The brain is a complex, densely wired circuit made out of heterogeneous cells, which vary in their shapes, molecular composition, and patterns of connectivity. In order to help discover how neural circuits implement brain functions, and how these computations go awry in brain disorders, we invent technologies to enable the scalable, systematic observation and control of biological structures and processes in the living brain. We have developed genetically-encoded reagents that, when expressed in specific neuron types in the nervous system, enable their electrical activities to be precisely driven or silenced in response to millisecond timescale pulses of light. I will give an overview of these "optogenetic"
tools, adapted from natural photosensory and photosynthetic proteins, and discuss new tools we are developing, including molecules with novel color sensitivities (e.g., Chrimson, Jaws) and other unique capabilities (e.g., Chronos). We are also developing optogenetic tools that enable activation of endogenous protein and signaling pathways (e.g., lumitoxins). Often working in interdisciplinary collaborations, we have developed microfabricated hardware to enable complex and distributed neural circuits to be controlled and observed in a fully 3-D fashion, as well as robots that can automatically record neurons intracellularly and integratively in live brain, and strategies for building 3-D brain circuits in vitro. These tools are in widespread use to enable systematic analysis of neural circuit functions, are also opening up new frontiers on the understanding and treatment of brain disorders, and may serve as components of new platforms for diagnosing and treating brain disease