Optogenetics: Development and Application

In 1979, Francis Crick delineated the major challenges facing neuroscience and called for a technology by which all neurons of just one type could be controlled, “leaving the others more or less unaltered”. A new set of technologies now called optogenetics, synthesizing microbial opsins and solid-state optics, has achieved the goal of millisecond-precision bidirectional control of defined cell types in freely behaving mammals. First, we found that neurons expressing Channel Rhodopsin-2 can fire light-triggered action potentials with millisecond precision. Second, we found that neurons targeted to express the light-activated chloride pump halorhodopsin can be hyperpolarized and inhibited from firing action potentials when exposed to yellow light in intact tissue. Third, we employed genomic strategies to discover and adapt for neuroscience a third major optogenetic tool, namely a cation channel with action spectrum significantly redshifted relative to ChR2, to allow tests of the combinatorial interaction of cell types in circuit computation or behavior. Fourth, we have created transgenic mice expressing microbial opsins in the brain. Finally, we have developed integrated fiberoptic and solid-state optical approaches to provide the complementary technology to allow specific cell types, even deep within the brain, to be controlled in freely behaving mammals. We also are now enhancing opsin function for long-term in vivo applications, and applying fast optical control and optical imaging to animal models of depression, Parkinson’s Disease, and altered social behavior relevant to autism, with insights into both normal circuit function and disease mechanisms beginning to emerge.