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Chronic ethanol consumption impairs spatial remote memory in rats but does not affect cortical cholinergic parameters.

We have studied learning, memory and cortical cholinergic parameters after oral administration of 20% v/v ethanol solution to male Fisher rats for 6 months. A group of rats were trained to behave efficiently in an eight-arm radial maze and after that split into two subgroups submitted to ethanol or control treatment. Ethanol-treated rats had more difficulty in relearning the same task 1 year later, compared to ethanol-untreated rats (control). Differences in working memory performance were found, but only in the first 10 training sessions. Another group of rats, which had not been pretrained, was also split into two subgroups submitted to ethanol or control treatment. After that, these rats were trained in the radial maze task for the first time. No significant difference was found between the reference memory performance of the untreated subgroup and the treated one. These two subgroups did not significantly differ in their working memory performance either. Moreover, there were no significant differences between treated and control subjects in the following biochemical brain cortical parameters: in vitro acetylcholinesterase (AChE) activity, and stimulated acetylcholine (ACh) release. This work presents an experimental design that allows assessment of remote memory performance after ethanol chronic consumption and shows that the experimental subject is able to retain the behaviors learned 1 year before. It was concluded that chronic ethanol treatment may cause retrograde amnesia, which does not seem to be linked with a cortical cholinergic deficit.

Acetylcholine↗

Educational level and age influence spatial working memory and Wisconsin Card Sorting Test performance differently: a controlled study in schizophrenic patients.

The influence of educational level and age on executive function, as evaluated by the Wisconsin Card Sorting Test (WCST), and 'working memory,' as evaluated by means of a visual-manual delayed-response task, has been investigated in 25 schizophrenic patients and 35 healthy controls matched for age. Different patterns of correlations between educational level, age and cognitive variables were seen for the 'working memory' task but not for the WCST. No significant correlations between the WCST and the 'working memory' task indexes have been observed. Based on multivariate analyses, poor performance of schizophrenic patients on working memory and executive function tasks was observed; after covarying for the educational level, group differences were no longer significant for executive functions, but the difference in 'working memory' performance persisted. The implications of sociodemographic variables as well as the role of statistical manipulation are evaluated and their differential impact on 'working memory' and executive functions is proposed in further support of these neurocognitive constructs that may be dissociable.

Adolescent↗

Effects of gonadal hormones and persistent pain on non-spatial working memory in male and female rats.

There are indications of a modulatory role carried out by gonadal hormones and pain in cognitive functions. We have examined this issue in male and female rats by assessing the impact of gonadectomy and persistent pain on the object recognition test. Intact and gonadectomized male and female rats were exposed to an open field (15 min) in which three objects were placed (Trial 1); the same test was repeated 2 h later (Trial 2), after the replacement of a "familiar" object with a novel one. Three days later (Day 2), the same procedure was repeated (Trial 3 and 4 with 2 h in between) but half of the animals were exposed to formalin-injection immediately before Trial 3. The latency, frequency and duration of approaching the three objects were recorded in each trial and compared by sex, gonadectomy and formalin treatment. The results showed that gonadectomized males and females had lower levels of approach to all objects and less locomotor/exploratory activity than intact animals in all experimental trials; their behaviour was not affected by repetition of the test or by pain. On Day 1, intact males showed a higher level of approach to the novel object than females. In intact males, the 2 h delay between the first and second trial failed to induce any significant modification of exploration of the novel object with respect to the familiar one, while in intact females the novel object was approached much less than the familiar one. Similarly on Day 2, the novel object was approached for a longer time by intact males than by all the other groups. In conclusion, our data show that physiological levels of circulating gonadal hormones significantly affected the performance of male but not female rats when exposed to the object recognition test.

Animals↗

Differences between appetitive and aversive reinforcement on reorientation in a spatial working memory task.

Tasks using appetitive reinforcers show that following disorientation rats use the shape of an arena to reorient, and cannot distinguish two geometrically similar corners to obtain a reward, despite the presence of a prominent visual cue that provides information to differentiate the two corners. Other studies show that disorientation impairs performance on certain appetitive, but not aversive, tasks. This study evaluated whether rats would make similar geometric errors in a working memory task that used aversive reinforcement. We hypothesized that in a task that used aversive reinforcement rats that were initially disoriented would not reorient by arena shape and thus make similar geometric errors. Tests were performed in a rectangular arena having one polarizing cue. In the appetitive condition water consumption was the reward. The aversive condition was a water maze task with reinforcement provided by escape to a hidden platform. In the aversive condition rats returned to the reinforced corner significantly more often than in the dry condition, and did not favor the diagonally opposite corner. Results show that rats can use cues besides arena shape to reorient in an aversive reinforcement condition. These findings may also reflect different strategies, with an escape/homing strategy in the wet condition and a foraging strategy in the dry condition.

Animals↗

The hippocampus and mechanisms of declarative memory.

The hippocampus is critical to declarative memory in humans and spatial memory in rodents. This review attempts to bridge between these two characterizations of hippocampal dependent memory, and in doing so reveal fundamental cognitive and neural coding mechanisms that are common to both. Evidence is presented that the hippocampus and its connections are critical to the establishment of a systematic organization of memories and to flexible expression of memory outside repetition of the training experience. In addition, evidence is presented that hippocampal neurons encode a broad range of experience and that these codings may be organized as representations of episodes in memory. It is suggested that these episodic codings are linked by common elements to construct an organized representation of acquired knowledge.

Animals↗

The effects of neonatal basal forebrain lesions on cognition: towards understanding the developmental role of the cholinergic basal forebrain.

Abnormal development of the cholinergic basal forebrain has been implicated in numerous developmental disabilities such as Rett Syndrome and Down Syndrome. This review summarizes recent data using two rodent animal models that involve interrupting cholinergic basal forebrain projections on postnatal day 1 and postnatal day 7 when basal forebrain fibers are beginning to innervate their neocortical and hippocampal targets, respectively. In one model, electrolytic lesions in mice aimed at the basal forebrain on postnatal day 1 transiently reduce cholinergic markers in neocortex which induce permanent alterations in neocortical anatomy that correlate with impairments on cognitive tasks. Furthermore, the lesion effects are sex dependent. In another model, 192 IgG saporin lesions in rats on postnatal day 7 permanently reduce cholinergic markers in neocortex and hippocampus, and result in mild impairments in spatial processing, acquisition and exploratory activities. These data suggest that during the first postnatal week of development the cholinergic basal forebrain system is critical for normal neocortical differentiation and, possibly synaptogenesis in neural circuits that will be important for spatial memory and acquisition of spatial data. During the second postnatal week of development, the cholinergic basal forebrain system appears to take on a role largely similar to its adult role in selective attention and processing of new information. These studies also suggest strongly that interrupting cholinergic basal forebrain innervation of neocortex and hippocampus leads to anatomical and neurochemical abnormalities that may serve as neural substrates for some of the cognitive deficits seen in disorders such as Rett Syndrome and Down Syndrome.

Acetylcholine↗

Ventral hippocampal ibotenic acid lesions block chronic nicotine-induced spatial working memory improvement in rats.

Chronic nicotine infusions have been found to significantly improve working memory performance in the radial-arm maze. This effect is blocked by co-infusions of the nicotinic antagonist mecamylamine. Acute nicotine injections also improve working memory performance in the radial-arm maze. This effect is also blocked by mecamylamine co-administration. Recent local infusions studies have demonstrated the importance of the ventral hippocampus for nicotinic involvement in memory. Local infusions of mecamylamine, DHbetaE or MLA impair working memory performance on the radial-arm maze. The current study was conducted to determine the importance of the ventral hippocampus for the chronic effects of nicotine. Rats were trained on the working memory task in an eight-arm radial maze. After acquisition they underwent either infusions of ibotenic acid lesions or vehicle infusions and received subcutaneous implants of osmotic minipumps that delivered either nicotine at a dose of 5 mg kg-1 day-1 or vehicle in a 2x2 design. The rats then were given 2 days of recovery and were tested on the radial-arm maze three times per week for the next 4 weeks. As seen in previous studies, in the sham lesioned group nicotine infusions caused a significant improvement in choice accuracy. In contrast no nicotine-induced improvement was seen in the rats after ibotenic acid lesions of the ventral hippocampus. The effect of nicotine was blocked even though this lesion did not cause a deficit in performance. Previous work showed that chronic nicotine infusion still caused a significant improvement in working memory performance in the radial-arm maze after knife-cut lesions of the fimbria-fornix carrying the septo-hippocampal cholinergic innervation. Thus it appears that it is the postsynaptic nicotinic receptors in the ventral hippocampus which are critically important for the expression of the chronic nicotine induced working memory improvement.

Animals↗

Spatiotemporal memory and rate of forgetting in acute schizophrenics.

Some schizophrenics show anomalies in the frontal and temporal lobes. It is uncertain whether the cognitive deficits shown by Type I schizophrenics are caused directly by such anomalies, or by a deficit in the exertion of attentional effort. In this study, 16 acute schizophrenics, who broadly fitted the Type I characterization and their controls were given a battery of cognitive tests. The patients were impaired on effort-demanding tasks such as the Wisconsin Card Sorting Test, a verbal fluency test and the WAIS, which are susceptible in varying degrees to frontal, temporal and parietal lobe lesions. Patients were not disproportionately impaired, however, on a test of temporal memory and another of spatial memory, an impairment pattern that selectively reflects frontal and medial temporal lobe lesions respectively, nor were they impaired on a rate of forgetting task sensitive to medial temporal lobe lesions. These tasks were chosen not only because performance on them is selectively sensitive to frontotemporal lobe lesions, but also because it seems to depend on exerting minimum amounts of attentional effort. It is tentatively concluded that the cognitive deficits shown by Type I schizophrenics are caused by a problem in exerting attentional effort of unknown origin.

Adult↗

Mediodorsal thalamic lesions impair radial maze performance in the rat.

The role of the mediodorsal thalamic nucleus (MD) in spatial memory processes was assessed. Animals were preoperatively trained on an 8-arm maze placed in a visually deprived environment. Following 50 acquisition trials, one group received bilateral electrolytic lesion of the MD thalamus, whereas the other group received sham lesions. On postoperative tests of radial maze performance, MD lesioned animals made significantly more errors, made more errors sooner, and emitted fewer correct responses before making an error than did sham controls. The lesioned subjects also exhibited considerable perseveration immediately postoperation and developed response patterning on postlesion trials. Lesions of the mediodorsal thalamus may fundamentally compromise memory systems and alter ability to respond appropriately in a minimally cued environment.

Animals↗

Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function.

Stress blocks hippocampal primed-burst potentiation, a low threshold form of long-term potentiation, thereby suggesting that stress should also impair hippocampal-dependent memory. Therefore, the effects of stress on working (hippocampal-dependent) and reference (hippocampal-independent) memory were evaluated. Rats foraged for food in seven arms of a 14-arm radial maze. After they ate the food in four of the seven baited arms, they were placed in an unfamiliar environment (stress) for a 4-hr delay. At the end of the delay they were returned to the maze to locate the food in the 3 remaining baited arms. Stress impaired only working memory. Stress interfered with the retrieval of previously stored information (retrograde amnesia), but did not produce anterograde amnesia. Stress appears to induce a transient disruption of hippocampal function, which is revealed behaviorally as retrograde amnesia and physiologically as a blockade of synaptic plasticity.

Amnesia, Retrograde↗

Fimbria-fornix lesions impair spatial working memory but not cognitive mapping.

Three experiments were designed to evaluate the relative merits of two theories of hippocampal function, the cognitive mapping theory and the working memory theory. Rats were tested in a series of maze tasks that varied in memory requirements. In the experiments that required cognitive mapping but not working memory (Experiments 1 and 3), rats with fimbria-fornix lesions reached stable levels of performance that were as accurate as those of control rats, and they also performed accurately during transfer tests, results demonstrating that they used a cognitive mapping strategy to solve the discrimination. In the experiment that required working memory (Experiment 2), rats with fimbria-fornix lesions performed at chance levels during all of postoperative testing, and they distributed their choices randomly between the correct and the incorrect goals. These results are seen as generally refuting the predictions made by the cognitive mapping theory and supporting the predictions made by the working memory theory. Additional analyses (Experiment 3) examined the nature of a transitory impairment exhibited by rats with fimbria-fornix lesions in two tasks that did not require working memory. Postoperatively, the performance of the rats with lesions was initially impaired but recovered to normal levels with a time course similar to that seen during preoperative acquisition. These results are seen as requiring an extension of the working memory theory of hippocampal function, and discussion is focused on the possibility of a temporary retrograde amnesia following fimbria-fornix lesions and the distinctions between different types of memory abilities.

Animals↗

A new approach in clinical neuropsychology to the assessment of spatial working memory: the block suppression test.

The Block Suppression Paradigm developed by Beblo, Klaver, Grubich, Wachowius, and Herrmann (1999) is based on the Corsi Block tapping test and requires that a subject reproduces every 2nd block in a given sequence. Results from two studies of a standardized version, the Block Suppression Test (BST), are presented here. In Study 1 the BST was administered to 48 healthy subjects along with a battery of comprehensive neuropsychological tests. The reliability of the BST proved satisfactory under psychometric analysis, while Principal Component Analysis (PCA) confirmed its validity. In Study 2 the BST was administered to a clinical sample of 31 brain-damaged patients to demonstrate its clinical practicability.

Adult↗

The selective disruption of spatial working memory by eye movements.

In the late 1970s/early 1980s, Baddeley and colleagues conducted a series of experiments investigating the role of eye movements in visual working memory. Although only described briefly in a book, these studies have influenced a remarkable number of empirical and theoretical developments in fields ranging from experimental psychology to human neuropsychology to nonhuman primate electrophysiology. This paper presents, in full detail, three critical studies from this series, together with a recently performed study that includes a level of eye movement measurement and control that was not available for the older studies. Together, the results demonstrate several facts about the sensitivity of visuospatial working memory to eye movements. First, it is eye movement control, not movement per se, that produces the disruptive effects. Second, these effects are limited to working memory for locations and do not generalize to visual working memory for shapes. Third, they can be isolated to the storage/maintenance components of working memory (e.g., to the delay period of the delayed-recognition task). These facts have important implications for models of visual working memory.

Adolescent↗

Spatial location memory in amnesia: binding item and location information under incidental and intentional encoding conditions.

Items located within an array were presented to alcoholic Korsakoff and nonalcoholic mixed-etiology amnesics and to alcoholic and normal controls. Recognition memory for the locations of items was tested after incidental and intentional encoding. When equated on item recognition, neither Korsakoff amnesics nor alcoholic controls benefited from intentional, relative to incidental, encoding instructions. Furthermore, Korsakoff amnesics showed neither disproportionately impaired incidental nor intentional location recognition memory relative to alcoholic controls. In contrast, mixed-etiology amnesics profited significantly from intentional location acquisition relative to incidental instructions, and were impaired somewhat in incidental, but not intentional, location memory relative to normal controls. We discuss these data in relation to Mayes' (1992) contextual memory deficit hypothesis and Hirst's (1982) automatic encoding deficit account, and propose an alternative framework in which the location memory deficit observed in mixed-etiology amnesics is interpreted as a disruption to the ability to bind item and location information.

Alcohol Amnestic Disorder↗

Spatial working memory as a cognitive endophenotype of schizophrenia: assessing risk for pathophysiological dysfunction.

Research suggests that first-degree relatives and individuals with schizophrenia spectrum personality disorders (SSPD) may represent nonpenetrant carriers of the genetic diathesis for schizophrenia. This study examined visuospatial working memory (SWM) as a cognitive endophenotype of schizophrenia by expanding the concept of risk for pathophysiological dysfunction beyond overt psychosis. Risk was thus defined by familial status and the presence or absence of SSPD. SWM was assessed in the following groups, in order of decreasing likelihood of genetic vulnerability: 23 patients with schizophrenia, 17 SSPD relatives of patients with schizophrenia, 23 non-SSPD relatives of patients with schizophrenia, 14 SSPD community members with no family history of psychosis, and 36 non-SSPD community members. SWM performance during a computer task was quantified by A-Prime. Relative risk ratios for SWM deficits were compared among the groups. Compared with community non-SSPD volunteers, relative risk (RR) of SWM deficits was significantly elevated in patients with schizophrenia (RR = 3.76, p = .002) and SSPD family members (RR = 2.97, p = .027), but not in the family non-SSPD (RR = 1.88, p = .241) or community SSPD (RR = 1.03, p = .971) groups. The pattern of SWM performance deficits reflected the proposed model of latent genetic liability, upholding SWM as a viable cognitive endophenotype. The results underscore the importance of including both familial liability and the schizophrenia spectrum when considering risk for schizophrenia and schizophrenia-related traits. This is particularly relevant for research efforts to identify pathophysiological components of the disease.

Adult↗

Extract of Ginkgo biloba leaves reverses yohimbine-induced spatial working memory deficit in rats.

Extract of Ginkgo biloba is used to alleviate age-related decline in cognitive function, which may be associated with the loss of catecholamines in the prefrontal cortex. The purpose of this study was to verify whether alpha-2 adrenergic activity is involved in the facilitative effects of extract of Ginkgo biloba on prefrontal cognitive function. Male Wistar rats were trained to reach criterion in the delayed alternation task (0, 25, and 50-s delay intervals). A pilot study found that 3 or 4 mg/kg of yohimbine (intraperitoneal) reduced the choice accuracy of the delayed alternation task in a dose and delay-dependent manner, without influencing motor ability or perseverative behaviour. Acute oral pre-treatment with doses of 50, 100, or 200 mg/kg (but not 25 mg/kg) of extract of Ginkgo biloba prevented the reduction in choice accuracy induced by 4 mg/kg yohimbine. These data suggest that the prefrontal cognition-enhancing effects of extract of Ginkgo biloba are related to its actions on alpha-2-adrenoceptors.

Adrenergic alpha-Antagonists↗