BRAIN EAGER: Genetically Encoded Light Sources for Non-Invasive Optogenetics

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PI: Hochgeschwender, Ute H.Proposal: 1450216Title: BRAIN EAGER: Genetically Encoded Light Sources for Non-Invasive OptogeneticsSignificanceThe realization of light-driven genetically targeted neuronal activation and silencing has led to unprecedented possibilities in manipulating neuronal activity in the behaving experimental animal.However, translation of this approach into the clinical arena for potential therapeutic applications is complicated by the need for implanting optical fibers in the brain as the light source for activating lightsensing opsins. This proposal describes an integrated research, education, and outreach program which focuses on developing a new generation of genetically encoded light sources for non-invasive manipulation of optogenetic sensors. If successful this will be a key threshold advance that will provide the foundation for new technologies enabling minimally invasive and highly efficient diagnostics and therapies. Currently there are no alternative approaches which would achieve, non-invasively, the full range of photonic control of neurons as proposed here.Technical DescriptionThe investigators will build on the highly innovative concept of combining optogenetics with bioluminescence. To exploit the concept?s potential for non-invasive light activation of optogenetic sensors in clinical settings, they will utilize protein engineering to both improve light output and extend the emission spectrum of the luciferase by optimizing intramolecular bioluminescence resonance energy transfer (BRET) between Gaussia luciferase and various fluorescent proteins. They will test the novel constructs for their efficiency in activating channelrhodopsins and proton and chloride pumps in vitro. The development of these concepts and reagents will have potentially transformative and broad impacts on the implementations of optogenetics in medicine.