The applicant describes the discovery of a new strain of rats that has an unusual, inherited forebrain abnormality. The behavior and external appearance of the affected animals are relatively normal, yet they possess an """"""""entirely new brain region"""""""". Best described as a large cortical ectopia, the new structure is located below the neocortical mantle and gives the gross appearance of a 'double-cortex'. The mutant region is bilateral and extends for nearly the entire rostral-caudal extent of the cortical mantle. The existence of this rat strain is exciting for two overlapping reasons. The first is that it offers the opportunity to test a variety of theories about the relationship between structure and function in the cortex and about the ground rules of its developmental program. The second is that the anomaly observed bears a striking resemblance to a human condition known as double cortex. The applicant proposes to study this newly described abnormality in several ways. First, the applicant will perform a descriptive analysis of the types, positions and orientations of neurons in the anomalous region of adult mutant animals, as well as any effects on composition or organization of the """"""""normal"""""""" cortex overlying the defect. Second, the applicant proposes to describe the development of the ectopia, by performing a longitudinal study at several developomental ages (during corticogenesis). These studies will be enhanced by the determination of the """"""""birthdays"""""""" of the constituent neurons of the ectopia and the overlying normal cortex using BrdU incorporation into pups after injection of the pregnant dams at various embryonic and early postnatal ages followed by sacrifice at """"""""adult"""""""" ages (P30 - 40). The ventricular source of the ectopic neurons and the course of their migration will be studied using short survival BrdU injections. Two to 48 hours after BrdU administration to a pregnant dam, her pups will be taken and the location of the labeled cells assessed. Third, connectivity within the ectopia and between the ectopia and other cortical and subcortical areas will be determined. Afferents to the affected region will be determined by injections of Fluoro ruby into one of three rostro/caudal sites within the anomalous region or the overlying cortex. The focus of analysis will be on the thalamic nuclei whose nuclei are associated with the overlying cortex. Efferents from the ectopia will be determined using the anterograde tracer PHA-lectin. Both of these results will be compared with similar injections from the overlying normal forebrain. The result should be a comprehensive description of the anatomy and development of this remarkable genetic anomaly.
