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PubMedDate not supplied

Neurotoxic effects of neonatal triethyltin (TET) exposure are exacerbated with aging.

Neonatal Long-Evans rats dosed with TET (5 mg/kg; IP) or saline on postnatal day (PND) 10 were examined across the life span for neural damage and performance on spatial learning tasks. A subset of rats were sacrificed to assess early damage with Nissl-staining, Timm's histochemistry, and glial fibrillary acidic protein (GFAP) immunohistochemistry 2, 7, or 14 days after dosing. Littermates were tested behaviorally in a T-maze spatial delayed alternation task on PND 23 or PND 90, and in a Morris water maze place learning task at 3, 12, or 24 months postdosing and then sacrificed for histological analysis. In neonatal rats, histological analysis indicated gliosis in discrete cortical regions, loss of Nissl-stained neurons in the hippocampal formation, entorhinal cortex and piriform cortex, and loss of Timm's staining in the entorhinal cortex. The behavioral assessment at PND 23 indicated a significant impairment in the T-maze. However, no significant impairments were observed in the T-maze at 3 months or the water maze at 3 or 12 months postdosing. At 24 months, TET-treated rats showed significant deficits in acquisition and retention of the water maze task compared with age-matched controls. Both groups of 24 months old rats were significantly impaired compared with young controls. At 24 months, there was a general age-related decrease in the optical density of Timm's staining in cortical regions (9%), compounded by a further decrease in the entorhinal cortex and outer molecular layer of the dentate gyrus of the hippocampus in TET treated rats (30%). These data indicate that early developmental exposure to an organometal resulted in morphological damage that was apparent behaviorally only during early postnatal development and with advanced aging.

Aging↗
PubMed2002

Hippocampal A beta 42 levels correlate with spatial memory deficit in APP and PS1 double transgenic mice.

We investigated the role of hippocampal amyloid pathology in spatial learning impairment of a new mouse line carrying mutated human amyloid precursor protein (APP) and presenilin-1 (PS1) transgenes. The APP + PS1 mice were tested in spatial navigation in the water maze and in position discrimination in the T-maze at ages of 3-4 and 11-12 months, before and after the appearance of first amyloid plaques. The APP + PS1 mice were impaired in water maze acquisition and retention only at the age of 11-12 months, but performed equally to controls in the T-maze task at both ages. In the impaired older age group, the levels of total Abeta1-42 in the hippocampus of APP + PS1 mice correlated negatively with the retention score. Here we show for the first time that the age-dependent impairment in memory retention in the traditional water maze of APP + PS1 mice correlates with the amount of total Abeta in hippocampus even at a stage when the amyloid deposits cover less than 1% of the hippocampal volume.

Age Factors↗
PubMed1994

Behavioral and anatomical deficits in mice homozygous for a modified beta-amyloid precursor protein gene.

The beta-amyloid precursor protein (beta APP) gene of the mouse was disrupted by inserting into exon 2 a cassette containing a neomycin resistance gene and a putative transcription termination sequence. Contrary to expectation, brain and other tissues from mice homozygous for the insertion still contained beta APP-specific RNA, albeit at a level 5- to 10-fold lower than wild type and lacking the disrupted exon, which had been spliced out. The brain contained shortened beta APP-specific protein at a low level. Mutant mice were severely impaired in spatial learning and exploratory behavior and showed increased incidence of agenesis of the corpus callosum.

Amyloid beta-Protein Precursor↗
PubMed1992

Nerve growth factor (NGF) in rat brain following long-term barbital treatment: relation to convulsions and cognitive function.

Nerve growth factor (NGF) protein has been implicated in alterations of cognitive function either following brain damage, selective lesions or aging. Groups of rats were given long-term (48 weeks) oral barbital treatment or tap water and following an extended period of abstinence (14 weeks) were tested for spatial learning ability in the Morris swim maze. Following the maze test, they were sacrificed and the NGF content of hippocampal and cortical brain regions were analyzed. Barbital treated rats were divided into convulsing and non-convulsing groups. It was found that there was a slight, significant increase (12%) in NGF content of the hippocampus in convulsing rats. Correlations between maze learning performance, brain weight and NGF in the cortex indicated a significant negative relationship between (a) performance and brain weight on day 1 of testing and (b) NGF content and performance on day 2. These data indicate some involvement of NGF in functions derived from a considerably different animal model to those applied previously.

Animals↗
PubMed2005

Prodynorphin knockout mice demonstrate diminished age-associated impairment in spatial water maze performance.

Dynorphins, endogenous kappa-opioid agonists widely expressed in the central nervous system, have been reported to increase following diverse pathophysiological processes, including excitotoxicity, chronic inflammation, and traumatic injury. These peptides have been implicated in cognitive impairment, especially that associated with aging. To determine whether absence of dynorphin confers any beneficial effect on spatial learning and memory, knockout mice lacking the coding exons of the gene encoding its precursor prodynorphin (Pdyn) were tested in a water maze task. Learning and memory assessment using a 3-day water maze protocol demonstrated that aged Pdyn knockout mice (13-17 months) perform comparatively better than similarly aged wild-type (WT) mice, based on acquisition and retention probe trial indices. There was no genotype effect on performance in the cued version of the swim task nor on average swim speed, suggesting the observed genotype effects are likely attributable to differences in cognitive rather than motor function. Young (3-6 months) mice performed significantly better than aged mice, but in young mice, no genotype difference was observed. To investigate the relationship between aging and brain dynorphin expression in mice, we examined dynorphin peptide levels at varying ages in hippocampus and frontal cortex of WT 129SvEv mice. Quantitative radioimmunoassay demonstrated that dynorphin A levels in frontal cortex, but not hippocampus, of 12- and 24-month mice were significantly elevated compared to 3-month mice. Although the underlying mechanisms have yet to be elucidated, the results suggest that chronic increases in endogenous dynorphin expression with age, especially in frontal cortex, may adversely affect learning and memory.

Age Factors↗
PubMed1999

Amelioration of fornix lesion induced learning deficits by self-stimulation rewarding experience.

Intracranial self-stimulation (ICSS) rewarding experience is known to modulate learning and memory and induce morphological and neurochemical changes in hippocampus. Therefore, we studied the effect of ICSS on the hippocampus-dependent operant and the spatial learning tasks in rats with bilateral electrolytic lesioning of fornix. Bilateral lesioning of fornix induced deficits in acquisition and performance of both the tasks, whereas exposure to 10 days of ICSS experience from ventral tegmental area reversed these behavioural deficits. Hence, we propose that the ICSS experience ameliorates the fornix lesion induced behavioural deficits, by inducing neuronal plasticity in the hippocampus which may act as a compensatory mechanism for the deficits produced by the lesioning of fornix.

Animals↗
PubMed2005

Does vestibular damage cause cognitive dysfunction in humans?

For more than a decade, evidence from animal studies has suggested that damage to the vestibular system leads to deficits in spatial navigation which are indicative of impaired spatial learning and memory. More recently, direct evidence has emerged to demonstrate that humans with vestibular disorders exhibit a range of cognitive deficits that are not just spatial in nature, but also include non-spatial functions such as object recognition memory. Vestibular dysfunction has been shown to adversely affect attentional processes and increased attentional demands can worsen the postural sway associated with vestibular disorders. Recent MRI studies also show that humans with bilateral vestibular damage undergo atrophy of the hippocampus which correlates with their degree of impairment on spatial memory tasks. These results are consistent with those from animal studies and, together, suggest that humans with vestibular disorders are likely to experience cognitive dysfunction which is not necessarily related to any particular episode of vertigo or dizziness, and therefore may occur even in patients who are otherwise well compensated. These findings may be related to the observation that patients with vestibular deficits experience a high incidence of depression and anxiety disorders.

Animals↗
PubMed2006

Water maze swim path analysis based on tracking coordinates.

In the Morris water maze, a task widely used to study spatial learning and memory in laboratory rodents, several parameters are employed to estimate cognitive abilities of animals by analyzing their swim path characteristics. An isolated view based on any one of these parameters is not always satisfactory, so multivariate procedures (factor analyses) are used to weight the parameters in context with the others. This method sheds light on some subtle differences in experimental animals' spatial memories or strategies. However, this approach has some subjective problems, because the definition of the parameters depends on the experimenter's opinion of appropriate measures; therefore, we suggest a bottom-up rather than a top-down analysis of swim paths by means of spatial coordinates. In the present study, swim paths were normalized to 100-element vectors and then subjected to a principal components analysis. Swim paths could be sufficiently described in terms of only three components, each of which accounted for specific characteristics of the trajectories. We found significant differences in swim path patterns between test groups of rats that could not be discriminated via standard water maze parameters. Thus, the components can be related to different aspects of spatial cognition not detectable by commonly used parameters.

Animals↗
PubMedDate not supplied

Involvement of BDNF receptor TrkB in spatial memory formation.

The N-methyl-D-aspartate (NMDA) receptors are involved in long-term potentiation (LTP), and are phosphorylated by several tyrosine kinases including a Src-family tyrosine kinase Fyn. Brain-derived neurotrophic factor (BDNF) is a neurotrophin, which also enhances hippocampal synaptic transmission and efficacy by increasing NMDA receptor activity. Here, we show that Fyn is a key molecule linking the BDNF receptor TrkB with NMDA receptors, which play an important role in spatial memory formation in a radial arm maze. Spatial learning induced phosphorylation of TrkB, Fyn, and NR2B, but not NR2A, in the hippocampus. Fyn was coimmunoprecipitated with TrkB and NR2B, and this association was increased in well-trained rats compared with control animals. Continuous intracerebroventricular infusion of PP2, a tyrosine kinase inhibitor, in rats delayed memory acquisition in the radial arm maze, but PP2-treated animals reached the same level of learning as the controls. The phosphorylation of Fyn and NR2B, but not TrkB, was diminished by PP2 treatment. Our findings suggest the importance of interaction between BDNF/TrkB signaling and NMDA receptors for spatial memory in the hippocampus.

Animals↗
PubMed1997

Hippocampally dependent and independent chronic spatial navigational deficits following parasagittal fluid percussion brain injury in the rat.

Previous reports have documented spatial navigational deficits following experimental traumatic brain injury (TBI), although the majority of the work to date has involved assessment at acute intervals following TBI, and has focused on tasks sensitive to hippocampal dysfunction. The present experiments were designed to investigate the chronic consequences of TBI, and the possible contribution of extrahippocampal dysfunction to TBI-induced spatial navigational deficits, in a moderate parasagittal fluid percussion TBI model. In Experiment 1, animals were pre-trained in a water maze, subjected to TBI or sham procedures, and re-evaluated in the water maze 48 h following the insult. Six to 8 weeks following TBI, the same animals were required to navigate to a different platform location. TBI animals exhibited significant deficits in retention of previously learned spatial information at the 48 h interval, and marginally impaired acquisition of a novel platform location during the chronic test sessions. In Experiment 2, animals were required to navigate to novel spatial locations using cued (to evaluate extrahippocampal function) as well as non-cued variants of the water maze task during the 8 week period following the insult. Injured animals exhibited deficits in both tasks which gradually diminished over the course of testing. The results of these experiments indicate that moderate TBI is accompanied by both retention and acquisition deficits, and that some of the navigational deficits observed in the water maze can be attributed to extrahippocampal damage. The possible recovery of spatial navigational ability following parasagittal TBI at moderate intensities is also discussed.

Acute Disease↗
PubMed2001

Exploration, anxiety, and spatial memory in transgenic anophthalmic mice.

Contradictory results are found in the literature concerning the role of vision in the perception of space or in spatial navigation, in part because of the lack of murine models of total blindness used so far. The authors evaluated the spatial abilities of anophthalmic transgenic mice. These mice did not differ qualitatively from their wild-type littermates in general locomotor activity, spontaneous alternation, object exploration, or anxiety, but their level of exploratory activity was generally lower. In the spatial version of the water maze, they displayed persistent thigmotaxic behavior and showed severe spatial learning impairments. However, their performances improved with training, suggesting that they may have acquired a rough representation of the platform position. These results suggest that modalities other than vision enable some degree of spatial processing in proximal and structured spaces but that vision is critical for accurate spatial navigation.

Animals↗
PubMed1994

Spatial correlates of firing patterns of single cells in the subiculum of the freely moving rat.

Hippocampal lesions cause spatial learning deficits, and single hippocampal cells show location-specific firing patterns, known as place fields. This suggests the hippocampus plays a critical role in navigation by providing an ongoing indication of the animal's momentary spatial location. One question that has received little attention is how this locational signal is used by downstream brain regions to orchestrate actual navigational behavior. As a first step, we have examined the spatial firing correlates of cells in the dorsal subiculum as rats navigate in an open-field, pellet-searching task. The subiculum is one of the few major output zones for the hippocampus, and it, in turn, projects to numerous other brain areas, each thought to be involved in various learning and memory functions. Most subicular cells showed a robust locational signal. The patterns observed were different from those in the hippocampus, however, in that cells tended to fire throughout much of the environment, but showed graded, location-related rate modulation, such that there were some localized regions of high firing and other regions with relatively low firing. There were slight quantitative differences between the proximal (adjacent to the hippocampus) and distal (farther from the hippocampus) subicular regions, with distal cells showing slightly higher average firing rates, spatial signaling, and firing field size. This was of interest since these two regions have different efferent connections. Examination of spike trains allowed classification of cells into bursting, nonbursting, and theta (putative interneuron) categories, and this is similar to subicular cell types identified in vitro. Interestingly, the bursting and nonbursting types did not differ detectably in spatial firing properties, suggesting that differences in intrinsic membrane properties do not necessitate differences in coding of environmental inputs. The results suggest that the subiculum transmits a robust, highly distributed spatial signal to each of its projection areas, and that this signal is transmitted in both a bursting and nonbursting mode.

Animals↗
PubMed1982

Synthesis of nonlinear control surfaces by a layered associative search network.

An approach to solving nonlinear control problems is illustrated by means of a layered associative network composed of adaptive elements capable of reinforcement learning. The first layer adaptively develops a representation in terms of which the second layer can solve the problem linearly. The adaptive elements comprising the network employ a novel type of learning rule whose properties, we argue, are essential to the adaptive behavior of the layered network. The behavior of the network is illustrated by means of a spatial learning problem that requires the formation of nonlinear associations. We argue that this approach to nonlinearity can be extended to a large class of nonlinear control problems.

Animals↗
PubMed2004

Mice lacking 5-HT receptors show specific impairments in contextual learning.

Using 5-HT(7) receptor knockout mice it has been shown that the 5-HT(7) receptor is the main mediator of serotonin-induced hypothermia but very little is known about the relevance of 5-HT(7) receptors in behaviour. We here report that lack of 5-HT(7) receptors leads to a specific learning deficit that is not due to general sensory or behavioural deficits. The knockout mice show impaired contextual fear conditioning but no significant deficits in motor and spatial learning or cued and operant conditioning. In addition, we demonstrate that 5-HT(7) receptor knockout mice display decreased long-term synaptic plasticity within the CA1 region of the hippocampus. The results indicate an important role for the 5-HT(7) receptor in contextual hippocampal-dependent learning and suggest a possible neuronal correlate for such a role is present within the CA1 region of the hippocampus.

Adaptation, Ocular↗
PubMed2006

Effects of Yukmijihwang-tang derivatives (YMJd) on ibotenic acid-induced amnesia in the rat.

The present study investigates the effects of Yukmijihwang-tang Derivatives (YMJd) on learning and memory through the Morris water maze task and the central cholinergic system of rats with excitotoxic medial septum (MS) lesion. In the water maze test, the animals were trained to find a platform in a fixed position for 6 d and then received a 60-s probe trial in which the platform was removed from the pool on the 7th day. Ibotenic lesion of the MS showed the impaired performance in the Morris water maze test and severe cell losses in the MS, as indicated by decreased choline acetyltransferase-immunoreactivity in the medial septum. Daily administrations of YMJd (100 mg/kg, i.p.) for 21 consecutive days produced significant reversals of ibotenic acid-induced deficit in learning and memory. These treatments also reduced the loss of choline acetyltransferase (ChAT) immunoreactivity in the MS induced by ibotenic acid. These results suggest that impairments of spatial learning and memory might be attributable to the degeneration of septohippocampal cholinergic (SHC) neurons and that YMJd treatment ameliorated learning and memory deficits partly due through neuroprotective effects on the central acetylcholine system. Our studies suggest that YMJd might be useful in the treatment of Alzheimer's disease.

Amnesia↗
PubMed2000

Modest neuropsychological deficits caused by reduced noradrenaline metabolism in mice heterozygous for a mutated tyrosine hydroxylase gene.

Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme for the biosynthesis of catecholamines that are considered to be involved in a variety of neuropsychiatric functions. Here, we report behavioral and neuropsychological deficits in mice carrying a single mutated allele of the TH gene in which TH activity in tissues is reduced to approximately 40% of the wild-type activity. In the mice heterozygous for the TH mutation, noradrenaline accumulation in brain regions was moderately decreased to 73-80% of the wild-type value. Measurement of extracellular noradrenaline level in the frontal cortex by the microdialysis technique showed a reduction in high K(+)-evoked noradrenaline release in the mutants. The mutant mice displayed impairment in the water-finding task associated with latent learning performance. They also exhibited mild impairment in long-term memory formation in three distinct forms of associative learning, including active avoidance, cued fear conditioning, and conditioned taste aversion. These deficits were restored by the drug-induced stimulation of noradrenergic activity. In contrast, the spatial learning and hippocampal long-term potentiation were normal in the mutants. These results provide genetic evidence that the central noradrenaline system plays an important role in memory formation, particularly in the long-term memory of conditioned learning.

Animals↗
PubMed2000

[Effects of chronic stress on the learning and memory ability and hippocampal LTP in rats].

AIM AND METHODS: A chronic stress model in 21 days with multi-stressors was applied to question the effects of stress on the learning and memory ability and the hippocampal neuronal synaptic plasticity in rats, using the Y maze test and LTP electrophysiological recording in vivo. RESULTS: The impairment of spatial learning and memory ability and an obvious suppression in LTP in hippocampal dentate gyrus was observed in stress group after chronic stress. CONCLUSION: The hippocampal synaptic plasticity may be decreased by the chronic stress. And then, the learning and memory ability may also be impaired consequently.

Animals↗
PubMed1997

A role for the Ras signalling pathway in synaptic transmission and long-term memory.

Members of the Ras subfamily of small guanine-nucleotide-binding proteins are essential for controlling normal and malignant cell proliferation as well as cell differentiation. The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm, induces Ras signalling in response to Ca2+ influx and activation of G-protein-coupled receptors in vitro, suggesting that it plays a role in neurotransmission and plasticity in vivo. Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact. Electrophysiological measurements in the basolateral amygdala reveal that long-term plasticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not reveal major deficits in spatial learning tasks such as the Morris water maze, a test that requires hippocampal function. Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories.

3T3 Cells↗