Nancy Huang

Dec 22nd 2021

Optogenetics Is Illuminating How the Brain Works

Optogenetics is technology that combines genetics and optics, allowing researchers to control the activity of genetically modified neurons with pulses of light. This amazing technology doesn’t just work on cells in a petri dish but can also control the activity of laboratory animals, including nematode worms, fruit flies and mice.

While this may sound like a horrible brain control experiment inspired by Frankenstein, the main purpose is to better understand how the brain works. Optogenetics has given us a better understanding of how dysfunction in the brain can lead to disorders such as addiction, depression, Parkinson’s disease and obsessive-compulsive disorder.

Nature Methods named optogenetics the Method of the Year in 2010 and produced a Nature Video that shows a mouse, fly and worm being controlled with pulses of light.

How It Started

The idea of activating individual neurons to understand their function was first proposed in 1979 by Nobel laureate Francis Crick, as a Scientific American article on the history of optogenetics explains.

Existing methods for neuroscience involved using electrodes to stimulate different parts of the brain, which is a crude way to understand such a complex organ. The human brain includes perhaps 100 billion neurons, which can each connect with thousands of other neurons. The mouse brain includes hundreds of millions of neurons, and the nematode worm has about 300 neurons.

A major step toward the goal of understanding individual neurons occurred in 2002, with the discovery of a light-sensitive ion channel in green algae. The protein was named channelrhodopsin. It sits in the cell membrane and is in contact with the inside and outside of the cell. When exposed to blue light, channelrhodopsin changes shape and opens within milliseconds, allowing ions like sodium to flow into the cell.

A similar mechanism is required for any neuron to fire and transmit signals from one cell to another. What made channelrhodopsin so unique was that a single protein could detect light and control ion flow. In most cells, this process requires multiple proteins.

The Floodgates Open

The dream of controlling individual neurons with light was first achieved in 2005 and published in Nature Neuroscience. Researchers took the channelrhodopsin gene and attached a sequence that would cause the protein to be produced in mouse cells. The whole thing was packaged inside a virus, which was used to infect mouse neurons in a Petri dish.

To the astonishment of the research community, this simple strategy worked surprisingly well. The resulting neurons fired in response to pulses of blue light, stopped firing when the blue light went away and fired again when the blue light reappeared. The neurons remained responsive to blue light for weeks after they were initially infected.

This discovery resulted in a flurry of new activity, with scientists applying knowledge from decades of basic research on manipulating and sequencing DNA, understanding how proteins work, and learning how to turn genes on and off in specific cells. Neuroscientists were soon using channelrhodopsin to better understand how specific types of neurons work in worms, flies, fish, mice, rats and primates.

Lasers or light-emitting diodes (LEDs) provided light that could be precisely controlled. Lasers were coupled to optical fibers, which were implanted into mice or rats that could then move freely inside an enclosure. Brain control of laboratory animals had become a reality.

Variations on a Theme

Proteins are molecular machines, so scientists almost immediately sought modified versions of channelrhodopsin to better suit different experimental needs. As described in a 2014 Nature Methods publication, 61 new channelrhodopsins were identified by sequencing 127 species of algae. These included a channelrhodopsin that responds to red light instead of blue light, which allows two different populations of neurons to be activated at different times in the same experiment.

Evolution and genetic engineering have produced channelrhodopsins that respond quickly or slowly, that cause or prevent neurons from firing, and that activate or inhibit different pathways in the cell. These tools are being used to develop a deeper understanding of how the brain works and how the activity of specific brain cells can give rise to thoughts, feelings and memories.

Beyond the Brain and Beyond the Lab

Research using optogenetics has extended beyond the brain, with one promising area being cardiac research, as described in Frontiers in Bioengineering and Biotechnology. Proper functioning of the heart requires neurons in the pacemaker to fire with precise timing and muscle cells to contract in response. Irregularities in timing are called arrhythmias and can be deadly. Current treatment options include implantable pacemakers and defibrillators, which can damage surrounding tissue and be painful.

Scientists imagine that optogenetic technology might eventually provide a safer, more effective way of managing arrhythmias. There are similar hopes for treating Parkinson’s disease, which in some patients is managed with deep brain stimulation. Optogenetic advances might also help patients with paralysis, certain types of blindness and constant pain.

In the meantime, optogenetics is being used to better understand disorders in laboratory animals and to accelerate preclinical testing of potential new drugs. When cells in a petri dish can respond to flashes of light, side effects become easier to detect. As time goes on, this technology will only continue to further our understanding of the brain and the way we treat certain conditions.

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