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 New type of photosynthesis discovered
17.06.2018 | Imperial College London

nachricht New ID pictures of conducting polymers discover a surprise ABBA fan
17.06.2018 | University of Warwick

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

Im Focus: Photoexcited graphene puzzle solved

A boost for graphene-based light detectors

Light detection and control lies at the heart of many modern device applications, such as smartphone cameras. Using graphene as a light-sensitive material for...

Im Focus: Water is not the same as water

Water molecules exist in two different forms with almost identical physical properties. For the first time, researchers have succeeded in separating the two forms to show that they can exhibit different chemical reactivities. These results were reported by researchers from the University of Basel and their colleagues in Hamburg in the scientific journal Nature Communications.

From a chemical perspective, water is a molecule in which a single oxygen atom is linked to two hydrogen atoms. It is less well known that water exists in two...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Scientists predict a new superhard material with unique properties

18.06.2018 | Materials Sciences

Squeezing light at the nanoscale

18.06.2018 | Physics and Astronomy

A sprinkle of platinum nanoparticles onto graphene makes brain probes more sensitive

15.06.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>