed to illness, because IL-1beta, which induces marked malaise, did not influence water-maze performance. Chronic IL-2 produced modest reductions in exploration and approach to a novel stimulus, effects not seen after acute treatment, but did not influence spontaneous alternation performance or behavior in an elevated plus-maze test. Thus, repeated IL-2 may influence spatial working memory without affecting habituation/ attentional processes or anxiety.

Animals↗
PubMed1992

Parenteral domoic acid impairs spatial learning in mice.

The present study is the first to examine the effect of a single intraperitoneal injection of the neuroexcitotoxin domoic acid on learning in mice. Compared to saline controls, animals exposed to domoic acid (2.0 mg/kg) showed significant impairment on the acquisition of the place task in the Morris water maze. Observation of swim paths taken by mice searching for the underwater platform revealed a failure on the part of the domoic acid-exposed mice to select the appropriate problem solving strategies. The results, along with neuroanatomic work done here and elsewhere, suggest that impairment of acquisition and retention of this spatial navigation task by domoic acid, involves a neuropathology that includes not only the hippocampus, but other limbic, and possibly extralimbic brain regions.

Animals↗
PubMed2002

Differential effects of chronic haloperidol and olanzapine exposure on brain cholinergic markers and spatial learning in rats.

RATIONALE: In psychiatric patients, haloperidol (HAL) induces a number of adverse extrapyramidal and cognitive symptoms, which appear to be less problematic with olanzapine (OLZ). In animals, HAL may initiate a number of harmful effects on central nervous system neurons, including damage to cholinergic pathways - an effect that could be especially deleterious to those experiencing memory dysfunction. The identification of the neurobiological substrates of such effects in animal models may help to improve the algorithms used for proper drug selection especially for long-term neuroleptic use. OBJECTIVES: The aim of this study was to compare the effects of chronic (45-day and 90-day), continuous oral exposure to HAL with OLZ for effects on cognitive performance and cholinergic markers in rats. METHODS: After chronic neuroleptic exposure (and a 4-day washout) spatial memory performance was measured in a water maze task, and choline acetyltransferase (ChAT) immunoreactivity was assessed with immunofluorescence staining. RESULTS: In water maze experiments, HAL and OLZ (relative to vehicle) administered for 90 days (but not 45 days) significantly impaired learning performance (i.e., higher mean latencies across several trials to reach a hidden platform). HAL administered for 90 days was associated with impairment across a greater number of trials than OLZ and it also impaired probe trial performance, as indicated by a reduced number of crossings over the previous platform area (when compared with OLZ or vehicle). Both 45 days and 90 days of HAL treatment reduced ChAT staining in the cortex and hippocampus when compared with OLZ or vehicle. CONCLUSIONS: The results in the rat suggest that OLZ (relative to HAL) may be more desirable as an antipsychotic for patients suffering from memory dysfunction especially for those in which cholinergic deficits may already be present.

Animals↗