[Paleopsych] kicking fear around with proteins

[HowlBloom at aol.com]

Put  the following two articles together and you get the following 
conclusion:   
The  protein stathmin kicks fear  into  high gear and the protein gastrin 
stomps the pedal of fear’s brakes.  
Gastrin  is a protein from the intestines, a protein involved in having a 
good meal.  So does being well fed should make you  fearless?  The folks who made 
up our  clichés may have been more accurate than they knew when they said 
that people  who are fearless “have guts.” 
By  the way, I’ve been looking for the stress-handling system in the brain 
for the  last decade.  It looks as if the  stathmin and gastrin system may be a 
part of it.   
When  I came down with Chronic Fatigue Syndrome in 1988 and my stress 
handling system  lost its inhibitory abilities and ramped up my stress sensitivity 
beyond all  imagining, was I overloaded with stathmin and stripped of gastrin?   
Howard 
________ 
Retrieved November 18, 2005, from the World Wide Web  
http://www.newscientist.com/article.ns?id=dn8337  
Gene turn-off makes  meek mice fearless  * 17:00 17 November 2005 * 
NewScientist.com news service  Deactivating a specific gene transforms meek mice into 
daredevils, researchers  have found. The team believe the research might one 
day enable people suffering  from fear – in the form of phobias or anxiety 
disorders, for example – to be  clinically treated. 
The research found that mice lacking an  active gene for the protein stathmin 
are not only more courageous, but are also  slower to learn fear responses to 
pain-associated stimuli, says geneticist Gleb  Shumyatsky, at Rutgers 
University in New Jersey, US.  In the experiments, the stathmin-lacking  mice 
wandered out into the centre of an open box, in defiance of the normal  mouse 
instinct to hide along the box’s walls to avoid potential predators.  And to test 
learned fear, the mice were  exposed to a loud sound followed by a brief electric 
shock from the floor below  them. A day later, normal mice froze when the 
sound was played again.  Stathmin-lacking mice barely reacted to the sound at 
all. Neural responses  In both mice and humans, the amygdala  area of the brain 
serves as the control centre of basic fear impulses. Stathmin  is found almost 
exclusively in this and related brain areas.  The protein is known to 
destabilise  microtubule structures that help maintain the connections between 
neurons. This  allows the neurons to make new connections, allowing the animal to 
learn and  process fear experiences, Shumyatsky says. Without it, the neural 
responses are  stilted.  The lack of the protein  does not appear to affect other 
learning experiences, as both sets of mice were  able to memorise the paths 
out of mazes equally well. “This is a good sign for  an eventual clinical 
application that could let people deal with their fears in  an entirely different 
way,” Shumyatsky says.  In 2002, Shumyatsky and colleagues  published a study on 
a similar gene encoding for a protein called GRP. But this  protein seems 
only to be associated with learned fear, and would therefore only  have clinical 
implications for conditions such as post-traumatic stress  disorder.  
Stathmin, on the other hand, seems to  affect both learned and innate fear, which 
could lead to treatments for a much  broader range of phobias and anxiety 
disorders, Shumyatsky says.  Journal reference: Cell (DOI:  
10.1016/j.cell.2005.08.038) Printable version Email to a friend RSS Feed Cover  of latest issue of New  
_________ 
Site:  ScienceDaily Magazine Page URL:  
http://www.sciencedaily.com/releases/2002/12/021213062425.htm  Original Source: Howard Hughes Medical  Institute 
Date Posted: 12/13/2002 Researchers Discover Gene That Controls  Ability To 
Learn Fear 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."  Editor's Note: The original news release  can be found here.  Note: This 
story  has been adapted from a news release issued for journalists and other 
members of  the public. If you wish to quote from any part of this story, 
please credit  Howard Hughes Medical Institute as the original source.   


----------
Howard  Bloom
Author of The Lucifer Principle: A Scientific Expedition Into the  Forces of 
History and Global Brain: The Evolution of Mass Mind From The Big Bang  to the 
21st Century
Recent Visiting Scholar-Graduate Psychology Department,  New York University; 
Core Faculty Member, The Graduate  Institute
www.howardbloom.net
www.bigbangtango.net
Founder:  International Paleopsychology Project; founding board member: Epic 
of Evolution  Society; founding board member, The Darwin Project; founder: The 
Big Bang Tango  Media Lab; member: New York Academy of Sciences, American 
Association for the  Advancement of Science, American Psychological Society, 
Academy of Political  Science, Human Behavior and Evolution Society, International 
Society for Human  Ethology; advisory board member: Institute for 
Accelerating Change ; executive  editor -- New Paradigm book series.
For information on The International  Paleopsychology Project, see: 
www.paleopsych.org
for two chapters from  
The Lucifer Principle: A Scientific Expedition Into the Forces of History,  
see www.howardbloom.net/lucifer
For information on Global Brain: The  Evolution of Mass Mind from the Big 
Bang to the 21st Century, see  www.howardbloom.net

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