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Psychopharmacology (Berl). 2004 Jun;174(1):111-25. Epub 2004 Jan 20.

Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia.

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Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA.



Working memory performance is considered to be a core deficit in schizophrenia and the best predictor of social reintegration and propensity for relapse. This cardinal cognitive process is critical for human reasoning and judgment and depends upon the integrity of prefrontal function. Prefrontal dysfunction in schizophrenia has been linked to altered dopaminergic and glutamatergic transmission. However, to date, antipsychotics provide no substantial relief from the debilitating cognitive consequences of this disease.


This review examines the key rodent and non-human primate models for elucidating the neural mechanisms of working memory and their neuromodulation. We compare the physiology and pharmacology of working memory between the normal state and experimentally induced models of prefrontal dysfunction and evaluate their relevance for schizophrenia.


Rodent models have demonstrated the significance of aberrant dopaminergic and glutamatergic signaling in medial prefrontal cortex for working memory. However, there is some question as to the extent to which rodent tests of working memory tap into the same process that is compromised in schizophrenia. Non-human primates provide an unexcelled model for the study of influences on prefrontal function and working memory due to the high degree of homology between human and non-human primates in the relationship between prefrontal cortex and higher cognitive capacities. Moreover, non-human primate models of prefrontal dysfunction including amphetamine sensitization, subchronic phencyclidine, and neurodevelopmental insult are ideal for the analysis of novel compounds for the treatment of cognitive dysfunction in schizophrenia, thereby facilitating the translation between preclinical drug development and clinical trials.

[Indexed for MEDLINE]
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Arch Gen Psychiatry. 1998 Dec;55(12):1097-103.

Cortical dysfunction in schizophrenia during auditory word and tone working memory demonstrated by functional magnetic resonance imaging.

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Department of Psychiatry, Yale University School of Medicine, New Haven, Conn, USA.



Verbal learning and memory deficits are among the most severe cognitive deficits observed in schizophrenia. We have demonstrated that such deficits do not extend to working memory for tones in a substantial number of patients even when verbal working memory is impaired. In this study we used functional magnetic resonance imaging to study the neural basis of this dissociation of auditory verbal and nonverbal working memory in individuals with schizophrenia.


While undergoing functional magnetic resonance imaging, 12 schizophrenic patients and 12 matched control subjects performed auditory Word Serial Position Task and Tone Serial Position Task.


Both tasks produced activation in frontal cortex and temporal and parietal lobes of the cerebrum in both groups. While robust activation was observed in the left inferior frontal gyrus (areas 6, 44, and 45) in the control group during the Word Serial Position Task, activation in the patient group was much reduced in these areas and failed to show the same task-specific activation as in controls. Reduced activation in patients was not confined to the inferior frontal gyrus, but also extended to a medial area during the Tone Serial Position Task and to premotor and anterior temporal lobe areas during both tasks.


These findings support the hypothesis that abnormalities in cortical hemodynamic response in the inferior frontal gyrus underlie the verbal working memory deficit in schizophrenia. The relationship of verbal working memory deficits to other cognitive functions suggests that abnormal functioning in the speech-related areas may reflect a critical substrate of a broad range of cognitive dysfunctions associated with schizophrenia.

[Indexed for MEDLINE]
J Neuropsychiatry Clin Neurosci. 1994 Fall;6(4):348-57.

Working memory dysfunction in schizophrenia.

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Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510.


Recent advances in anatomical, behavioral, and physiological techniques have produced new information about the nature of prefrontal function, its cellular basis, and its anatomical underpinnings in nonhuman primates. These findings are changing our views of prefrontal function and providing insight into possible bases for human mental disorder. A major advance is the recognition that various prefrontal areas are engaged in holding information "on line" and updating past and current information on a moment-to-moment basis. Studies of animals and of cognitive function in normal, brain-injured, and schizophrenic subjects support the theory that a defect in working memory--the ability to guide behavior by representations--may be the fundamental impairment leading to schizophrenic thought disorder.

[Indexed for MEDLINE]
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