Implant-free optogenetics minimizes brain damage during neuronal stimulation

Summary: Researchers genetically engineered neurons to produce a newly developed, light-sensitive protein called SOUL. They then used optogenetic technology to shine a light through the skull and alter neural responses through an entire mouse brain.

Source: Cell Press

A minimally invasive optogenetic technique that does not require brain implants successfully manipulated the activity of neurons in mice and monkeys, researchers report April 29th in the journal Neuron. The researchers first genetically engineered neurons to produce a newly developed, extremely light-sensitive protein called SOUL. They then demonstrated that it is possible to shine light through the skull to alter neuronal responses throughout the entire mouse brain, and through a thick membrane called the dura to reach superficial regions of the macaque brain.

“This new tool will allow neuroscientists to apply optogenetics in animal experiments while ensuring that the brains being studied are minimally damaged during the experiments,” says co-senior study author Guoping Feng of the Massachusetts Institute of Technology (MIT). “In particular, monkey models are critical for our understanding of high cognitive function and its dysfunction in brain disorders such as schizophrenia and Alzheimer’s disease, and for developing treatments for these devastating brain disorders.”

Optogenetics is a method that involves using light to activate or deactivate neurons that are genetically modified to produce light-responsive proteins called opsins. This approach has allowed neuroscientists to examine the causal role of different types of neurons in a variety of behavioral and cognitive processes. But one major drawback is that this technique typically requires the implantation of optical fibers, which can cause brain damage and inflammation and increase the risk of infection.

“Prior to our study, a few studies have contributed in various ways to the development of optogenetic stimulation methods that would be minimally invasive to the brain,” says co-senior study author Robert Desimone of MIT. “However, all of these studies had various limitations in the extent of brain regions they could activate. One major novelty of our study is that it is the first to demonstrate a method to activate any mouse brain region independent of its location with light from outside the skull.”

In the new study, the researchers used the light-sensitive protein SOUL to manipulate the activity of neurons in the lateral hypothalamus–one of the deepest regions of the mouse brain. They did so by shining light through an optical fiber positioned above the intact skull. To confirm that the approach was working, they also monitored neuronal responses in that brain region using electrophysiological recordings.

The delivery of blue light stimulated the neurons and disrupted feeding behavior, which is controlled by the lateral hypothalamus. In addition, orange light deactivated the neurons and restored normal food consumption. Further analysis confirmed that this approach did not cause brain inflammation or injury.

The researchers had to modify their technique in macaques, which have much thicker skulls than mice. They delivered light through an optical fiber placed outside the dura–a thick membrane made of dense tissue that surrounds the brain. These experiments showed that SOUL can be used in monkeys to alter neuronal responses in cortex–the outer layer of neural tissue in the brain. According to the authors, no prior study had demonstrated an optogenetic method with such minimal invasiveness in macaques.

Surprisingly, the technique was able to induce and disrupt local field potential oscillations–rhythmic, synchronized electrical activity of neurons. Until now, it has been very difficult to manipulate oscillations to study their causal role in brain functions.

“These oscillations are believed to be very important for many functions of the brain, including memory, attention, sleep, and decision-making,” says co-first author Diego Mendoza-Halliday of MIT. “It was exciting to discover that our new opsin can be used as a method to turn on and off these brain waves at will, since it will allow us to better study the role of these waves in multiple brain functions.”

This is a diagram from the study
This figure depicts how light stimulation of deep brain region neurons from outside skull leads to suppression of feeding behavior in mice. Image is credited to Guoping Feng.

Moving forward, SOUL-based optogenetics opens many new avenues of research. For example, this approach could shed light on early brain development, which is especially susceptible to severe tissue damage caused by long-term optical fiber implants. Due to its superior light sensitivity, SOUL can be used to control neuronal responses in larger-scale neural circuits involved in various brain functions. Moreover, SOUL remains active for more than 30 minutes, allowing scientists to study longer-term behaviors of freely moving animals that are not restricted by optical fibers.

For their own part, the researchers will work on improving the sensitivity of SOUL so they could manipulate neuronal activity through the thick skulls of large animals to reach deeper brain regions. In addition to revealing the causes of neurological and psychiatric disorders in animals, this approach could one day be used for the treatment of these disorders in humans.

Although the technique reduces the invasiveness and brain damage associated with optogenetics, it is still a long way from clinical translation. “Before optogenetics can be considered a viable treatment option, the potential risks of such treatments in patients need to be carefully evaluated, particularly those associated with expression of the opsin, a foreign protein, in the brain,” Feng says.

Funding:This work was primarily supported by the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, the James and Patricia Poitras Center for Psychiatric Disorders Research at MIT, the Simons Center for the Social Brain at MIT, the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, and NIH/NINDS. The Broad Institute of MIT and Harvard and the authors are submitting a patent application related to this work.

About this neuroscience research article

Cell Press
Media Contacts:
Carly Britton – Cell Press
Image Source:
The image is credited to Guoping Feng.

Original Research: Closed access
“An Ultra-Sensitive Step-Function Opsin for Minimally Invasive Optogenetic Stimulation in Mice and Macaques”. by Gong, Mendoza-Halliday, and Ting et al.
Neuron doi:10.1016/j.neuron.2020.03.032


An Ultra-Sensitive Step-Function Opsin for Minimally Invasive Optogenetic Stimulation in Mice and Macaques

• We introduce SOUL, a new step-function opsin with ultra-high light sensitivity
• SOUL activates deep mouse brain and change behaviors via transcranial illumination
• SOUL activates macaque cortical neurons via illumination through the dura
• Transdural activation of SOUL in macaques induces oscillatory activity reversibly


Optogenetics is among the most widely employed techniques to manipulate neuronal activity. However, a major drawback is the need for invasive implantation of optical fibers. To develop a minimally invasive optogenetic method that overcomes this challenge, we engineered a new step-function opsin with ultra-high light sensitivity (SOUL). We show that SOUL can activate neurons located in deep mouse brain regions via transcranial optical stimulation and elicit behavioral changes in SOUL knock-in mice. Moreover, SOUL can be used to modulate neuronal spiking and induce oscillations reversibly in macaque cortex via optical stimulation from outside the dura. By enabling external light delivery, our new opsin offers a minimally invasive tool for manipulating neuronal activity in rodent and primate models with fewer limitations on the depth and size of target brain regions and may further facilitate the development of minimally invasive optogenetic tools for the treatment of neurological disorders.

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