Scientists find fear, courage switches in brain

May 2, 2018, Stanford University Medical Center
Credit: CC0 Public Domain

Researchers at the Stanford University School of Medicine have identified two adjacent clusters of nerve cells in the brains of mice whose activation levels upon sighting a visual threat spell the difference between a timid response and a bold or even fierce one.

Located smack-dab in the middle of the brain, these clusters, or nuclei, each send signals to a different area of the brain, igniting opposite behaviors in the face of a visual threat. By selectively altering the activation levels of the two nuclei, the investigators could dispose the to freeze or duck into a hiding space, or to aggressively stand their ground, when approached by a simulated predator.

People's brains probably possess equivalent circuitry, said Andrew Huberman, PhD, associate professor of neurobiology and of ophthalmology. So, finding ways to noninvasively shift the balance between the signaling strengths of the two nuclei in advance of, or in the midst of, situations that people perceive as threatening may help people with excessive anxiety, phobias or post-traumatic stress disorder lead more normal lives.

"This opens the door to future work on how to shift us from paralysis and fear to being able to confront challenges in ways that make our lives better," said Huberman, the senior author of a paper describing the experimental results. It will be published online May 2 in Nature. Graduate student Lindsey Salay is the lead author.

Perilous life of a mouse

There are plenty of real threats in a mouse's world, and the rodents have evolved to deal with those threats as best they can. For example, they're innately afraid of aerial predators, such as a hawk or owl swooping down on them. When a mouse in an open field perceives a raptor overhead, it must make a split-second decision to either freeze, making it harder for the predator to detect; duck into a shelter, if one is available; or run for its life.

To learn how brain activity changes in the face of such a visual threat, Salay simulated a looming predator's approach using a scenario devised some years ago by neurobiologist Melis Yilmaz Balban, PhD, now a postdoctoral scholar in Huberman's lab. It involves a chamber about the size of a 20-gallon fish tank, with a video screen covering most of its ceiling. This overhead screen can display an expanding black disc simulating a bird-of-prey's aerial approach.

Looking for brain regions that were more active in mice exposed to this "looming predator" than in unexposed mice, Salay pinpointed a structure called the ventral midline thalamus, or vMT.

Salay mapped the inputs and outputs of the vMT and found that it receives sensory signals and inputs from regions of the brain that register internal brain states, such as arousal levels. But in contrast to the broad inputs the vMT receives, its output destination points were remarkably selective. The scientists traced these outputs to two main destinations: the basolateral amygdala and the medial prefrontal cortex. Previous work has tied the amygdala to the processing of threat detection and fear, and the medial prefrontal cortex is associated with high-level executive functions and anxiety.

Further inquiry revealed that the nerve tract leading to the basolateral amygdala emanates from a nerve-cell cluster in the vMT called the xiphoid nucleus. The tract that leads to the medial prefrontal cortex, the investigators learned, comes from a cluster called the nucleus reuniens, which snugly envelopes the xiphoid nucleus.

Next, the investigators selectively modified specific sets of in mice's brains so they could stimulate or inhibit signaling in these two nerve tracts. Exclusively stimulating xiphoid activity markedly increased mice's propensity to freeze in place in the presence of a perceived aerial predator. Exclusively boosting activity in the tract running from the nucleus reuniens to the in mice exposed to the looming-predator stimulus radically increased a response seldom seen under similar conditions in the wild or in previous open-field experiments: The mice stood their ground, right out in the open, and rattled their tails, an action ordinarily associated with aggression in the species.

This "courageous" behavior was unmistakable, and loud, Huberman said. "You could hear their tails thumping against the side of the chamber. It's the mouse equivalent of slapping and beating your chest and saying, 'OK, let's fight!'" The mice in which the nucleus reuniens was stimulated also ran around more in the chamber's open area, as opposed to simply running toward hiding places. But it wasn't because nucleus reuniens stimulation put ants in their pants; in the absence of a simulated looming predator, the same mice just chilled out.

In another experiment, the researchers showed that stimulating mice's nucleus reuniens for 30 seconds before displaying the "looming predator" induced the same increase in tail rattling and running around in the unprotected part of the chamber as did vMT stimulation executed concurrently with the display. This suggests, Huberman said, that stimulating nerve cells leading from the nucleus reunions to the prefrontal cortex induces a shift in the 's internal state, predisposing mice to act more boldly.

Another experiment pinpointed the likely nature of that internal-state shift: arousal of the autonomic nervous system, which kick-starts the fight, flight or freeze response. Stimulating either the vMT as a whole or just the nucleus reuniens increased the mice's pupil diameter—a good proxy of autonomic arousal.

On repeated exposures to the looming-predator mockup, the mice became habituated. Their spontaneous vMT firing diminished, as did their behavioral responses. This correlates with lowered autonomic arousal levels.

Human brains harbor a structure equivalent to the vMT, Huberman said. He speculated that in people with phobias, constant anxiety or PTSD, malfunctioning circuitry or traumatic episodes may prevent vMT signaling from dropping off with repeated exposure to a stress-inducing situation. In other experiments, his group is now exploring the efficacy of techniques, such as deep breathing and relaxation of visual fixation, in adjusting the arousal states of people suffering from these problems. The thinking is that reducing vMT signaling in such individuals, or altering the balance of signaling strength from their human equivalents of the xiphoid nucleus and reuniens may increase their flexibility in coping with stress.

Explore further: Amphetamine abuse disrupts development of mouse prefrontal cortex

More information: A midline thalamic circuit determines reactions to visual threat, Nature (2018). nature.com/articles/doi:10.1038/s41586-018-0078-2

Related Stories

Amphetamine abuse disrupts development of mouse prefrontal cortex

January 8, 2018
Recreational drug use during adolescence may disrupt development of an understudied part of the prefrontal cortex, according to a study of male mice published in eNeuro.

Animal study connects fear behavior, rhythmic breathing, brain smell center

April 20, 2018
"Take a deep breath" is the mantra of every anxiety-reducing advice list ever written. And for good reason. There's increasing physiological evidence connecting breathing patterns with the brain regions that control mood ...

Researchers discover what makes mice freeze or flee

August 4, 2016
Mice are likely to freeze at the sight of small slow-moving shapes and flee from fast approaching ones, finds new UCL research.

These carbon dioxide-sensing neurons wake up mice

January 29, 2018
Stimulating a population of neurons in the midbrain with carbon dioxide (CO2) awakens adult male mice without enhancing breathing, finds a study published in JNeurosci. These findings are relevant to understanding disorders ...

New neural pathway for fear found in mice

September 6, 2016
(Medical Xpress)—A team of researchers with the Chinese Academy of Sciences has found that there is a previously unknown neural pathway in the mouse brain that leads from the lateral amygdala to the auditory cortex. In ...

Activating MSc glutamatergic neurons found to cause mice to eat less

December 13, 2017
(Medical Xpress)—A trio of researchers working at the State University of New York has found that artificially stimulating neurons that exist in the medial septal complex in mouse brains caused test mice to eat less. In ...

Recommended for you

Dehydration alters human brain shape and activity, slackens task performance

August 21, 2018
When dehydration strikes, part of the brain can swell, neural signaling can intensify, and doing monotonous tasks can get harder.

'It's all in the eyes': The role of the amygdala in the experience and perception of fear

August 21, 2018
Researchers have long believed that the amygdala, an almond-shaped structure in the brain, is central to the experience and perception of fear. Studies initiated in the 1990s of a patient with a rare condition affecting the ...

Study sheds light on how brain lets animals hunt for food by following smells

August 21, 2018
Most animals have a keen sense of smell, which assists them in everyday tasks. Now, a new study led by researchers at NYU School of Medicine sheds light on exactly how animals follow smells.

Powerful molecules provide new findings about Huntington's disease

August 21, 2018
Researchers at Lund University in Sweden have discovered a direct link between the protein aggregation in nerve cells that is typical for neurodegenerative diseases, and the regulation of gene expression in Huntington's disease. ...

Study: 'Sound' differences between age groups

August 21, 2018
By exploring differences in the way younger and older adults respond to sounds, Western neuroscientists have found that our brains become more sensitive to sounds as we age, likely leading to hearing challenges over a lifetime.

Largest brain study of 62,454 scans identifies drivers of brain aging

August 21, 2018
In the largest known brain imaging study, scientists from Amen Clinics (Costa Mesa, CA), Google, John's Hopkins University, University of California, Los Angeles and the University of California, San Francisco evaluated 62,454 ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.