The developmental hypothesis of schizophrenia suggests that prenatal perturbation of early brain development results in a latent defect expressed in post-adolescent life in the form of profound mental illness. In the Section of Neurobiology at Yale, a primate animal model of schizophrenia has been developed over the past decade which produces behavior deficits in working memory capacity, perhaps the most prominent cognitive deficit observed in schizophrenic patients, and mimics several prominent morphologic correlates of the disease. Irradiation of the fetal rhesus monkey brain during a critical period in early gestation results in deletion of developing thalamic neurons and, ultimately in the adult monkey, in behavioral deficits on tasks that are mediated by the prefrontal cortex, features that have been reported in schizophrenic patients. The goal of the study is (1) to determine the extent to which anatomical abnormalities generated in the non-human primate brain by fetal exposure to x-irradiation replicate anomalies previously described in postmortem studies of the human schizophrenic brain and (2) to utilize this animal model to explore morphological disruption of the cortex that is not feasible in the disease human brain. These goals will be achieved by a comprehensive anatomical investigation of the fetally x-irradiated primate model with particular focus on the dorsolateral prefrontal cortex, including application of the latest stereologic methodology to assess neuronal and glial density, cell size, as well as cortical and ventricular volume, morphometric analysis of neuronal dendritic structure, and quantitation of chemically identified cell populations. In addition, ultra-structural analyses, which is not feasible in postmortem human brains will be used to directly examine the neuropil compartment of the prefrontal cortex. These finding should provide insights into neurodevelopmental mechanisms leading to cognitive dysfunction and cortical pathology in schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH059329-03
Application #
6392612
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Meinecke, Douglas L
Project Start
1999-09-01
Project End
2004-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
3
Fiscal Year
2001
Total Cost
$265,315
Indirect Cost
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Selemon, L D; Zecevic, N (2015) Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry 5:e623
Selemon, L D; Friedman, H R (2013) Motor stereotypies and cognitive perseveration in non-human primates exposed to early gestational irradiation. Neuroscience 248:213-24
Aldridge, Kristina; Wang, Lei; Harms, Michael P et al. (2012) A longitudinal analysis of regional brain volumes in macaques exposed to X-irradiation in early gestation. PLoS One 7:e43109
Friedman, Harriet R; Selemon, Lynn D (2010) Fetal irradiation interferes with adult cognition in the nonhuman primate. Biol Psychiatry 68:108-11
Selemon, Lynn D; Begovi?, Anita; Rakic, Pasko (2009) Selective reduction of neuron number and volume of the mediodorsal nucleus of the thalamus in macaques following irradiation at early gestational ages. J Comp Neurol 515:454-64
Selemon, Lynn D; Wang, Lei; Nebel, Mary Beth et al. (2005) Direct and indirect effects of fetal irradiation on cortical gray and white matter volume in the macaque. Biol Psychiatry 57:83-90
Selemon, Lynn D; Rajkowska, Grazyna; Goldman-Rakic, Patricia S (2004) Evidence for progression in frontal cortical pathology in late-stage Huntington's disease. J Comp Neurol 468:190-204
Selemon, L D; Rajkowska, G (2003) Cellular pathology in the dorsolateral prefrontal cortex distinguishes schizophrenia from bipolar disorder. Curr Mol Med 3:427-36
Selemon, Lynn D; Mrzljak, Jasna; Kleinman, Joel E et al. (2003) Regional specificity in the neuropathologic substrates of schizophrenia: a morphometric analysis of Broca's area 44 and area 9. Arch Gen Psychiatry 60:69-77
Selemon, Lynn D; Kleinman, Joel E; Herman, Mary M et al. (2002) Smaller frontal gray matter volume in postmortem schizophrenic brains. Am J Psychiatry 159:1983-91

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