Large-scale, high-resolution light-sheet microscope for whole brain connectomics

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To break the mysteries of the normal and diseased brain we must be able to visualize the very complex circuitry of the brain with high resolution (thousandths of millimeters). This can be achieved with light microscopy which offers high resolution but also the ability to visualize wide areas at once. Yet, imaging the entire brain with light is a major challenge because the brain is relatively opaque to light (because it scatters light this is why it tends to look white when one looks at it). Recent breakthrough technologies are able to render animal and human brain samples virtually transparent opening the door to imaging entire brains at once. The challenge remains of building a microscope capable of doing this. The proposal builds on a recent technology we have developed using a novel type of lens called axicons, which generates extreme long lines of light that can traverse the entire brain and enable its visualization from the side. Producing light lines with sufficient energy remains challenging. We have a solution with the use of novel powerful lasers called regenerative-amplifier pulsed lasers. The combination of these technologies will allow us to develop, for the first time, a type of microscope capable of generating high resolution, large scale images of entire brain areas (centimeter-wide regions). This technology promises to transform our ability to understand the neuro-circuitry of the brain and thus significantly advance understanding of neurological and psychiatric diseases which involve remodeling of brain connections.