Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Discover Gene that Controls Learned Fear

13.12.2002


Researchers have discovered the first genetic component of a biochemical pathway in the brain that governs the indelible imprinting of fear-related experiences in memory.

The gene identified by researchers at the Howard Hughes Medical Institute at Columbia University encodes a protein that inhibits the action of the fear-learning circuitry in the brain. Understanding how this protein quells fear may lead to the design of new drugs to treat depression, panic and generalized anxiety disorders.

The findings were reported in the December 13, 2002 issue of the journal Cell, by a research team that included Howard Hughes Medical Institute (HHMI) investigators Eric Kandel at Columbia University and Catherine Dulac at Harvard University. Lead author of the paper was Gleb Shumyatsky, a postdoctoral fellow in Kandel’s laboratory at Columbia University. Other members of the research team are at the National Institutes of Health and Harvard Medical School.



According to Kandel, earlier studies indicated that a specific signaling pathway controls fear-related learning, which takes place in a region of the brain called the amygdala. "Given these preliminary analyses, we wanted to take a more systematic approach to obtain a genetic perspective on learned fear," said Kandel.

One of the keys to doing these genetic analyses, Kandel said, was the development of a technique for isolating and comparing the genes of individual cells, which was developed at Columbia by Dulac with HHMI investigator Richard Axel.

Shumyatsky applied that technique, called differential screening of single-cell cDNA libraries, to mouse cells to compare the genetic activity of cells from a region of the amygdala called the lateral nucleus, with cells from another region of the brain that is not known to be involved in learned fear. The comparison revealed two candidate genes for fear-related learning that are highly expressed in the amygdala.

The researchers decided to focus further study on one of the genes, Grp, which encodes a short protein called gastrin-releasing peptide (GRP), because they found that this protein has an unusual distribution in the brain and is known to serve as a neurotransmitter. Shumyatsky’s analysis revealed that the Grp gene was highly enriched in the lateral nucleus, and in other regions of the brain that feed auditory inputs into the amygdala.

"Gleb’s finding that this gene was active not only in the lateral nucleus but also in a number of regions that projected into the lateral nucleus was interesting because it suggested that a whole circuit was involved," said Kandel. Shumyatsky next showed that GRP is expressed by excitatory principal neurons and that its receptor, GRPR, is expressed by inhibitory interneurons. The researchers then undertook collaborative studies with co-author Vadim Bolshakov at Harvard Medical School to characterize cells in the amygdala that expressed receptors for GRP. Those studies in mouse brain slices revealed that GRP acts in the amygdala by exciting a population of inhibitory interneurons in the lateral nucleus that provide feedback and inhibit the principal neurons.

The researchers next explored whether eliminating GRP’s activity could affect the ability to learn fear by studying a strain of knockout mice that lacked the receptor for GRP in the brain.

In behavioral experiments, they first trained both the knockout mice and normal mice to associate an initially neutral tone with a subsequent unpleasant electric shock. As a result of the training, the mouse learns that the neutral tone now predicts danger. After the training, the researchers compared the degree to which the two strains of mice showed fear when exposed to the same tone alone — by measuring the duration of a characteristic freezing response that the animals exhibit when fearful.

"When we compared the mouse strains, we saw a powerful enhancement of learned fear in the knockout mice," said Kandel. Also, he said, the knockout mice showed an enhancement in the learning-related cellular process known as long-term potentiation.

"It is interesting that we saw no other disturbances in these mice," he said. "They showed no increased pain sensitivity; nor did they exhibit increased instinctive fear in other behavioral studies. So, their defect seemed to be quite specific for the learned aspect of fear," he said. Tests of instinctive fear included comparing how both normal and knockout mice behaved in mazes that exposed them to anxiety-provoking environments such as open or lighted areas.

"These findings reveal a biological basis for what had only been previously inferred from psychological studies — that instinctive fear, chronic anxiety, is different from acquired fear," said Kandel.

In additional behavioral studies, the researchers found that the normal and knockout mice did not differ in spatial learning abilities involving the hippocampus, but not the amygdala, thus genetically demonstrating that these two anatomical structures are different in their function.

According to Kandel, further understanding of the fear-learning pathway could have important implications for treating anxiety disorders. "Since GRP acts to dampen fear, it might be possible in principle to develop drugs that activate the peptide, representing a completely new approach to treating anxiety," he said. However, he emphasized, the discovery of the action of the Grp gene is only the beginning of a long research effort to reveal the other genes in the fear-learning pathway.

More broadly, said Kandel, the fear-learning pathway might provide an invaluable animal model for a range of mental illnesses. "Although one would ultimately like to develop mouse models for various mental illnesses such as schizophrenia and depression, this is very hard to do because we know very little about the biological foundations of most forms of mental illness," he said. "However, we do know something about the neuroanatomical substrates of anxiety states, including both chronic fear and acute fear. We know they are centered in the amygdala.

"And while I don’t want to overstate the case, in studies of fear learning we could well have an excellent beginning for animal models of a severe mental illness. We already knew quite a lot about the neural pathways in the brain that are involved in fear learning. And now, we have a way to understand the genetic and biochemical mechanisms underlying those pathways."

Jim Keeley | EurekAlert!
Further information:
http://www.hhmi.org/

More articles from Life Sciences:

nachricht Modern genetic sequencing tools give clearer picture of how corals are related
17.08.2017 | University of Washington

nachricht The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

NASA Protects its super heroes from space weather

17.08.2017 | Physics and Astronomy

Spray-on electric rainbows: Making safer electrochromic inks

17.08.2017 | Materials Sciences

Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

17.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>