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No Implants Needed For Precise Control Deep Into The Brain

Optogenetics can now control neural circuits at unprecedented depths within living brain tissue without surgery

3 min read
A new, non-invasive technique turned on these brain cells (serotonergic dorsal raphe cells) with millisecond-precision
A new, non-invasive technique turned on these brain cells (serotonergic dorsal raphe cells) with millisecond-precision.
Image: Ritchie Chen and Karl Deisseroth

The first time Karl Deisseroth used light to control brain cells in a dish, people had a lot of questions, three in particular. Can the technique be used in living animals? Can it target different cell types? Can it work without implanting a light source into the brain?

In the years since that initial groundbreaking 2004 experiment, Deisseroth’s team and others found the answers to the first two questions: yes and yes. This month they answered the third question with another yes, successfully introducing an implant-free version of the technique. It is the first demonstration that optogenetics—which uses a combination of light and genetic engineering to control brain cells—can accurately switch the cells on and off without surgery.

“This is kind of a nice bookend to 16 years of research,” says Deisseroth, a neuroscientist and bioengineer at Stanford University. “It took years and years for us to sort out how to make it work.” The result is described this month in the journal Nature Biotechnology.

Optogenetics involves genetically engineering animal brains to express light-sensitive proteins—called opsins—in the membranes of neurons. The opsins’ reactions to pulses of light can either induce a neuron to “fire” or suppress its ability to fire. Optogenetics has been used to map brain pathways, identify how complex behaviors are regulated, create false memories in mice, and much more. It’s also been used to develop an optogenetic pacemaker, among other technologies.

Most of the time, getting the pulses of light inside the brain to control cells has required invasive implants: from tethered optical fibers, to peppercorn-sized wireless implants, to stretchy spinal implants.

In April, Guoping Feng and colleagues at MIT, along with Deisseroth, demonstrated a minimally invasive optogenetic system that required drilling a small hole in the skull, then being able to control opsin-expressing neurons six millimeters deep into the brain using blue light. This approach used of a type of opsin that slowly activates neurons in a step-wise manner. 

In the most recent study, Deisseroth and colleagues sought to instead enable both deep and fast optogenetics without surgery. The Stanford team expressed in the brain cells of mice a powerful new opsin called ChRmine (pronounced like the deep-red color “carmine”), discovered by Deisseroth’s group last year in a marine organism. Then, they shined a red light outside the skull and were able to activate neural circuits in the midbrain and brainstem at depths of up to 7 millimeters. With the technique, the scientists turned on and off brain circuits with millisecond precision. “It really worked well, far better than we even expected might be possible,” says Deisseroth.

The team then tested the effectiveness of the system. In one instance, they used light to quickly and precisely stop seizures in epileptic mice, and in another to turn on serotonin-producing neurons to promote social behavior in mice.

Most optogenetic techniques involve injecting viruses with an opsin gene of choice directly into the brain with a needle. To avoid this, the Stanford team used a type of PHP virus developed at CalTech that can be injected in the blood. The virus then crosses the blood-brain barrier to deliver its payload, an opsin gene, to brain cells. In this case, even the delivery of the gene is noninvasive—no needle penetrates the brain.

Deisseroth’s team is now testing the non-invasive technique in fish and collaborating with others to apply it to non-human primates. They’re also working with the Seattle-based Allen Institute to develop mouse lines bred with ChRmine in their cells. “We hope these will be a broadly available and applicable research tool,” says Deisseroth. “We’re just excited to share this capability with everybody.”

The Conversation (1)
Aurelien Demont11 Oct, 2021
INDV

Wow ! Such a powerful knowledge to have!

A photo showing machinery in a lab

Foundries such as the Edinburgh Genome Foundry assemble fragments of synthetic DNA and send them to labs for testing in cells.

Edinburgh Genome Foundry, University of Edinburgh

In the next decade, medical science may finally advance cures for some of the most complex diseases that plague humanity. Many diseases are caused by mutations in the human genome, which can either be inherited from our parents (such as in cystic fibrosis), or acquired during life, such as most types of cancer. For some of these conditions, medical researchers have identified the exact mutations that lead to disease; but in many more, they're still seeking answers. And without understanding the cause of a problem, it's pretty tough to find a cure.

We believe that a key enabling technology in this quest is a computer-aided design (CAD) program for genome editing, which our organization is launching this week at the Genome Project-write (GP-write) conference.

With this CAD program, medical researchers will be able to quickly design hundreds of different genomes with any combination of mutations and send the genetic code to a company that manufactures strings of DNA. Those fragments of synthesized DNA can then be sent to a foundry for assembly, and finally to a lab where the designed genomes can be tested in cells. Based on how the cells grow, researchers can use the CAD program to iterate with a new batch of redesigned genomes, sharing data for collaborative efforts. Enabling fast redesign of thousands of variants can only be achieved through automation; at that scale, researchers just might identify the combinations of mutations that are causing genetic diseases. This is the first critical R&D step toward finding cures.

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