Understanding brain systems by cell type-specific changes in gene expression

Despite impressive advances in almost every field of neuroscience, our understanding of brain function remains largely confined to its building blocks at the microscopic level, and to phenomenological descriptions at the macroscopic level. The introductio n of transgenic mice has provided neuroscience with countless correlations between microscopic and macroscopic levels, but because most gene knockouts have lacked regional and temporal specificity, insights into computational mechanisms remain scarce. Und erstanding how complex mental functions originate from electrical and chemical processes in brain cells requires an integrated systems-biological analysis focused on the intermediate level of neuronal microcircuits, where myriads of intricately connected neurons with different properties act together. Microcircuit computations could be comprehended if it were possible to restrict genetic interventions to particular brain regions and particular cell types. Technologies for this purpose have been developed only recently and are not part of existing FUGE platforms in Norway. The aim of the present project is to exploit these recent developments to develop, within Channel 3 of the FUGE2 program, a set of tools for addressing functions of neuronal microcircuit s in rats. Using the spatial representation system of the rat as an experimental model, we shall introduce molecular markers into specific cell types of the hippocampus and entorhinal cortex by stereotaxic injection of viral vectors, and viral vectors wil l be used to introduce, upregulate, downregulate or modify expression of critical proteins in target cells, which is necessary if we are to determine the functions of these cell types. Because technologies for selective genetic manipulation are likely to completely transform systems neurobiology in the next decade, we shall use the proposed projects as a fundament for dissemination of the new technology to other systems neurobiology groups in Norway and elsewhere.