Genetic dissection of cortical neuron type trajectories: from developmental origin to behavioral function

The vast neural circuits of the cerebral cortex underlying high-level brain functions are built from a set of basic templates shared by individuals of the species and conserved across mammalian evolution. To a great extent, cortical circuits self-assemble during development guided by information in the genome and are then individually customized through learning and experience. A key challenge in understanding cortical circuitry is deciphering the nature and organization principle of diverse glutamatergic projection neuron (PN) “types” which, through their elaborate long axons, mediate the myriad cortical processing streams and output channels. Meeting this challenge requires strategies and methods to integrate multi-modal PN phenotypes and track their multi-faceted developmental trajectories, from origin in neural progenitors to circuit elements in behavior. In this seminar, I will highlight our progress in 1) building genetic tools, including the recent RNA-programmable CellREADR technology, to systematically dissect and fate map PN types and their progenitors; 2) exploring the role of direct and indirect neurogenesis mediated by radial glia and intermediate progenitors, respectively, in shaping PN types; and 3) studying the function of genetic- and projection-defined PN types in skilled motor control. We aim to integrate the developmental genetic, systems neuroscience, and evolutionary explanations of PN diversity and organization that shape cortical circuit architecture.