MAPPING ABNORMAL NEURODEVELOPMENT IN AN ANIMAL MODEL

Washington University, Saint Louis MO

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Abstract

The hypothesis that the thalamus is a primary site of pathology in schizophrenia and that thalamic pathology will be tested, as well as consequent pathology in other brain regions, could arise from a prenatal insult. Toward this aim, fetal monkeys have been exposed to x-irradiation in order to substantially reduce thalamic volume and neuron number. During the current grant cycle, the high dimensional brain mapping (HDBM) method developed by and colleagues has been used to assess thalamic volume in fetally irradiated monkeys (FIMs) and has established that fetal irradiation during the time of thalamogenesis produces thalamic pathology in the fully mature macaque that can be detected with neuroimaging techniques. In this grant period, HDBM will be used to examine how other brain regions, specifically the frontal cortex and hippocampus, are affected by early gestational depletion of thalamic neurons and whether the pathology in these regions is comparable to that observed in schizophrenia. The volume and thickness of individual cortical areas, e.g., dorsolateral prefrontal area 46, will be assessed through a novel combination of postmortem histologic and magnetic resonance imaging methodologies. In addition, postmortem analyses of the cytoarchitecture of the hippocampus will probe the cellular basis of alterations in volume and shape of the hippocampus that have been detected via in vivo imaging in FIMs; these analyses may provide insight into the structural underpinnings of similar conformational alterations in schizophrenia patients. Finally, application of the HDBM methodology to a new cohort of FIM and control monkeys at selected developmental intervals will provide a longitudinal picture of the normal development of brain morphology and the interaction of a prenatal lesion on the normal maturational process.