Optogenetics is a tool that combines optical and genetic methods to manipulate neural networks in vivo. Optogenetics is used to study behavior, physiology and pathology in animals such as rats, mice and zebrafish and for studying neural circuit foundations of behavior in invertebrates such as nematode and fruit fly. In optogenetics light-activated transmembrane proteins called opsins are manipulated using light in order to control target cell populations. Targeting opsins, which are the optogenetic actuators, to specific neural cells is done using virus-based transfection or through the generation of transgenic animal lines that express opsins in cell specific manner. Typically light is delivered through an optical fiber inserted with stereotactic guidance.
Opsins function as light-activated ion pumps, light-gated ion channels and G-protein coupled receptors and are grouped into superfamilies type I (derived from microbes) or type II (derived from animals). Channelrhodopsin-2 (ChR-2), an algal protein from Chlamydomonas reinhardtii is a light-activated cation channel. When transfected into neurons and expressed on the cell membrane, these proteins allow for optical control of the polarization of the neuron's cell membrane. For instance, neurons expressing ChR-2 will depolarize when exposed to blue light and activate synaptic events. Inhibitory opsins such as halorhodopsins are a class of inward chloride pumps. By using light to induce them to pump chloride into a cells, halorhodopsins are used to hyperpolarize neurons to mediate rapid and reversible silencing of neuronal activities. Engineering of color-tuned chimeras allows different light wavelengths to be applied to the same neuronal circuit for multimodal manipulation.
Microbial opsin genes encode microbial rhodopsin proteins, which are functionally distinct and not related in primary sequence to the rhodopsins in the vertebrate eye that mediate phototransduction. Whereas vertebrate rhodopsins couple intracellular second-messenger cascades to indirectly influence ion channels, microbial rhodopsins directly transduce photons into electrical current. Bacteriorhodopsins, halorhodopsins and channelrhodopsins are microbial rhodopsins used in optogenetics. Bacteriorhodopsins pump protons out of the cell and halorhodopsins pump chloride ions into the cell and both are normally inhibitory in neural systems because they cause hyperpolarizing current that makes it harder for neurons to fire action potentials. The naturally occurring channelrhodopsins are depolarizing and excitatory as they allow positively charged ions to flow through the opsin pore. Inhibitory chloride-conducting channels were engineered in 2014 and a natural chloride-conducting channelrhodopsin was discovered in 2015.
Next-Generation Optical Technologies for Illuminating Genetically Targeted Brain Circuits
Karl Deisseroth, Guoping Feng, Ania K. Majewska, Gero Miesenböck, Alice Ting and Mark J. Schnitzer
Journal of Neuroscience 11 October 2006, 26 (41) 10380-10386; DOI: https://doi.org/10.1523/JNEUROSCI.3863-06.2006
ChR2 was activated with pulses of light to mediate defined trains of spikes or synaptic events at the millisecond-timescale temporal resolution.
Millisecond-timescale, genetically targeted optical control of neural activity
Nat Neurosci 8, 1263–1268 (2005)
Stanford University, Max-Planck-Institute of Biophysics
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