Controlling the Brain with Optogenetics

By Scott Goldberg

Imagine controlling neuronal activity with nothing but a miniature flashlight. Shine the light on a set of neurons and they fire up, sending action potentials across the brain and back. Turn the light off and they’re back to resting state. Though perhaps a bit of an exaggeration, this idea basically captures the essence of optogenetics, which in more scientific terms refers to the use of light responsive “opsin” proteins to produce genetically modified neurons. Such neurons express light sensitive ion channels and fire when exposed to specific wavelengths of light. This neuromodulation method allows scientists to control and manipulate groups of simultaneously firing neurons, otherwise known as neuronal circuits, with unprecedented precision in order to see how they work together to produce movement, motivation, pain and many other neural functions.

Stanford Professor Karl Deisseroth is widely considered a founding father of optogenetics. A neuroscientist and psychiatrist who studies neural mechanisms associated with mental illnesses, Deisseroth is driven to understand the brain’s neural-circuitry. In an attempt to detect the biological underpinnings of anxiety, Deisseroth and a team of Stanford researchers engineered mice to express light-sensitive proteins in specific cells of the amygdala that send axons to different substructures. Using a specially designed fiber-optic cable implanted into the mice’s brains, they found that aiming a light to activate one particular circuit in the amygdala had an immediate effect on mouse behavior. Under normal circumstances, the mice would poke their heads out and scurry into a corner. With the light turned on, the mice began exploring a platform with no visible signs of anxiety (Tye et. al, 2011). Deisseroth hopes that optogenetic experiments like his will allow us to define and describe circuit connections and to eventually develop targeted and efficient treatments.

Perhaps the most widely conducted optogenetic experiments are those exploring Parkinson’s disease. In one study, researchers introduced two opsin proteins into subthalamic nucleus (STN) neurons of mice. They found that abnormal electrical firing of these neurons was reversed by aimed light of various intensities. This reversal of abnormal electrical firing led to substantial improvements in spontaneous rotating behaviors and heightened physical activity levels in open cage environments (Kaplitt, 2014). Researchers hope that optogenetic light techniques can eventually produce similar motor function improvements in human Parkinsons patients.

The recent use of optogenetics to study animal models of motor system degeneration has allowed researchers to gain fundamental insights into the diseased circuitry at play in Parkinson’s disease. Whereas therapies like Deep Brain Stimulation (DBS) apply electrical stimuli to general areas of the brain, optogenetic implants could potentially strengthen specific circuits associated with the disease.

One private biopharmaceutical company is in the process of performing the first ever optogenetic study on humans. In March 2016, RetroSense Therapeutics began the first clinical safety trial of an optogenetic therapy to treat the vision disorder retinis pigmentosa, which destroys photoreceptors in the eye. In the absence of these receptors, the treatment seeks to confer light sensitivity to retinal ganglion cells, which normally function to pass visual signals from photoreceptors to the brain. The therapy involves injecting blind patients with viruses carrying genes that encode the light-sensitive channelrhodopsin protein, which algae use to move closer to sunlight. When stimulated with blue light, the genetically modified ganglion cells should fire and pass visual information to the brain. Though unlikely to regain full vision, patients may be able to see the world in blurry black-and-white (Birch, 2016).

The future of optogenetics is bright, as some researchers forecast its clinical application within a matter of years. Its potential to identify specific brain circuits associated with behaviors and disorders holds promise for the possibility of more targeted and efficient treatments in psychiatry and neurology.


References

1. Birch, David G. "Phase I/IIa, Open-Label, Dose-Escalation Study of Safety and Tolerability of Uniocular Intravitreal RST-001 in Patients With Retinitis Pigmentosa (RP)." (n.d.): n. pag. Clinicaltrials.gov. Web. 3 Feb. 2017.

2. Kaplitt, Michael G. "Optogenetic Restoration of Basal Ganglia Function to Treat Parkinson’s Disease." (2014): n. pag. Michael J. Fox Foundation for Parkinson's Research. Web. 3 Feb. 2017.

3. Tye, Kay M., Rohit Prakash, Sung-Yon Kim, Lief E. Fenno, Logan Grosenick, Hosniya Zarabi, Kimberly R. Thompson, Viviana Gradinaru, Charu Ramakrishnan, and Karl Deisseroth. "Amygdala Circuitry Mediating Reversible and Bidirectional Control of Anxiety." Nature 471.7338 (2011): 358-62. Web.