The Center on """"""""Dopamine Dysfunction in Schizophrenia"""""""" will test the central hypothesis that striatal dopaminergic hyperactivity during development leads to prefrontal cortical dopamine (DA) dysfunction in schizophrenia (SCZ) and the cognitive deficits that characterize the disorder. Thus, dysregulation of DA transmission in the striatum during development and its ultimate effect on prefrontal cortical (PFC) DA transmission and PFC circuit function contribute to positive symptoms, negative symptoms and cognitive deficits. This hypothesis is based on a convergence of recent findings from Center investigators: 1) the striatal DAergic excess in schizophrenia is greatest in the associative striatum (AST), 2) the AST receives convergent input from dorsolateral-prefrontal cortex (DLPFC), the anterior cingulate cortex (ACC) and limbic frontal cortical regions, rendering it crucial for integration of affective and cognitive processes, 3) striatal DA D2 receptor overexpression during development in mice results in frontal cortical dopamine alterations, PFC dysfunction, as evidenced by irreversible learning deficits, as well as rnotivational and social deficits. Thus,integration of incoming information from the PFC 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 DA function. Our five Projects supported by 4 Cores are organized to test this hypothesis. We will test in patients with SCZ compared to healthy controls whether the striatal DA pathology predicts: 1) cortical DA pathology measured with Positron Emission Tomography (PET) (P1) and 2) PFC-mediated cognitive functioning as assessed with working memory tasks and the associated changes in PFC activity as measured with Functional Magnetic Resonance Imaging (fMRI) (P2). We will create transgenic mice with early developmental overexpression of D2 receptors in striatum (P4) or alterations in midbrain DA firing patterns and striatal DA release (P5). These mouse models will be used to understand possible mechanisms underlying abnormal frontal cortical DA transmission as well as cognitive and behavioral abnormalities mediated by PFC-striatal circuits in SCZ. We will also determine the critical alterations in signal transduction in the striatum mediating these effects (P4), the underlying circuitry both in monkeys and in rodents (P3), and possible neurochemical mediators of DA imaging endophenotypes associated with SCZ (P5). This set of studies in humans, monkeys and mice will establish the role of striatal DA dysregulation in the pathogenesis of PFC dysfunction in SCZ, and by doing so will serve as a critical first step to novel approaches to treatment that interrupt this pathogenic mechanism.

Public Health Relevance

Disordered cognition leads to severe functional impairment in schizophrenia. Our new perspective on a key alteration in this illness, which is DA dysfunction, and the set of mechanistic studies we propose in order to test it, will lead to 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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-F (07))
Program Officer
Zalcman, Steven J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York State Psychiatric Institute
New York
United States
Zip Code
Cassidy, Clifford M; Van Snellenberg, Jared X; Benavides, Caridad et al. (2016) Dynamic Connectivity between Brain Networks Supports Working Memory: Relationships to Dopamine Release and Schizophrenia. J Neurosci 36:4377-88
Bolkan, S S; Carvalho Poyraz, F; Kellendonk, C (2016) Using human brain imaging studies as a guide toward animal models of schizophrenia. Neuroscience 321:77-98
Van Snellenberg, Jared X; Girgis, Ragy R; Horga, Guillermo et al. (2016) Mechanisms of Working Memory Impairment in Schizophrenia. Biol Psychiatry 80:617-26
Slifstein, Mark; van de Giessen, Elsmarieke; Van Snellenberg, Jared et al. (2015) Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: a positron emission tomographic functional magnetic resonance imaging study. JAMA Psychiatry 72:316-24
Ward, Ryan D; Winiger, Vanessa; Higa, Kerin K et al. (2015) The impact of motivation on cognitive performance in an animal model of the negative and cognitive symptoms of schizophrenia. Behav Neurosci 129:292-9
Krabbe, Sabine; Duda, Johanna; Schiemann, Julia et al. (2015) Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area. Proc Natl Acad Sci U S A 112:E1498-506
Van Snellenberg, Jared X; Slifstein, Mark; Read, Christina et al. (2015) Dynamic shifts in brain network activation during supracapacity working memory task performance. Hum Brain Mapp 36:1245-64
Avlar, Billur; Kahn, Julia B; Jensen, Greg et al. (2015) Improving temporal cognition by enhancing motivation. Behav Neurosci 129:576-88
Cazorla, Maxime; Kang, Un Jung; Kellendonk, Christoph (2015) Balancing the basal ganglia circuitry: a possible new role for dopamine D2 receptors in health and disease. Mov Disord 30:895-903
Chuhma, Nao; Mingote, Susana; Moore, Holly et al. (2014) Dopamine neurons control striatal cholinergic neurons via regionally heterogeneous dopamine and glutamate signaling. Neuron 81:901-12

Showing the most recent 10 out of 23 publications