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For years, neuroscientists have been fixated on understanding how behavior and cognition arise from neural circuit activity.

To begin investigating these questions, scientists originally employed slow pharmacological and imprecise electrical stimulation techniques to control neuron activity. However, with different classes of neurons communicating through vast, complex networks and fast electrical signals, it is essential to identify a method with both high spatial and high temporal resolution to precisely control select neurons and to causally decode the function of neural circuit activity.

In 1979, Francis Crick proposed a novel solution: use light to control neuron (1). Derived from this very idea and with the effort from many other scientists, the revolutionary technique optogenetics was born.

Optogenetics, a genetic method to turn select neurons on or off with light, was invented in 2005 by Karl Deisseroth and Edward Boyden (1). Notably, their development of optogenetics began with the discovery by Peter Hegemann, who successfully expressed the blue light-depolarizing opsin, channelrhodopsin-2 (ChR2), in cell culture (2).

Expanding upon these findings, Deisseroth and Boyden virally expressed ChR2 in neurons, and miraculously, they demonstrated for the first time that neurons could be activated using blue light (1).

With millisecond precision, optogenetics enabled the fast control of neuronal spiking. As a technique using both optics and genetics, the term opto-genetics was coined from their extraordinary findings.

Optogenetic-expressing cells (in blue) are activated by blue light illumination.

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How Does Optogenetics Work?

Optogenetics has been possible through the discovery of opsins, such as ChR2. Opsins are light sensitive channels that cause depolarization or hyperpolarization of the cell through mechanisms such as the influx of ions or protein signaling cascades (3). Opsins are sensitive to specific wavelengths of light.

For example, blue light (~470 nm) activates ChR2, leading to an influx of Na+ ions in turn depolarizing the neuron (1). Viral expression has enabled researchers to express optogenetic opsins in the brain of animals, such as rodents.

Multi-disciplinary collaborations between neuroscientists, biologists, and engineers have led to the expansion of the optogenetic toolbox. Opsins have been discovered for manipulating neurons on or off at varying speeds and with different wavelengths of light (see Table 1).

For example, Halorhdopsin, an inhibitory opsin, was found to turn off neurons, and red-activated opsins, such as JAWS, were developed to penetrate deeper in the brain (3). Furthermore, viral strategies for expressing optogenetic proteins in the brain have advanced, enabling scientists to manipulate the activity of specific cell classes to explore brain-wide projections (3).

Optogenetic ConstructExcitation WavelengthFunction
ChR2470nmActivation
GtACR2470nmInhibition
ArchT540nmInhibition
C1v1560nmActivation
NpHr590nmInhibition
bReaChES590nmActivation
Chrimson590nmActivation
ReaChR620nmActivation
JAWS620nmInhibition

What are the Applications of Optogenetic Stimulation?

Optogenetics has benefited many scientific fields by allowing scientists to control the activity of different cell-types with millisecond precision.

In neuroscience, optogenetics has enabled scientists to causally link neural circuits, behaviour, and function (3). In addition, optogenetics can be performed in both in vitro experiments with electrophysiology, or in a behaving animal to investigate the link between cell-types and behaviour. Of great benefit to neuroscientists, the use of optogenetics has been adapted for use in rodents, primates, C.elegans, drosophila, and zebrafish to study the neural correlates of cognition and behavior.

As a precise method to control cellular activity, optogenetics has impacted scientific fields beyond neuroscience, with recent contributions to cell biology and cardiac research (4,5).

From a clinical perspective, the application of optogenetics has begun to be used for exploring vision restoration and deep-brain stimulation in motor diseases (6).

With a causal method to meticulously analyze the function of neuron activity in real-time, optogenetics has advanced our understanding of the brain and may one day have significant clinical implications.

An example demonstrating the use of optogenetics in slice electrophysiology.

Next Post

What Equipment Do You Need to Perform Optogenetics?

References

  1. Boyden E et al. (2005). Millisecond-Timescale, Genetically Targeted Optical Control of Neural Activity. Nature Neuroscience, 8, 1263-1268.
  2. Nagel G et al. (2003). Channelrhodopsin-2, a Directly Light-Gated Cation-Selective Membrane Channel. PNAS, 100(24), 13940-13945.
  3. Kim KK, Adhikari A, & Deisseroth K. (2017). Integration of Optogenetics With Complementary Methodologies in Systems Neuroscience. Nature Reviews Neuroscience, 18(4), 222-235.
  4. Repina NA et al. (2017). At Light Speed: Advances in Optogenetic Systems for Regulating Cell Signaling and Behavior. Annual Review of Chemical and Biomolecular Engineering, 8, 13-39.
  5. Ferenczi EA, Tan X, & Huang CLH. (2019). Principles of Optogenetic Methods and Their Application to Cardiac Experimental Systems. Frontiers in Physiology.
  6. Towne C & Thompson KR. (2016). Overview on Research and Clinical Applications of Optogenetics. Current Protocols in Pharmacology, 75(1).

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