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PubMed2004

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release.

Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be critical for the treatment of many neurological and psychiatric disorders. Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry, where they modulate NMDA receptor-mediated signal transduction. Therefore, pharmacological manipulation of mGlu5 receptor may provide a treatment strategy for cognitive disorders that are associated with NMDA receptor dysfunction. We sought to determine whether the recently described molecular and cellular interactions between NMDA and mGlu5 receptors coregulate higher order behaviors. We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801, on locomotion, stereotypy, working memory, instrumental learning, and corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired working memory and instrumental learning, transiently increased dopamine release in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg of MPEP enhanced the detrimental effects of MK-801 on cognition. These results demonstrate that an mGlu5 receptor antagonist can potentiate the motoric, cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5 receptors appear to play a major role in regulating NMDA receptor-dependent cognitive functions such as learning and working memory. By extension, these results suggest that pharmacological potentiation of mGlu5 receptors may ameliorate the cognitive and other behavioral abnormalities associated with NMDA receptor deficiency.

Analysis of Variance↗
PubMedDate not supplied

Effects of nicotinic dimethylaminoethyl esters on working memory performance of rats in the radial-arm maze.

Nicotine has been found to improve memory performance in a variety of tests, including the radial-arm maze. This improvement, together with the consistent finding of a decline in cortical nicotinic receptor concentration in Alzheimer's patients, has fueled the search for novel nicotinic ligands with therapeutic potential. In the current studies, a series of nicotinic compounds was tested for effects on working memory performance in the radial-arm maze. One of the three compounds tested, DMAE II (dimethylaminoethanol cyclohexyl carboxylate fumurate), produced significant improvements in working memory performance. In the first experiment, this drug produced a biphasic dose-response curve with improved performance at the 20-mg/kg dose but not at 10 or 40 mg/kg. In a second round of DMAE II administration, the same rats showed a significant improvement with the 40-mg/kg dose. In the second experiment, a new set of rats also showed a biphasic dose-response to DMAE II. The 20-mg/kg dose caused a significant improvement whereas the 40-mg/kg dose did not. Interactions of DMAE II with nicotine and mecamylamine were also studied. Nicotine (0.2 mg/kg) by itself caused a significant improvement in working memory performance. No additive effects of DMAE II with nicotine were seen. In fact, some attenuation of response was seen with the combination. Choice accuracy data for mecamylamine could not be analyzed because of excessive sedation and nonresponding. These studies show that, like nicotine, the nicotinic ligand DMAE II causes an improvement in radial-arm mace choice accuracy. The lack of additivity with nicotine may have been to the partial agonist effects of DMAE II.

Animals↗
PubMed1996

Estrogen affects performance of ovariectomized rats in a two-choice water-escape working memory task.

To determine if estrogen would protect treated rats from deficits in performance on a working memory task across time, 18 female 6-month-old Sprague-Dawley rats were trained to a criterion on a water-escape spatial delayed matching-to-sample problem. Following training, rats were ovariectomized, and nine were maintained on estrogen (polyestradiol-phosphate, 0.5 mg every 3 weeks) and nine on its vehicle for 200 days. After recovery from surgery, the rats were tested for performance every 6 weeks under three conditions: 5 min retention interval (RI); 30 min RI; and 30 min RI with an emotional experience during the RI. Analysis of correct choices revealed that estrogen-treated rats made more correct choices (p < .05) than controls on the 5 min undisturbed interval; estrogen tended to impair performance on the emotionally distracting interval. Estrogen apparently protected working memory on the undisturbed trials and might be pertinent to the maintenance of memory in female mammals.

Animals↗
PubMed2005

Binding and inhibition in working memory: individual and age differences in short-term recognition.

Two studies investigated the relationship between working memory capacity (WMC), adult age, and the resolution of conflict between familiarity and recollection in short-term recognition tasks. Experiment 1 showed a specific deficit of young adults with low WMC in rejecting intrusion probes (i.e., highly familiar probes) in a modified Sternberg task, which was similar to the deficit found in old adults in a parallel experiment (K. Oberauer, 2001). Experiment 2 generalized these results to 3 recognition paradigms (modified Sternberg, local recognition, and n back tasks). Old adults showed disproportional performance deficits on intrusion probes only in terms of reaction times, whereas young adults with low WMC showed them only in terms of errors. The generality of the effect across paradigms is more compatible with a deficit in content-context bindings subserving recollection than with a deficit in inhibition of irrelevant information in working memory. Structural equation models showed that WMC is related to the efficiency of recollection but not of familiarity.

Adolescent↗
PubMed2001

Working memory of identification of emotional vocal expressions: an fMRI study.

The distribution of brain activation during working memory processing of emotional vocal expressions was studied using functional magnetic resonance imaging (fMRI) in eight female subjects performing n-back tasks with three load levels (0-back, 1-back, and 2-back tasks). The stimuli in the n-back tasks were the Finnish female name [Saara] uttered in an astonished, angry, frightened, commanding, and scornful mode, and the subjects were instructed to memorize the emotional connotation of the stimuli. Subregions in the prefrontal, parietal, and visual association areas were load-dependently activated during the performance of the n-back tasks. The most consistently activated areas in the prefrontal region were detected in the inferior frontal gyrus corresponding to Brodmann's areas (BAs) 44 and 45 and in the middle and superior frontal gyri (BAs 6/8). Activation was also found in the inferior parietal lobe and intraparietal sulcus (BAs 40/7) and visual association areas including the lingual and fusiform gyri. The results suggest that a distributed neuronal network in occipital, parietal, and frontal areas is involved in working memory processing of emotional content of aurally presented information.

Adult↗
PubMed2001

Long-term working memory in text production.

In reading and other high-level cognitive tasks, Ericsson and Kintsch (1995) proposed that the limited capacity of short-term working memory (STWM) is supplemented by long- term working memory (LTWM) for individuals with a high degree of domain-specific knowledge. In Experiment 1, college students (N = 80) wrote persuasive and narrative texts concerning baseball; domain-specific knowledge about baseball and verbal ability was assessed. The results showed that verbal ability and domain-specific knowledge independently affected writing skill, supporting the view that literacy depends on both knowledge sources and refuting one argument raised in support of the LTWM hypothesis. Experiment 2 (N = 42) replicated this outcome and tested the prediction that a high degree of domain-specific knowledge would lessen interference on a secondary task. The data supported the interference prediction, offering evidence that LTWM plays a role in the production of text.

Adult↗
PubMed2006

Exogenous cortisol shifts a motivated bias from fear to anger in spatial working memory for facial expressions.

Studies assessing processing of facial expressions have established that cortisol levels, emotional traits, and affective disorders predict selective responding to these motivationally relevant stimuli in expression specific manners. For instance, increased attentional processing of fearful faces (attentional bias for fearful faces) is associated with fear and anxiety and diminishes after administration of the anxiolytic hormone testosterone. Conversely, attentional bias for angry faces has been associated with higher levels of approach motivation (e.g. anger) and testosterone, but lower levels of cortisol. This negative relation between cortisol levels and bias for angry faces was also seen in a test of biased working memory performance. However, previous research suggests that exogenous glucocorticoids acutely decrease fearful and inhibited behavior and increase aggressiveness. Hypothesizing from these findings, the present study tested this spatial working memory for faces of various emotional expressions (neutral, happy, fearful, and angry) after double-blind, placebo-controlled administration of 40 mg cortisol in 18 healthy young men. It was predicted that cortisol would acutely attenuate memory bias for fearful expressions while increasing memory bias for angry expressions, in effect creating a shift in biased motivated memory from fear to anger. Results largely confirmed the hypotheses. This is the first causal evidence that cortisol differentially regulates spatial working memory for different facial expressions. Possible biological mechanisms are discussed.

Adolescent↗
PubMed1996

Coordination in visual working memory.

Coordination of mental procedures is considered in terms of control processes (Baddeley, 1989) in visual working memory and appears to be a separable aspect of the demand imposed by cascaded serial processes (Carlson & Lundy, 1992). The main task required subjects to indicate whether symbolically suggested rotations and reflections correctly describe the difference between matrix patterns of filled-in squares within a 3 x 3 grid or between line drawings. Experiments were carried out to show that coordination is a separable component in this transformation task. A marker for coordination is the difference between the time taken to execute two transformations as a whole and the sum of the component transformations in isolation. The separate coordination demand was found in an experiment with matrix patterns mentioned, in an experiment with letter-like line drawings, and also in an experiment that forced subjects to maintain whole-pattern representations. A last experiment checked whether coordination is carried out by an autonomous control unit. There was a self-paced control of serial presentation of transformation symbols instead of a simultaneous presentation of those symbols. This additional external triggering resulted in a substantial decrease in the demand for coordination. Coordination of mental procedures and temporary representations is a fundamental constraint on the use of working-memory processes.

Adult↗
PubMed2003

Disrupting attention: the need for retrieval cues in working memory theories.

Sometimes in conversation, something is said that causes us to want to comment, but before our impending but implicit thoughts can be expressed, the conversation is disrupted. Later, we cannot recall what we wanted to say, but still later, we can. We used the extralist cuing task to model this phenomenon, and across experiments we varied the strength, direction, and directness of the relationship between the retrieval cues and the targeted information. Disruption was varied by switching attention to a different task before testing and by changing the testing context. Such disruptions reduced recall for the target and its implicitly activated memories. Following a disruption, stronger cues that were related to the target or to both the target and its implicit memories were more effective than those that were related to implicit memories. The findings were consistent with a model of long-term working memory that attributes forgetting to a loss of access to what has been activated, which loss is relative to the strength of the retrieval cue. Decay alone does not explain the results, indicating that many models of working memory need to be revised to take the nature of retrieval cues into account.

Attention↗
PubMed1996

Nicotinic, muscarinic and dopaminergic actions in the ventral hippocampus and the nucleus accumbens: effects on spatial working memory in rats.

Acetylcholine (ACh) systems have been widely shown to be important for memory. In particular, ACh hippocampal neurons are critical for memory formation, though ACh innervation of other areas such as the nucleus accumbens may also be important. There has also been increasing interest in ACh and dopaminergic (DA) interactions with regard to short-term spatial memory. In a series of studies, we have found that ACh and DA agonists and antagonists given systemically interact to influence memory. The critical neural loci of these interactions are not currently known. In the present study, we used local infusion techniques to examine the role of ACh and DA transmitter systems in the nucleus accumbens and the ventral hippocampus on radial-arm maze (RAM) working memory performance. Into the nucleus accumbens of rats, we infused the nicotinic ACh agonist nicotine, the nicotinic ACh antagonist mecamylamine, the DA agonist apomorphine, or the DA antagonist haloperidol. Into the ventral hippocampus, we infused nicotine, mecamylamine, the muscarinic ACh agonist pilocarpine, or the muscarinic ACh antagonist, scopolamine. The nicotinic ACh and DA interaction was tested by a hippocampal infusion of mecamylamine alone or together with the DA D2 agonist quinpirole given via subcutaneous injection. The results confirmed that both nicotinic and muscarinic ACh receptors in the ventral hippocampus play a significant role in spatial working memory. Blockade of either nicotinic or muscarinic ACh receptors caused significant impairments in RAM choice accuracy. However, infusion of either nicotinic or muscarinic agonists failed to improve choice accuracy. The interaction of DA D2 systems in different with hippocampal nicotinic blockade than with general nicotinic blockade. Systemic administration of quinpirole potentiated the amnestic effect of mecamylamine infused into the ventral hippocampus, whereas it was previously found to reverse the amnestic effect of systemically administered mecamylamine. In contrast to the significant effects of mecamylamine in the hippocampus, no effects were found after infusion into the nucleus accumbens. Nicotine also was not found to have a significant effect on memory after intra-accumbens infusion. Neither the DA agonist apomorphine nor the DA antagonist haloperidol had a significant effect on memory after infusion into the nucleus accumbens. This study provides support for the involvement of nicotinic and muscarinic receptors in the ventral hippocampus in memory function. Ventral hippocampal nicotinic systems have significant interactions with D2 systems, but these differ from their systemic interactions. In contrast, nicotinic ACh and DA systems in the nucleus accumbens were not found in the current study to be important for working memory performance in the RAM.

Animals↗
PubMed2005

Opposite behaviours in the forced swimming test are linked to differences in spatial working memory performances in the rat.

Despite consistent evidence of an association between depression and impaired memory performance, only a few studies have investigated memory processes in animal models of depression. The aim of the present study was to determine if rats selected for marked differences in their immobility response in the forced swimming test (FST, i.e. high-immobility, [HI] and low-immobility [LI] rats) exhibit differences in spatial and non-spatial memory performances. In a classic radial maze elimination task, we observed that HI rats made significantly more errors than LI rats, and their first error appeared significantly earlier. In a delayed spatial win-shift procedure where rats have to hold spatially relevant information in working memory across a 30 min delay, HI rats tended initially to perform more poorly than LI rats. HI rats made more across-phase errors, the occurrence of the first error was earlier and by the end of the experiment the differences between the two groups disappeared. Thus, HI rats present more difficulties to learn the rules in a spatial task and show weaker performances in spatial working memory in comparison to LI rats. On the other hand, performances in the two groups of animals were similar in a non-spatial task, the object recognition task. Complementary behavioral data indicate that the differences observed between the two groups are not attributable to opposite locomotor activities or to different levels of anxiety. Overall we can conclude that opposite swimming behavior in the FST could parallel some differences in cognitive performances, more specifically linked to spatial working memory.

Animals↗
PubMed2000

Working memory capacity and time course of predictive inferences.

A naming task assessed activation of inference concepts during reading. A predicting, or a control, context sentence was followed by a target word to be named, which represented the predicted event or an inconsistent event. The interval between the end of the context and the onset of the target word varied between 50 and 1050 msec. Individual differences in working memory capacity were assessed by the reading span task. As reflected by facilitation in naming latencies in the predicting condition, relative to the control condition, (a) inferences were not made within the first 50 msec after the context, regardless of reading span; (b) only the high-span participants drew inferences within a 550-msec interval; and, (c) both the high- and the low-span participants generated them within a 1050-msec interval. These results indicate that high working memory capacity accelerates the time course of predictive inferences, although they do not become automatic. We propose that this effect occurs because these inferences involve time-consuming elaborations that place demands on the effortful and limited resources of working memory. Deficiencies in word knowledge, speed of lexical access, or comprehension of explicit information do not account for low-span readers' difficulties in generating predictive inferences.

Adult↗
PubMed1993

Working memory in clinical depression: an experimental study.

This study compared clinically depressed subjects with normal controls on a range of working memory tasks. The findings suggested the articulatory loop and visuospatial sketch pad components of working memory to be unimpaired in depression. On a range of clinical tasks likely to involve central executive function, depressed subjects showed impairment only on some tasks.

Adult↗
PubMed2000

Updating of working memory in a running memory task: an event-related potential study.

The aim of the study was to identify central executive activity in the event-related potential (ERP) in the time and space domain. Lists of three to eight consonants were presented sequentially. After each list the ordered recall of the three most recent items was required. In this running memory task the updating of working memory contents from the fourth letter on may be understood as a control process. ERPs elicited from each consonant presented in the lists were subtracted from those of a control condition that was also applied to the participants. The difference waveforms showed fronto-central distributed positivities, probably indicating the activity of a postulated central executive. This finding confirms those of neuroimaging studies that localize executive activity to prefrontal brain areas.

Adult↗
PubMed2002

Normative data for a working memory test: the four word short-term memory test.

A number of tests of short-term memory based on the Brown-Peterson paradigm (recall of either trigrams or short words after varying distractor intervals) have been utilized by neuropsychologists in both clinical practice and in research protocols. The present study provides normative data for a large group of subjects (N=350) aged 18-65 on the Four Word Short-Term Memory Test, a measure of working memory based on the Brown-Peterson paradigm. The Four Word Short-Term Memory Test presents subjects with four words at the rate of one word per second and subjects are then asked to recall the words following a distractor interval of counting backwards by threes for 5, 15 or 30 s. Normative data is stratified by age and education and presented in overlapping midpoint intervals. Percentile rankings based on age and education are also provided.

Adolescent↗
PubMed2004

Relationship of behavioural and symptomatic syndromes in schizophrenia to spatial working memory and attentional set-shifting ability.

BACKGROUND: Behavioural syndromes (thought disturbance, social withdrawal, depressed behaviour and antisocial behaviour) offer a different perspective from that of symptomatic syndromes on the disability that may be associated with schizophrenia. Few studies have assessed their relationship with neuropsychological deficits. We hypothesized that these syndromes may represent behavioural manifestations of frontal-subcortical impairments, previously described in schizophrenia. METHOD: Long-stay inpatients (n=54) and community patients (n=43) with enduring schizophrenia were assessed, using measures of symptoms and behaviour and tests of executive functioning. The relationship between syndromes and neuropsychological function was assessed using multiple regression and logistic regression analyses. RESULTS: Significant associations were found between performance on the spatial working memory task and the psychomotor poverty symptomatic syndrome, and between attentional set-shifting ability and both disorganization symptoms and the thought disturbance behavioural syndrome. These results were not explained by the effect of premorbid IQ, geographical location, length of illness or antipsychotic medication. Length of illness was an independent predictor of attentional set-shifting ability but not of working memory performance. CONCLUSION: The specific relationship between negative symptoms and spatial working memory is consistent with involvement of the dorsolateral prefrontal cortex. The associations between difficulty with set-shifting ability and both disorganization symptoms and behaviours may reflect inability to generalize a rule that had been learned and impaired ability to respond flexibly. The specific relationship of illness duration to set-shifting ability may suggest progressive impairment on some executive tasks. The nature of these relationships and their neurobiological and rehabilitation implications are considered.

Adult↗
PubMed2005

The functional neuroanatomy of working memory: contributions of human brain lesion studies.

Studies of patients with focal brain lesions remain critical components of research programs attempting to understand human brain function. Whereas functional imaging typically reveals activity in distributed brain regions that are involved in a task, lesion studies can define which of these brain regions are necessary for a cognitive process. Further, lesion studies are less critical regarding the selection of baseline conditions needed in functional brain imaging research. Lesion studies suggest a functional subdivision of the visuospatial sketchpad of working memory with a ventral stream reaching from occipital to temporal cortex supporting object recognition and a dorsal stream connecting the occipital with parietal cortex enabling spatial operations. The phonological loop can be divided into a phonological short-term store in inferior parietal cortex and an articulatory subvocal rehearsal process relying on brain areas necessary for speech production, i.e. Broca's area, the supplementary motor association area and possibly the cerebellum. More uncertainty exists regarding the role of the prefrontal cortex in working memory. Whereas single cell studies in non-human primates and functional imaging studies in humans have suggested an extension of the ventral and dorsal path into different subregions of the prefrontal cortex, lesion studies together with recent single-cell and imaging studies point to a non-mnemonic role of the prefrontal cortex, including attentional control of sensory processing, integration of information from different domains, stimulus selection and monitoring of information held in memory. Our own data argue against a modulatory view of the prefrontal cortex and suggest that processes supporting working memory are distributed along ventral and dorsal lateral prefrontal cortex.

Attention↗
PubMed2005

Stimulus similarity decrements in children's working memory span.

Two experiments investigated the impact of the relationship between processing and storage stimuli on the working memory span task performance of children aged 7 and 9 years of age. In Experiment 1, two types of span task were administered (sentence span and operation span), and participants were required to recall either the products of the processing task (sentence-final word, arithmetic total) or a word or digit unrelated to the processing task. Experiment 2 contrasted sentence span and operation span combined with storage of either words or digits, in tasks in which the item to be remembered was not a direct product of the processing task in either condition. In both experiments, memory span was significantly greater when the items to be recalled belonged to a different stimulus category from the material that was processed, so that in sentence span tasks, number recall was superior to word recall, and in operation span tasks, word recall was superior to number recall. Explanations of these findings in terms of similarity-based interference and response competition in working memory are discussed.

Age Factors↗