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Cognitive deficits and CNS damage after a 4-day binge ethanol exposure in rats.

Impairments of learning and memory are common neuropsychological sequelae of chronic alcohol abuse. Alcoholics often have impairments of anterograde memory, including spatial memory dysfunction, and a tendency toward response perseveration. This study was designed to assess the effects of binge ethanol exposure on neurodegeneration and cognitive function. Rats were given ethanol three times daily for 4 days. Silver staining revealed neurodegeneration in the olfactory bulb, piriform cortex, perirhinal cortex, entorhinal cortex, and dentate gyrus. After withdrawal, behavioral testing in the Morris water maze revealed significant differences in reversal learning between treatment groups. Ethanol-treated animals required more trials to learn the reversal task, entered the previously trained quadrant more often, and spent more time there than controls. [3H]PK-11195 binding, an index of CNS damage, was elevated in the piriform cortex of ethanol-treated animals. Thus, binge ethanol exposure resulted in neurodegeneration of a corticolimbic circuit with common excitatory inputs from the olfactory bulb and was associated with perseverative responding on a spatial learning task. These studies suggest that a single binge drinking episode could cause neurodegeneration and cognitive dysfunction in humans. The perseverative nature of the behavioral deficit could be related to both cognitive dysfunction and the behavioral components of the addiction process.

Animals↗

Blood oxygen level dependent response and spatial working memory in adolescents with alcohol use disorders.

BACKGROUND: Previous studies have suggested neural disruption and reorganization in young and older adults with alcohol use disorders (AUD). However, it remains unclear at what age and when in the progression of AUD changes in brain functioning might occur. METHODS: Alcohol use disordered (n = 15) and nonabusing (n = 19) boys and girls aged 15 to 17 were recruited from local high schools. Functional magnetic resonance imaging data were collected after a minimum of 5 days' abstinence as participants performed spatial working memory and simple motor tasks. RESULTS: Adolescents with AUD showed greater brain response to the spatial working memory task in bilateral parietal cortices and diminished response in other regions, including the left precentral gyrus and bilateral cerebellar areas (clusters > or =943 microl; p < 0.05), although groups did not differ on behavioral measures of task performance. No brain response differences were observed during a simple finger-tapping task. The degree of abnormality was greater for teens who reported experiencing more withdrawal or hangover symptoms and who consumed more alcohol. CONCLUSIONS: Adolescents with AUD show abnormalities in brain response to a spatial working memory task, despite adequate performance, suggesting that subtle neuronal reorganization may occur early in the course of AUD.

Adolescent↗

Neurocognitive effects of methylphenidate in adult attention-deficit/hyperactivity disorder.

RATIONALE: Features of childhood attention-deficit/hyperactivity disorder (ADHD) often persist into adulthood. It has been shown that adult ADHD is associated with various neurocognitive deficits, including impairments in spatial working memory (SWM) and attention. It is not known whether these deficits are ameliorated by methylphenidate in adult ADHD. OBJECTIVES: The aim of this study was to evaluate the neurocognitive effects of a single dose of methylphenidate on SWM, visual memory, spatial span and sustained attention in adult ADHD. METHODS: Twenty-four adult patients, recruited from a specialised clinic for the assessment of adult ADHD, were entered into a double-blind, randomised, placebo-controlled crossover study using a single 30 mg dose of methylphenidate. RESULTS: Eighteen patients met DSM-IV criteria for adult ADHD. Methylphenidate resulted in an improvement in SWM performance and sustained attention, together with a speeding in response time, in these patients. Six patients with attentional difficulties, who did not meet a DSM-IV diagnosis of ADHD, showed a different pattern of response to methylphenidate compared to the ADHD group. For the combined group, moderate correlations were shown between childhood ratings of ADHD (both self-reported and informant ratings) and response to methylphenidate on the SWM task. CONCLUSIONS: Adults with ADHD had a similar neurocognitive response to methylphenidate to that previously reported for childhood ADHD. Our results provide further support for the validity of the ADHD syndrome as defined by DSM-IV and indicate possible neurocognitive substrates for clinical improvement with chronic methylphenidate.

Adult↗

Spatial and reversal learning in congeneric lizards with different foraging strategies.

Environmental demands that require intensive search for mates, food and nest sites are correlated with efficient spatial memory in many mammalian and avian species. This convergence of evidence has led to the view that spatial memory, and the neurological structures associated with it, have been selected in niches that require memory for the location of goal objects. Whether such evolutionary demands are also correlated with nonspatial abilities that require flexible use of associations similar to those required for spatial memory has not been well studied. In addition, correlations between niche types and the use of spatial or nonspatial memory have not been investigated in nonmammalian, nonavian taxa. In this study, we investigated the relationship between foraging strategies and performance on two tasks, one spatial and the other nonspatial, in congeneric lizard species: Acanthodactylus boskianus, an active forager that collects clumped sedentary prey, Acanthodactylus scutellatus, a sit-and-wait predator that collects distributed mobile prey. The two species did not differ in their performance of a spatial memory task, but A. boskianus, the active forager, performed better on the reversal of a visual discrimination, a nonspatial task. These findings question the generality of the spatial adaptation model for vertebrates. We present the pliancy hypothesis, which we developed to account for these results. Copyright 1999 The Association for the Study of Animal Behaviour.

Journal Article↗

Low doses of ethanol impair spatial working memory and reduce hippocampal theta activity.

Low doses of ethanol can alter neural activity in the septohippocampal pathway, a pathway critical for spatial working memory. The present study was designed to determine whether acute ethanol induces impairments in working memory and disrupts septohippocampal function as measured by the hippocampal theta rhythm. Rats were preoperatively trained on delayed alternation. A within-subject design was used to evaluate the effects of ethanol (0.25, 0.5, 0.75 and 1.0 g/kg, intraperitoneally) on performance 10 min and 90 min after injection as compared with preinjection baseline. Ethanol produced dose-, delay-, and time-dependent impairments in working memory as indicated by a change in choice accuracy in the delayed alternation task. Ethanol did not affect performance time, the ability to complete the task, or response bias. Thus, the impairment does not appear to result from a decrement in general performance, but rather from an impairment in spatial working memory. Hippocampal theta activity was suppressed by ethanol at the same doses, 0.75 g/kg and 1.0 g/kg, that impaired working memory. The interaction of ethanol with functions of the septohippocampal pathway are discussed.

Animals↗

Spatial working memory in rats: no differences between the sexes.

In a number of mammalian species, males appear to have superior spatial abilities to females. The favoured explanations for this cognitive difference are hormonal, with higher testosterone levels in males than females leading to better spatial performance, and evolutionary, where sexual selection has favoured males with increased spatial abilities for either better navigational skills in hunting or to enable an increased territory size. However, an alternative explanation for this sex difference focuses on the role of varying levels of oestrogen in females in spatial cognition (the 'fertility and parental care' hypothesis). One possibility is that varying oestrogen levels result in variation in spatial learning and memory so that, when tested across the oestrous cycle, females perform as well as males on days of low oestrogen but more poorly on days of high oestrogen. If day in the oestrous cycle is not taken into account then, across an experiment, any sex differences found would always produce male superiority. We used a spatial working memory task in a Morris water maze to test the spatial learning and memory abilities of male and female rats. The rats were tested across a number of consecutive days during which the females went through four oestrous cycles. We found no overall sex differences in latencies to reach a submerged platform in a Morris water maze but, on the day of oestrus (low oestrogen), females took an extra swim to learn the platform's location (a 100% increase over the other days in the cycle). Female swim speed also varied across the oestrous cycle but females were no less active on the day of oestrus. These results oppose the predictions of the fertility and parental care hypothesis.

Animals↗

Emotion-induced amnesia in rats: working memory-specific impairment, corticosterone-memory correlation, and fear versus arousal effects on memory.

We have shown previously that psychological stress (predator exposure) impairs spatial memory in rats. We have extended that finding here to show that predator stress selectively impaired recently acquired (hippocampal-dependent) spatial working memory without affecting long-term (hippocampal-independent) spatial reference memory. We also investigated why predator exposure impairs memory. Was spatial memory impaired because of the fear-provoking aspects of predator exposure or only because the cat was a novel and arousing stimulus? If the latter possibility was correct, then any novel and arousing stimulus, independent of its emotional valence (i.e., aversive or appetitive), would impair memory. We found that spatial working memory was not impaired when the male rats were exposed to a sexually receptive female rat, a stimulus that was novel and arousing to them, but not aversive. We also found that there was an equivalent increase in serum corticosterone levels in male rats exposed to either a cat or a female rat, but only the cat-exposed rats exhibited a significant correlation between corticosterone levels and impaired memory. Overall, this series of experiments demonstrates that (1). predator stress selectively impaired working (hippocampal-dependent), but not reference (hippocampal-independent), memory; (2). a fear-provoking stimulus, and not merely novelty and increased arousal, impaired spatial memory; and (3). increased corticosterone levels correlated with impaired spatial working memory only under predator exposure, that is, fear-provoking conditions.

Amnesia↗

Multiple-dose pharmacokinetics and safety of a potential memory-enhancing compound, CL 275,838, in healthy male volunteers.

The pharmacokinetics and safety of CL 275,838, a new potential memory-enhancing compound, were examined after 14 daily doses (50 and 100 mg) in 16 healthy male volunteers, age 20 to 59 years, in a randomized, double-blind, placebo-controlled, parallel group study. Trough blood samples (predose) were collected on days 2, 4, 7, 10, and 14, and further samples were drawn after the final dose (day 14) to define the multiple-dose kinetics of the parent compound and its metabolites II and IV. Intercurrent clinical events, vital functions, EEG, ECG, and cognitive tests (attention, verbal memory, and spatial memory) were considered as outcome measures of safety. Performance in cognitive tests was also studied to collect preliminary information on possible therapeutic action. Predose plasma concentrations of the parent compound and its two metabolites increased approximately in proportion to the dose, and accumulation was complete within 7 days, regardless of the dose. At steady state, mean Cmax and AUC of the parent compound and its two metabolites were dose related. Mean wash-out t1/2 was 18 to 20 hours for the parent compound, 22-23 hours for metabolite II, and 28-33 hours for metabolite IV; these elimination t1/2 are comparable for the two doses, and are similar to those observed in single-dose studies. For the 50-mg-dose group, predicted and observed average plasma concentrations (Css) of CL 275,838 and its two metabolites did not differ significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Relative lack of cognitive effects of methylphenidate in elderly male volunteers.

RATIONALE: Methylphenidate, a dopaminergic and noradrenergic reuptake inhibitor, has been shown in young, healthy adult volunteers to produce pronounced effects on working memory and sustained attention. We were interested in assessing whether similar improvements could be conferred upon elderly volunteers in order to gain a more complete understanding of the effects of age on monoaminergic manipulations of working memory and attention, as well as to explore the potential for pharmacological intervention in attention and executive dysfunction disorders in this age group. OBJECTIVES: The main aim of the study was to characterise the dose-related effects of methylphenidate on a range of neuropsychological functions in elderly healthy volunteers. METHODS: Sixty healthy elderly adult male volunteers received either a single oral dose of placebo, 20 mg or 40 mg methylphenidate prior to performing a variety of tasks designed to assess memory, attention and executive function. A randomised double-blind, between-subjects design was used. RESULTS: Methylphenidate had significant cardiovascular and subjective effects. However, unlike in younger volunteers, no significant effects of drug on working memory (spatial span and spatial working memory), response inhibition (stop-signal) or sustained attention (rapid visual information processing) were seen. Subtle effects on latency similar to those in younger volunteers were identified: both doses of methylphenidate resulted in a slowing in response time during set-shifting and decision-making. CONCLUSIONS: The results of this study demonstrate that, in elderly subjects, the cognitive effects of methylphenidate are grossly attenuated and distinct from the profile previously described in younger volunteers. It is suggested that methylphenidate may not be appropriate as a pharmacological intervention in elderly patient groups, such as those reporting age-related cognitive decline.

Administration, Oral↗

Radial maze in the water tank: an aversively motivated spatial working memory task.

An 8-arm radial maze with 40 X 40 X 12 cm channels was inserted into a circular tank (120 cm in diameter, 60 cm high) filled 30 cm deep with 25 degrees C opaque water. Rats (n = 13) had to escape from the central area of the maze (30 cm in diameter) onto an invisible bench (1 cm below water surface) at the far end of each channel. Twenty sec after each choice the bench was collapsed and the animal was forced to choose again until all 8 channels had been visited. From the very beginning rats performed better than chance. The acquisition and performance of this aversively motivated radial maze test is similar as in conventional elevated 8-arm radial mazes.

Animals↗

Are the neurochemical and behavioral changes induced by lesions of the nucleus basalis in the rat a model of Alzheimer's disease?

A review of the work on the neurochemical, electroencephalographic and behavioral changes induced in the rat by lesions of the nucleus basalis is presented. The similarities and differences between the effects of the lesions and the neurochemical and clinical alterations characterizing senile dementia of Alzheimer type are pointed out. The decrease in choline acetyltransferase (ChAT) activity in the cortex following unilateral or bilateral electrolytic or neurotoxic lesions of the nucleus basalis are described and compared with the decrease in ChAT activity found in the cortex and hippocampus of patients affected by senile dementia. At variance with the latter condition, in rats with lesions of the nucleus basalis a spontaneous recovery in cortical ChAT activity has been observed 3-6 months after the lesion. The lesions of the nucleus basalis decrease high affinity choline uptake activity which, however, undergoes a rapid recovery. Lesions also decrease spontaneous and drug-stimulated ACh release from the cerebral cortex. Transitory changes in the number of muscarinic binding sites have been reported in the cerebral cortex of the lesioned rats while a decrease in the number of muscarinic binding sites has generally been found in the cerebral cortex of patients with senile dementia. [3H] glutamate uptake in the striatum of the lesioned rats was not affected. In both lesioned rats and patients affected by senile dementia, a decrease of low voltage high frequency electrocortical activity has been reported. Unilateral and bilateral lesions of the nucleus basalis bring about an impairment of the acquisition of active and passive avoidance responses and of the rewarded alternation discriminatory tasks involving working memory and spatial memory. On the other hand, memory impairment is a typical symptom of senile dementia. In conclusion, the lesions of the nucleus basalis only partly mimic the complex clinical picture of senile dementia of Alzheimer type. They offer, nevertheless, a useful tool for understanding the critical role of the central cholinergic pathways in some of the cognitive processes and identifying potentially useful pharmacological treatments.

Alzheimer Disease↗

Early dysregulation of hippocampal proteins in transgenic rats with Alzheimer's disease-linked mutations in amyloid precursor protein and presenilin 1.

The response of the hippocampal proteome to expression of mutant proteins present in familial forms of Alzheimer's disease (AD) was studied using transgenic rats. These animals carry both the amyloid precursor protein Swedish and 717 mutation (APP(SW+717)) as well as the presenilin 1 Finnish mutation (PS1(FINN)). This transgenic rat model displays intracellular amyloid beta (Abeta) in neurons of the neocortex and the hippocampus (CA2 and CA3). The hippocampus was selected as it is one of the first brain regions affected in AD and is involved in the processing of short-term memory and spatial memory. Applying a proteomic approach, we demonstrate that the expression of APP(SW+717) and PS1(FINN) transgenes causes changes in expression of hippocampal proteins, some of which have been previously linked to learning and memory formation. The protein alterations documented here occur in the absence of plaque formation and prior to the onset of cognitive deficits later observed in these transgenic rats. This indicates that molecular changes take place in the hippocampal neurons in response to expression of mutant proteins APP(SW+717) and PS1(FINN), which precede the occurrence of overt extracellular accumulation of extracellular amyloid. The implications of these findings on our understanding of the early stages of AD are discussed.

Alzheimer Disease↗

The nature of the spatial deficit in young females with Fragile-X syndrome: a neuropsychological and molecular perspective.

Spatial performance in a group of young Fragile-X syndrome females with FMR-1 full mutation was compared to two control groups of mainstream schoolchildren. Performance was assessed across a wide range of spatial tasks including visuo-spatial, visuo-construction, visuo-motor, visuo-perception and spatial-memory. A spatial deficit emerged only on those tasks which comprised a visuo-constructive component, with the Fragile-X group performing worse overall. All other tasks were performed at a comparable level across the three groups. Molecular analysis of the lymphocyte DNA found minimal evidence for a correlation between expansion size and spatial performance. In addition, there was no evidence for a correlation between the proportion of active to inactive unmethylated FMR-1 genes (activation ratio) and spatial performance. These results conflict with recent reports of a correlation between activation ratio and intellectual functioning.

Adolescent↗

Cognitive factors in schizophrenia: causes, impact, and treatment.

Greater attention has been given to the cognitive dimension in schizophrenia in recent years. This has resulted from increased recognition that cognitive impairment and negative symptoms of the disease have a greater impact on quality of life (QOL) compared to positive symptoms. Successful treatment of positive symptoms in patients with schizophrenia has not been shown to robustly translate into improvements in employment status or social relationships, while cognitive improvements are strongly associated with these important aspects of QOL and independence. These findings are based on extensive testing with standard cognitive tests for measuring executive function, verbal learning and memory, word recall, verbal working memory, spatial working memory, attention, and vigilance. Verbal learning and executive function, in particular, have been found to be valid predictors of employment success independent of the degree of severity of positive symptoms.

Antipsychotic Agents↗

Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice.

Nerve growth factor (NGF) delivery to the brain of patients appears to be an emerging potential therapeutic approach to neurodegenerative disease, such as Alzheimer's disease (AD). The intranasal route of administration could provide an alternative to intracere-broventricular infusion and gene therapy. We previously showed that intranasal administration of NGF determined an amelioration of cholinergic deficit and a decrease in the number of phosphotau-positive neurons and of beta-amyloid accumulation in AD11 mice, which express transgenic antibodies neutralizing NGF action and exhibit a progressive Alzheimer-like neurodegeneration. In this study, we report that the Alzheimer-like neurodegeneration in AD11 mice is linked to progressive behavioral deficits in visual recognition memory and spatial memory starting from 4 months of age. To establish whether intranasal administration of NGF, started after the appearance of the first memory deficits, could revert the cognitive deficits in AD11 mice, we assessed the performance of NGF-treated or control AD11 mice in the object recognition test and in a test of memory for place and context. Deficits exhibited by untreated AD11 mice could be rescued by the intranasal administration of NGF. Thus, this route of administration provides a promising way to deliver NGF to the brain in a therapeutic perspective.

Administration, Intranasal↗

Developmental dysmnesia in a poor reader.

A 22-yr-old subject with moderate developmental dyslexia experienced poor memory from an early age. In spite of normal intelligence he had great difficulty in learning historical and geographical names, mathematical formulae, poems and songs, and verbal series such as the letters of the alphabet and the months of the year. His recognition of familiar faces was also faulty at times. A battery of memory tests confirmed a moderate deficit of verbal as well as visual memory, whereas spatial memory was preserved. Other cognitive functions were intact, except for a mild reading disability. No evidence of brain pathology was provided by his history, neurological examination and CT scanning.

Adult↗

Homology in behavioural pharmacology: an approach to animal models of human cognition.

The distinction in biology between homology and analogy is examined for possible application to studies in behavioural pharmacology. It is argued that the concept of homology is central to understanding the 'construct validity' of animal models of human cognition. It is suggested that we capitalize on known correspondences across species in brain structure and development which may mediate homologous behavioural functions. Manipulation of specific receptors in defined areas may be achieved by local and systemic administration of drugs with relatively specific actions; this will complement an alternative criterion of construct validity, based on clinical treatments. This argument will be illustrated by a critique of successful extrapolations across species that are sometimes initiated by work in animals and sometimes by work in humans, especially in the clinical setting. The examples used will include analyses of spatial working memory, spatial attention and attentional set-shifting, studied in rats, monkeys and humans.

Animals↗

Hippocampal volume and food-storing behavior are related in parids.

The size of the hippocampus has been previously shown to reflect species differences and sex differences in reliance on spatial memory to locate ecologically important resources, such as food and mates. Black-capped chickadees (Parus atricapillus) cached more food than did either Mexican chickadees (P. sclateri) or bridled titmice (P. wollweberi) in two tests of food storing, one conducted in an aviary and another in smaller home cages. Black-capped chickadees were also found to have a larger hippocampus, relative to the size of the telencephalon, than the other two species. Differences in the frequency of food storing behavior among the three species have probably produced differences in the use of hippocampus-dependent memory and spatial information processing to recover stored food, resulting in graded selection for size of the hippocampus.

Animals↗