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Patrick R. Hof, M.D.
The organization of the primate cerebral cortex is the major interest of my laboratory. I am studying the distribution and morphological characteristics of neuronal populations that form corticocortical pathways in macaque monkeys, as well as their relationships to other elements of the cortical circuitry. My interest in these particular neuronal classes is related to the fact that they subserve association pathways that are involved in cognitive and memory function and are known to be severely affected in pathological conditions such as Alzheimer's disease and that undergo a certain degree of involution during the physiological process of normal brain aging. I am analyzing these circuits using combined approaches including tract-tracing, cell loading, immunohistochemistry, quantitative mapping, three-dimensional cell reconstruction, stereology, and confocal and electron microscopy. These methods are used to provide a detailed, accurate, and quantitative map of the distribution of the neurons of interest and a refined analysis of their geometric properties as well as a comprehensive evaluation of their neurochemical phenotype, in the context of identified cortical circuits. Such data are of particular relevance in respect to the cell class-specific alterations that are observed in Alzheimer's disease. Work from my laboratory has established that the large neocortical neurons of origin of association pathways are the most susceptible to develop the neurofibrillary degeneration that is typical of Alzheimer's disease and that this vulnerability pattern is crucially linked to the neurochemical specialization of these neurons. My team is currently performing exhaustive stereologic analyses of such neurons in the human brain to study the dynamic patterns of lesion formation in the course of the dementing process. We are also characterizing the myelination patterns in schizophrenia. The spatial distribution and ultrastructural pathology of oligodendrocytes is analyzed in key fiber pathways and areas of the prefrontal cortex in brains from schizophrenic patients. The effect of alterations of myelination on the functional morphology of pyramidal neurons is tested in dysmyelinating mouse models using single cell morphometry. Another research interest of my laboratory is a large-scale comparative analysis of neocortical organization in mammals. I have demonstrated that the quantitative distribution specific classes of neurons identified by their neurochemical phenotype can be used as reliable regional markers that define the parcellation of the macaque monkey and human neocortex into recognizable regions, thus defining a chemoarchitectonic map. I am studying the variability of such maps as well as the distribution of taxon-specific neuronal types not only in primates but also in a large sample of species that to date includes all mammalian orders. These chemoarchitectural features may be used as evolutionary markers that help understanding the phylogenetic relationships among mammalian groups. A particular emphasis of this project is the relationships of cetaceans with related ungulate and carnivore clades and a detailed mapping of the brain of great apes in comparison to other primates. I am also investigating the patterns of brain aging in great apes using a quantitative neuropathological approach in comparison to the studies of the aging human brain described above. Finally, a recent orientation of my research is the development of comparative brain atlases. Currently, a stereotactic comparative and interactive atlas of the two mouse strains used to generate most genetically modified models of diseases has been developed. I will expand this atlas to additional inbred strains of mice using classic histologic methods as well as magnetic resonance microscopy to provide accurate comparison of the genetic basis of diversity in brain morphology in these models. |