domingo, 23 de junio de 2013

Optogenetics: Lighting Up the Brain

ORIGINAL: OxBridgeBiotech
Friday, 21st June 2013

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As a child, the year 2000 seemed utterly distant and futuristic to me. The realization that I would likely live to see it filled me with awe. Surely, in the coming age we would have flying cars, personal jetpacks, and teleportation!

A dozen years into the new millennium, I am still waiting for my jetpack. But some of the technologies that I encounter as a scientist make me think that perhaps my childhood visions were not that far off after all. Take optogenetics – a revolutionary technique that would have sounded like something straight out of science fiction not too long ago.

As its name suggests, optogenetics combines tools from optics and genetics; the result is the awe-inspiring ability to control brain cell activity using light. While the “cool” factor is undeniable, optogenetics was developed to address very practical problems. To figure out how neurons, the nerve cells that make up our brain, influence various biological functions and diseases, it is not enough just to observe their activity during certain behaviors or illnesses. After all, while it is possible that a given neuronal activity caused a behavior, it could just as easily be that the behavior caused the neurons’ firing pattern, or that some third factor independently caused both – correlation does not prove causation, as the saying goes. However, if researchers can directly trigger a certain neuronal firing pattern, and it always produces a given behavior, they can conclude with much greater confidence that the neuronal activity indeed contributes to the behaviour.

Previous approaches to controlling neuron activity all had significant limitations. Inserting electrodes into the brain allows researchers to stimulate neurons directly. However, there are a wide variety of different types of neurons, often tightly intermingled in a given brain region. Zapping an area of the brain with an electrode will stimulate all of the different neuron types in the vicinity, making it difficult to untangle which of them actually produced the observed effects. Alternatively, researchers can chemically stimulate neurons with drugs targeted at specific neuron types. However, the effects of drugs stretch over minutes or even hours – eternities compared to the rhythms of neuron signals, which last for milliseconds.

Photo: Stanford, Karl Deisseroth's Lab
Enter optogenetics. 
While early forms of optogenetics made use of a range of light-sensitive molecules, modern incarnations mainly rely on so-called ‘channel rhodopsins’ (ChRs), a type of ion channel. Ion channels sit on the cell membrane surrounding the neuron and allow certain kinds of electrically charged particles – ions – to enter or leave the cell. By doing so, they can alter the neuron’s electrical charge, which in turn can trigger the neuron to fire. In contrast to most ion channels, which open and close in response to chemical signals, ChRs open in response to light. If ChRs are inserted into the membrane of a neuron, the neuron can then be prompted to fire by shining light onto it. Researchers can use various genetic tools to ensure that only a specific neuron type is “enhanced” with ChRs. For example, they can insert the ChR gene behind a promoter (a kind of genetic “on switch”) that is only activated in the neuron of interest, or they can use selective viruses to “smuggle” the ChR genetic material into specific neuron types. With computer-generated rapid light flashes, researchers can then control the activity of only their selected neuron type down to a few milliseconds.

If that is not exciting enough, different ChRs respond to different wavelengths of light. Thanks to both naturally occurring varieties and bioengineered manipulations, researchers now have a toolbox of different ChRs that open only in response to, say, blue, green, or yellow light. Moreover, similar molecules called ion pumps can be used to silence neurons instead of stimulating them. By inserting the right ChRs and light-sensitive ion pumps into specific neuron types, a researcher can, for example, create a situation in which blue light stimulates all neurons of type A while keeping all neurons of type B from firing, whereas yellow light causes all type B neurons to fire while silencing all type A neurons.

With a neuron grown inside a cell culture dish, experimenters can simply shine the light directly onto the dish. In the case of live organisms, more sophisticated hardware is needed. Thin optical fibers can be inserted into the relevant brain area to conduct light to the neurons being studied. Often, these fibers are connected to an external light source by a cable; the animal is therefore “leashed” during the study, although it still has some freedom of movement. More recently, using miniature LEDs (light-emitting diodes) and batteries, researchers have constructed small, self-contained light sources that can be attached to the animal and allow completely free motion. Optical, chemical or electrical sensors may also be inserted into the same area to allow measurement of neuron activity and how it is changed by light stimulation.

Using optogenetics, neuroscientists have been able to show conclusively that the activity of specific neurons can produce certain behaviors. For example, when experimenters in Karl Deisseroth’s lab at Stanford made a type of “reward” neurons fire rapidly using optogenetics whenever animals were placed in a certain environment, these animals began to prefer this environment over others. And simply activating these neurons was not enough – the pattern of signals mattered. When the same neurons were made to fire more slowly, the effect disappeared. Similar studies have helped scientists to further unravel the mechanisms underlying brain disorders like Parkinson’s disease, addiction, and depression. In the future, optogenetics may even yield new treatments for these diseases. Of course, many obstacles remain before optogenetics can be used in humans. Safe ways to insert ChRs into human neurons would be needed, along with less invasive methods of delivering light pulses into relevant brain regions. Nonetheless, at least one biotechnology company, Circuit Therapeutics, is focusing on the development of optogenetic therapies.

Controlling the brain with light. It’s no personal jetpack, but it does make me feel like I am already living in the future.

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