Optogenetics offers cell type-specific activation of neurones for treatment of neural disorders
Developed in large part as a treatment for psychiatric illness, optogenetics is a method of turning neurons on and off with millisecond resolution by activation of light-sensitive proteins with specific wavelengths of light. The light-sensitive proteins, called opsins, are genetically encoded ion channels embedded in a neuron’s outer surface that essentially convert light into changes in the electrical potential across the neuron’s membrane; sufficient positive changes trigger individual action potentials or ‘spikes’, whereas sufficient negative changes prevent spikes from occurring.
Individual brain functions are thought to be controlled by distinct populations of neurons, motivating neuroscientists interested in modifying brain function to develop tools to selectively activate specific neural populations. Though electrical stimulation of neural tissue has been possible for decades, it is difficult to control the spatial spread of the stimulation; even modest electrical current activates hundreds to thousands of neurons. More importantly, the diffuse nature of this type of stimulation makes it impossible to produce cell-type specific neural activation, possibly leading to unwanted side effects.
Optogenetic tools, on the other hand, can target specific cell types (e.g., only cells that express a certain type of protein), providing detailed information about their functions. Also, the ability to control the firing of specific populations of neurons within well-described neural circuits with laser light can lead to therapies for many types of perceptual,movement, and affect disorders. These therapies can work because, often, the disorders they treat are caused by deficiencies in a single cell type, which can be selectively targeted with optogenetics. For example, some forms of blindness that are caused by degeneration of the eye’s photoreceptors can be treated by opsin-mediated light activation of bipolar cells, a type of neuron immediately downstream from photoreceptors that transmits visual information to the brain.
Who, Where, and When?
Stanford University neuroscientist Karl Deisseroth, who is also a practicing psychiatrist, has been working to develop optogenetics in mammals since 2005. He initially conceived the technology as a way to selectively manipulate specific populations of cells that have been implicated in a number of psychiatric disorders like depression and addiction.
Deisseroth has shared his optogenetic tools, which have been successfully used in monkeys, mice, rats, zebrafish, worms and fruitflies, with hundreds of labs around the world. Two former students of Deisseroth’s, Ed Boyden and Feng Zhang, have contributed significantly to the technological advancement of optogenetics at their own labs at MIT.
Alexander Gottschalk of Goethe University has also been developing optogenetic tools since 2005, recently demonstrating a multimodal illumination system that can both track the behavior of ‘freely’ moving worms and direct the worms’ movements via light-activated control of motor neurons.
Peter Hegemann of Humboldt-Universitat has made important modifications to opsin molecules to greatly expand their functionality, giving researchers finer control over the timing of light-driven neural activation.,
Genes controlling the production of opsins in microorganisms, such as green algae, can be introduced to brain tissue by direct injection of a virus into which the opsin gene and a promoter have been spliced. The promoter ensures that only specific kinds of neurons will express the opsin protein. More recently, a transgenic line of mice that endogenously express opsin genes has been developed.
Light of a specific wavelength activates the opsin, opening its internal ion channel and leading to rapid fluxes of ions into or out of the cell and either the activation (via channelrhodopsins) or inhibition (via halorhodopsins and bacteriorhodopsins) of the neuron. Molecular modifications to these opsins, as well as the discovery of additional opsins in the natural world, are giving researchers the option to control the activity of mixed populations of neurons (for example, via two types of channelrhodopsin – one activated by blue light and the other by yellow light), control the timing and duration of action potentials (via “fast”\cite and “slow” channelrhodopsin mutants), and even control biochemical events within specific cells.
Implanted LEDs can be used to activate neurons close to the surface of the brain, whereas fiberoptic-coupled diodes are needed to illuminate and activate neurons in deep brain structures. A wireless, head-mounted interface incorporating a compact LED has recently been developed to allow experiments to be conducted remotely and in an automated fashion. The device, dubbed a “wireless router for the brain”, weighs only three grams and makes possible high-throughput studies of the brain’s control of behavior.
Despite being chosen as 2010 ‘Method of the Year’ across all scientific and engineering disciplines by Nature Methods, optogenetics has a number of limitations preventing this relatively new field from delivering medical therapies.
No natural opsin has been found that has an absorption maximum greater than 535 nm, limiting their use in high light-scattering media such as the brain. Also, the current classes of opsins in the optogenetic toolbox are not optimized for ion selectivity or ion conductance, conferring less fine-tuned control and making them less efficient, respectively. Efforts are being made to modify existing ion channels with more favorable properties to be light sensitive.
Many behaviors are controlled by neurons that are distributed over several brain regions. However, in vivo optical stimulation is currently limited to single brain regions no larger than 1 mm, extremely limiting the ability to optogenetically control complex behaviors.
Another problem is that, a safe method for the viral transference of the genes encoding light-sensitive opsins to neurons—clearly critical for any practical application of the technique—has yet to be found. Finally, although the technique has been shown to produce dramatic effects (for example, wireless control of locomotion in freely behaving mice), it is so far quite invasive and not ready for therapeutic use in humans.
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