Elucidating the subcircuit organization of mouse dorsal striatum via the development of a monosynaptically- restricted, cell-type specific viral toolbox

Our ability to understand the organization of the brain and its myriad connections has advanced greatly, particularly in the last century, but the fine scale connectivity of many brain structures remains poorly understood. At its most technologically primitive, investigators laboriously dissected out the fiber tracts that connected one brain region to another. More recently, scientists have developed a number of tools that allow the visualization of connections that link brain regions together. However, a defined brain structure is not monolithic, and often consists of multiple physiologically distinct cell types that perform different functions in a brain circuit. Although the point to point connectivity of the brain has been painstakingly analyzed via traditional neuroanatomical techniques such as tract tracing and electron micrography, and the roles of specific cell types have been probed via electrophysiological manipulations in reduced circuits, no method yet existed to unequivocally label the direct, monosynaptic inputs to specified cell types. I developed a set of viral tools that allow for cell-type specific interrogation of brain connectivity, providing an effective method for generating subcircuit maps of information flow onto multiple different neuron types, even if they inhabit the same brain region. I then used these newly-developed tools to reveal the fine-scale organization of inputs to the dorsal striatum, a region of the brain that possesses two intermingled, but genetically distinct projection cell types with opposing effects on motor output. I demonstrated that the two major projection pathways of the basal ganglia do indeed receive asymmetric input; direct pathway projection cells within the striatum receive preferential input from sensory and limbic structures, whereas neighboring projection cells of the indirect pathway preferentially received input from motor cortex. This segregation of connectivity provides a substrate for differential information processing; rather than simply treating the direct pathway as a "Go" stream and the indirect pathway as a "NoGo" stream, the direct pathway may preferentially process contextual information for purposes of selecting relevant action sequences, whereas the indirect pathway may receive an efference copy of motor production in order to facilitate switching to a new action or to suppress competing action sequence