Scientists have been busy in recent years probing how best to alter patterns of communication between neurons in the brain. Having this capability would not only expand our understanding of how we think and form memories but pave the way for new treatments for a host of brain dysfunctions that compromise emotional stability and cognition.
A technology lighting the way to better manipulation of neuronal connections is, literally, light itself. The discovery of genes responsive to light has fostered the field of optogenetics, which makes it possible to use light to visualize and alter patterns of neural connectivity with incredible precision.
“Optogenetics has absolutely changed neuroscience…It allows you to decipher circuits in a way that was not possible before.” While electrical stimulation can alter signals between neurons, it cannot distinguish between different types of neurons. Drugs that affect cell activity also lack the ability to target specific cells, and they perform much more slowly than the brain’s normal speed. Optogenetics overrides these drawbacks by only activating neurons that have genes with light sensitivity. Especially exciting: Light-sensitive genes can be inserted or removed from individual cells to provide the desired sensitivity.
Research led by Gero Miesenböck, M.D., at Memorial Sloan-Kettering Cancer Center and Ehud Isacoff, Ph.D., Richard H. Kramer, Ph.D., and Dirk Trauner, Ph.D., at the University of California, Berkeley, led to development of a chemical that can make a protein responsive to ultraviolet light. Light-responsive proteins are known as opsins, and scientists are now able to mutate opsins to provide a high degree of control over both the timing and duration of action potentials (which allow neurons to fire and send signals to each other). In some cases, this control can be achieved using just single pulses of light.
Because of its precision and relatively noninvasive, painless delivery, the use of light has great appeal for investigating the workings of the brain. “Optogenetics has absolutely changed neuroscience,” noted Roberto Malinow, M.D., Ph.D., a brain scientist at the University of California, San Diego, during an NPR broadcast. “It allows you to decipher circuits in a way that was not possible before.”
Erase Painful Memories…and Resurrect Forgotten Ones
Optogenetics offers the potential to change the status of our memories, which could be a boon for people haunted by past traumas. Memories are based on the strength of connections between neurons; the stronger the connections, the more entrenched the memory. If these connections are weakened, the memory fades. If the connections are eliminated, so is the memory.
“This technology may also play an increasing role in the assessment and treatment of other psychiatric diseases, including anxiety and depression.” Dr. Malinow’s laboratory conducted an experiment with rodents that demonstrates how optoelectronics can alter contextual fear memories—when a neutral situation originally associated with an aversive experience becomes feared itself, even when the aversion is absent. Optogenetics was used to stimulate certain cells that established a fear memory, in a fashion similar to associating a shock with a sound. Typically, this memory would fade over time with subsequent exposure to the sound without an accompanying shock. Instead, Malinow’s researchers strengthened the connections to make the fear return. Then they weakened the connections, which eliminated the rats’ fear. These findings demonstrate the potential for optogenetics to eliminate fear memories symptomatic of post-traumatic stress disorder (PTSD).
This technology may also play an increasing role in the assessment and treatment of other psychiatric diseases, including anxiety and depression. As noted in Scientific American by Karl Deisseroth, M.D., Ph.D., a professor of bioengineering and psychiatry and behavioral sciences at Stanford University: “One of the unique and most versatile features of optogenetics (modulation of defined neural projections) is well aligned with what may be a core feature of psychiatric disease (altered function along pathways of neural communication).” Optogenetics has already demonstrated benefits for treating sleep disorder narcolepsy, as well as enhanced our understanding of the diseased neural circuitry of Parkinson’s disease. It also supports a long-held theory that the social dysfunction and compromised information processing of autism and schizophrenia may be due to an imbalance in the excitation and inhibition of certain neurons. Further research with this targeted light therapy may improve our understanding of how to alter the flow of information between neurons—and even change the neurobiology associated with aggression and violence.
Optoswitches: Using Light to Turn Off Pain and Turn On Vision
A revolutionary way to use light to relieve pain and potentially treat neurological diseases has been developed by Dr. Trauner at the University of Munich. His method can enable all types of neuroreceptors to be controlled by light. “This is achieved by using synthetic molecular compounds that react specifically to light as switches for natural receptors,” he says. “The combination results in hybrid photoreceptors, which effectively make the nerve cells that bear them responsive to light.” By modifying the synthetic painkiller fentanyl, Trauner and his team have been able to make the brain’s natural opioid receptors, which help relieve pain, sensitive to light. This allows precise control of the brain’s natural painkilling response using light alone. Another study found that a single injection of a chemical “photoswitch” helps restore retinal response to light in mice that had lost this light sensitivity—a finding that has promising implications for treatment of vision-stealing diseases such as macular degeneration.
Current fiber-optic tools allow application of light to almost any area of the brain in mammals, opening the door to using optogenetics to better understand—and ultimately treat—many types of compromised connections between neurons.
There is clearly “light” at the end of this tunnel.
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