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The Past, Present and Future of Light-Gated Ion Channels and Optogenetics

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The Past, Present and Future of Light-Gated Ion Channels and Optogenetics FEATURE ARTICLE 2018 GAIRDNER AWARDS The past, present and future of light-gated ion channels and optogenetics Abstract The discovery of the mechanisms underlying light-gated ion channels called channelrhodospins and the subsequent development of optogenetics illustrates how breakthroughs in science and technology can span multiple levels of scientific inquiry. Our knowledge of how channelrhodopsins work emerged from research at the microscopic level that investigated the structure and function of algal proteins. Optogenetics, on the other hand, exploits the power of channelrhodospins and similar proteins to investigate phenomena at the supra-macroscopic level, notably the neural circuits involved in animal behavior that may be relevant for understanding neuropsychiatric disease. This article is being published to celebrate Peter Hegemann, Karl Deisseroth and Ed Boyden receiving a 2018 Canada Gairdner International Award "for the discovery of light-gated ion channel mechanisms, and for the discovery of optogenetics, a technology that has revolutionized neuroscience". SHEENA A JOSSELYN The award, part I: Light-gated ion encoding a cation channel, by Hegemann (then channels at the University of Regensburg) and co-workers icrobial opsin genes encode light-sen- in 2002 (Nagel et al., 2002). Although the back- M sitive proteins that are found mostly bone of the channelrhodopsin protein is a famil- in archaea and bacteria. Examples iar 7-transmembrane structure common to many include bacteriorhodopsins (which are proton proteins (including the G-protein coupled recep- pumps), halorhodopsins (ion pumps) and chan- tor family of proteins that is targeted by many nelrhodopsins (ion channels). Channelrhodospins drugs), channelrhodospins are distinct in their are unique in that they are the only class of light- ability to conduct particular ions in response to activated ion channels identified in biology to certain colors of light, all within milliseconds. date. They are also the foundations on which the Precisely how channelrhodopsin accomplished research that is being recognized by one of the this remarkable feat became a biological 2018 Canada Gairdner International Awards was mystery. built. Over the next fifteen years or so, Hegemann Over many years, Peter Hegemann and col- (who moved to Humboldt University in Berlin in leagues studied the behavior of the single-celled 2004), Karl Deisseroth (Stanford University) and green alga Chlamydomonas. These algae alter colleagues uncovered the functional operating the direction in which they swim in response to principles of channelrhodopsin, down to the flashes of light. Based on the fast time course of level of determining the individual amino acids this phototactic response, Hegemann hypothe- that regulate ion flow, gating kinetics and color sized the presence of a single protein with two selectivity (Deisseroth and Hegemann, 2017). Copyright Josselyn. This article is key components (one to ’sense’ the light, and The high-resolution crystal structures of the cat- distributed under the terms of the one to ’respond’ to the light by initiating an ion-conducting channelrhodopsins were solved Creative Commons Attribution electrical signal that leads to a change in the earlier this decade (Kato et al., 2012), and the License, which permits unrestricted direction they are swimming). This work culmi- structures of anion-conducting channelrhodop- use and redistribution provided that the original author and source are nated in the molecular and functional identifica- sins have just been solved (Kim et al., 2018; credited. tion of the first channelrhodopsin gene, Kato et al., 2018). Josselyn. eLife 2018;7:e42367. DOI: https://doi.org/10.7554/eLife.42367 1 of 5 Feature article 2018 Gairdner Awards The past, present and future of light-gated ion channels and optogenetics The development of optogenetics animals. The development of opsins for neuronal silencing rounded out the optogenetics toolbox cleanly splits neuroscience, and (Han and Boyden, 2007; Zhang et al., 2007; many other branches of science, Chow et al., 2010; Gradinaru et al., 2010). Optogenetics allows scientists to achieve precise into pre- and post-optogenetic eras. temporal control over the activity of defined populations of cells in the brain of a behaving animal, and thus probe the circuits mediating both brain function and dysfunction. These structural insights also enabled a series The development of optogenetics cleanly of further advances: examples include engi- splits neuroscience, and many other branches of neered channelrhodopsins that respond to light science, into pre- and post-optogenetic eras. As faster than wildtype channelrhodopsins with any new technique, the first findings using (Gunaydin et al., 2010); channelrhodopsins that optogenetics were simply confirmatory. But, as act as bi-stable switches (Berndt et al., 2009); scientists grew past the ’gee whiz’ factor and channelrhodopsins that are activated by differ- became more adept at designing experiments ent wavelengths of light (Zhang et al., 2008; that fully exploited this new way of investigating Yizhar et al., 2011); and channelrhodopsin- brain function, novel – and perhaps previously based chloride channels (Berndt et al., 2014; unknowable – insights began to emerge. Wietek et al., 2014). This series of fundamental Among the many notable scientific insights scientific discoveries examining how channelrho- enabled by optogenetics, I would include: dopsins (and related proteins) respond to light . Uncovering how complex behavioral states with such speed and precision also led to a new (such as anxiety) arise from individual state experimental tool, optogenetics, that could be features (including changes in respiration used to control the activity of selected cells and risk-avoidance behavior), and the deep within systems as complex as the mamma- brain circuit components underlying these lian brain with extraordinary temporal and spa- states (Kim et al., 2013). Optogenetics, tial precision. As the prize citation notes: for the first time, enabled the independent "optogenetics is a technology that has revolu- manipulation of the activity of different tionized the field of neuroscience". output projections originating from the same brain region, thereby allowing com- plex behavioral states to be dissected into The award, part II: Optogenetics component features and mapped across Understanding the brain has been described as the brain. one of the final frontiers of science. Of course, Identifying the long-sought cell ensembles there was significant progress towards this goal (engrams) underlying memory (Liu et al., 2012), and taking advantage of optoge- before optogenetics entered the scientific lexi- netic actuators to both increase and con. But a step change in the type of scientific decrease activity in the same neurons to questions that could be asked, and the practical discover how these ensembles control the ways in which many scientists conduct research, separation or integration of individual can be traced back to a single paper from Dei- memories (Rashid et al., 2016). sseroth’s lab in which he and co-workers – Ed . Illuminating the cell ensembles that sup- Boyden, Feng Zhang (who shared the 2016 Can- port basic survival drives and control the ada Gairdner International Award for his work most fundamental functions (for example, on CRISPR-Cas and genome editing), hunger, thirst, energy balance, respiration, along with Ernst Bamberg and Georg Nagel – arousal, sleep, circadian rhythm). These cir- reported that the activity of neurons in a dish cuits contained cell types with diverse (even opposite) functional roles and there- expressing channelrhodopsin could be driven by fore required the power of optogenetics simply shining a light (Boyden et al., 2005). to resolve them (beginning with Subsequent papers described the develop- Adamantidis et al., 2007). ment of other, equally important, optogenetic . Determining specific cells and neural path- components – tools for targeting opsins ways controlling normal and abnormal (Tsai et al., 2009) and light (Adamantidis et al., motor action patterns. A long-standing 2007) to circuit elements of interest in behaving question in movement initiation was Josselyn. eLife 2018;7:e42367. DOI: https://doi.org/10.7554/eLife.42367 2 of 5 Feature article 2018 Gairdner Awards The past, present and future of light-gated ion channels and optogenetics answered with optogenetic experiments neuromodulators, intracellular signaling and which revealed the differential roles of other brain molecules. intermixed striatal direct vs. indirect path- Optogenetics ushered in an era of neurosci- ways (Kravitz et al., 2010). In addition to ence in which neuronal circuits became the new increasing our understanding of adaptive basic unit of inquiry. In many ways, the ’optoge- movement regulation, this insight also has netic revolution’ echoed, and perhaps to some clinical relevance for Parkinsonism and extent eclipsed, an earlier revolution in molecu- related disorders. Discovering the essential circuit basis of lar neuroscience. Further evolution of neurosci- reward; with optogenetics, bursts of activ- ence as field, though, may demand the seamless ity in midbrain dopamine neurons were integration of these two pillars. The develop- finally and formally shown to constitute a ment of artificial light-inducible molecules is one reward signal, beginning with relatively way to increase interactions between the circuit simple Pavlovian conditioning
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