Aspects of the conceptual inspiration for optogenetics can be traced to the 1970s. In 1979 Francis Crick, taking note of the complexity of the mammalian brain and the fact that electrodes cannot readily distinguish different cell types (Crick, 1979), suggested that a major challenge facing neuroscience was

the need to precisely control activity in one cell type while leaving the others unaltered. GW-572016 cell line Crick later speculated in lectures that light might be a relevant control tool, but without a concept for how this could be done. Yet years earlier (in an initially unrelated line of research), bacteriorhodopsin had been identified (Oesterhelt and Stoeckenius, 1971 and Oesterhelt and Stoeckenius, 1973) as a microbial single-component light-activated ion pump. Further work in thousands of papers over the ensuing decades led not only to deeper understanding of bacteriorhodopsin but also to the discovery of many new members of this microbial opsin family, which includes membrane-bound ion pumps and channels such as halorhodopsins (Matsuno-Yagi and Mukohata, 1977) and channelrhodopsins (Nagel et al., 2002) that transport Crizotinib datasheet various ions across the membrane in response to light (Matsuno-Yagi and Mukohata, 1977, Lanyi and Oesterhelt, 1982, Schobert and Lanyi, 1982, Béjà et al., 2000, Nagel et al., 2002, Nagel et al., 2003,

Ritter et al., 2008 and Zhang et al., 2008). It took decades for these two concepts to be brought together by neuroscientists,

although microbial opsin genes were widely known and had long been understood to give rise to single-component light-activated regulators of transmembrane ion conductance. But there were fundamental caveats for those who considered such a possibility for optical neural control over the decades, including the presumption that photocurrents would be too weak and slow to control neurons efficiently, the presumption that microbial membrane proteins in fragile mammalian neurons would be poorly expressed or toxic, and most importantly the presumption that additional cofactors such as all-trans retinal (the separate organic light-absorbing chromophore employed by microbial Bay 11-7085 opsins) would have to be added to any intact-tissue experimental system. These preconceptions (strikingly similar to those that slowed the development of green fluorescent protein) were all reasonable enough to deter experimental implementation, and efforts were therefore focused elsewhere. Yet in the summer of 2005 it was reported that introduction of a single-component microbial opsin gene into mammalian neurons (without any previously tested or other component) resulted in reliable sustained control of millisecond-precision action potentials ( Boyden et al., 2005); many additional papers from work conducted contemporaneously appeared over the next year ( Li et al., 2005, Nagel et al.