Prefrontal Modulation of Cognitive Deficits

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Abnormalities in attention are a major component of, and contribute essentially to the cognitive impairments in schizophrenia (Braff, 1993;Nuechterlein et al., 1994;Silver and Feldman, 2005). However, efforts to develop models of schizophrenia in order to reproduce the cognitive impairments that persist during periods of remission have been largely unsuccessful. These attempts failed to recognize that increases in cognitive load and top-down control may be necessary, conceptually and empirically, to reveal persistent impairments. Only by increasing attentional demands are robust impairments revealed in clinically stable schizophrenic patients (Grillon et al., 1990;Nuchterlein et al., 1994;Gold et al., 2007). A promising animal model of the cognitive impairments in schizophrenia has been developed based on the lasting consequences of initial interactions between a psychotogenic treatment regimen with amphetamine and attentional task performance. As a result, attentional performance remains extremely vulnerable to drug challenges (Kozak et al., 2007), consistent with a hyper-responsive mesolimbic DA system observed during acute disease periods in schizophrenia (Laruelle, 2000;Laruelle et al., 1999). Preliminary data suggest that increasing attentional demands by introducing distracters produces robust attentional impairments in this animal model, making it one of the first animal models to dissociate between attentional deficits observed during acute and chronic disease states of schizophrenia. Microdialysis of acetylcholine in the prefrontal cortex is anticipated to reveal cholinergic dysregulation during distractor presentation in this animal model. Additional studies will examine local dopaminergic and cholinergic influence over this neural dysregulation. The final study will examine the synergistic effects of using both cholinergic and dopaminergic manipulations in an effort to improve attention by modulating performance-associated cholinergic release. This is of immediate relevance as any treatments developed for the cognitive symptoms of schizophrenia will likely be used in conjunction with current treatments that act through dopaminergic mechanisms. As demands on top-down regulation are common in natural situations, the demonstration of impairments in this animal model is highly relevant for modeling disease-associated cognitive symptoms that persist in medicated schizophrenic patients, and provides further validation for use of this model. The studies designed to characterize the neural circuitry involved in impaired performance will have a significant impact on our understanding of the enduring cognitive deficits observed in schizophrenia, and will contribute significantly to efforts designed to detect and characterize treatments that will assist in returning patients to a productive life. PUBLIC HEALTH RELEVANCE: The proposed research addresses key hypotheses concerning the use of distracters to model attentional deficits that persist in schizophrenic patients during remission periods, and the neurobiological mechanisms modulating these impairments. This model is expected to contribute significantly to efforts designed to detect and characterize treatments that will assist in returning patients to a productive life.