Visual working memory and attention depend on coordinated neural activity between the posterior parietal cortex (PPC) and dorsolateral prefrontal cortex (DLPFC). These two regions are directly linked by projections from layer 3 pyramidal cells (PCs) that are predicted to mediate their functional connectivity (Project 4). Consequently, cell-autonomous abnormalities in the neurons furnishing these projections are posited to impair functional connectivity between PPC and DLPFC in schizophrenia (Project 5), leading to deficits in WM and attention. A key element ofthis Central Hypothesis is that region-specific properties of layer 3 PCs moderate the severity of the molecular (Projecti) and morphological (Project 2) pathology of these neurons in schizophrenia;specifically, the pathology of layer 3 PCs is predicted to be more severe in DLPFC than in PPC, and thus the projections from DLPFC-to-PPC are predicted to be more impaired than those from PPC- to-DLPFC (Project 5). This project serves as a critical bridge between Project 1&2 studies of all layer 3 PCs in human PPC and DLPFC and the Project 4 studies that focus on the layer 3 connections between PPC and DLPFC in monkeys as follows:
Aim 1 provides key assessments of our translational strategy for testing the Central Hypothesis. First, it tests the idea that regional differences in layer 3 PC gene expression between human PPC and DLPFC are conserved in monkeys. Second, by focusing on the layer 3 PCs that interconnect PPC and DLPFC, it provides a robust test of the idea that region of origin accounts for differences in gene expression by controlling for other factors known to be associated with differences in certain molecular features or dendritic morphology of PCs. Thus, Aim 1 provides a key transition from Project 1&2 studies in humans of all layer 3 PCs (which cannot currently be divided into subsets based on their principal axon projection) to studies of the subset that interconnect PPC and DLPFC in monkeys. These region-defined differences in gene expression are predicted to be associated with differences in morphological (Aim 2), and neurophysiological (Aim 3) properties of layer 3 PCs that provide the cellular basis for the functional connectivity between monkey PPC and DLPFC studied in Project 4.

Public Health Relevance

This project will inform our understanding ofthe neural circuitry basis for attention and working memory impairments in schizophrenia through the use of a non-human primate model system to determine, with specificity at the levels of cell types, local circuits and inter-regional connections, the critical properties of the same neural circuitry studied at the functional and behavioral levels in human subjects.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZMH1-ERB-L (01))
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University of Pittsburgh
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Moyer, Caitlin E; Shelton, Micah A; Sweet, Robert A (2015) Dendritic spine alterations in schizophrenia. Neurosci Lett 601:46-53
Hu, Wei; MacDonald, Matthew L; Elswick, Daniel E et al. (2015) The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann N Y Acad Sci 1338:38-57