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 Seeing on the Quick: New Insights into Active Vision in the Brain
15.08.2018 | Eberhard Karls Universität Tübingen

nachricht New Approach to Treating Chronic Itch
15.08.2018 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Unraveling the nature of 'whistlers' from space in the lab

A new study sheds light on how ultralow frequency radio waves and plasmas interact

Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

Im Focus: The “TRiC” to folding actin

Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.

Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...

Im Focus: Lining up surprising behaviors of superconductor with one of the world's strongest magnets

Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur

What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

2018 Work Research Conference

25.07.2018 | Event News

 
Latest News

Interactive software tool makes complex mold design simple

16.08.2018 | Information Technology

Study tracks inner workings of the brain with new biosensor

16.08.2018 | Health and Medicine

Fraunhofer HHI develops next-generation quantum communications technology in the UNIQORN project

16.08.2018 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>