The Silvio O. Conte center dopamine dysfunction in Schizophrenia

nyspifacadefaded The Silvio O. Conte Center
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Participate in a brain imaging study

Our focus

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The Center on Dopamine Dysfunction in Schizophrenia will test the central hypothesis that striatal dopaminergic hyperactivity during development leads to prefrontal cortical dopamine dysfunction in schizophrenia and the cognitive deficits that characterize the disorder. Our hypothesis represents a radical reconceptualization of dopaminergic dysregulation in schizophrenia, with a focus on the striatum as a key integrative structure in regulating the development and ultimate function of prefrontal cortical circuits.

Our hypothesis is based on a convergence of recent findings from the Center investigators:

  • The striatal dopaminergic excess in schizophrenia is greatest in the associative striatum.
  • The associative striatum receives convergent input from dorsolateral-prefrontal cortex, the anterior cingulate cortex and limbic frontal cortical regions, rendering it crucial for integration of affective and cognitive processes.
  • Striatal dopamine D2 receptor overexpression during development in mice results in frontal cortical dopamine alterations and prefrontal cortex dysfunction, as evidenced by irreversible learning deficits as well as motivational and social deficits.
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Thus, integration of incoming information from the prefrontal cortex may be altered by excessive D2 signaling in the associative striatum, which impairs cortical flow of information across cortico-striato-pallido-thalamo-cortical loops and alters midbrain dopaminergic function.

Our Center Structure

The Conte Center consists of five projects supported by four cores, providing a rigorous translational framework for testing our hypothesis.

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Our Projects

Our five projects will examine:

P1. Whether striatal dopaminergic pathology predicts cortical dopaminergic pathology as measured with Positron Emission Tomography (PET) in patients with schizophrenia compared to healthy controls.

P2. Prefrontal Cortex-mediated cognitive functioning as assessed with working memory tasks and the associated changes in prefrontal cortex activity as measured with Functional Magnetic Resonance Imaging (fMRI) in patients with schizophrenia compared to healthy controls.

P3. The underlying neural circuitry both in monkeys and in rodents.

P4. The critical alterations in signal transduction in the striatum that mediate these effects in transgenic mice with early developmental overexpression of D2 receptors in striatum.

P5. Possible neurochemical mediators of dopaminergic imaging endophenotypes associated with schizophrenia in transgenic mice with alterations in midbrain dopamine cell firing patterns and striatal dopamine release.

Together these studies in humans, monkeys and mice will establish the role of striatal dopamine dysregulation in the pathogenesis of prefrontal cortex dysfunction in schizophrenia, and by doing so will serve as a critical first step towards the development of novel treatment approaches to interrupt this pathogenic mechanism. The Conte Center projects are carried out at the New York State Psychiatric Institute, Columbia University Medical Center and at Rochester University Medical Center.

Potential Impact

Our new perspective on a key alteration in this illness - dopamine dysfunction - and the set of mechanistic studies with which we will test it, will lead to a new and better understanding of the disorder. This in turn may lead to preventive or therapeutic strategies that can be developed, based on this new understanding.

History of the Conte Centers

Since 1988, NIMH has encouraged scientists to seek funding for projects in which a unifying, well-defined scientific question would be approached from many angles and at many levels (for example, genetic, molecular, clinical, and behavioral) via its Centers for Neuroscience of Mental Disorders and Centers for Neuroscience Research. In 1993, these centers were renamed in memory of Silvio O. Conte, a former congressman from Massachusetts, who throughout his political career passionately advocated for federally funded research of mental disorders through the National Institutes of Health.

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