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PubMedDate not supplied

Differential effects of age on subpopulations of hippocampal theta cells.

The possible contribution of age-related changes in the firing properties of hippocampal theta cells to spatial learning deficits was addressed in the present study. The behavioral correlates of theta cells in strata oriens, pyramidale, and granulosum were compared as young and old rats performed a radial maze spatial working memory task. Behaviorally, the old animals made significantly more errors on the maze and required more time to solve the task than did young animals. Firing rates were compared in four different locomotion states: still, running radially inward and radially outward, and forward motion. The discharge rates of theta cells in strata pyramidale and granulosum were significantly modulated by these movements in both age groups. Stratum oriens theta cells recorded from young animals, on the other hand, were not movement-sensitive, while similar cells from old animals demonstrated exaggerated responses to movement. In old animals, the mean discharge rates were higher in stratum granulosum and lower in stratum oriens than in the young rats. The discharge rates of cells in stratum pyramidale did not differ between age groups. These region specific changes in the firing characteristics of hippocampal theta cells are likely to have important consequences for information processing in this structure.

Aging↗
PubMedDate not supplied

A longitudinal study of reaction time performance in Long-Evans rats.

This study was undertaken to examine individual differences in the progression of age-related decline on a measure of sensorimotor function. Twenty-one adult rats were trained on a simple reaction time (RT) task and assessed every 6 weeks from 14.5 to 25 months of age. An overall slowing of RT latencies associated with chronological age was observed. However, some rats maintained a stable performance with age while others slowed considerably. Another measure within the RT task, accuracy of performance, appeared to represent a stable individual characteristic that was insensitive to the effects of age. However, no measure of performance on the RT task at 14.5 months of age predicted later impairment in RT latency. At the completion of longitudinal testing, spatial learning in the Morris water maze was assessed in these aged rats along with a young comparison group. The aged rats were impaired relative to young controls in locating the escape platform. Measures of cognitive function and sensorimotor function within the spatial task were, however, unrelated to slowing of RT latency.

Aging↗
PubMed2003

A differential involvement of the shell and core subterritories of the nucleus accumbens of rats in memory processes.

The role of the core and the shell subterritories of the nucleus accumbens in conditioned freezing and spatial learning was investigated by means of selective N-methyl-D-aspartate lesions. Shell-lesioned rats showed reduced conditioned freezing to context and a tendency toward reduced freezing to the discrete stimulus compared with controls. However, lesions of the core did not modify the freezing response either to the context or to the discrete stimuli. Although spatial memory, as assessed by a water-maze paradigm, was not disrupted by the lesions, in a 4-arm baited, 4-arm unbaited radial-arm maze paradigm, the shell-lesioned rats showed selective deficits in working memory, but not in reference memory. In contrast, core-lesioned rats showed no memory deficits.

Animals↗
PubMed2005

Melatonin improves learning and memory performances impaired by hyperhomocysteinemia in rats.

Oxidative stress has been proposed as a possible mechanism underlying many neurodegenerative diseases associated with hyperhomocysteinemia. In the present study, we investigated the possible link between oxidative stress, expression of neural cell adhesion molecules and spatial learning deficits induced by chronic hyperhomocysteinemia. Furthermore, the effectiveness of antioxidant melatonin against homocysteine neurotoxicity was also examined. Male Wistar rats were treated with either saline or methionine to induce hyperhomocysteinemia and half of methionine-treated rats administered daily melatonin in a dose of 10 mg/kg. We observed that chronic administration of melatonin significantly reduced the lipid peroxidation and restored the decreased glutathione levels induced by chronic hyperhomocysteinemia. Chronic hyperhomocysteinemia significantly impaired learning and memory performance in the passive avoidance test and Morris water maze task. We also found that these cognitive deficits were reversed by chronic treatment with antioxidant melatonin. Furthermore, melatonin administration was able to modulate the expression pattern of neural cell adhesion molecules in hippocampus. The results provide evidence that homocysteine induces long-lasting behavioral deficits, which are possibly caused by oxygen reactive species generation, and by changing in synaptic plasticity and also suggest that melatonin treatment has the ability to prevent nervous system against homocysteine toxicity.

Analysis of Variance↗
PubMed2004

Norleucine1-Angiotensin IV alleviates mecamylamine-induced spatial memory deficits.

The brain angiotensin AT4 receptor subtype has been implicated in cognitive processing. We initially established that intracerebroventricular administration of the nAChR-antagonist mecamylamine (mec) interfered with spatial memory performance in male Sprague-Dawley rats. Next we demonstrated that mec-induced deficits in spatial memory were overcome by the AT4 receptor-agonist Norleucine1-Angiotensin IV (Nle1-Ang IV). Nle1-Ang IV could not, however, compensate for spatial learning impairments precipitated by both mec and the mAChR-antagonist scopolamine. These findings support the importance of the AT4 receptor in cognitive processing and suggest that the ability of Nle1-Ang IV to improve spatial memory deficiencies may be dependant upon the brain cholinergic system.

Angiotensin II↗
PubMed2000

Mice lacking the cell adhesion molecule Thy-1 fail to use socially transmitted cues to direct their choice of food.

BACKGROUND: Thy-1 is a major cell-surface glycoprotein of mature neurons and certain other cells, including those of the lymphoreticular system. Despite being the simplest member of the immunoglobulin superfamily, the biological role of Thy-1 has proved elusive. Analysis of Thy-1 null mice has shown the presence of excessive GABAergic inhibition of neurotransmission in the dentate gyrus of the hippocampal formation selectively, without any neurological or behavioural effects being apparent. RESULTS: We show here that Thy-1 null mice are unable to make the appropriate dietary choice in the test for social transmission of food preference, despite showing a normal level of social interaction with the demonstrator mouse, normal neophobia, and normal learning in a T-maze using scented food as cues. The mice also performed normally in tests of anxiety, locomotor activity, exploration of a novel environment, habituation to novelty and spatial learning. This phenotype is maintained on two different strain backgrounds, is rescued by transgenic expression of Thy-1 and by administration of the GABA(A) receptor antagonist pentylenetetrazole. CONCLUSIONS: The test for social transmission of food preference is based on the normal ability of mice in a colony to learn from each other which foods are safe to eat. The lack of this key survival behaviour in Thy-1 null mice could act as an evolutionary pressure point to conserve expression of Thy-1. Furthermore, the specific cognitive defect caused by inactivation of the Thy-1 gene suggests that it would be worthwhile to determine the role of Thy-1 in certain human familial forms of mental retardation that map to chromosome 11q22-23 in the region of the Thy-1 locus rather than the nearby ataxia telangiectasia locus.

Animal Communication↗
PubMedDate not supplied

Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5.

Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA) and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization. Blockade of these sites with the drug aminophosphonovaleric acid (AP5) does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of hippocampal long-term potentiation (LTP) following brief high-frequency stimulation. We now report that chronic intraventricular infusion of D,L-AP5 causes a selective impairment of place learning, which is highly sensitive to hippocampal damage, without affecting visual discrimination learning, which is not. The L-isomer of AP5 did not produce behavioural effects. AP5 treatment also suppressed LTP in vivo. These results suggest that NMDA receptors are involved in spatial learning, and add support to the hypothesis that LTP is involved in some, but not all, forms of learning.

2-Amino-5-phosphonovalerate↗
PubMed2005

Auditory processing deficits in rats with neonatal hypoxic-ischemic injury.

Hypoxia-ischemia (HI) refers to reduced blood oxygenation and/or a diminished amount of blood perfusing the brain, and is associated with premature birth/very low birth weight (VLBW). HI represents a common cause of injury to the perinatal brain. Indeed, a significant number of premature/VLBW infants go on to demonstrate cognitive/behavioral deficits, with particularly high incidence of disruptions in language development. Auditory processing deficits, in turn, have been suggested to play a causal role in the development of language impairments. Specifically, the inability to identify fast elements in speech is purported to exert cascading detrimental effects on phonological discrimination, processing, and identification. Based on this convergent evidence, the current studies address auditory processing evaluation in a rodent model of HI injury induced on postnatal days 1, 7, or 10 (which in turn is well accepted as modeling HI-related injury to the perinatal human). Induced injuries were followed by a battery of auditory testing, and a spatial maze assessment, performed both during juvenile and adult periods. Results indicate that rats suffering from these early HI insults performed significantly worse than shams on tasks requiring rapid auditory processing, and on a test of spatial learning (Morris water maze (MWM)), although these effects were not seen on simpler versions of auditory tasks or on a water escape assessment (thus ruling out hearing/motor impairments). Correlations were found between performance on rapid auditory and spatial behavioral tasks and neuroanatomical measures for HI animals such as: the volume of the hippocampus, cerebral cortex, ventricles, and/or the area of the corpus callosum. Cumulative findings suggest that perinatal HI injury in the rat may lead to neurodevelopmental damage associated, in turn, with auditory processing and/or learning and memory impairments. As such, the current model may have critical implications for the study of neurophysiological underpinnings of cognitive deficits in premature/VLBW infants.

Aging↗
PubMed1994

[Aging of memory mechanisms].

Human amnesia cases (after surgical removal of the hippocampi or brain anoxia) have clearly established the critical role of the hippocampal formation in anterograde amnesia. Other parts of the brain may also contribute to anterograde amnesia (mammillary bodies, medial thalamus). In neurodegenerative diseases (and specially in Alzheimer's disease) amnesia is often the prominent symptom, but the brain lesions are not restricted to the hippocampal formation. In Alzheimer's disease they involve also the cerebral cortex and several subcortical nuclei. Physiological brain aging is also associated with some degree of memory impairment, but much less severe than in Alzheimer's disease. The issue of the nature and the mechanisms of the memory impairment associated with age and with Alzheimer's disease is very important, because the frequency of these problems increases dramatically as the populations of the world is growing older. There is some evidence that neuronal loss and alterations in neurotransmitter systems occur in the aged subject, but the relationship between such changes and the age-related memory deficit is far from being clear. In Alzheimer's disease, the loss of memory is likely to be due to neuronal loss in cerebral cortex and hippocampal formation, along with alterations in neurotransmitter systems (specially cholinergic, monoaminergic and aminoacidergic systems). The work in experimental animals has largely confirmed the critical role of the hippocampal formation, as well as identified other critical structures. The mechanisms of the age-related memory impairment can be to some extent investigated in aged animals. In the aged rat there is evidence that several neurotransmitter networks are altered. Alteration in the dopaminergic and cholinergic systems have been extensively studied, but the involvement of other systems is likely. Learning and memory deficits are consistently observed in a sub-population of aged rodents (as well as in other species including non-human primates). For instance some aged rats do have a deficit in the performance of a spatial learning task such as the "water maze". There is some evidence that this deficit is due, at least in part, to alterations in the functions of the hippocampal formation. In other words, if aged rats have a spatial memory deficit, it might be due to changes in hippocampal neuronal circuitry. The study of age-related alterations in hippocampal neuronal networks, using electrophysiological techniques have shown that several neuronal properties such as resting membrane potential, membrane resistance or sodium spike amplitude are not altered in the aged rat hippocampus.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1998

Sulpiride infused into the nucleus accumbens posttraining impairs memory of spatial water maze training.

A variety of nucleus accumbens (NA) manipulations induce deficits in spatial learning and memory tasks. It is not known, however, if these deficits reflect influences on memory or on other processes affecting performance. The experiments in this article were undertaken to examine the involvement of the NA in memory consolidation in a spatial task. Rats were given 1 training session in a spatial water maze immediately followed by intra-NA infusions of sulpiride or saline vehicle. A probe test 2 days later revealed an impairing effect of sulpiride on several retention measures. Sulpiride infused into the NA either 2 hr posttraining in the spatial task or immediately posttraining in a cued water maze task did not affect retention performance. These findings suggest that the impairing effects of immediate posttraining sulpiride in the spatial task are due to interference with spatial water maze-specific consolidation processes involving the NA.

Analysis of Variance↗
PubMed1992

Chronic sodium azide treatment impairs learning of the Morris water maze task.

A reduction in the activity of cytochrome oxidase, a respiratory chain enzyme, has been recently identified in mitochondria from blood platelets and postmortem brain tissue from Alzheimer's disease (AD) patients. We have developed an animal model of this deficit in rats by chronic subcutaneous infusion of sodium azide, a selective inhibitor of cytochrome oxidase, delivered via Alzet 2ML4 osmotic minipumps. In previous work, azide-treated rats were impaired in an appetitively motivated spatial learning task, the radial arm maze. In the present investigation, we tested male Sprague-Dawley rats (350-400 g), which were tonically infused with azide or saline, on an aversively motivated spatial task, the Morris water maze. Azide-treated rats were impaired on both acquisition and retention of this task, without showing evidence of a motor impairment. Thus, the present results are consistent with previous findings showing that chronic azide treatment produces a learning and memory deficit. These findings strengthen the hypothesis that azide treatment in rats produces a useful animal model of some aspects of AD.

Animals↗
PubMed2006

Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing.

Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memory-associated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders.

Acetylcholine↗
PubMed2005

Cognitive performance is highly sensitive to prior experience in mice with a learning and memory deficit: failure leads to more failure.

The impact of a previously successful or unsuccessful experience on the subsequent acquisition of a related task is not well understood. The nature of past experience may have even greater impact in individuals with learning deficits, as their cognitive processes can be easily disrupted. Mice with a targeted disruption of the alpha and delta isoforms of the cAMP-response element-binding protein (CREB) gene (CREB(alphadelta-)-deficient mice) have a genetic vulnerability to impaired learning and memory that is highly influenced by experimental conditions. Thus, we studied the impact of prior successful and unsuccessful experiences on the degree to which CREB(alphadelta-)-deficient mice exhibit impaired spatial learning and memory in the Morris water maze (MWM). In Experiment 1, we replicated the cognitive deficit of CREB(alphadelta-)-deficient mice when given two trials per day with a 1-min intertrial interval (MWM2), and labeled this experience as a "failure." We rescued the deficit using four trials per day with a 3- to 5-min intertrial interval (MWM4) and labeled this experience a "success." In Experiment 2, a new, naive set of wild-type (WT) and CREB(alphadelta-)-deficient mice were randomly assigned to one of two sequence protocols to assess the influence of a success or a failure on subsequent performance. In Group 1, mice were first exposed to the MWM4 condition, followed by the more difficult MWM2 task. As expected, CREB(alphadelta-)-deficient mice performed well in the MWM4; they also performed well during reversal testing (MWM4R) where the goal location is changed. With this initial successful learning experience, the CREB(alphadelta-)-deficient mice then performed as well as WT mice in the MWM2, the condition in which they are known to be impaired. In contrast, CREB(alphadelta-)-deficient mice in Group 2 had an unsuccessful experience when first exposed to the MWM2 condition, and then also showed impairment in the MWM4, the condition in which they would normally perform well. This deficit was amplified when CREB(alphadelta-)-deficient mice were then tested in the reversal test. Sex differences in learning among CREB(alphadelta-)-deficient mice were amplified upon exposure to an unsuccessful learning experience. These data indicate that, under conditions of cognitive impairment, past experience can-depending on its nature-significantly facilitate or hinder future performance.

Animals↗
PubMed2003

Effects of hippocampal cholinergic deafferentation on learning strategy selection in a visible platform version of the water maze.

Recent evidence has suggested that the relative levels of acetylcholine (ACh) between brain structures may be an important factor in the choice of behavioral strategy in settings in which either hippocampal or dorsal striatal brain systems can be employed both effectively and independently (McIntyre and Gold. 1999. Soc Neurosci Abs 25:1388). The current investigation used the neurotoxin 192 IgG-saporin to deplete the hippocampus of ACh selectively, while leaving ACh in other brain regions, including dorsal striatum, intact. Rats were then trained on a version of the Morris water maze, in which behavioral strategies attributed to the hippocampus and dorsal striatum are placed in direct competition. It was predicted that rats with hippocampal ACh depletion would display a cue bias. Contrary to this prediction, depleting hippocampal ACh did not bias against and, in fact, promoted use of a hippocampal place strategy in this task, as indicated by choice in competition tests and performance on hidden platform training trials. These data add to a growing literature demonstrating that the septohippocampal cholinergic system is not required for accurate spatial learning and suggest a complex role for basal forebrain projections in processing information about the spatial environment.

Acetylcholine↗
PubMed2006

Estradiol's effects on learning and neuronal morphology vary with route of administration.

Estrogen's effects on performance and neuronal morphology are variable, and the reasons for this variability are not yet understood. In this study, the authors compared the effects of 2 delivery routes of 17 beta-estradiol on spatial learning and dendritic spine densities in young ovariectomized rats; estradiol was administered by implanted capsules or by daily oral gavage. Estradiol treatment via capsules improved performance in the radial-arm water maze and increased spine densities on dendrites of CA1 pyramidal neurons in the hippocampal formation. In contrast, daily oral administration of estradiol did not affect either measure. These data demonstrate that estradiol delivery is a critical variable in animal studies and that clinical studies comparing the effects of different estradiol treatment routes on cognition are warranted.

Animals↗
PubMed2004

Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor.

A diet high in total fat (HF) reduces hippocampal levels of brain-derived neurotrophic factor (BDNF), a crucial modulator of synaptic plasticity, and a predictor of learning efficacy. We have evaluated the capacity of voluntary exercise to interact with the effects of diet at the molecular level. Animal groups were exposed to the HF diet for 2 months with and without access to voluntary wheel running. Exercise reversed the decrease in BDNF and its downstream effectors on plasticity such as synapsin I, a molecule with a key role in the modulation of neurotransmitter release by BDNF, and the transcription factor cyclic AMP response element binding protein (CREB), important for learning and memory. Furthermore, we found that exercise influenced the activational state of synapsin as well as of CREB, by increasing the phosphorylation of these molecules. In addition, exercise prevented the deficit in spatial learning induced by the diet, tested in the Morris water maze. Furthermore, levels of reactive oxygen species increased by the effects of the diet were decreased by exercise. Results indicate that exercise interacts with the same molecular systems disrupted by the HF diet, reversing their effects on neural function. Reactive oxygen species, and BDNF in conjunction with its downstream effectors on synaptic and neuronal plasticity, are common molecular targets for the action of the diet and exercise. Results unveil a possible molecular mechanism by which lifestyle factors can interact at a molecular level, and provide information for potential therapeutic applications to decrease the risk imposed by certain lifestyles.

Animals↗
PubMed2006

NF-kappaB/Rel regulates inhibitory and excitatory neuronal function and synaptic plasticity.

Changes in synaptic plasticity required for memory formation are dynamically regulated through opposing excitatory and inhibitory neurotransmissions. To explore the potential contribution of NF-kappaB/Rel to these processes, we generated transgenic mice conditionally expressing a potent NF-kappaB/Rel inhibitor termed IkappaBalpha superrepressor (IkappaBalpha-SR). Using the prion promoter-enhancer, IkappaBalpha-SR is robustly expressed in inhibitory GABAergic interneurons and, at lower levels, in excitatory neurons but not in glia. This neuronal pattern of IkappaBalpha-SR expression leads to decreased expression of glutamate decarboxylase 65 (GAD65), the enzyme required for synthesis of the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) in GABAergic interneurons. IkappaBalpha-SR expression also results in diminished basal GluR1 levels and impaired synaptic strength (input/output function), both of which are fully restored following activity-based task learning. Consistent with diminished GAD65-derived inhibitory tone and enhanced excitatory firing, IkappaBalpha-SR+ mice exhibit increased late-phase long-term potentiation, hyperactivity, seizures, increased exploratory activity, and enhanced spatial learning and memory. IkappaBalpha-SR+ neurons also express higher levels of the activity-regulated, cytoskeleton-associated (Arc) protein, consistent with neuronal hyperexcitability. These findings suggest that NF-kappaB/Rel transcription factors act as pivotal regulators of activity-dependent inhibitory and excitatory neuronal function regulating synaptic plasticity and memory.

Animals↗
PubMedDate not supplied

Effects of intraventricular encapsulated hNGF-secreting fibroblasts in aged rats.

Exogenous NGF administered into the central nervous system (CNS) has been reported to improve cognitive function in aged rats. However, concerns have been expressed about the risks involved with supplying NGF to the CNS. In this study, baby hamster kidney cells (BHK) genetically modified to secrete human NGF (hNGF) were encapsulated in semipermeable membranes and implanted intraventricularly. ChAT/LNGFR-positive basal forebrain neurons were shown to atrophy and degenerate with age, especially in cognitively impaired rats. The encapsulated BHK-NGF cells produced less than 10% of doses previously reported to be effective, but this was sufficient to increase the size of ChAT/LNGFR-positive basal forebrain neurons in the aged and learning-impaired rats to the size of the neurons in young healthy rats. The hNGF from these encapsulated cells also improved performance in a repeated-acquisition version of the Morris water maze spatial learning task in learning-impaired 20.6- and 26.7-mo-old rats. Furthermore, there was no evidence that these doses of hNGF impaired Morris water maze performance in the youngest 3.3-5.4 mo rats, and analyses of mortality rates, body weights, somatosensory thresholds, potential hyperalgesia, and activity levels, suggested that these levels of exogenous hNGF are not toxic or harmful to aged rats. These results suggest that CNS-implanted semipermeable membranes, containing genetically modified xenogeneic cells continuously producing these levels of hNGF, attenuate age-related cognitive deficits in nonimmunosuppressed aged rats, and that both the surgical implantation procedure and long-term exposure to low doses of hNGF appear safe in aged rats.

Aging↗