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Essay

Understanding the brain is a daunting challenge. Each of the many billions of nerve cells in the human brain may make thousands of contacts with other neurons, resulting in an astronomical number of synaptic connections. The tools that allow us to trace and regulate neural networks in experimental animals have emerged in recent years thanks to the discoveries of our Shaw Life Science Awardees for 2020: Gero Miesenböck of Oxford University, Peter Hegemann of Humboldt University, Berlin, and Georg Nagel of the University of Würzburg.

 

Neuroscientists had long sought methods to control the activity of individual nerve cells in order to understand the networks in which they communicate and define the processes they control. Direct activation of nerve cells by physical or chemical means had been used for over two centuries, but the dream had been to modify nerve cells genetically so that electrical signals could be induced or suppressed remotely, allowing a less invasive and more precise means of controlling the function of neural networks in an intact organism. The first key breakthrough came in 2002 with the development of an optogenetic tool devised by Gero Miesenböck. Using a naturally light-responsive protein, rhodopsin, which serves as the pigment on which we rely for vision, his team inserted the Drosophila (fruitfly) genes necessary to express the light-responsive rhodopsin into a vertebrate nerve cell culture. As a result, cells in the culture showed patterns of neuronal activity elicited by light. Building on this initial finding, Miesenböck was the first to show that this approach could be applied to an intact animal, and that by optically activating particular circuits one could alter specific behaviours of the animal. His subsequent studies of sexually dimorphic behaviour, the neural basis of reinforcement, and the regulation and function of sleep demonstrated the full potential of optogenetics beyond the proof-of-principle stage. In his first report Miesenböck concluded that “Since sensitivity to light is built into each target neuron, advance knowledge of its spatial coordinates is unnecessary. Large numbers of neurons can be addressed simultaneously and precisely, without undesirable cross-talk to neighbouring cells that are functionally distinct”. Miesenböck’s approach represented the first chapter in the new era of optogenetics.

 

In the application of this approach to animals, the fruitfly rhodopsin had certain technical disadvantages in terms of speed of response to light and genetic simplicity. Fortunately, soon after Miesenböck’s work a simpler photo-responsive channel protein emerged from studies on the detection of light by an alga, Chlamydomonas. Rhodopsins had been discovered in certain archaeal microorganisms, but the speedy phototactic and photoelectrical response of the algal rhodopsin suggested that a single receptor protein may be sufficient to elicit a change in membrane current. In early work published in 1991, Peter Hegemann discovered the rhodopsin-based photocurrent in Chlamydomonas. After years of further work on this light response, Hegemann teamed up with Georg Nagel, who had since 1995 characterized microbial rhodopsins in heterologous expression systems and measured the first photocurrents of bacteriorhodopsin, a light-activated proton pump, in vertebrate cells. In two papers published in 2002 and 2003, they demonstrated by expression in oocytes that the two discovered Chlamydomonas rhodopsins are light-responsive channel proteins that unify light sensing and channel functions. They named these proteins Channelrhodopsins, ChR1 and ChR2. Crucially, Nagel discovered that ChR2 elicits an extremely fast, light-induced change in membrane current when expressed in oocytes or cultured human cells. These discoveries represented the second major step in the development of optogenetics. Hegemann and Nagel characterized ChRs in molecular detail by a wide range of biophysical techniques. The many mutants they and their colleagues generated led to the deciphering of the channel mechanism, including gating and ion selection.

 

The discovery of ChRs by Hegemann and Nagel has enabled various functional applications in a variety of cells and tissues. In 2005/2006, five teams independently showed the power of ChR2 for light activation of neurons: Deisseroth, Boyden, and Nagel and, a few months later, Herlitze, Landmesser, and Hegemann as well as Ishizuka and Yawo. In parallel, Nagel and Gottschalk demonstrated the optical modulation of C. elegans behaviour, and the team of Huo-Zhuo Pan restored vision in blind mice.

 

As a result of these foundational, basic science discoveries, we now have the tools needed to precisely control specific neural networks in the brain. These discoveries presage a golden age of exploration of the mysteries of cognition and emotion, with potential applications in psychiatry disorders that are only now being defined at the level of genes and cells.

 

 

20 May 2021   Hong Kong