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.
Showing the most recent 10 out of 13 publications
