Ion channels and neurotransmitter receptors are amongst the most important molecules in the nervous system. They support the high-speed physiological processes that enable neurons to function, they are implicated in many neurological and psychiatric disorders, and they present an incredibly important set of drug targets for treating these diseases. In order to enable a better understanding of how specific ion channels and receptors contribute to behaviors and pathologies, we propose to engineer a toolbox of fully genetically encoded reagents that, when expressed in specific neurons in the brain, enable specific ion channels and ionotropic neurotransmitter receptors to be driven or blocked in a temporally precise fashion, using pulses of light. We anticipate that these tools will find widespread use in both basic and clinical neuroscience, and in other fields of biology, for revealing the roles that specific ion channels and receptors (or changes in their activity levels) play in neural computations, behaviors, and disease states, and for revealing more specific drug targets.
Ion channels and neurotransmitter receptors are molecules that are implicated in a diversity of neurological and psychiatric disorders, and are targets for many important drugs. In order to understand how the modulation of ion channels and receptors might alter the complex circuitry of the brain, we will develop a set of tools that enable selective perturbation of these molecules in targeted cells within the brain. By revealing which cells are most likely to be modulated by a given drug, our technology will enable the development of better drugs with fewer side effects, revealing principles for designing future therapies. NOTE: The purpose of the EUREKA initiative is to foster exceptionally innovative research that, if successful, will have an unusually high impact on the areas of science that are germane to the mission of one or more of the participating NIH Institutes. EUREKA is for new projects. EUREKA is not for the continuation of existing projects. EUREKA is not for support of pilot projects (i.e., projects of limited scope that are designed primarily to generate data that will enable the PI to seek other funding opportunities). Rather, it is anticipated that EUREKA projects will begin and be completed during the funding period. Please provide an overall impact/priority score to reflect your assessment of the likelihood the project will exert a sustained, powerful influence on the research field(s) involved, Significance and Innovation should be the major determinants of your overall impact score. The approach should be evaluated for general feasibility. An application should score poorly if it is clear to the reviewers that the proposed methodology has no probability at all of being successful, either because it is inherently illogical or because the same approach has already been attempted and shown not to be feasible. Remember that unavoidable risk, which is intrinsic to novel and innovative approaches, is expected for these applications and reviewers are instructed that the presence or absence of preliminary data should not be taken into account when determining the score.
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| Schmidt, Daniel; Tillberg, Paul W; Chen, Fei et al. (2014) A fully genetically encoded protein architecture for optical control of peptide ligand concentration. Nat Commun 5:3019 |
| Chuong, Amy S; Miri, Mitra L; Busskamp, Volker et al. (2014) Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat Neurosci 17:1123-9 |
| Glaser, Joshua I; Zamft, Bradley M; Marblestone, Adam H et al. (2013) Statistical analysis of molecular signal recording. PLoS Comput Biol 9:e1003145 |
| Kodandaramaiah, Suhasa B; Boyden, Edward S; Forest, Craig R (2013) In vivo robotics: the automation of neuroscience and other intact-system biological fields. Ann N Y Acad Sci 1305:63-71 |
| Bernstein, Jacob G; Garrity, Paul A; Boyden, Edward S (2012) Optogenetics and thermogenetics: technologies for controlling the activity of targeted cells within intact neural circuits. Curr Opin Neurobiol 22:61-71 |
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