Fear factor: Missing brain enzyme leads to abnormal levels of fear in mice

July 15, 2013, University of Southern California

A little bit of learned fear is a good thing, keeping us from making risky, stupid decisions or falling over and over again into the same trap. But new research from neuroscientists and molecular biologists at USC shows that a missing brain protein may be the culprit in cases of severe over-worry, where the fear perseveres even when there's nothing of which to be afraid.

In a study appearing the week of July 15 in the Proceedings of the National Academy of Sciences, the researchers examined mice without the enzymes monoamine oxidase A and B (MAO A/B), which sit next to each other in our as well as on that of mice. Prior research has found an association between deficiencies of these enzymes in humans and along the autism spectrum such as clinical perseverance – the inability to change or modulate actions along with .

"These mice may serve as an interesting model to develop interventions to these ," said senior author Jean C. Shih, USC University Professor and Boyd & Elsie Welin Professor of Pharmacology and Pharmaceutical Sciences at the USC School of Pharmacy and the Keck School of Medicine of USC. "The severity of the changes in the MAO A/B knockout mice compared to MAO A knockout mice supports the idea that the severity of autistic-like features may be correlated to the amounts of monoamine levels, particularly at early developmental stages."

Shih is a world leader in understanding the neurobiological and biochemical mechanisms behind such behaviors as aggression and anxiety. In this latest study, Shih and her co-investigators—including lead author Chanpreet Singh, who was a doctoral student at USC at the time of the research and is now at CalTech, and Richard Thompson, USC University Professor Emeritus and Keck Professor of Psychology and Biological Sciences at the USC Dornsife College of Letters, Arts and Sciences—expand their past research on MAO A/B, which regulates neurotransmitters known as monoamines, including serotonin, norepinephrine and dopamine.

Comparing mice without MAO A/B with their wild-type littermates, the researchers found significant differences in how the mice without MAO A/B processed fear and other types of learning. Mice without MAO A/B and wild mice were put in a new, neutral environment and given a mild electric shock. All mice showed learned fear the next time they were tested in the same environment, with the MAO A/B knockout mice displaying a greater degree of fear.

But while wild mice continued to explore other new environments freely after the trauma, mice without the MAO A/B enzymes generalized their phobia to other contexts—their fear spilled over onto places where they should have no reason to be afraid.

"The neural substrates processing fear in the brain is very different in these mice," Singh said. "Enhanced learning in the wrong context is a disorder and is exemplified by these mice. Their brain is not letting them forget. In a survival issue, you need to be able to forget things."

The mice without MAO A and MAO B also learned eye-blink conditioning much more quickly than wild mice, which has also been noted in autistic patients but not in mice missing only one of these enzymes.

Importantly, the mice without MAO A/B did not display any differences in learning for spatial skills and object recognition, the researchers found, "but in their ability to learn an emotional event, the [MAO A/B knockout ] are very different than wild types," Singh said.

He continued: "When both enzymes are missing, it significantly increases the levels of neurotransmitters, which causes developmental changes, which leads to differential expression of receptors that are very important for synaptic plasticity—a measure of learning—and to behavior that is quite similar to what we see along the autism spectrum."

Explore further: Scared of the wrong things: Lack of major enzyme causes poor threat-assessment in mice

More information: Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice, www.pnas.org/cgi/doi/10.1073/pnas.1308037110

Related Stories

Scared of the wrong things: Lack of major enzyme causes poor threat-assessment in mice

August 10, 2011
Do you run when you should stay? Are you afraid of all the wrong things? An enzyme deficiency might be to blame, reveals new research in mice by scientists at the University of Southern California.

Hulk smash? Maybe not anymore: scientists block excess aggression in mice

June 19, 2012
Pathological rage can be blocked in mice, researchers have found, suggesting potential new treatments for severe aggression, a widespread trait characterized by sudden violence, explosive outbursts and hostile overreactions ...

Study may offer clues to reverse cognitive deficits in humans

April 26, 2012
The ability to navigate using spatial cues was impaired in mice whose brains were minus a channel that delivers potassium — a finding that may have implications for humans with damage to the hippocampus, a brain structure ...

Researchers pinpoint genetic connection to traumatic experience

February 1, 2012
Rutgers scientists have uncovered genetic clues as to why some mice no longer in danger are still fearful while others are resilient to traumatic experiences – knowledge that could help those suffering with crippling ...

Drugs found to both prevent and treat Alzheimer's disease in mice

May 21, 2013
Researchers at USC have found that a class of pharmaceuticals can both prevent and treat Alzheimer's Disease in mice.

Recommended for you

Researchers identify protein involved in cocaine addiction

January 16, 2018
Mount Sinai researchers have identified a protein produced by the immune system—granulocyte-colony stimulating factor (G-CSF)—that could be responsible for the development of cocaine addiction.

New study reveals why some people are more creative than others

January 16, 2018
Creativity is often defined as the ability to come up with new and useful ideas. Like intelligence, it can be considered a trait that everyone – not just creative "geniuses" like Picasso and Steve Jobs – possesses in ...

Neuroscientists suggest a model for how we gain volitional control of what we hold in our minds

January 16, 2018
Working memory is a sort of "mental sketchpad" that allows you to accomplish everyday tasks such as calling in your hungry family's takeout order and finding the bathroom you were just told "will be the third door on the ...

Brain imaging predicts language learning in deaf children

January 15, 2018
In a new international collaborative study between The Chinese University of Hong Kong and Ann & Robert H. Lurie Children's Hospital of Chicago, researchers created a machine learning algorithm that uses brain scans to predict ...

Preterm babies may suffer setbacks in auditory brain development, speech

January 15, 2018
Preterm babies born early in the third trimester of pregnancy are likely to experience delays in the development of the auditory cortex, a brain region essential to hearing and understanding sound, a new study reveals. Such ...

BOLD view of white matter

January 15, 2018
The brain consists of gray matter, which contains the nerve cell bodies (neurons), and white matter, bundles of long nerve fibers (axons) that until recently were considered passive transmitters of signals between different ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

VendicarE
5 / 5 (1) Jul 15, 2013
Perhaps a lack of this chemical explains why Republicans are so easily controlled by Republican fear mongering.

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.