Neuroengineering, the field of creating new tools for neuroscience, is an emerging field which includes the invention of technologies to activate and silence electrical activity in the brain, technologies to read out electrical activity from cells in the brain, and tools for mapping the brain. In this talk I will give an overview of technologies that recently emerged from our lab. First, recent optogenetic tools have begun to reach the physical limits of performance. The optogenetic molecules (opsins) Chronos and Chrimson enable activation of distinct neural populations with multiple colors of light, and Jaws is a red shifted inhibitor of neural activity that enables noninvasive neural silencing. Since opsins express all along cell membranes, light focused on one cell body will result in artifactual activation of multiple cells, whose processes are physically touching the neuron of interest. To tackle this problem, we designed a class of somatic opsins that express mainly at the cell body. This, in combination with holographic stimulation enables single cell optogenetics at millisecond temporal resolution.

Activity sensors represent an area of great interest in neuroengineering. The voltage sensor Archon is an archaerhodopsin-based molecule with a high voltage sensitivity and brightness compared to its predecessors. The aforementioned cross talk problem also pertains to sensors: since cell-processes are touching cell bodies, the signal coming from a cell body could in principle originate from nearby cells. To solve this problem we developed a GCaMP6f molecule that is retained in the cell body only, called somaGCaMP6f. This molecule enables low crosstalk physiological imaging in mice and fish.

Lastly, we have developed a technology that greatly facilitates the mapping of the brain. Optical super-resolution techniques are slow and costly, and accordingly do not scale well to large-scale brain circuitry. Instead of improving the resolving power of the microscope, we have found a way to physically expand biological specimens 4x-20x in linear dimension, in an isotropic fashion. This method, which we call expansion microscopy (ExM), enables the mapping of molecules of interest across cells and tissues of extended scale, and thus facilitates the analysis of neural circuits across scales of relevance to understanding brain function.