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Under the direction of David A. Lewis, MD, the Silvio O. Conte Center for Translational Mental Health Research (CTMHR) at the University of Pittsburgh focuses on the mechanisms that link the pathology, pathophysiology and clinical features of schizophrenia. The investigations of the Center reflect the synergistic scientific interactions among Center investigators from the University of Pittsburgh Schools of Medicine and Arts and Sciences, and Carnegie Mellon University, and the resulting development and implementation of innovative experimental designs and research tools to achieve these goals. Collectively, the Center represents a broad array of expertise spanning molecular, systems, cognitive, computational and clinical neuroscience.

Functional outcome in individuals with schizophrenia and related disorders is primarily determined by the degree of impairment in certain core cognitive abilities. For example, subjects with schizophrenia exhibit deficits in visual working memory and attention, and altered patterns of cortical activity during tasks that tap these abilities. These patterns of activity depend on the proper temporal firing of neurons distributed across a network that includes primary visual (V1), posterior parietal (PPC) and dorsolateral prefrontal DLPFC) cortices. These findings highlight an unanswered critical question: What are the cortical cellular, circuitry and connectivity bases for the impairments in visual working memory and attention in schizophrenia?

To answer this question, complementary studies in the Center will test the following central hypothesis:

Cell type-autonomous molecular disturbances in layer 3 pyramidal cells of the neocortex give rise to morphological abnormalities in these neurons, the severity of which is moderated by normal differences across cortical regions. This pathology alters cortical circuitry within and between regions, impairs functional connectivity and neural synchrony across regions, and disturbs both ‘bottom up’ and ‘top down’ processes during working memory and attention in individuals with schizophrenia.

The Center is comprised of five research projects and two cores that are designed to provide convergent tests of this hypothesis. The synergism of these projects facilitates a translational approach to schizophrenia research, making laboratory findings readily relevant to clinical treatment. The proposed studies have high clinical relevance as the combination of molecular-cellular-circuit level analyses with in vivo indices of brain function offers a platform for subsequent identification of novel, pathologically-based targets for therapeutic interventions that are accompanied by pathophysiologically-informed biomarkers that can be used to predict and monitor the efficacy of such interventions.

In addition to its specific research objectives, the Center provides a rich environment for training and career development in which undergraduate, graduate and medical students, postdoctoral fellows and psychiatry residents can become involved in studies that bring the methods and knowledge base of basic neuroscience to address critical questions in clinical research. The CTMHR hopes to propel the development of new and more effective treatments for individuals with schizophrenia and provide a vehicle for disseminating the importance of, and the knowledge gained from, translational studies of schizophrenia and related disorders to the broader scientific and lay communities.
 
Silvio O. Conte Center for Translational Mental Health Research
Funded by the National Institute of Mental Health (MH103204)

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