NEURONAL VULNERABILITY AND INFORMATICS IN HUMAN DISEASE

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This P20 application under Phase I of the Human Brain Project will support a group collaboration to develop computer-assisted quantitative microscopy data acquisition and analysis software, to construct a complex hierarchical, relational, object oriented database based on brain atlas templates, and establish means to make these data accessible through high speed electronic networks. Each of the scientific teams will use the data acquisition and analysis systems on microscope system and computers of their preference on inter-related molecular and cellular mapping studies designed to reveal neurons vulnerable to degeneration in human diseases. Six scientists will participate in the collaboration by extensions of already funded research projects: 1) Dr. Floyd Bloom, The Scripps Research Institute (TSRI), La Jolla will be Principal Investigator, and Dr. Warren Young, TSRI, La Jolla will be co-PI with overall responsibility for software development. The Bloom/Young Project will develop 3 critical software tools: a) digital atlases of the primate, feline, and rodent nervous systems, (using as an experimental base, animal models of human immunodeficiency virus syndrome); b) a comprehensive neuronal circuitry database for the major vertebrate central nervous systems; c) a cross-platform neuroscience workstation environment that operates on both local and wide area networks, interconnecting the 5 research projects, and the required programs for data acquisition, storage, analysis, and communication. 2) Dr. John Morrison, Mt. Sinai Medical School, New York, NY, will develop the fourth essential tool with Young: a computerized microscopy data acquisition system which integrates neuroanatomical paradigms of experimental observation at all levels of resolution from macroscopic to ultrastructure. The Morrison Project will generate quantitative data on primate and human neocortex glutamate receptor distribution and other molecules related to neurodegenerative vulnerability (e.g., neurofilament protein) or resistance (e.g., calcium binding proteins). 3) Dr. Harvey Karten, UCSD Medical School, La Jolla will develop a database of the molecular, cellular and physiological characteristics of vertebrate retinas, and link this database using our group microscope data collection methods. This retina database will include both normative adult and developmental data and pathological changes, and compare species. 4) Dr. Steve Foote, UCSD Medical School, La Jolla will evaluate quantitative long term changes in dopamine receptor expression (mRNA and protein) in the primate neocortex consequent to repeated psychostimulant administration using our group microscope data collection methods. These structural parameters of dopamine re-ceptor alteration will be integrated int he object oriented database with electrophysiological, behavioral, and in situ microdialysis dopamine release data. 5) Dr. Edward Jones, UC-Irvine California College of Medicine, will employ the computer- assisted microscopy methods to quantify specific neuronal populations in the major nuclei of the human reticular nucleus and dorsal thalamus and their immunocytochemically defined monoamine and neuropeptide afferent fiber systems in brains from adult patients with schizophrenia, Parkinson's disease and Alzheimer's disease and matched controls and in mid-trimester fetal material. This normative and disease-related data collection will quantitatively test the hypothesis that activity- dependent regulation of gene expression and cellular morphology can reveal functional disconnection of these particular thalamic nuclei. In the Morrison, Foote, Karten, and Jones Projects, data will be collected in common formats modified from existing software that are easily accessed and specifically prepared for incorporation into the large scale atlases and databases to be prepared by the Bloom/Young Component. We will utilize the quantitative data atlases and databases to establish norms of cellular, circuitry, and neurochemical information which will then serve to detect and define experimental and pathological variations, and to generate explanatory hypotheses.