Using Light to Manipulate Thoughts

The video below is exactly what it looks like: a pulse of light is being delivered directly into the mouse’s brain — its motor cortex — and forcing it to turn left. When the light turns off, the mouse returns back to its normal behavior. You’ve now seen first-hand what the emerging branch of science, termed optogenetics, is capable of doing.

A little under 60 years ago, Watson and Crick revolutionized biology and discovered the double-helical structure of a DNA molecule. A little under 45 years ago, Neil Armstrong imprinted the first foot-stamp for mankind on lunar dust. All this happened while the Beatles rocked out of Liverpool and onto the world’s music stage. Has our generation seen anything close to such game-changing revolutions? According to David Brooks, whom fellow blogger Alex Beradino dismantles whole-heartedly here, the answer is no.

I whole-heartedly disagree with DB (heh), and here’s one riveting example why Brooks misses the mark. More than 30,000 brain enthusiasts attended this past November to see what more than 16,000 researchers had to present at the Society for Neuroscience’s annual meeting in San Diego. For all the exciting science going on in laboratories world-wide, at center stage was a field that is hardly even a decade old: optogenetics, the discipline concerned with modulating neuronal activity with light.

As a brief reminder: neurons are surrounded in a kind of fluid that contains all sorts of charged molecules, many of them positively charged. Each neuron contains pores that can selectively let in or push out one or more of these molecules. When these pores open, positively charged molecules can flow into the neuron (“depolarizing” it) and charge it up so that it may spit out biochemical information to cells further down the line. In short, neurons encode and relay information by responding to external chemical signals, transforming this into an electrical signal within the neuron, and conveying this information to adjacent neurons either by chemical or electrical means.

If we can control when these pores open, then we can control when a neuron fires, and thus when it conveys information. This works in the other direction too: if we can shut these pores or allow only certain pores to open, then we can also shut down a neuron’s activity. Finally, if we can control this repeatedly over time (i.e. the neuron’s firing frequency), then we can now control the information that the neuron conveys.

Optogenetics does just this on the timescale at which neurons communicate — milliseconds. It requires, of course, a light source, which has been achieved by coupling fiber optic technology with cells that are genetically engineered to respond to light. That is what you see in the video above.

The speed at which optogenetics has developed as a field is staggering. In 2002, University of Oxford physiologist Gero Miesenböck developed a way to genetically engineer genes that encode for light-sensitive proteins, which ultimately integrated themselves into the membranes of neurons. In just 3 years, they were able to change the behavior of fruit flies with light.

In 2005, a team lead by Stanford’s Karl Deisseroth, along with his students Ed Boyden and Feng Zhang (both now at MIT), one-upped this technology. They combined a family of proteins termed opsins — light-sensitive proteins originally from green algae, which use opsins to move towards or away from light — with a virus that will integrate itself into a mammalian cell’s genome. (Here’s a great primer from Deisseroth.) These opsins can be engineered to mimic one of the abovementioned “pores” so as to selectively permit certain charged molecules into or out of a cell. The result is the ability to activate or inactivate neurons on a millisecond timescale with light.

Before neurons could be controlled on a millisecond timescale in a live organism, older manipulations took on the order of seconds to hours to weeks. This temporal improvement is nothing short of astonishing. We used to probe the brain at 56K; we can now modulate neuronal activity with high-speed cable.

Not surprisingly, in 2010, optogenetics was voted “Method of the Year” by Nature. 600+ labs are now using optogenetics. Rutgers University neurophysiologist György Buzsáki proclaims, “[Optogenetics] is a fantastic revolution. If [Deisseroth] doesn’t do anything else, if he just sits in his office, he will get a Nobel Prize–there is no question in my mind.”

Think about the possibilities. Parkinson’s, schizophrenia, obsessive compulsive disorder, epilepsy, to name a few, are only part of a growing list of neurodegenerative disorders characterized at least partly by too much or too little neural activity. Coupling fiber optic technology with nifty genetic engineering gives us a tool to directly modulate any brain area, or even any area outside the nervous system too, for that matter. Here’s a recent article on how light stimulation of the frontal cortex mimics anti-depressant effects.

In another experiment, neurons were once again genetically tricked to respond to light. These neurons are located in the amygdala, a teardrop-shaped structure that is thought to be involved in regulating states of anxiety. Optical stimulation caused for the light-sensitive protein called channelrhodopsin-2 to open up along the surface of the cell. This opening permitted for an influx of molecules that then caused a specified population of amygdala neurons to turn on. Remarkably, by turning only these brain cells on or off, the authors were able to reversibly increase or decrease anxiety states in their subjects.

The field is indeed promising, but it should not be overlooked that it does require substantial expertise. Lowering one or more optic fibers in a live animal’s brain, coupled with sensitive laser equipment, is no trivial task. Keeping the fiber from overheating after extensive pulses of light, too, is still a problem since no one wants a deep-fried hippocampus. Finally, using this technique is only as powerful as the question being answered — some questions in neuroscience simply do not require millisecond precision. Many, however, do, and for these optogenetics provides unparalleled spatial and temporal resolution.

Modulating neural activity with light gives us one of the most powerful methods to perturb the flow of information in the brain. It is the most convincing method I can think of to demonstrate a neuron’s causal role in producing all aspects of cognition, from an algae’s movements towards or away from light to the stuff that comprises human thoughts. Optogenetics confers millisecond control over turning parts of the brain on (“gain of function” experiments) and turning them off (“loss of function” experiments). And, these two experiments are the gold standard in science in order to claim causality, which finally is a realistic claim that modern neuroscience can be proud of.

It may not be the Beatles, but it’s sorta bloody brilliant since, if the ball don’t lie, and if the hips really don’t lie, then the data sure as heck don’t lie.


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