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 (VI), 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, the complementary studies in the proposed Center are designed to test the following Central Hypothesis: Intrinsic molecular disturbances in layer 3 pyramidal cells of the neocortex give rise to morphological abnormalities in these neurons. The severity of this cellular pathology is moderated across cortical regions as a function of normal regional differences in the properties of layer 3 pyramidal cells. This cellulr pathology alters cortical circuitry within and between regions, impairs functional connectivity across regions, and results in disturbances in both bottom up and top down processes during visual working memory and attention in individuals with schizophrenia. The five inter-related projects (P) of the proposed Center provide convergent tests of this hypothesis at the molecular, cellular, laminar and local circuitry levels in postmortem human brain (P1&P2), and at the regional and distributed circuitry levels through imaging and neurophysiological studies in never-medicated subjects with a first-episode of psychosis (P5);these studies are both informed and constrained by parallel studies in monkeys (P3&P4). A key innovation of this approach is the integration of studies with multiple levels of resolution, from molecules to behavior, that provide a translational assessment of both bottom up and top down explanations of cortical dysfunction in schizophrenia.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-L (01))
Program Officer
Zalcman, Steven J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Yan, Zhen; Kim, Eunjoon; Datta, Dibyadeep et al. (2016) Synaptic Actin Dysregulation, a Convergent Mechanism of Mental Disorders? J Neurosci 36:11411-11417
Murty, Vishnu P; Calabro, Finnegan; Luna, Beatriz (2016) The role of experience in adolescent cognitive development: Integration of executive, memory, and mesolimbic systems. Neurosci Biobehav Rev 70:46-58
Ramachandran, Suchitra; Meyer, Travis; Olson, Carl R (2016) Prediction suppression in monkey inferotemporal cortex depends on the conditional probability between images. J Neurophysiol 115:355-62
Datta, Dibyadeep; Arion, Dominique; Roman, Kaitlyn M et al. (2016) Altered Expression of ARP2/3 Complex Signaling Pathway Genes in Prefrontal Layer 3 Pyramidal Cells in Schizophrenia. Am J Psychiatry :appiajp201616020204
Chung, Daniel W; Fish, Kenneth N; Lewis, David A (2016) Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia. Am J Psychiatry 173:1131-1139
Hall, Nathan J; Colby, Carol L (2016) Express saccades and superior colliculus responses are sensitive to short-wavelength cone contrast. Proc Natl Acad Sci U S A 113:6743-8
Chung, Daniel W; Volk, David W; Arion, Dominique et al. (2016) Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression. Am J Psychiatry 173:60-8
Aminoff, Elissa M; Li, Yuanning; Pyles, John A et al. (2016) Associative hallucinations result from stimulating left ventromedial temporal cortex. Cortex 83:139-44
Hoftman, Gil D; Datta, Dibyadeep; Lewis, David A (2016) Layer 3 Excitatory and Inhibitory Circuitry in the Prefrontal Cortex: Developmental Trajectories and Alterations in Schizophrenia. Biol Psychiatry :
Chen, Cho-Yi; Logan, Ryan W; Ma, Tianzhou et al. (2016) Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. Proc Natl Acad Sci U S A 113:206-11

Showing the most recent 10 out of 17 publications