This project offers a unique opportunity to use stat-of-the-art MRI scanning and neuromorphometric assessment methods to assess volumetric and shape changes in cortical and subcortical structures following an early developmental lesion in a non-human primate model of schizophrenia. The high dimensional brain mapping (HDBM) method pioneered by Miller and Csernansky will be used to generate precise, 3-D maps of selected cortical gyri, the thalamus and the ventricular system of fetally x-irradiated monkeys at multiple time points prior to sacrifice. Postmortem assessment of the irradiated monkeys (independently funded except for the hippocampus) will include a battery of quantitative anatomical studies, i.e., stereologic cell counting, immunocytochemistry, Golgi, and EM analysis, on the same structures that are analyzed with HDBM. Thus, changes in the conformation of structures assessed with MRI can be correlated with alterations in cell density, process outgrowth, and synaptic input in the cortex and thalamus. The working hypothesis of this project is that MRI can be used to detect relatively subtle changes inbrain morphology consequent to a mild prenatal insult, an experimental paradigm with direct relevance to the developmental model of schizophrenia. This project has the following specific aims:
Aim 1. To deliver low doses of x-irradiation in mid-gestation selectively eliminate dividing progenitor cells destined to form the thalamus. Volumetric and shape measurements from HDBM will then be correlated with data from postmortem stereologic analysis of thalamic volume, cell number, and dendritic arborization, as well as ventricular size.
Aim 2. To assess cortical measures of cell density and thickness using techniques for stereological morphometric analysis in animals given low doses of x- irradiation. Measures of cortical thickness and contouring for the principal sulcal, anterior cingulate, entorhinal and hippocampal gyri will then be correlated with cellular measures.
Aim 3. To perform HDBM at 4 stages of development in normal and fetally irradiated monkeys to yield a normative data base from which to assess the impact of lesions, drug treatment and other experimental protocols. Repeated HDBM in the same monkeys at multiple developmental will allow us to monitor radiation-induced pathology and its changing course through the critical adolescent period of synaptic pruning while minimizing the number of animals required for the study.
