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Light Switches Brain Pathway On-and-Off to Dissect How Anxiety Works

Turns Cowering Mice into Instant Adventurers

Science Update

Scientists, for the first time, have switched anxiety on-and-off in active animals by shining light at a brain pathway. Instinctively reclusive mice suddenly began exploring normally forbidding open spaces when a blue laser activated the pathway – and retreated into a protected area when it dimmed. By contrast, anxiety-like behaviors increased when an amber laser inhibited the same pathway.

Researchers, supported in part by NIMH, used a virus, genetic engineering  and fiber-optics to control the pathway in the brain's fear center with millisecond precision.

"Our findings reveal how balanced antagonistic brain pathways are continuously regulating anxiety," explained Karl Deisseroth, M.D., Ph.D., of Stanford University, a practicing psychiatrist as well as a neuroscientist. "We have pinpointed an anxiety-quelling pathway and demonstrated a way to control it that may hold promise for new types of anti-anxiety treatments."

NIMH grantees Deisseroth, Kay M. Tye, Ph.D., and colleagues, report on their findings March 17, 2011 in the journal Nature.

Optogenetic alchemy

Anxiety disorders are the most common type of psychiatric illness, affecting more than 1 in 4 people at some time during their lives. To understand the neural basis of these disorders, researchers are studying the workings of circuitry in the fear center, called the amygdala, in rodents.

Deisseroth's team has pioneered a method, called optogenetics, of experimentally activating brain activity with light. They incorporate a protein borrowed from light-reactive organisms to make brain tissue similarly light-responsive. Previously, they used this tool to activate particular types of neurons. The new study is the first to use it to reversibly manipulate a specific projection of a neuron (see picture below). It's also the first time the technique has been used to study anxiety as opposed to fear – a generalized state versus a transient reaction to an immediate threat.

The researchers borrowed a gene that codes for a light-sensitive protein from algae and delivered it to the amygdala pathway via a virus. In the algae, the protein's function is to activate a pathway that causes the organism to swim toward blue spectrum light. Hence a blue light now activated the amygdala pathway. When they wanted to inhibit the pathway in response to light, they similarly borrowed a gene from a light-responsive bacterium that codes for a protein that inhibits a pathway in response to a particular spectrum of light — in this case amber — and infected the amygdala pathway with that gene.

When the researchers optogenetically activated whole neuronal cell bodies in the amygdala, it increased anxiety-like behavior: mice hunkered down in a protected corner of a maze and wouldn't venture into more exposed areas. These and related findings led the researchers to hypothesize that they would get the same effect if they narrowed the focus of the activation to just a specific neuronal projection (see picture below).

A post-doc's eureka! moment

But it turned out that the opposite was true.

When they activated the projection with the blue laser, the engineered mice suddenly seemed to summon the courage to explore the more exposed parts of the maze that they would normally avoid (see video below).

"I was quite surprised. We did not see aversion. We did not see fear. We did not see any of these things I expected to see," said Tye, whose post-doctoral study  is supported by a NIMH-funded training grant . "I suddenly got this huge, dramatic effect of reduction in anxiety-related behaviors and I had to follow it up. So I pretty much dropped my original ideas of what I was going to study during my fellowship and started pursuing this."

When the researchers blocked activity in the projection with the amber laser, the animals showed even more anxiety-like behavior than they usually do. The experiments hint at how the brain is able to regulate anxiety levels — on a millisecond timescale — by dialing activity up and down in such antagonistic amygdala pathways.

Futuristic anxiety treatment?

Tye said she and Deisseroth plan to follow up with further dissection of anxiety pathways. She also hopes to examine whether such optogenetic manipulations, sustained over hours or days, might induce long-lasting adaptations — perhaps for weeks –– in the set-points of anxiety pathways.

A future anxiety disorder treatment that might similarly target such specific pathways could, theoretically, quell anxiety instantly without producing unwanted side effects, such as drowsiness, often experienced with current anti-anxiety medications. For patients with severely debilitating anxiety, a treatment something like deep brain stimulation for depression, but more precisely targeted at a specific pathway, might someday be feasible, she suggested.

"Everything else in your brain should be unperturbed, because the manipulation would be so specific," explained Tye.



Researchers were surprised to discover that activating the whole cell body of an amygdala neuron increased anxiety in mice, while activating just one of its projections had the opposite effect. So unraveling the secrets of how anxiety works might require dissecting the action of each such pathway individually, say the researchers.



Amygdala circuitry mediating reversible and bidirectional control of anxiety . Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H, Thompson KR, Gradinaru V, Ramakrishnan C, Deisseroth K. Nature. 2011 Mar 17;471(7338):358-62. Epub 2011 Mar 9. PMID: 21389985