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Brains, memory, and behavior


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#1 Lazarus Long

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Posted 10 July 2003 - 12:08 PM


I would like to suggest this thread be more an open data file with loose analysis of what is thought to be the mechanism and relationships involved. For starters I have two articles hot off the presses but we can fill in with many, many examples from history as well. Comments are welcome and encouraged but if we develop the substance of a clearer thread then we will spin it off.

I think we can all say there is a relationship between the three elements listed in the title, now try to define the relationship. We have whole branches of medicine designed to preserve subtly different perspectives on the "chemistry" of these cognitive aspects. Memory is is clearly a function of the brain, it is also a function of personality (whatever that is?). Is the personality governed by memory?

Or is behavior a consequence of personality that is hardwired into the brain, influenced by memory(experience) and determined as behaviors that can be self reinforcing or self defeating?

These are by far not the only questions raised so I thought to start here as I said by introducing some examples to ponder and then once this thread is large enough perhaps we can spin off the science of it as a CIRA topic but for now think of it more as a kiosk where we can post articles and graffiti our comparative notes to one another.

The second article also crosses over into Keith Hansen's articulate discussion on Evolutionary Psychology and will clearly be effected by successful longevity as relationships and behavior evolve in response to longer life expectancy.

LL/kxs

http://story.news.ya...ds&e=3&ncid=533
Ark. Man Says First Words After 19-Year Coma
46 minutes ago Health - AP
By DAVID HAMMER, Associated Press Writer

MOUNTAIN VIEW, Ark. - The last time Terry Wallis was conscious of the world around him, Ronald Reagan (news - web sites) was president, Bill Clinton (news - web sites) was the governor, the Soviet Union was the enemy and the World Trade Center still stood.

Thrown into a stupor after an auto accident in 1984, he recently spoke his first words in 19 years: "Mom. Pepsi. Milk."

Only in the last two weeks has the 39-year-old Wallis realized that Reagan no longer is president, answering "I don't know" when asked who is in office now.

"He's beginning to realize he's in a different place now," said his physician, Dr. James Zini. "We never thought he'd regain this kind of cognitive level."

Wallis and a friend were in a car on July 13, 1984, when it ran off the road. Both men were found beneath a bridge the next day. The friend died; Wallis was left a quadriplegic and fell into a coma for three months.

He soon emerged partially from the coma. But for 18 years, he could communicate only by blinking his eyes or grunting.

Then, on June 13, he called out "Mom" to his mother and later asked for a Pepsi. While home from the hospital for a weekend, he said he wanted milk with his breakfast. Since then, he has steadily increased his vocabulary, and he is considered fully emerged from his stupor.

Wallis is eager to learn, now that the world is opening up to him again. Propped up in bed Wednesday at the nursing home where he lives, Wallis clutched small blue cushions that have kept his withered hands from closing shut over years of disuse.

He tells a visitor that he loves to talk and is happy, but he doesn't acknowledge, or isn't able to explain, the long gap in his life.

"I never had no accident," he said.

A speech therapist works with Wallis three days a week, and his doctor wants to give him more intensive physical therapy now that he can better comply with instructions. Nurses have been told to ask Wallis open-ended questions to help him develop answers beyond just "Yes" and "No."

Wallis has re-entered a world where so much was different. The World Trade Center, Pentagon (news - web sites) and the Oklahoma City federal building were all attacked by terrorists. The Berlin Wall is gone, as is the Soviet Union.

The Internet in 1984 was a loose affiliation of computers of interest only to academics. National League and American League baseball teams never played each other until the World Series (news - web sites). Roger Maris was still the home run king.

Wallis' daughter, Amber, was 6 weeks old at the time of the accident. Wallis said it is his goal to walk for her. During a visit with her last month, he was able to tell her, "You're pretty" and "I love you."

His long-term memory is keen. He remembered the telephone number of a long-dead grandmother and recalled driving a car whose transmission had failed, forcing him to drive in reverse.


Over the past 19 years, the Wallis family would pick him up at the Stone County Nursing and Rehabilitation Center and take him home or to family functions.

Zini said that probably aided in a gradual recovery that began with him reacting to a six-figure doctor's bill.

Eighteen years ago, Wallis shook his head violently when a doctor told the family that medical bills were running about $125,000 — as if to say the price was not acceptable, said his father, Jerry Wallis.

Later on, Wallis would react to Chevrolet TV commercials.

"He wouldn't drive a Chevrolet and when the commercials would come on the TV he'd have a fit. He'd shake his head from one side to the other and give some kind of hollering," Jerry Wallis said.


http://story.news.ya...nce_geniuses_dc

Geniuses, Criminals Do Best Work in Their 30s
Wed Jul 9, 5:54 PM ET Science - Reuters

LONDON (Reuters) - Geniuses and criminals may not seem to have much in common but they both do their best work in their 30s -- and mainly to impress the opposite sex.

When Satoshi Kanazawa, of the University of Canterbury in New Zealand, studied biographies of prominent, mostly male scientists he discovered that they made their key discovery before their mid 30s, around the same age that criminal behavior peaks.

He believes the male competitive urge to attract females is a driving force for the scientific and criminal achievements, according to New Scientist magazine.

"They do whatever they do in order to get laid," said Kanazawa.

He added that the competitive drive decreases with age and as men's priority shifts from competing for women to taking care of their offspring.

"Kanazawa also found that marriage dampens the drive in both arenas," the magazine added.

#2 Lazarus Long

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Posted 10 September 2003 - 07:25 PM

I have noticed a link to a behavior that may effect many members of our community and I suggest this is related to a mutation effecting our species at a cerebral level. It also appears to correlate to heightened intelligence and is commonly called Asperger Syndrome. I am also pursuing the additional complexity of associated dyslexia as characteristic of this mutation, or group of mutations.

Follow the links out and see if some of the description holds when we look in the mirror but also understand the linkage to genetics as it is possibly linked to the "X" chromosome.

Scientists Highlight the X Factor in Autism
Tue Sep 9, 9:43 AM ET Science - Reuters
By Jeremy Lovell

MANCHESTER (Reuters) - X may mark the spot in the search for the cause of autism, a brain disorder affecting millions of people across the globe, a leading research scientist said on Tuesday.

A part of the brain that is key to reading expressions in people's faces and which is affected by the X chromosome could give a new insight into the causes of the disease, says Professor David Skuse of the Britain's Institute of Child Health.
{excerpts}
http://story.news.ya...ience_autism_dc

http://www.newscient...p?id=ns99994145


Einstein and Newton showed signs of autism
New Scientist
19:00 30 April 03
Hazel Muir

They were certainly geniuses, but did Albert Einstein and Isaac Newton also have autism? According to autism expert Simon Baron-Cohen, they might both have shown many signs of Asperger syndrome, a form of the condition that does not cause learning difficulties.

Although he admits that it is impossible to make a definite diagnosis for someone who is no longer living, Baron-Cohen says he hopes this kind of analysis can shed light on why some people with autism excel in life, while others struggle.

Autism is heritable, and there are clues that the genes for autism are linked to those that confer a talent for grasping complex systems - anything from computer programs to musical techniques. Mathematicians, engineers and physicists, for instance, tend to have a relatively high rate of autism among their relatives.
{excerpts}
http://www.newscient...p?id=ns99993676

Generalist genes 'cause all learning disabilities'
http://www.newscient...p?id=ns99994146


**************

I would very much encourage everyone to follow back to the original links as there are additional studies and links on each page that can be very helpful in pursuing this subject. Also this comment does not actually belong in this thread but I thought it was nevertheless relevant to the general subject and tone of the posts so I thought to share it here but this post actually belongs linked to genetics.

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#3 Cyto

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Posted 10 January 2004 - 11:22 PM

How Sea Slugs Make Memories

Posted Image

Researchers studying how memories are made have discovered a protein that is critical to the process. They have also found that the protein works in an unusual way that may help neurons store memories for days or even weeks.

The protein changes its shape in a way similar to the prion protein that has been linked to mad cow disease. But unlike the prion protein, which in its altered state causes brain disease in cows, sheep, and humans, the newly discovered protein does a good thing, by helping nerve cells connect to each other.

Eric Kandel and his coworkers at Columbia University in New York City use a sea slug species known as Aplysia to study memory. The ugly slug uses a relatively simple system of neurons to remember certain stimuli and react to them. For example, the slugs can remember being pinched in the gill, and they learn to react by withdrawing the gill.

By the same token, in the brain, the trick to storing memories is to strengthen a specific synapse, a small gap between connecting neurons.

Kandel already knew that once a neuron receives a signal through one of its many synapses, that the synapse is somehow “marked.” But he didn’t know whether the proteins and protein precursors needed to strengthen the connection know which synapses to go to--or whether they go to all synapses but are used only where needed.

In new studies reported in Cell, Kausik Si, a member of Kandel’s lab, and his colleagues find that a protein called CPEB gets sent to all the synapses in a neuron. But at synapses that have been stimulated, the protein wakes up other molecules already there to produce new proteins that help strengthen the connection.

“New growth of synapses occurs in front of your eyes over the course of a day,” says Kandel.

For a long-term memory—one that lasts days and not hours—those connections must be maintained. But how does CPEB maintain the synaptic connection?

The researchers noticed that the protein has an unusual structure, similar to a yeast version of the prion protein. They found that when the slug memory protein is produced in yeast, it undergoes a similar change in shape.

“Usually, when these kinds of proteins change shape, they aggregate, and that can cause disease,” says Kandel. “But we found that it is the altered shape of the protein that is active. That was a surprise.”

The CPEB protein is also found in the neurons of humans, mice and fruit flies. Kandel hopes the studies will help researchers eventually understand how humans store long-term memories.
_____________________________________________-
For a great review on molecular processes (for what we know so-far) behind memory formation...

STRUCTURAL PLASTICITY AND MEMORY

PM me for any questions :))

#4 bacopa

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Posted 11 January 2004 - 06:58 PM

Lazarus great thread idea I think that memory, personality, and consciousness in general are all intertwined and the quest to find exactly how is an exciting field of research...like the guy coming out of the coma our personalities seemingly must be strongly influenced by our experiences. That man must have felt in the present the way he did back in the fifties growing up. I believe our personalities are interlinked with what we do, what we remember we did, and how others define us this is just a basic belief.

#5 Lazarus Long

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Posted 12 January 2004 - 05:23 PM

How we study the psychology of a person recovering from a coma is how we need to prepare for a cryogenic reanimation. I call this the Rip Van Winkle syndrome.

Again we find images from literature as modern myth can help us formulate an approach. Cultural and social aspects will conspire to produce a profound psychological dislocation in a person that has left the past for the present and the same would be true for a person among us that "died" only to be returned (resurrected) at a point reasonably distant in the future.

The lack of personal markers or anchors, friends, family members now dramatically older than when you last saw them, or even older than you when they were younger when last known. Aspects of how people eat, talk, greet one another, and 'function' within a socio-economic milieu would all be different. Getting acclimated is not an impossible feat but it is an issue that requires redress.

How we see memory is itself a part of the concern. I mentioned on a Cognitive Psyche thread that memory is a complex problem of filtered information. Think about the average search engine now, well the mind has the same problem all the time as it keeps constant telemetric data associated with conscious data.

I didn't mention another movie theme of a Philip K Dick novel but Total Recall comes to mind when I think about the problem. If we can turn a complete memory on then how would we distinguish it from real experience?

If enough data could be associated with the transfer of a memory the two events might be indistinguishable as the sensory data we normally depend upon to define experience would be conveyed and if while we were receiving the data for the first time we were "conscious" then for all intents and purposes we have returned to the dilemma of the matrix. Especially if the data flow is capable of being "tweaked" by the handler that is a true super-intelligent AI.

#6 bacopa

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Posted 13 January 2004 - 04:09 PM

Interesting anaylisis on the whole idea of dissociated thought and memory. It would seem that a Cryonics suspensioin is defineitely akin to Rip Van Winkle and his experiences. So you're saying that once we can control data flow we can than gain control over conscious experience this is an interesting idea.

The mind being like a search engine certainly is a good analogy...I would imagine that it would be very cool if we could play around with the filter and recall totally certain events verbatim. But I think one day intelligent AI or even simply greater human intellect will allow us to play around with certain parts of the brain responsible for the filtering of information.

I also think that there is no limit to how humans will one day be able to utilize more than just the 10% part of the brain assuming that statistic to be true, however I think that as in the other thread at the Tribe site that whoever said that we probably use more of our brains just not at the same time is probably correct.

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#7 Cyto

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Posted 05 February 2004 - 09:32 PM

MIT team discovers memory mechanism

"What we have discovered that hasn't been established before is that there is a direct activational signal from the synapse to the protein synthesis machinery," said Tonegawa, the Picower Professor of Biology and Neuroscience MIT's Departments of Brain and Cognitive Sciences and Biology. The central component of this pathway, an enzyme called "mitogen-activated protein kinase" (MAPK), effectively provides a molecular switch that triggers long-term memory storage by mobilizing the protein synthesis machinery.

Acting on a hunch that MAPK might be an important part of such a "memory switch," Ray Kelleher, a postdoctoral fellow in Tonegawa's laboratory and lead author of the study, created mutant mice in which the function of MAPK was selectively inactivated in the adult brain. Intriguingly, he found that these mutant mice were deficient in long-term memory storage. In contrast to normal mice's ability to remember a behavioral task for weeks, the mutant mice could remember the task for only a few hours. Similarly, the researchers found that synaptic strengthening was also much more short-lived in neurons from the mutant mice than in neurons from normal mice.

Realizing that the pattern of impairments in mutant mice suggested a problem with the production of new proteins, the researchers then performed an elegant series of experiments that revealed precisely how MAPK translates synaptic stimulation into increased protein synthesis. Based on molecular comparisons of neurons from normal and mutant mice, they found that synaptic stimulation normally activates MAPK, and the activated form of MAPK in turn activates several key components of the protein synthesis machinery. This direct regulation of the protein synthesis machinery helps explain the observation that activation of MAPK enhanced the production of a broad range of neuronal proteins.

"Many people had thought that long-term memory formation involved only boosting the synthesis of a very limited set of proteins," said Tonegawa. "But to our surprise, this process involves 'up-regulating' the synthesis of a very large number of proteins."


I know of two pathways involved during synapse. One is activation of survival prots and the other is force of differentiation/stall in G0 phase. "Conditional expression of a dominant-negative form of MEK1 in the postnatal murine forebrain inhibited ERK activation and caused selective deficits in hippocampal memory retention and the translation-dependent, transcription-independent phase of hippocampal L-LTP.(from cell paper)" Since the mouse already had differentiated neural nuclei (specialization of neural groups) I don't see how ERK 1/2 would have any effect on memory retention. Of course there is the pathway right next to it, the survival prots - these prots such as brain derived neurotrophic factor, glial derived neurotrophic factor and nerve growth factor do have documented involvement in forming and sustaining synapses.(resources upon request) Overall, Erk 1/2 is known for being apart of apoptosis, differentiation, stress, cell cycle actions. Since Mek 1/2 is apart of the pathway that activates IKK and leads to survival prot production which are the ones involved during synapse formation, I don't see how this is centered on Erk 1/2. I'll have to look at the full article later.

#8 kevin

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Posted 06 February 2004 - 09:09 AM

After reading the article below it is becoming more apparent how important our freedom to alter out cognitive abilities will become.


Link: http://www.eurekaler...t-mtd020404.php
Date: Feb 6, 2004

Contact: Elizabeth Thomson
thomson@mit.edu
617-258-5402
Massachusetts Institute of Technology

MIT team discovers memory mechanism
CAMBRIDGE, Mass. -- MIT neuroscientists have discovered a new brain mechanism controlling the formation of lasting memories. This mechanism explains how signals between neurons stimulate production of the protein building blocks needed for long-term memory storage.
The study, which will appear in the Feb. 6 issue of the journal Cell, has broad implications for our understanding of how learning and memory normally occur, and how these abilities may be undermined in psychiatric and neurologic diseases.

Long-lasting memories are stored in the brain through strengthening of the connections, or synapses, between neurons. Researchers have known for many years that neurons must turn on the synthesis of new proteins for long-term memory storage and synaptic strengthening to occur, but the mechanisms by which neurons accomplish these tasks have remained elusive.

The MIT research team, led by Nobel laureate Susumu Tonegawa, director of the Picower Center for Learning and Memory, has now identified a crucial molecular pathway that allows neurons to boost their production of new proteins rapidly during long-term memory formation and synaptic strengthening.

"What we have discovered that hasn't been established before is that there is a direct activational signal from the synapse to the protein synthesis machinery," said Tonegawa, the Picower Professor of Biology and Neuroscience MIT's Departments of Brain and Cognitive Sciences and Biology. The central component of this pathway, an enzyme called "mitogen-activated protein kinase" (MAPK), effectively provides a molecular switch that triggers long-term memory storage by mobilizing the protein synthesis machinery.

Acting on a hunch that MAPK might be an important part of such a "memory switch," Ray Kelleher, a postdoctoral fellow in Tonegawa's laboratory and lead author of the study, created mutant mice in which the function of MAPK was selectively inactivated in the adult brain. Intriguingly, he found that these mutant mice were deficient in long-term memory storage. In contrast to normal mice's ability to remember a behavioral task for weeks, the mutant mice could remember the task for only a few hours. Similarly, the researchers found that synaptic strengthening was also much more short-lived in neurons from the mutant mice than in neurons from normal mice.

Realizing that the pattern of impairments in mutant mice suggested a problem with the production of new proteins, the researchers then performed an elegant series of experiments that revealed precisely how MAPK translates synaptic stimulation into increased protein synthesis. Based on molecular comparisons of neurons from normal and mutant mice, they found that synaptic stimulation normally activates MAPK, and the activated form of MAPK in turn activates several key components of the protein synthesis machinery. This direct regulation of the protein synthesis machinery helps explain the observation that activation of MAPK enhanced the production of a broad range of neuronal proteins.

"Many people had thought that long-term memory formation involved only boosting the synthesis of a very limited set of proteins," said Tonegawa. "But to our surprise, this process involves 'up-regulating' the synthesis of a very large number of proteins."

An immediate question that Tonegawa and colleagues are pursuing is how neurons target the newly synthesized proteins to the specific synapses participating in memory formation while not modifying other synapses.

In addition to Tonegawa and Kelleher, the study's other authors (all in Tonegawa's lab) are graduate student Arvind Govindarajan and postdoctoral fellows Hae-Yoon Jung and Hyejin Kang.

Potential clinical impact

About the potential clinical impact of the study, Tonegawa observed, "As we continue to map out the molecular and cellular mechanisms of cognitive function, we will better understand the basis of disorders of memory impairment. Improved understanding makes it far more likely that we can develop drugs for specific molecular targets."

Defects in the strengthening and growth of synaptic connections are associated with a variety of psychiatric and neurologic conditions affecting the developing and adult brain, raising the possibility that disturbances in the mechanism identified in this study may contribute to these disorders, said Tonegawa. The next step will be to determine whether abnormalities in the regulation of protein synthesis can be identified in the affected brain regions in specific neuropsychiatric disorders.


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#9 LifeMirage

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Posted 25 February 2004 - 05:36 AM

FASEB J. 2004 Jan 8
Prenatal choline supplementation advances hippocampal development and enhances MAPK and CREB activation.

Mellott TJ, Williams CL, Meck WH, Blusztajn JK.

Choline is an essential nutrient for animals and humans. Previous studies showed that supplementing the maternal diet with choline during the second half of gestation in rats permanently enhances memory performance of the adult offspring. Here we show that prenatal choline supplementation causes a 3-day advancement in the ability of juvenile rats to use relational cues in a water maze task, indicating that the treatment accelerates hippocampal maturation. Moreover, phosphorylation and therefore activation of hippocampal mitogen-activated protein kinase (MAPK) and cAMP-response element binding protein (CREB) in response to stimulation by glutamate, N-methyl-D-aspartate, or depolarizing concentrations of K(+) were increased by prenatal choline supplementation and reduced by prenatal choline deficiency. These data provide the first evidence that developmental plasticity of the hippocampal MAPK and CREB signaling pathways is controlled by the supply of a single essential nutrient, choline, during fetal development and point to these pathways as candidate mechanisms for the developmental and long-term cognitive enhancement induced by prenatal choline supplementation.

http://www.ncbi.nlm....5&dopt=Abstract

Edited by LifeMirage, 28 March 2005 - 06:09 AM.


#10 MichaelAnissimov

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Posted 26 February 2004 - 02:14 AM

I see discoveries like this about *human memory specifically*, and say "hm, we learned something new about memory as it exists in a certain type of biological primate, but what does this tell us about a GENERAL THEORY of memory, the type of general theory we'd use to build memories in some AGI?" Even if the discovery is seemingly focused on memory-as-it-exists-in-humans, it is sure to inadvertantly uncover new information on general theories of memory, the area that I am genuinely concerned about. The thing is, however, since the focus is on the former rather than the latter, we should expect it to contain more new, useful information on human memory than memory-in-general, although you never know. When I was 16, I figured that any sufficiently intelligent AI would be benevolent, so I probably would have slightly rolled my eyes at an article like this, saying something like;

"Jeez, why are these scientists so excited about some discovery in human memory? If they put more effort towards theories of memory in general, then AI could be here sooner, and blah blah blah.""

Nowadays, though, I figure that most easy-to-build AGIs would *not* be benevolent, so I'd rather that the specialized knowledge of general theories of intelligence be concentrated in the minds of the people who know what they're dealing with... so, let's break this down a bit, in table form!

How would the following people react to the news article posted above?



Person Reaction Underlying Goal
Human Brain Enthusiast Yay! Understand H. sapiens brain
Reckless AGI Enthusiast Psh, big whup! Create any seed AI
Cautious AGI Enthusiast That's sorta neat. Create FAI specifically


(Hm, wondering what is up with all that whitespace. If any editors read this, feel free to change my post so the emptyness goes away...)

#11 Bruce Klein

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Posted 26 February 2004 - 03:39 AM

the forum software interprets spaces as a line brake.. to correct, one can eliminate the spaces. (i've made the space eliminations)

#12 bacopa

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Posted 26 February 2004 - 11:18 PM

Very intersting findings this seems to be right up the alley of research that will yield even better and more effective drugs to help us think better in this transition period from cruder drugs to more effective drugs to one day changing the whole apparatus of the wet ware to nano-enhanced brains I would imagine

#13 kevin

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Posted 27 February 2004 - 01:15 AM

Link: http://www.eurekaler...b-nfo022604.php

Contact: Karen Richardson
krchrdsn@wfubmc.edu
336-716-4587
Wake Forest University Baptist Medical Center


New findings on memory could enhance learning
Reasearchers find the existence of "Category Neurons" in hippocampus
WINSTON-SALEM, N.C. – New research in monkeys may provide a clue about how the brain manages vast amounts of information and remembers what it needs. Researchers at Wake Forest University Baptist Medical Center have identified brain cells that streamline and simplify sensory information – markedly reducing the brain's workload.
The findings are reported in the on-line edition of the Proceedings of the National Academy of Sciences.

"When you need to remember people you've just met at a meeting, the brain probably doesn't memorize each person's facial features to help you identify them later," says Sam Deadwyler, Ph.D., a Wake Forest neuroscientist and study investigator. "Instead, it records vital information, such as their hairstyle, height, or age, all classifications that we are familiar with from meeting people in general. Our research suggests how the brain might do this, which could lead to ways to improve memory in humans."

The researchers found that when monkeys were taught to remember computer clip art pictures, their brains reduced the level of detail by sorting the pictures into categories for recall, such as images that contained "people," "buildings," "flowers," and "animals." The categorizing cells were found in the hippocampus, an area of the brain that processes sensory information into memory. It is essential for remembering all things including facts, places, or people, and is severely affected in Alzheimer's disease.

"One of the intriguing questions is how information is processed by the hippocampus to retain and retrieve memories," said Robert Hampson, Ph.D., co-investigator. "The identification of these cells in monkeys provides evidence that information can be remembered more effectively by separating it into categories. It is likely that humans use a similar process."

The researchers measured individual cell activity in the hippocampus while the monkeys performed a video-game-like memory task. Each monkey was shown one clip art picture, and after a delay of one to 30 seconds, picked the original out of two to six different images to get a juice reward.

By recording cell activity during hundreds of these trials in which the pictures were all different, the researchers noticed that certain cells were more active when the pictures contained similar features, such as images of people – but not other objects. They found that different cells coded images that fit different categories.

"Unlike other cells in the brain that are devoted to recording simply an object's shape, color or brightness, the category cells grouped images based on common features – a strategy to improve memory," said Terry Stanford, Ph.D., study investigator. "For example, the same cell responded to both tulips and daisies because they are both flowers."

The researchers found, however, that different monkeys classified the same pictures differently. For example, with a picture of a man in a blue coat, some monkeys placed the image in the "people" category, while others appeared to encode the image based on features that were not related to people such as "blue objects" or "types of coats."

While such categorization is a highly efficient memory process, it may also have a downside, said the researchers.

"The over generalization of a category could result in errors," said Deadwyler. "For example, when the trials included more than one picture with people in it, instead of different images, the monkeys often confused the image with a picture of other people." The researchers said that learning more about how the brain remembers could have far reaching benefits.

"If we can understand in advance how the brain works when decisions are made, we can predict when the brain will make a mistake, and correct it," said Tim Pons, Ph.D., an expert in monkey research and team member. "This finding about how large amounts of information are processed by the brain will help us to ultimately achieve that goal."

"This discovery by the Wake Forest team could be the solution to a big puzzle," said Mortimer Mishkin, Chief of the Section on Cognitive Neuroscience, National Institutes of Mental Health. "Recollection -- bringing back to mind a past event -- depends critically on the hippocampus, but we haven't known how this works. The team's new findings suggest that hippocampal 'category ' neurons are some of the ones that help remind us of things we experienced before."


###
The research was funded by the National Institute on Drug Abuse, the National Institute of Mental Health and the Defense Advanced Research Projects Agency.

Media Contacts: Karen Richardson, krchrdsn@wfubmc.edu, or Shannon Koontz, shkoontz@wfubmc.edu, at 336-716-4587.

#14 kevin

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Posted 05 April 2004 - 06:16 AM

http://www.nytimes.c...ml?pagewanted=6

A really good article on how close we are to being able to help people forget unwanted memories and the 'ethical' reasons for not.




The Quest to Forget
By Robin Marantz Henig, 4/4/2004

A 29-year-old paralegal was lying in the middle of Congress Street in downtown Boston after being run over by a bicycle messenger, and her first thought was whether her skirt was hiking up. ''Oh, why did I wear a skirt today?'' she asked herself. ''Are these people all looking at my underpants?''

Her second thought was whether she would be hit by one of the cars speeding down Congress -- she wasn't aware that other pedestrians had gathered around, some of them directing traffic away from her. And her third thought was of a different trauma, eight years earlier, when driving home one night, she was sitting at a red light and found herself confronted by an armed drug addict, who forced his way into her car, made her drive to an abandoned building and tried to rape her.

''I had a feeling that this one trauma, even though it was a smaller thing, would touch off all sorts of memories about that time I was carjacked,'' said the woman, whose name is Kathleen. She worried because getting over that carjacking was something that had taken Kathleen a long time. ''For eight months at least,'' she said, ''every night before I went to bed, I'd think about it. I wouldn't be able to sleep, so I'd get up, make myself a cup of decaf tea, watch something silly on TV to get myself out of that mood. And every morning I'd wake up feeling like I had a gun against my head.''

Would Kathleen have been better off if she had been able to wipe out the memory of the attack rather than spending months seeing a psychologist and avoiding the intersection where the carjacking occurred? The answer seems straightforward: if you can ease the agony that people like Kathleen suffer by dimming the memory of their gruesome experiences, why wouldn't you? But some bioethicists would argue that Kathleen should hold on to her nightmarish memory and work through it, using common methods like psychotherapy, cognitive behavior therapy or antidepressants. Having survived the horror is part of what makes Kathleen who she is, they say, and blunting its memory would diminish her and keep her from learning from the experience, not to mention impair her ability to testify against her assailant should the chance arise.

Scientists who work with patients who suffer from post-traumatic stress disorder see the matter quite differently. As a result, they are defending and developing a new science that can be called therapeutic forgetting. True post-traumatic stress can be intractable and does not tend to respond to most therapies. So these scientists are bucking the current trend in memory research, which is to find a drug or a gene that will help people remember. They are, instead, trying to help people forget.

All of us have done things in our lives we'd rather not have done, things that flood us with remorse or pain or embarrassment whenever we call them to mind. If we could erase them from our memories, would we? Should we? Questions like these go to the nature of remembrance and have inspired films like ''Memento'' and, most recently, ''Eternal Sunshine of the Spotless Mind,'' in which two ex-lovers pay to erase their memories of each other. We are a long way from the day when scientists might be able to zap specific memories right out of our heads, like a neurological neutron bomb, but even the current research in this area ought to make us stop and think. Aren't our memories, both the good and the bad, the things that make us who we are? If we eliminate our troubling memories, or stop them from forming in the first place, are we disabling the mechanism through which people learn and grow and transform? Is a pain-free set of memories an impoverished one?

After her bike-messenger collision, Kathleen was taken to the emergency room of Massachusetts General Hospital. Once her physical wounds were attended to -- she wasn't badly hurt; just a few cuts and bruises -- she was approached by Anna Roglieri Healy, a psychiatric nurse. Healy was engaged in a pilot study to test whether administering drugs immediately after a traumatic event could prevent the development of post-traumatic stress disorder. Did Kathleen want to be part of the study?

''I thought it might be a good idea,'' Kathleen said recently. ''Not that I really thought I'd develop problems after this bike accident, but I knew I was prone to post-traumatic stress disorder because I developed it after my carjacking.''

Kathleen signed on to the study, which was being directed by Roger Pitman, a professor of psychiatry at Harvard Medical School. (Pitman requested that Kathleen's last name not be used for this article because of her status as a research subject.) Like the 40 other subjects, she took a blue pill four times a day for a week and a half and then gradually reduced the dosage over the course of another nine days -- a total of 19 days of treatment. Half of the subjects were taking an inert placebo pill and half were taking propranolol, which interferes with the action of stress hormones in the brain.

When stress hormones like adrenaline and norepinephrine are elevated, new memories are consolidated more firmly, which is what makes the recollection of emotionally charged events so vivid, so tenacious, so strong. If these memories are especially bad, they take hold most relentlessly, and a result can be the debilitating flashbacks of post-traumatic stress disorder. Interfering with stress hormone levels by giving propranolol soon after the trauma, according to Pitman's hypothesis, could keep the destructive memories from taking hold. He doesn't expect propranolol to affect nonemotional memories, which don't depend on stress hormones for their consolidation, but he said it could possibly interfere with the consolidation of highly emotional positive memories as well as negative ones.

Pitman's hypothesis, if it is confirmed experimentally, might lead to a basic shift in our understanding of remembering and forgetting, allowing us someday to twist and change the very character of what we do and do not recall.


The idea that forgetting could ever be a good thing seems counterintuitive, especially in a culture steeped in fear of Alzheimer's disease. When it comes to memory, most people are looking for ways to have more of it, not less. If you can boost your ability to remember, you can be smarter, ace the SAT's, perform brilliantly in school and on the job, stay sharp far into old age.


But with memory, more is not always better. ''At the extreme,'' James McGaugh, director of the Center for the Neurobiology of Learning and Memory at the University of California at Irvine, said recently, ''more is worse.''

McGaugh recalled the Jorge Luis Borges short story ''Funes, the Memorious,'' in which Ireneo Funes is thrown from a horse. The injury paralyzes his body and turns his memory into a ''garbage heap.'' Funes remembers everything: ''He knew the forms of the clouds in the southern sky on the morning of April 30, 1882, and he could compare them in his memory with the veins in the marbled binding of a book he had seen only once. . . . The truth was, Funes remembered not only every leaf of every tree in every patch of forest, but every time he had perceived or imagined that leaf.''

And yet, as Borges writes, such a prodigious memory is not only not enough -- it is much too much: ''[Funes] had effortlessly learned English, French, Portuguese, Latin. I suspect, nevertheless, that he was not very good at thinking. To think is to ignore (or forget) differences, to generalize, to abstract. In the teeming world of Ireneo Funes there were nothing but particulars -- and they were virtually immediate particulars.''

Most of us are quite capable, sometimes far more capable than we'd like, of forgetting the particulars. Where did you park your car at the train station this morning? What's another word for pretty? What year was the Constitution ratified? So many details seem out of reach, lost in a murky mental morass. But McGaugh has found that certain memories -- the ones associated with the strongest emotions -- tend to stay locked in longer, sometimes for life. You can't possibly remember every time you and your wife kissed, but you probably remember the first time.

At the memory center in Irvine, McGaugh and his colleague Larry Cahill did a simple recall test that demonstrated how much more sharply people remember emotional memories than neutral ones. Cahill showed subjects a series of 12 slides and told them a story to accompany the images. The slides were always the same, but the words to the story changed from one group to another. To the first group, Cahill told an emotionally neutral story: a boy and his mother leave their home and cross the street and pass a car that has been damaged in an accident. They visit the boy's father, who works in a hospital. During their visit, the staff is having a disaster-preparation demonstration. The boy and his mother see people with makeup on to make them appear as if they have been injured. The mother makes a telephone call, goes to the bus and goes home.

To the second group, Cahill told a different story. It began the same way -- a boy and his mother leave their home and cross the street -- but then it diverged: the boy is hit by a car. The boy is seriously injured and is rushed to the hospital. At the hospital, surgeons work frantically to save the boy's life and to reattach his severed legs. The second story ended just the way the first one did: the mother makes a telephone call, goes to the bus and goes home.

When the subjects were taken back to the laboratory two weeks later, they were asked to describe what they had seen on the slides. Don't tell the story, they were instructed; just say what you remember about the pictures -- how many people were there, what were they wearing and so on.

The people who had been told the neutral story remembered all three parts of it with the same degree of accuracy. Those who had been told the exciting story had significantly better recall of the slides corresponding to the boy's injury and operation. To McGaugh, this experiment underlines the phenomenon observed by Rene Descartes more than three centuries ago. ''The usefulness of all the passions consists in their strengthening and prolonging in the soul thoughts which are good for it to conserve,'' Descartes wrote. ''And all the harm they can do consists in their strengthening and conserving . . . others which ought not to be fixed there.''

Cahill took the experiment one step further: he gave a dose of propranolol to a new batch of subjects and showed them the same slides with the same gory story. Propranolol is one of a class of drugs known as beta blockers, usually given to heart patients to inhibit the action of adrenaline on the beta-adrenergic receptors in the heart. (Unlike some beta blockers, it acts directly on the brain.) This time, the gory story did not prove more memorable. Those receiving propranolol were able to recall the pictures no better than those who had heard the emotionally blander story. This was the first suggestion that it might be possible in humans to interfere pharmacologically with the recollection of intense memories.

McGaugh and Cahill's work gave Roger Pitman of Harvard the idea for his own study of propranolol in post-trauma treatment. It seemed to Pitman, who had spent much of his career studying post-traumatic stress in Vietnam veterans, that the drug could eventually offer relief to people disabled by horrifying, intrusive memories of battle.

''Working with veterans made it clear that post-traumatic stress disorder is different from just having bad memories,'' Pitman said. ''These men said that frequently when they remembered Vietnam, every detail came back to them -- the way it smelled, the temperature, who they were with, what they heard.''

The subjects in Pitman's study had all, at one time or another, been taken to the Mass. General emergency room after a variety of traumas. Several had been sexually assaulted; one had smashed her car into a tree; another had fallen into one of the huge pits created by the Big Dig construction project that has bewildered Boston's pedestrians and drivers for more than a decade. But while Anna Healy was pleased at how many people agreed to be part of the study, not everyone in the E.R. said yes. According to Pitman, several seemed too shaken to want to relive their traumas, even under controlled experimental conditions.

While she was enrolled in Pitman's study, Kathleen said she believed she was in the placebo group, since the pills made her feel no different -- no better, no worse. Three months after her accident, she went back to Mass. General and related the details of her collision, which a researcher compiled into a 100-word narrative and read into a tape recorder. A week later, Kathleen came back and listened to the tape while her physiological stress indicators (sweating, heart rate, muscle tension) were measured and compared with those of the other study subjects. When they heard the scripts of their traumas, 43 percent of the placebo group responded with increased physiological measures of stress. In the propranolol group -- of which Kathleen, despite her suspicions, was part -- no one did.

But when Pitman asked Kathleen and the other study subjects whether they believed that memories of their trauma were impairing their daily lives, he found no significant difference between the propranolol and the placebo groups.

The National Institute of Mental Health found these preliminary results intriguing enough to want more information about propranolol's usefulness after a trauma. The goal is nothing at all like the fictional goal in ''Eternal Sunshine of the Spotless Mind''; even if Pitman's treatment does everything he hopes, it would succeed only in easing the pain of the troubling memory, not erasing it. This summer, Pitman will begin recruiting participants for a new study financed by the institute, aiming for a total of 128. Once again he will give propranolol to half of them and a placebo pill to the other half, and he will test their physiological stress response to imagery of the trauma one and three months after it occurs.

''I'm prepared for the possibility that this second study will have negative results,'' Pitman said. ''But even if there's, say, just a 20 percent chance that I'm right, that's a 20 percent chance of finding a method that works in the secondary prevention of post-traumatic stress disorder. Think of the amount of human suffering that we would be able to avoid.''

Pitman's approach to post-traumatic stress disorder, however, is a blunt instrument. It could mean giving a drug to all the people who come to the E.R. after a trauma -- at least 70 percent of whom will never develop any long-term problems even if they're left alone. The drug is a relatively safe one, with a long track record of use for hypertension, but even relatively safe drugs carry risks. (Propranolol is not used much for heart disease anymore; the beta blockers now more commonly prescribed don't tend to reach the brain and probably don't have much impact on emotional memories.) If Pitman's research leads to making propranolol standard treatment in post-trauma care, this might mean that someday people who would have recovered from their trauma quite well on their own would be given a preventive medication they didn't need.

The better approach would be to target the people prone to the disorder and to treat them immediately. The trick, of course, is knowing who they are. Studies have shown that patients with post-traumatic stress disorder tend to have a smaller than normal hippocampus -- a brain region involved in memory. But is this size difference a cause of post-traumatic stress disorder or an effect? Pitman sought the answer in the brains of identical twins. He found 135 pairs of twins in which one twin had gone to Vietnam but the other had not. Some of the veterans developed post-traumatic stress disorder; others had no such problems. The noncombatant twins of the traumatized vets had smaller hippocampi than the twins of the vets who fared better psychologically. This finding suggests that a small hippocampus is a marker for susceptibility to post-traumatic stress disorder.

Another alternative to a propranolol-for-everyone approach would be to wait awhile after exposure to a trauma to see who develops debilitating symptoms. But no one is quite sure how long you can wait. When is it too late to keep these corrosive memories from taking hold? According to Barbara O. Rothbaum, director of the Trauma and Anxiety Recovery Program at Emory University, it takes at least a couple of weeks to see who will encounter long-term psychiatric problems after trauma.

''In general, the initial response is not predictive of who is going to have a chronic disorder,'' she said. Immediate problems, according to Rothbaum, are almost inevitable: nightmares, difficulty sleeping, obsessive thoughts about the trauma.

''Most people come down a lot after the first month,'' she said. ''After that, the people who are going to improve continue to improve.'' And the ones who don't improve stay stuck. The rule of thumb, Rothbaum said, is that people with symptoms after four months will probably still have symptoms after four years -- and if left untreated, some of those symptoms may persist not just for years but for decades. The problem is that if you wait until you know who really needs treatment, you may lose the chance to make that treatment effective.

One way out of this dilemma may be through the window opened by memory reconsolidation. Memories, even intense and troubling memories, seem to be vulnerable to erasure at many points during a person's lifetime. This means that it could work to hold off on propranolol or other drug therapy until recurring problems develop.

''When you retrieve a memory, that's a time when you update it with all the relevant things that happened since you stored it,'' said Joseph LeDoux, the Henry and Lucy Moses Professor of Neuroscience at New York University. When a traumatic memory is brought forth, he said -- the scripted imagery used in Pitman's experiment is one way to accomplish this -- it is in a fragile state. And research suggests that unless it is reconsolidated with the formation of new proteins in the brain, the memory starts to disappear.

LeDoux and his colleague Karim Nader have studied the mechanism of memory reconsolidation in laboratory rats. He trained the rats to be afraid of a musical tone by following the tone with a mild electrical shock to the foot. Twenty-four hours later, he played the tone once more, thus reactivating the traumatic ''fear memory'' in the rats. But instead of giving a shock, he delivered a dose of anisomycin directly into the rats' brains. Anisomycin, a compound approved only for use in experimental animals, inhibits the synthesis of protein, which is needed to form the new synapses that are part of both memory consolidation and reconsolidation.

For about two hours the fear memory persisted: the rats heard the tone, and they froze in fear. But 24 hours later, playing the tone elicited no such fear response. ''It was as though the fear memory had totally disappeared,'' LeDoux said. Anisomycin had prevented the synthesis of protein -- and without new protein, the reconsolidated memory could not be glued into place, and the original memory apparently vanished.

What LeDoux doesn't know is whether the original memory is lost or simply can't be retrieved. ''We have trouble determining whether the failure to show the fear memory is because you've blocked encoding of the memory itself or of its retrieval,'' he said. ''Maybe the memory is still in the brain, but the animal just can't get at it.'' The distinction is relevant because memories that appeared to be lost sometimes have a habit of re-emerging.

Pitman points to rat research suggesting that the original memory is indeed still there, deep inside the brain, even if the animal's behavior makes it look as if it is lost. In one intriguing extension of LeDoux's experiment, the rats looked perfectly serene when the original fear-inducing musical tone was played: no frightened freezes. However, their amygdala, the region of the brain activated by fear, had not forgotten to be afraid; it remained just as ready to generate a fear response. What seemed to be happening was that another region of the brain, the infralimbic cortex, was signaling that fear was no longer necessary. The infralimbic cortex was keeping the amygdala from generating the fear response -- but the fear was still there, blocked and buried.

According to Pitman, this finding indicates that long-dormant fears can reawaken and might explain why Kathleen's relatively minor dust-up with the bike messenger set off memories of her earlier, deeper terror after the carjacking and sexual assault. Or it could explain why a World War II veteran, who had recovered from post-traumatic stress disorder decades earlier, gets a diagnosis of prostate cancer in his 60's and begins having nightmares about battlefield horrors that took place 40 years before.


If memories of a horrific trauma are haunting someone, overwhelming him with fresh, immobilizing feelings whenever he remembers the original event, should he be forced to hold onto those memories? Some would answer yes. Late last year, the President's Council on Bioethics issued a report called ''Beyond Therapy: Biotechnology and the Pursuit of Happiness,'' which dealt in part with the possibility of therapeutic forgetting. It concluded that it was not necessarily wise.

''Changing the content of our memories or altering their emotional tonalities, however desirable to alleviate guilty or painful consciousness, could subtly reshape who we are,'' the council wrote in ''Beyond Therapy.'' ''Distress, anxiety and sorrow [are] appropriate reflections of the fragility of human life.'' If scientists found a drug that could dissociate our personal histories from our recollections of our histories, this could ''jeopardize . . . our ability to confront, responsibly and with dignity, the imperfections and limits of our lives and those of others.''

One council member, Rebecca Dresser, expressed the majority sentiment during a council session in late 2002. The ability to suffer the ''sting'' of a painful memory is ''where a lot of empathy comes from,'' said Dresser, a professor of ethics in medicine at Washington University in St. Louis. ''That is, when we have an embarrassing experience, we develop empathy for others who have a similar experience. . . . We want some of that sting. So the question is: what is dysfunctional sting?''

The difficulty is defining ''dysfunctional,'' since the sting that's dysfunctional for an individual is different from the sting that's dysfunctional for society. As Dresser pointed out, society has a stake in having its citizens retain their own painful, awkward memories as a check on behavior. ''There probably is some sting that we would rather not have as individuals,'' she said, ''but it's good for the rest of us that others have it.''

Some ethicists add that it's also good for the people who are suffering themselves; the painful memories, they say, are all part of what makes us who we are, and diminishing them would diminish our humanity.

''Would dulling our memory of terrible things make us too comfortable with the world, unmoved by suffering, wrongdoing or cruelty?'' asks the bioethics council in its report. ''Does not the experience of hard truths -- of the unchosen, the inexplicable, the tragic -- remind us that we can never be fully at home in the world, especially if we are to take seriously the reality of human evil?'' The council also asked whether the blunting of our recollections of ''shameful, fearful and hateful things'' might also blunt our memories of the most wondrous parts of our lives. ''Can we become numb to life's sharpest arrows without becoming numb to its greatest joys?''

Still, to scientists who study memory, there is nothing beneficial, for either individuals or for society, about debilitating, unbidden memories of combat, rape or acts of terrorism. ''Going through difficult experiences is what life is all about; it's not all honey and roses,'' said Eric Kandel, a professor of psychiatry and physiology at Columbia University. ''But some experiences are different. When society asks a soldier to go through battle to protect our country, for instance, then society has a responsibility to help that soldier get through the aftermath of having seen the horrors of war.''

Of course, post-battlefield remorse serves as a check on our militaristic tendencies. Vietnam veterans haunted by memories of combat were among the most forceful opponents of the war after their return home. But have we the right to buy a surrogate conscience at the cost of thousands of ruined lives? If we have the responsibility to treat veterans' physical wounds, don't we also have a responsibility to ease their psychic suffering?

The human condition remains rich and complicated even without that psychic pain, said William May, an emeritus professor of ethics at Southern Methodist University in Dallas and a former member of the President's Council on Bioethics. ''Perhaps just as dangerous as writing out memory,'' May said at the same council session at which Dresser spoke, ''is the reliving of a past event that is so wincing in memory that one engages in a kind of suffering all over again, which is unproductive of a future.'' Remorse can be ''unavailing,'' he said, and can leave a person stuck ceaselessly in the past.

Without witnessing the torment of unremitting post-traumatic stress disorder, it is easy to exaggerate the benefits of holding on to bitter memories. But a person crippled by memories is a diminished person; there is nothing ennobling about it. If we as a society decide it's better to keep people locked in their anguish because of some idealized view of what it means to be human, we might be revealing ourselves to be a society with a twisted notion of what being human really means.

#15 kevin

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Posted 16 April 2004 - 06:14 AM

Link: http://www.nature.co...2/040412-3.html



Memory bottleneck limits intelligence
Single spot in brain determines size of visual scratch pad.

15 April 2004
TANGUY CHOUARD



Posted Image
Your working memory can be
seen on a scan.
© Photodisc

The number of things you can hold in your mind at once has been traced to one penny-sized part of the brain.

The finding surprises researchers who assumed this aspect of our intelligence would be distributed over many parts of the brain. Instead, the area appears to form a bottleneck that might limit our cognitive abilities, researchers say.

"This is a striking discovery," says John Duncan, an intelligence researcher at the Cognition and Brain Sciences Unit in Cambridge, UK.

Most people can hold three or four things in their minds at once when given a quick glimpse of an image such as a collection of coloured dots, or lines in different orientations. If shown a similar image a second later, they will be able to recognise whether three or four of these spots and lines are identical to the first set or not.

But some people can only catch one or two things in a glance, while others can capture up to five.

This very short-term memory capacity is thought to be related to intelligence. In the same way that a computer with a larger working memory can crank through problems more quickly, people with a greater capacity for holding images in their heads are expected to have better reasoning and problem-solving skills.

A person's working memory capacity can be determined using simple psychological tests. But now two teams of researchers report in Nature that they can see it in brain scans too.

Keep it in mind

One of the teams, led by Edward Vogel of the University of Oregon in Eugene, found that the electrical activity in a single section of the brain, as detected through electrodes attached to the scalp, is directly related to short-term working memory1.

The team first tested subjects with an image of two coloured dots, waiting a second between flashes and asking the subjects if the image had changed. They then ramped up the test to four dots.

A large increase in the subject's brain activity on the four-dot test indicated that his or her memory capacity had not been pushed to its limit. No increase in electrical activity indicated that his or her working memory had topped out on the two-dot test. By graphing these responses, the team worked out the exact size of each subject's working memory.

A second team, led by René Marois of Vanderbilt University in Nashville, Tennessee, used functional magnetic resonance imaging during similar tasks to accurately locate the part of the brain being used for short-term visual memory2.

Both teams concluded that everything depended on the same tiny spot in the posterior parietal cortex.

"It is amazing that both groups should converge on the same area in the end," says Duncan. Since the task involves remembering many different aspects of each object, including spatial position, orientation and colour, most people thought that several parts of the brain would be involved, he says.

There are still many other aspects to human intelligence that are governed by other parts of the brain, the authors of both studies warn. But the capacity of one's working memory may form a bottleneck for certain kinds of intelligence, they say.

Tanguy Chouard is a senior biological sciences editor at Nature


References
Vogel, E. K. & Machizawa, M. G. . Nature, 428, 748 - 751, doi:10.1038/nature02447 (2004). |Article|
Todd, J. J. & Marois, R. . Nature, 428, 751 - 754, doi:10.1038/nature02466 (2004). |Article|

#16 randolfe

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Posted 22 April 2004 - 12:52 AM

Kevin, I see that you only posted an excerpt from the New York Times Magazine article. To access it now, they ask for $2.95 purchase fee.

I understand something of copyright laws. However, I am not clear regarding reproducing them without a profit motive. Politicians and others routinely reproduce favorable articles about themselves as literature.

Also, political groups print articles to underscore an argument they are making. While I seriously doubt anyone would bother "pressing charges", I am really unclear as to whether people posting articles, rather than just links, actually place this group at any risk for liability.

I usually limit an excerpt to 250 words, which I understand is the "legal limit", and put a link up if possible. However, I noted Lazarus Long frequently copies New York Times articles and posts them because he knows they will become "unavailable" in seven days (I believe). I did the same with an article about MRI imaging of the brain for political reactions just a few minutes ago. Do you know exactly what the parameters are?

#17 kevin

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Posted 22 April 2004 - 03:14 AM

Hi Randolfe,

I've managed to find an entire copy of the original article which I didn't post in its entirety as it was pretty long and I forgot that there would be a time limit on the article.

There was some discussion some time ago as to copyright and at the time it was decided that we would post links and give credit, but that it would be left up to the poster to decide how much of the article to post. I've been frustrated way too many times by the same thing you found that suddenly.. you have to pay money to get an article that is free... or worse.. that the article has been removed, never to be found again. As there is no charge for participation in the forums we are definitely not making money on reproducing the material and we are all making fair comment on the contents of the articles so are onside as far as using the articles for discussion which is important.

I would contend that we qualify as a library and as a resource for study although some may beg to differ.

#18 kevin

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Posted 07 May 2004 - 12:30 AM

Link: http://www.eurekaler...t-suh050604.php


Public release date: 6-May-2004
Contact: Laura Greer
laura.greer@sickkids.ca
416-813-5046
University of Toronto

Scientists uncover how brain retrieves and stores older memories
TORONTO (May 6, 2004) -- Scientists at The Hospital for Sick Children (Sick Kids) and UCLA have pinpointed for the first time a region of the brain responsible for storing and retrieving distant memories. This research is reported in the May 7, 2004 issue of the journal Science.

"It was previously known that the hippocampus processes recent memory, but that the hippocampus did not store memories permanently. We were able to determine that it is the anterior cingulate cortex where older, or lifelong, memories are stored and recalled," said Dr. Paul Frankland, the study's co-lead author, a scientist in the Sick Kids Research Institute, and assistant professor of physiology at the University of Toronto.

The formation of new memories is thought to involve the strengthening of synaptic connections between groups of neurons. Remembering involves the reactivation of the same group, or network, of neurons. As memories age, the networks gradually change. Initially, memories for everyday life events appear to depend on networks in the region of the brain called the hippocampus. However, over time, these memories become increasingly dependent upon networks in the region of the brain called the cortex.

"We believe there is active interaction between the hippocampus and cortex, and that the transfer process of memories between these two regions in the brain occurs over several weeks, and likely during sleep," added Dr. Frankland, holder of the Canada Research Chair in Cognitive Neurobiology.

The researchers used a series of strategies with mice, including a mouse model with an altered form of a gene called CaMkinase II, which eliminates the ability to recall old memories, to identify the role of the anterior cingulate cortex.

"Most people define memory as their collective lifetime experiences. These memories colour who we are, yet until now, we've been mystified by how the brain saves and retrieves them," said Dr. Alcino Sliva, the study's principal investigator and professor of neurobiology, psychiatry and psychology at the David Geffen School of Medicine at UCLA. "Now that we know where to look, we're one step closer to developing drugs to target genes or processes of the brain that may be related to memory disorders."

Other authors on the paper include Dr. Bruno Bontempi, co-lead author, Dr. Lynn Talton, and Dr. Leszek Kaczmarek. The US National Institute on Aging funded the study.


###
The Hospital for Sick Children, affiliated with the University of Toronto, is Canada's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health. For more information, please visit www.sickkids.ca.

#19 Lazarus Long

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Posted 09 May 2004 - 09:29 PM

This opinion and perspective piece belongs here I think. I want to post it along with a link to a new site on Neuroinformatics. It is from abroad but can help be a kiosk for us all.

The Neuroinformatics Portal Pilot This site presents the Neuroinformatics Portal Pilot. This project is part of a larger effort to promote the exchange of neuroscience data, data-analysis tools, and modeling software. For this pilot project, we do not aim at providing substantial resources. We rather develop the basic infrastructure needed for an optimal utilization of the many available resources at a later point in time.
http://www.neuroinf.de/

I am really beginning to question what some see as disorder could also be seen as adaptive mutation. How familiar are you folks with the symptoms of Asperger's Syndrome?
http://www.udel.edu/bkirby/asperger/

One of the difficulties is the inability to conduct interpersonal affairs as they are so globally minded they cannot cope well with common chit chat. That for example sounds like a survival skill in the Globalizing world, a down right advantage.

http://www.nytimes.c...harm.html?8hpib
Posted Image
NEURODIVERSITY FOREVER
The Disability Movement Turns to Brains
By AMY HARMON
Published: May 9, 2004

NO sooner was Peter Alan Harper, 53, given the diagnosis of attention deficit disorder last year than some of his family members began rolling their eyes.

To him, the diagnosis explained the sense of disorganization that caused him to lose track of projects and kept him from completing even minor personal chores like reading his mail. But to others, said Mr. Harper, a retired journalist in Manhattan, it seems like one more excuse for his inability to "take care of business."

He didn't care. "The thing about A.D.D. is how much it affects your self-esteem,'' Mr. Harper said. "I had always thought of myself as someone who didn't finish things. Knowing why is such a relief.''

As the number of Americans with brain disorders grows, so has skepticism toward the grab bag of syndromes they are being tagged with, from A.D.D. to Asperger's to bipolar I, II or III.

But in a new kind of disabilities movement, many of those who deviate from the shrinking subset of neurologically "normal" want tolerance, not just of their diagnoses, but of their behavioral quirks. They say brain differences, like body differences, should be embraced, and argue for an acceptance of "neurodiversity."

And as psychiatrists and neurologists uncover an ever-wider variety of brain wiring, the norm, many agree, may increasingly be deviance.

"We want respect for our way of being," said Camille Clark, an art history graduate student at the University of California at Davis who has Asperger's syndrome, a form of autism often marked by an intense interest in a single subject. "Some of us will talk too long about washing machines or square numbers, but you don't have to hate us for it."

Last month, Ms. Clark helped start an Internet site called the Autistic Adults Picture project (http://www.isn.net/~...AuSpin/a2p2.htm), where dozens of people list their professions and obsessions next to a photograph. The idea is to show normal-looking people, whose peculiarities stem from their brain wiring - and who deserve compassion rather than exasperation.

Overcoming the human suspicion of oddity will be hard, the more so because the biological basis of many brain disorders can't be easily verified. Usually, all anyone has to go on is behavior.

"It's a tough one," wrote one participant in an online discussion of Asperger's syndrome. "Was that woman," he asked, just "unwilling to think about others' feelings, not caring about whether she's boring me with the minute details of her breakfast wrap?" Or, he asked, was she "really truly incapable of adapting herself to social mores?"

Science is beginning to clear up such questions, said Dr. Antonio Damasio, a neurologist at the University of Iowa Medical Center, by identifying distinct brain patterns and connecting them to behavior. But, he added, only society can decide whether to accommodate the differences.

"What all of our efforts in neuroscience are demonstrating is that you have many peculiar ways of arranging a human brain and there are all sorts of varieties of creative, successful human beings," Dr. Damasio said. "For a while it is going to be a rather relentless process as there are more and more discoveries of people that have something that could be called a defect and yet have immense talents in one way or another."

For example, when adults with A.D.D. look at the word "yellow" written in blue and are asked what the color is and then what the word is, they use an entirely different part of the brain than a normal adult. And when people with Asperger's look at faces, they use a part of the brain typically engaged when looking at objects.

Dr. Damasio and others compare the shifting awareness about brain function to the broader conception of intelligence that has evolved over the last two decades, driven in part by the theory of Howard Gardner, a Harvard education professor, that children who don't excel in "traditional" intelligence - the manipulation of words and numbers - may shine in other areas such as spatial reasoning or human relations.

Skeptics, like Mr. Harper's family, and some medical professionals argue that clinicians are too quick to hand out a diagnosis to anyone who walks through the door. In an effort to rein in the number of diagnoses, the American Psychiatric Association imposed a new criterion in its latest edition of the Diagnostic Statistical Manual: an individual must now suffer from "impairment" to qualify as having one of its 220 psychological disorders. "We're not adequately differentiating normal from pathological if we just use the criteria that are in the syndrome definitions," said Dr. Darrel A. Regier, director of research for the American Psychiatric Association.

The definition of "impairment,'' however, remains vague. And many clinicians chafe at the manual's rigid diagnostic criteria.

"Say the diagnostic category for a depressive disorder is four out of eight symptoms, and you have two," said Dr. John Ratey, a Harvard University psychiatrist. "What are you, just miserable?"

For patients, being given a name and a biological basis for their difficulties represents a shift from a "moral diagnosis" that centers on shame, to a medical one, said Dr. Ratey, who is the author of "Shadow Syndromes," which argues that virtually all people have brain differences they need to be aware of to help guide them through life.

But the most humane approach, some experts argue, may lie in redefining the expanding set of syndromes as differences rather than diagnoses.

"We're doing a service on the one hand by describing many more of these conditions and inviting people to understand themselves better," said Dr. Edward Hallowell, a leading authority on A.D.D. "But when we pathologize it we scare them and make them not want to have any part of it. I think of these as traits, not disorders."

Knowing you are a mild depressive, for instance, could induce you to exercise often. A bipolar person could adapt their lives to fit their mood swings, or treat them with drugs if that works better. And a neurologically tolerant society would try to accommodate as well as understand behavior that remained aberrant.

Others take a more pragmatic approach to the newly available information about how the brain works. In his recent book, "Mind Wide Open: Your Brain and the Neuroscience of Everyday Life" (Scribner), Steven Johnson undergoes a barrage of neurological tests to learn more about his own quirks. "For a long time when scientists talked about the brain it was, 'the human brain functions this way,' '' Mr. Johnson said. "But the great promise of this moment is that we can begin to understand what makes us different as well as what makes us all alike. Enough about the human race - I want to hear about me."

Mr. Johnson, who found himself to be better at language than visual processing, said his wife used to get annoyed when he couldn't recall details about a house they were planning to renovate. Now, he says, they understand that she is better at visual tasks, and he tries harder to compensate.

Many of those who advocate greater tolerance for brain quirks caution that it should not serve as an excuse for individuals to behave inappropriately. "It's not a get-out-of-jail-free card," Dr. Ratey said. "It's an awareness of what you need to do or accept about yourself and then decide, 'Do I want to fit in more or not?' ''

The answer, increasingly, may be "not." Many A.D.D. adults say their condition contributes to their creativity, and some with Asperger's are now critiquing those they call "neurotypicals."

On Internet sites like the Institute for the Study of the Neurologically Typical (isnt.autistics.org), autistics satirize the cultural fascination with deviance. "Neurotypical individuals," states the Web site, "find it difficult to be alone" and "are often intolerant of seemingly minor differences in others."

"Tragically," it adds, "as many as 9,625 out of every 10,000 individuals may be neurotypical."

#20 kevin

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Posted 15 May 2004 - 03:47 PM

Link: http://www.scienceda...40514065817.htm

What's Related
Scientists Enhance Fruit Fly Memory Using Mouse Protein: New Clue To Fundamental Brain Mechanism

Scientists Switch Memory Recall On And Off In Fruit Flies

Researchers Identify Enzyme That May Turn Fleeting Experience Into Lasting Memory


Study In Flies Allows Researchers To Visualize Formation Of A Memory
For the first time, researchers have used a technique called optical imaging to visualize changes in nerve connections when flies learn. These changes may be the beginning of a complex chain of events that leads to formation of lasting memories. The study was funded in part by the NIH's National Institute of Neurological Disorders and Stroke (NINDS) and appears in the May 13, 2004, issue of Neuron.*

Scientists have long been captivated by the questions of how memories form and how they are represented in the brain. The answers to these questions may help researchers understand how to treat or prevent memory problems, drug addiction, and other human ailments. Thousands of changes in gene expression, neuron formation, nerve signaling, and other characteristics may be involved in the formation of just a single memory. Scientists refer to any learning-induced change in the brain as a "memory trace."

In the new study, Ronald L. Davis, Ph.D., and colleagues at Baylor College of Medicine in Houston developed fruit flies with special genes that caused the flies' neuronal connections to become fluorescent during nerve signaling (synaptic transmission). They then exposed the flies to brief puffs of an odor while they received a shock. This caused them to learn a new association between the odor and the shock – a type of learning called classical conditioning.

Using a high-powered microscope to watch the fluorescent signals in flies' brains with as they learned, the researchers discovered that a specific set of neurons, called projection neurons, had a greater number of active connections with other neurons after the conditioning experiment. These newly active connections appeared within 3 minutes after the experiment, suggesting that the synapses which became active after the learning took place were already formed but remained "silent" until they were needed to represent the new memory. The new synaptic activity disappeared by 7 minutes after the experiment, but the flies continued to avoid the odor they associated with the shock.

This is the first time that optical imaging has been used to visualize a memory trace, Dr. Davis says. "It's phenomenally powerful, like a movie appearing in front of you," he adds. The study suggests that the earliest representation of a new memory occurs by rapid changes – "like flipping a switch" – in the number of neuronal connections that respond to the odor, rather than by formation of new connections or by an increase in the number of neurons that represent an odor, he adds.

The fact that the flies continued to show a learned response even after the new synaptic activity waned suggests that other memory traces found at higher levels in the brain took over to encode the memory for a longer period of time, Dr. Davis suggests. If so, the rapid changes of nerve transmission that the researchers saw may be the all-important switch that initiates the formation of new memories.

This research suggests a previously unknown mechanism for how memories are formed, Dr. Davis says. While this study looked only at learning related to odors, this newly identified process may be at work in many other kinds of learning as well. It is likely that these or similar mechanisms are important for memory in humans and other animals, he adds.

"This is a remarkable study which uses molecular genetic approaches to visualize memory formation in a living organism. It demonstrates that, in this model system, short term memory involves the recruitment of new synaptic connections into pre-existing ensembles of synapses. It will be critical to determine whether similar principles control memory formation in higher organisms," says Robert Finkelstein, Ph.D., a program director at NINDS.

The researchers now plan to put fluorescent genes into a variety of other neurons of the brain in order to determine which ones respond to different kinds of stimuli. This will allow them to learn how the changes they identified affect higher-level neurons. They also hope to begin studying similar mechanisms in other animal models, such as mice.

###

The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation's primary supporter of biomedical research on the brain and nervous system.

*Yu D, Ponomarev A, Davis RL. "Altered representation of the spatial code for odors after olfactory classical conditioning: memory trace formation by synaptic recruitment." Neuron, May 13, 2004, Vol. 42, No. 3, pp. 437–449.

Editor's Note: The original news release can be found here.

#21 kevin

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Posted 24 June 2004 - 05:43 AM

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Link: http://www.eurekaler...i-pbt062304.php


Public release date: 23-Jun-2004

Contact: Jason Bardi
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Protein believed to control formation of memory identified by Scripps & UCSD scientists
Scientists at The Scripps Research Institute and the University of California, San Diego (UCSD) School of Medicine have demonstrated that the action of a protein called CBP is essential for the stabilization of long-term memory, a discovery that may help children with a rare but debilitating developmental disorder.

They found that when the functions of normal CBP is suppressed in adult rodents, the animals had trouble forming long-term memories, suggesting that CBP is required for the formation of long-term memory and that defects in CBP are involved in cognitive dysfunction.

Furthermore, the scientists found that they were able to correct this defect by administering a drug that restored CBP's function.

"This is significant," says Mark Mayford, Ph.D., an associate professor of cell biology and a member of the Institute for Childhood and Neglected Diseases at Scripps Research. Before moving to Scripps Research four years ago, Mayford was a faculty member at UCSD, where together with another UCSD scientist Edward Korzus, Ph.D., they initiated the research.

"There is a link between this molecule and very severe problems in humans," Mayford added, noting that the findings may be significant for children with the rare but severe developmental disorder known as Rubinstein-Taybi syndrome, which causes growth and mental retardation and several anatomical abnormalities. These children have mutations in their CBP genes.

Protein Memories

Scientists have long known that when laboratory animals are treated with a class of drugs known as protein synthesis inhibitors, which stops the production of proteins in the animals' brains, these animals lose their long-term memory. This observation has led scientists to predict that the formation of long-term memory requires new protein synthesis.

This prediction has since been borne out in experiments repeated in many different species -- from mice to fruit flies.

After this fact was established, a number of scientists around the country began looking for the specific genes and proteins that could stabilize long-term memory.

One such signal had already been discovered by other scientists when they began their work -- the protein CREB. CREB is what is known as a transcription factor, a protein that interacts with the DNA of a gene and controls the early steps in "turning on" the expression of a new protein. Mutations in CREB prevent the activation of certain genes, and animals with defective forms of CREB have problems forming long-term memories.

But, scientists asked, was CREB the only protein that controls memory formation?

A few years ago, Korzus and Mayford were working at the UCSD School of Medicine, where in a collaboration with Michael G. Rosenfeld, M.D., who is a Howard Hughes Medical Institute Investigator and Professor of Medicine at UCSD, they began looking for other signals in neurons that affected the formation of long-term memory. Korzus and Mayford continued their work at Scripps Research, focusing on a mutation in rodents that affected a protein associated with CREB called CREB binding protein (CBP). CBP is what is known as a coactivator of transcription -- it works with CREB to control the expression of genes.

CBP is sort of like a molecular haberdasher. It grooms proteins involved in gene expression by fitting them with chemicals that turn them on or off. Specifically, CBP attaches acetyl groups to other proteins, and these acetyl accoutrements modulate their behavior in the cell.

One of the proteins in neurons that CBP acetylates are histones. Histones are short cylindrical proteins that associate with DNA in the nuclei of cells.

Histones are the fashion mavens of the molecular world. They must be wearing something! Normally, they have an affinity for wrapping themselves with DNA, and so DNA wraps around them in the cell, forming a compact bundle of DNA and protein called chromatin. This allows the DNA in a cell to maintain a compact form. Seen under a microscope, the DNA and histones appear as distinct bundles known as chromosomes.

But when a gene is going to be expressed, such as during the formation of long-term memory, the chromatin must be opened up and the DNA unwound from the histones. CBP plays a critical role in this process because it acetylates amino acids known as lysine on the histones, and this makes the histones lose their affinity for the DNA and facilitates the expression of genes on that DNA.

Losing and Regaining Memory Ability

Korzus and Mayford performed an experiment in which they could turn on a defective form of CBP in adult rodents. They found that the defective CBP cannot acetylate the histones, and this prevents the DNA wound around the histones from releasing. This, in turn, prevents protein synthesis, and that prevents the formation of long-term memory.

Significantly, Korzus and Mayford were able to correct the long-term memory defect in the animals by administering a leukemia drug called histone deacetylase inhibitor Trichostatin A, which put the acetyl group back on the histones.

Their results suggest that remodeling of chromatin is important in learning and memory. It also provides a new mechanism for influencing cognitive function. And it suggests a possible treatment for the mental retardation associated with Rubinstein-Taybi syndrome.

The article, "CBP histone acetyltransferase activity is critical component of memory consolidation" by Edward Korzus, Michael G. Rosenfeld, and Mark Mayford appears in the June 24, 2004 issue of the journal Neuron. See http://www.neuron.org.



###
This work was supported by the National Institutes of Health, the National Institute of Mental Health, the Howard Hughes Medical Institute, and the Institute for Childhood and Neglected Diseases at Scripps Research.

About The Scripps Research Institute
The Scripps Research Institute in La Jolla, California, is one of the world's largest, private, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases and synthetic vaccine development.

#22 Cyto

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Posted 24 July 2004 - 05:30 PM

Researchers have found a family of molecules that play a key role in the formation of synapses, the junctions that link brain cells, called neurons, to each other. The molecules initiate the development of these connections, forming the circuitry of the mammalian nervous system.

Scientists from Harvard University and Washington University in St. Louis describe the findings in the July 23 issue of the journal Cell.

"This is very basic work, far from any clinical applications at this point," says author Joshua R. Sanes, professor of molecular and cellular biology in Harvard's Faculty of Arts and Sciences. "Still, one can think of lots of cases, from normal aging to mental retardation to neurodegenerative disease, where making more synapses or preventing synapse loss might be beneficial. This finding may eventually point the way to new therapies."

The work, using mice as a model, was conducted while Sanes and co-author Hisashi Umemori were at Washington University.

Synapses are the sites where neurons communicate with each other to form the large and complex information-processing networks of the brain. These networks are highly modifiable because the synapses between neurons are plastic, leading to changes that underlie learning. Synapses are also the targets of nearly all psychoactive drugs, including both prescription medications and illicit drugs.

"We knew that the apparatus for sending and receiving chemical and electrical signals was concentrated at the synapses where neurons connect with each other," Sanes says. "We wanted to determine how these special sites form."

As the early nervous system develops into a dense tangle of neurons, synapses sprout at places where neurons grow close to one another. In order for a synapse to actually form, Sanes and Umemori believed, certain key molecules would have to flow across the gap between two neurons to commence development of a synapse linking them.

Umemori spent several years scanning neurons in culture for these pioneering molecules that set in motion the linking of neural networks. In the end he fingered a molecule called FGF22, along with several of its close relatives, as key to setting in motion the construction of synapses. Umemori confirmed FGF22's role by showing that mice in which FGF22 was inactivated failed to grow synapses; conversely, when added to neurons in culture, the molecule stimulates synapse formation.

Sanes and Umemori determined that FGF22 works to build synapses in the brain's cerebellum, a critical center for motor control; it's unclear whether it also serves as a signal to foster synapse growth between neurons in other areas. Two other members of the FGF family, FGF7 and FGF10, are very similar in structure, and may play similar roles in other areas of the nervous system.


Link

#23 kevin

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Posted 07 October 2004 - 03:24 AM

Link: http://www.eurekaler...i-bcm100604.php


Public release date: 6-Oct-2004

Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute

Brain circuit may permit scientists to eavesdrop on memory formation

Howard Hughes Medical Institute researchers have identified a circuit in the brain that appears crucial in converting short-term memories into long-term memories. The circuit links the major learning-related area of the brain to another region that governs the brain's higher functions.
The studies open the way for eavesdropping on one of the central processes in learning and memory, says HHMI investigator Erin M. Schuman. She and Miguel Remondes of the California Institute of Technology published their findings in the October 7, 2004, issue of the journal Nature.

According to Schuman, the finding sheds light on a central question in learning and memory research that concerns the roles of two brain structures, the hippocampus, which is involved in memory formation, and the neocortex, which is associated with higher brain functions.

"There are two key findings required to understand the present work," said Schuman. "First, lesions of the hippocampus prior to training can prevent the formation of some kinds of short-term memory. Second, if one delays the hippocampal lesion to days after training, one can observe that as the delay increases, the memory deficit decreases. These data suggest that the importance of the neocortex as a memory storage site increases with the lifetime of the memory. In addition, there is a clear need for the hippocampus and cortex to talk to one another."

One candidate for the communication conduit is the temporoammonic (TA) projection, "a pathway that we have been chipping away at understanding for years," said Schuman. "We and others had studied the physiology of this very direct connection between the two areas, but no one had directly studied this pathway's importance in learning."

For the experiments, Remondes perfected a technique to make precise electrical lesions of the TA projection in the brains of rats. In the first set of experiments, he created the lesions in animals and then tested their ability to learn to navigate a tank full of opaque water to find a submerged platform. When the researchers tested the rats the day after the electrical lesions were made, they still recalled the platform's location. But they lost that memory four weeks after training.

"There were two possible explanations for this result," said Schuman. "Either we had selectively impaired the process of converting short-term memories into long-term memories. Or, short-term and long-term memories are on parallel pathways, and the lesion had selectively affected the long-term memory pathway."

So, in a second set of experiments, the researchers created the TA lesions in animals 24 hours after they had learned the position of the platform. These animals still retained short-term memory; but four weeks later they lost that memory as well. Since the lesion was made after learning, this experiment suggested that the animals had problems converting their short-term memory into a long-term memory -- a process also called consolidation."

"If this really was a process of memory consolidation, it implies that there's a window of vulnerability that will close," said Schuman. "Thus, in the last experiment, we waited three weeks for the memory to consolidate and then made the lesion. When tested a week later, a majority of the animals remembered the platform location even though they had just received the lesion; that is, it appeared that they had already adequately consolidated the memory in the three weeks post-training prior to the lesion.

"These experiments tell us that the TA projection is an important part of the dialog between the hippocampus and the cortex that occurs after learning," said Schuman. "Now, what is needed is an exploration of the specific firing patterns of neurons that make up the TA projection during learning and the consolidation period. It's interesting that a lot of the important activity likely takes place off-line, when the animal is removed from the direct behavioral experience."

Future studies could give insight into the role of sleep in memory consolidation, which has been suggested by many researchers, said Schuman. Studies by other researchers have shown that there is distinctive coordinated brain activity between the hippocampus and neocortex during sleep, she said.


###

#24 Lazarus Long

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Posted 24 November 2004 - 06:20 PM

I suggest that a *Sixth Sense* exists and should be considered a subtle yet demonstrable property of the integrated brain/mind. Its perceptional field is *time* and its sensory organs and tissues are inclusive of but not specific to the brains’ memory sustaining neural network as it functions for both long and short memory but also as it integrates the *whole body’s* physiological timing, from breathing to heart rate, from puberty and menstruation to assimilating circadian rhythm and general cellular senescence.

Before presuming this is mere philosophical hyperbole, please understand that there are at least two distinct elements that support this conjecture:

Time is a property of our reality that is a component of what Einstein called space/time

and

Second, it is *perceived* as the continuity of experiential *memory*, ordered within our minds contributing to how we define our *selves* but composed of many tangible conscious and less than conscious, yet still tangible sensory data feedback loops of our body functions in relation to environmental stimuli.

We have often discussed here whether or not there exists a *chronometer* for the body, a biological clock so to speak but this is perhaps both too simple and too misleading a way to define it.

It does appear that there are a number of subtle sensors for such at a cellular level from circadian rhythms to menstrual and pubescent cycles, however as we have also discussed none of these reflect a controlling influence directly over aging.

I am suggesting here that we are also overlooking one obvious yet normally unconnected form of measure of time and that is *memory itself.*

What evolutionary function could memory fulfill?

Many, from an evolutionary psychology AND biology position might argue that *memory* is necessary to learning but we should not confuse the two. It is after all only one component of sentience.

We can all understand many of its advantages but why does it exist?

I would suggest that we perhaps should consider it another (physical) *sense* and a way of lending order to experience but its development in our species is also altering the very function of how life evolves through the creation of a growing bank of memory collectively shared by our species externally sustained and independent of just individuals. (all right, this is a separate topic ;)

Why should we consider the idea of memory a sense?

Because time can be considered a physical entity in a *sense* (sic); a fourth *dimension.* It is an integrated aspect of what composes Universal Space/Time. The creation of memory as a function of a *Sense of Time* allows the individual life form to *order* their experience and define their lives.

It is commonly believed that we have five (physical) senses that provide a variety of complex data to the brain through a complex but discernible sensory web that is the result of specific physical receptor cells that are either distributed throughout the body or consolidated in specific areas and organs.

We can all appreciate how important these five sources of physical information are to creating experience but try and do so without memory. Unlike the way most people talk of an intangible *sixth sense* to provide mythical properties of clairvoyance, telepathy, and telekinesis that are related to undiscovered biological systems, I am basing this proposition that we should be able to connect the *perception of time* to real and identifiable loci in the brain and a neural web combination of related loci.

For this reason I am suggesting we alter how we think about memory and begin to analyze it just as we would other physical senses as having individualized levels of sensitivity and an ability to be *trained* as well as probably the most complex integrated relationship to all other senses. In this a *Super Sense* that all other senses are contributing to.

These loci are probably not found in a simple single lobe or set of neurons but are likely to be a system of functions integrated within the brain on a level of complexity beyond which, even our three dimensional vision is created; in other words a systems integration function that relates a variety of informational sources to one another to create continuity and only one step removed from the complex super structure of our consciousness itself.

The brain in essence has one *sense* that it does not depend on any specific external sensory net to deliver to it and this sense measures time and does so as an internally operative function retaining both conscious and autonomic memory.

I am putting this here to encourage a serious discussion of this observation and theoretical proposal. Please feel free to contribute.

#25 Lazarus Long

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Posted 26 November 2004 - 12:34 AM

This weeks Nature magazine has an article that I find interesting and I think is another piece of the puzzle we are trying to unravel here. It concerns the relationship of Mitochondrial function and intelligence.

Enjoy

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http://www.nature.co...l/041122-5.html

Published online: 23 November 2004; | doi:10.1038/news041122-5
Energetic cells may have boosted the brain
Roxanne Khamsi

Did rapid mutation of cell powerhouses guide our neural evolution?

A good brain needs lots of energy in order to function, and human brains are exceptionally good. Now geneticists have found that humans may also be exceptional in terms of the energy output of our cells, and are wondering whether this is linked to our intellectual prowess.

Brains use more energy than one might expect. In humans this organ makes up only 2% of a person's body weight, on average. But it is estimated to account for about 20% of the energy used by the body at rest.

One solution to providing more energy is simply to have more cells. In the development of the human brain, "the obvious difference that everyone talks about is the huge increase in size," says John Kaas, a neuroscientist at Vanderbilt University in Nashville, Tennessee.

But there are limits to how much more power size can provide. Bigger brains come with additional overhead costs and problems with heat exchange. Something else must have helped to improve our brains.


The powerhouses

Within each cell, tiny structures called mitochondria are responsible for producing the energy-carrying molecules known as adenosine triphosphate or ATP. Electrons are passed through a chain of specialized proteins in the mitochondria, creating ATP as an end product.

One solution to generating more energy in a single cell, therefore, is to increase its numbers of mitochondria. But in the brain, cells have long, thin arms called axons for connecting to other cells, and scientists suspect that these cannot physically accommodate ever larger numbers of mitochondria.

So where did our brain cells get the power they needed? Lawrence Grossman, a biologist at the Wayne State University School of Medicine in Detroit, and his colleagues think it may have come from improvements inside the mitochondria themselves.


Quick change

Grossman and his team studied the genes for a protein in the electron transport chain known as complex IV, or COX. They compared the genetic sequence across many different mammalian species and found that the human lineage has undergone an exceptional number of changes.

For example, there have been 11 changes in the part of the DNA that codes for a certain protein subunit in the past 58 million years, compared with just one change in the 25 million years before that. None of the rodents, lemurs or other mammals that they examined showed more than two or three changes in the same time period.

The production of energy is such a fundamental process that the genes encoding the proteins involved in the electron transport chain generally do not vary across species.

"Usually if you line up the genes from many species, you find that there is a high conservation of protein sequences. That's why we were so surprised when we saw such big changes happening in a short evolutionary period," says Grossman.

He suggests that these changes could have given human brain cells a serious evolutionary boost, by increasing the amount of energy available to them. He and his team describe their theory in Trends in Genetics1.


Food for thought

The group's findings fit with a growing body of evidence that our brains evolved with the help of a better energy supply. Research in modern primates has shown that there is a strong correlation between quality of diet and relative brain size, says Bill Leonard, who studies energetics at Northwestern University in Evanston, Illinois.

"Humans are an extreme example of this: they have very large brains and a high quality, energy-dense diet," he says.

The next step for Grossman and his colleagues is to explore the functions of various mitochondrial protein subunits. They still have to link specific changes in the DNA with improvements in the efficiency of the electron transport chain, before anyone can start to work out how efficient cells led to better brains.


References
Grossman L., Wildman D. E., Schmidt T. R. & Goodman M. et al. Trends Genet., 20. 578 - 585 (2004).
| Article | PubMed | ChemPort |

#26 hyoomen

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Posted 03 December 2004 - 03:01 PM

"Stress Interferes with Working Memory," Science 29 October 2004; 306: 775 [DOI: 10.1126/science.306.5697.775l] (in This Week in Science)
"Protein kinase C overactivity impairs prefrontal cortical regulation of working memory," Science. 2004 Oct 29;306(5697):882-4.

Out of curiosity, does anybody on here have access to Science.com with which they could grab the full article? I'm curious to read it, as I'd like to better understand the effect PKC has on memory (short- as well as long-term). It seems I recall reading a few different sites which mentioned PKC activation as a positive in relation to a few nootropics, so it seems confusing that it might now be implicated in distraction and impaired working memory. If PKC activation is a feature of nootropics, perhaps this explains the anecdotal reports of "focused distraction" some users report?

Furthermore, would it be reasonable to assume that we could determine an appropriate stack or find a new class of nootropics which might selectively activate PKC in such a way so as to prevent this observed distraction?

#27 nootropi

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Posted 04 December 2004 - 05:47 PM

In my humble opinion, stress is subjective, so an exact prescription of what may or may not repair the stress that is affecting you is largely illusive; if I were you, and you can afford it, try meditation for an hour a day through a binaurial audio program. If you want a specific recommendation as to which program I would recommend, ask me through the private message system.

Be well.

#28 hyoomen

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Posted 05 December 2004 - 12:21 AM

Yes, I'd agree that the very vague term of 'stress' is subjective. Nevertheless, this study fairly specifically argues in favor of prefrontal cortical impairment in the presence of excessive PKC activation. I did finally find a friend who was kind enough to offer me a copy of the article's full-text, and it is quite fascinating (I am somewhat journal-naive).

I have not, at present, been able to locate any specific documents regarding the activation of PKC by Piracetam, though a couple of have popped up via Google searches. Specifically, http://www.bentham.o...gualtiei-ms.htm lists a smattering of studies regarding PKC activation by several Piracetam analogues (Nefiracetam, Oxiracetam, etc). I suppose that PKC activation via Piracetam is probable, but it seems strange there is no peer-reviewed study claiming this. Any nootropists out there with specific evidence supporting it? Studies have been done which demonstrate nootropic-induced PKC activation in the hippocampus (which is thought to be part of the cognitive-boosting mechanism), but does this PKC activation occur in the prefrontal cortex as a result of the nootropics as well? If so, this is an issue.

The next step would be to determine a reasonable mechanism for selective prefrontal cortical inhibition of PKC. The study listed above indicates successful inhibition of PKC activation through the use of chelerythrine, though I'm thus unclear as to whether that inhibition was 100% successful by itself or required additional treatment.

Of course, if PKC activation does occur simultaneously in the hippocampus and prefrontal cortex, perhaps there is an indication that our brains are meant to function in a balancing way in which spatial/working memory is delayed and hippocampal functions are boosted.

And on a final note, perhaps I should stop ingesting so many thought-encouraging substances.

#29 Lazarus Long

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Posted 16 December 2004 - 04:27 PM

Where Fear Lives
Dec 15 2004
http://health.discov....jsp?aid=522904

WEDNESDAY, Dec. 15 (HealthDayNews) -- Researchers have found the specific area of the brain that stores your unconscious fears.

A team at the Columbia University College of Physicians and Surgeons pinpointed a specific region of the amygdala, an almond-shaped structure deep in the brain that encodes the emotional content of memories. The amygdala's influence on this emotional encoding can, for example, determine the degree to which a memory of emotional trauma is imprinted on the brain.

Not only does this study provide important information about an area of the brain that processes frightening events, it also may offer a method of measuring the success of treatments for anxiety disorders.

The researchers used magnetic resonance imaging (MRI) to scan the brains of volunteers who were shown images of fearful faces.

"These findings provide a biological basis for the unconscious emotional vigilance characteristic of normal and pathological anxiety, as well as a new means for investigating the mechanisms and efficacy of treatments for anxiety states," the study authors wrote.

The study appears in the current issue of Neuron.

Individual Differences in Trait Anxiety Predict the Response of the Basolateral Amygdala to Unconsciously Processed Fearful Faces
Abstract w/ link to full text

The American Academy of Family Physicians has more about anxiety and panic.

To book this BIOSCIENCE ad spot and support Longecity (this will replace the google ad above) - click HERE.

#30 Lazarus Long

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Posted 16 December 2004 - 06:06 PM

Actually given the general development of cybernetics and the importance of the concern over chemical memory structuring to cryo, and the theory of neural networks for understanding our brain/mind function and design, this recent study and its results may be highly important and interesting to many in our forum.

Not only that but inquiring minds want to know, is this a distant relative Susan?

http://www.neuron.or...896627304007135

I suggest that anyone seriously interested avail themselves of the full text as the links from that page are too numerous to bring over and there are larger clearer versions of the graphic results and analysis.


Copyright © 2004 Cell Press.
Neuron, Vol 44, 1011-1020, 16 December 2004


Competing for Memory: Hippocampal LTP under Regimes of Reduced Protein Synthesis
Rosalina Fonseca,1 U. Valentin Nägerl,1 Richard G.M. Morris,2 and Tobias Bonhoeffer1

1Max-Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 München-Martinsried, Germany
2Laboratory for Cognitive Neuroscience, Centre for Neuroscience, The University of Edinburgh, 1 George Square, Edinburgh, EH8 9LE, Scotland United Kingdom 
Correspondence:
Tobias Bonhoeffer
49 (89) 8578 3750 (phone)
49 (89) 8995 0050 (fax)
tobias.bonhoeffer@neuro.mpg.de

Summary

The persistence of synaptic potentiation in the hippocampus is known to depend on transcription and protein synthesis. We report here that, under regimes of reduced protein synthesis, competition between synapses for the relevant intracellular proteins can be demonstrated. Under such circumstances, the induction of additional protein synthesis-dependent long-term potentiation for a given set of postsynaptic neurons occurs at the expense of the maintenance of prior potentiation on an independent pathway. This new phenomenon, which we call “competitive maintenance,” has important functional consequences, and it may be explained in terms of dynamic interactions between synapses and “plasticity factors” over extended periods of time.


Introduction
 
Long-term potentiation (LTP) in the hippocampus is a prominent cellular model of memory formation (Bliss et al., 2003). To persist for a sustained period of time, it is thought to involve gene transcription and translation (Frey et al., 1988; Goelet et al., 1986; Huang et al., 1996; Krug et al., 1984). Exactly how the persistence of LTP depends on protein synthesis and, in particular, how the relevant synapse-to-nucleus and nucleus-to-synapse signaling is achieved is still a matter of debate (Deisseroth et al., 1996; Silva et al., 1998). Recent experiments point to a mechanism that sets “synaptic tags” at potentiated synapses, whose role is to sequester “plasticity factors” in order to stabilize the expressed potentiation in an input-specific manner (Frey and Morris, 1997, 1998b; Martin et al., 1997). These experiments established the concept and function of synaptic tagging and the idea that plasticity factors induced through the activation of one input might be shared with other synapses upon their subsequent activation. However, sharing is only one side of the coin, and we reasoned that, when the availability of plasticity factors is limited, tagged synapses would compete for them, and it should then be possible to observe this competition. We achieved this by limiting protein synthesis during the reactivation of LTP and observed that stabilizing the potentiation of synapses on one input pathway afferent to a population of postsynaptic neurons was at the expense of maintained potentiation on another independent pathway.


Results  

In adult hippocampal brain slices, competition was set up between two independent pathways, hereafter called the “reactivated pathway” (RP; red symbols in Figure 1A and thereafter; single traces shown in Figure 1B) and the “test pathway” (TP; blue symbols in Figure 1A and thereafter; single traces shown in Figure 1B), respectively. After recording baseline postsynaptic potentials in independent pathways (see Experimental Procedures), the RP received a weak tetanus that, by itself, induced little or no LTP (100 Hz for 0.25 s; open arrows in Figure 1A and thereafter), whereas the TP received strong tetanization that resulted in clear-cut LTP (100 Hz for 1 s; filled arrow in Figure 1A, and thereafter). Both weak and strong tetanizing stimuli were then applied simultaneously (concurrent open and filled arrow in Figure 1A; also see the insert in Figure 1A), and the resulting associativity between the two inputs induced LTP on both pathways (Barrionuevo and Brown, 1983). This protocol serves as a control for possible heterosynaptic interactions between the two pathways during potentiation while also enabling associative LTP on both inputs.


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Figure 1. Competitive Interaction between Two Potentiated Pathways

(A) Weak and strong tetani were used to induce associative LTP in two CA3 to CA1 synaptic pathways (also see inset in the upper right corner). Four hours after the start of the experiment, the protein synthesis inhibitor anisomycin (ANI) was bath applied to the slice (yellow bar). Forty minutes later, one of the pathways (reactivated pathway [RP], red symbols) received another (weak) tetanus, while the other pathway (test pathway [TP], blue symbols) continued to receive only test pulses. Potentiation of the reactivated pathway is at the expense of persistence of LTP in the test pathway, provided the experiment is performed under anisomycin (filled symbols). In the control case (open symbols), no such effect can be observed. In this and subsequent figures, the statistical significance of the difference between test pathways in the presence or absence of anisomycin, expressed in p values, is plotted by the green triangles. The significance value of p = 0.05 is always displayed as dashed line. Repeated-measures ANOVA values: F(1,13) = 20.12; p = 0.00061. The inset in the upper right corner shows the initial hour of the experiment displayed at a more conventional time scale. The data are the same as in the main panel. Only the binning of the data is different (one data point per minute in the inset; one data point per four minutes in the main panel).

(B) Example traces of fEPSPs for the test and reactivated pathways at times indicated by the colors and the circled numbers (also see [A]).

© The competitive maintenance effect at an expanded time scale (synaptic transmission before the second potentiation in the test and reactivated pathways was normalized to 100%).

(D) Correlation between the potentiation of the reactivated pathway and the decrease of the test pathway are plotted for each experiment, either in the presence (filled symbols) or absence (open symbols) of anisomycin. A linear regression shows for the anisomycin experiments a clear correlation of the amount of potentiation in the reactivated pathway with the amount of decay in the test pathway while there is no correlation for the control cases.

(E) The effect only occurs on a potentiated pathway: an unpotentiated control pathway (CP, blue symbols) does not show decay in response to reactivation of the other pathway (RP, red symbols), which was subjected to an initial tetanus (filled arrow) and then a second tetanus (filled arrow) in the presence of anisomycin.

(F) Time course of the synaptic responses in two pathways that both expressed associative LTP. Anisomycin alone does not cause decay in either pathway (RP and TP only in analogy to [A]; no reactivation is applied). n, number of slices.


The key finding of “competitive maintenance” emerged in the next phase of our protocol. LTP on both the “red” and “blue” pathways was maintained for the next 4 hr (Figure 1A), indicating that the long-lasting, protein synthesis-dependent form of LTP (L-LTP) had been induced. Four hours after the start of the experiment, anisomycin was applied to the slice to block any ongoing or further synthesis of new proteins (yellow bar in Figure 1A and thereafter). Forty minutes later, a further weak tetanus (open arrow in Figure 1A, blowup in Figure 1C) was applied to the RP, thereby reactivating it (hence the name “reactivated pathway”). According to the tagging hypothesis, this reactivated pathway should display additional early LTP, at the same time setting further synaptic tags that would sequester the now limited supply of plasticity factors available due to the earlier tetanization and so enabling its stabilization as persistent or late LTP. This prediction was upheld (Figures 1A and 1C, enhancement of the RP; filled red squares after 5 hr), in line with earlier reports (Frey and Morris, 1997). The application of anisomycin, however, had an important additional effect: the potentiation of the reactivated pathway was at the expense of the enhancement of the test pathway (filled blue circles), which started vanishing immediately after LTP in the reactivated pathway had been induced (Figures 1A and 1C).

Our proposed explanation of this unexpected “competition” between the two input pathways is that sustained enhancement of the reactivated pathway “uses up” the plasticity factors at the expense of the stabilization of the test pathway, which gradually weakens as a result. Such a competition hypothesis is bolstered by plotting the magnitude of the strengthening of the RP against the decay in the TP on an experiment-by-experiment basis (Figure 1D, filled data points and regression line). This reveals a clear correlation between enhancement and decay (r2 values and p values always given in the figures). Importantly, this correlation only holds under anisomycin, i.e., when the pool of putative plasticity factors is limited (controls in Figure 1D as open data points and dashed regression line).

It was important to check that this phenomenon could not be explained by established principles, for the decay of maintained potentiation on the test pathway is reminiscent of a range of activity-dependent depression phenomena that are sometimes observed during the induction of LTP. However, none of these is likely to provide an explanation for the effect. First, as the test pathway did not itself receive tetanization when the reactivated pathway was restimulated, the decay cannot be due to homosynaptic long-term depression (Bear and Abraham, 1996; Dudek and Bear, 1992; Mulkey and Malenka, 1992) or depotentiation (Staubli and Lynch, 1990). Second, the competitive maintenance effect did not occur unless protein synthesis was blocked (control experiments in Figures 1A, 2A, 2C, and 3A) or if synapses had not been potentiated previously (Figure 1E). This argues against heterosynaptic LTD (Abraham et al., 1985; Abraham and Goddard, 1983; Lynch et al., 1977; Scanziani et al., 1996) as a potential underlying mechanism, as heterosynaptic LTD should occur regardless of the potentiation history of the synapses. Third, the effect is not some inevitable consequence of protein synthesis inhibition, as a further control showed that the application of anisomycin without synaptic reactivation (Figure 1F) yielded no effect. Thus, the competition effect is in the domain of LTP maintenance, not its induction.

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Figure 2. Competitive Maintenance Does Not Occur under APV but It Is Also Observed with an Alternative Protein Synthesis Blocker, Emetine

(A and B) Competitive interaction does not occur if AP-5 is present during the reactivation. (A) Experiment similar to the one shown in Figure 1A but in the presence of AP-5 and anisomycin or anisomycin alone. For clarity, only the relevant 6.5 hr of the experiment are shown (responses 20 min before the last tetanus were normalized to 100%). Under AP-5, NMDA receptors are blocked, and no further potentiation is obtained by the reactivation. No decay was observed for the test pathway in turn. Without APV, the same competitive interaction displayed in Figure 1A occurs. Repeated-measures ANOVA values: F(1,10) = 6.921; p = 0.025. (B) The experiments performed with anisomycin alone (solid circles) show a clear correlation between potentiation in the reactivated pathway and decay in the test pathway, whereas the experiments performed with anisomycin and APV yield no correlation (compare also to Figure 1D). n, number of slices.

(C and D) Competitive interactions are also induced when protein synthesis is blocked with emetine. © Experiment similar to the one shown in Figure 1A, only with emetine as protein synthesis blocker instead of anisomycin. Again, only the relevant 6.5 hr of the experiment are shown (responses 20 min before the last tetanus were normalized to 100%). Repeated-measures ANOVA values: F(1,4) = 30.073; p = 0.0053. (D) The emetine experiments also show a clear correlation between potentiation in the reactivated pathway and decay in the test pathway. n, number of slices.


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Figure 3. Modulation of Protein Availability Influences Competitive Maintenance

(A and B) Competitive interaction is increased after prolonged application of anisomycin. (A) Experiment similar to the one shown in Figure 1A; however, anisomycin was bath applied for a period of 3 hr, presumably limiting the availability of plasticity factors even further. The decline observed in the test pathway due to the reactivation is increased. For clarity, only the relevant 6.5 hr of the experiment are shown (responses before the last tetanus were normalized to 100%). Repeated-measures ANOVA values: F(1,10) = 26.57; p = 0.00042. (B) Potentiation in the reactivated pathway plotted against the potentiation (resp. decay) in the test pathway, either in the presence (filled symbols) or absence (open symbols) of anisomycin. The correlation analysis reveals a stronger correlation between potentiation in the reactivated pathway and decay in the test pathway as well as a stronger effect (denoted by the steeper slope of the regression line).

(C and D) Competitive interaction is decreased by reducing the time period between initial LTP induction and reactivation. © In this case, the reactivating tetanus was applied already after 2 hr, causing the competition to vanish (p values as green triangles). For clarity, only the relevant 8.5 hr of the experiment are shown (responses 20 min before the last tetanus were normalized to 100%). Repeated-measures ANOVA values: F(1,15) = 0.625; p = 0.4416. (D) Linear regression returns no correlation. n, number of slices.



Before further characterizing the determinants of competitive maintenance, we wanted to ascertain that the effect is genuine and cannot be explained by side effects of the stimulation or the drugs used. Two types of control experiments were conducted. First, to rule out any unspecific effect of the stimulation to the reactivated pathway, we examined what would happen to the competitive maintenance effect if the attempted induction of LTP in the RP was blocked by AP-5 (Figures 2A and 2B). The experiment was (except for the presence of AP-5) identical to the one described in Figure 1A, with an initial phase in which the TP and RP were prepotentiated. Here, however, for reasons of clarity, we chose to display only the relevant portion of the experiment (see colored and grayed out portions of the experiment in the scheme above Figure 2A) and normalized the electrophysiological responses before the last (weak) tetanus to 100%, (see Experimental Procedures). We observed that, in the presence of AP-5, competitive maintenance does not occur, indicating that successful enhancement in the RP is needed to observe the decrease in the TP (Figures 2A and 2B). An additional feature of these experiments was that a third control pathway was also recorded simultaneously (diamonds in Figure 2A). Its stability demonstrates that the decay observed in the TP in the absence of AP-5 (blue circles) must be genuine and cannot be attributed to any overall “run down” of the slice. Second, we also wanted to ensure that the observed effect was not caused by a pharmacological side effect of anisomycin. We therefore repeated the experiment with another protein synthesis blocker, emetine. It yielded an identical competitive maintenance effect (Figures 2C and 2D).

If competitive maintenance has to do with protein availability, several further predictions can be made. First, the decay of the test pathway should be enhanced by increasing the duration of the anisomycin application, thereby decreasing protein availability and intensifying competition. With the protein synthesis inhibitor applied for a longer time (3 hr instead of 1 hr 40 min; Figures 3A and 3B), we indeed observed that the decay of the test pathway was increased. This effect can be seen in the population analysis of the data (Figure 3A) as well as in the correlation analysis (Figure 3B).

On the other hand, the competition effect should be decreased when the time between induction and reactivation is reduced, because a greater supply of plasticity factors should still be available from the initial potentiation. In keeping with this prediction, when the interval between the LTP induction and its reactivation was reduced from 4 to 2 hr, enhancement of the reactivated pathway resulted in almost no decay of LTP in the test pathway (Figure 3C). The correlation function also became flattened (Figure 3D).

Third, the distance between the potentiated synapses should influence the extent to which the two input pathways can compete for diffusing plasticity factors. To limit competition, one stimulating electrode was placed in the stratum radiatum (test pathway), stimulating synapses localized on the apical dendritic tree, and a second electrode was placed in the stratum oriens (reactivated pathway), stimulating synapses localized on the basal dendrites (Figure 4B) . Apart from the greater distance of the stimulating electrodes, the experimental conditions were identical to those in Figure 1A. Under these circumstances, we observed no interaction between the two pathways: the RP was enhanced, but no concomitant decay was observed in the TP (population data, Figure 4A; correlation analysis, Figure 4C). This again supports our hypothesis that competition may explain the observed effect.

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Figure 4. Competitive Interaction Is Absent when Input Pathways Are in Separate Dendritic Domains

(A) Experiment similar to the one shown in Figure 1A. This time, however, stimulation electrodes were spatially separated. Fibers in the stratum oriens served as the reactivated pathway, whereas the fibers of the stratum radiatum defined the test pathway. With this spatial separation, the competitive interaction between the two potentiated pathways vanished. For clarity, only the relevant 6.5 hr of the experiment are shown (responses 20 min before the last tetanus were normalized to 100%). Repeated-measures ANOVA values: F(1,13) = 0.294; p = 0.5966.

(B) Illustration of the positions of recording and stimulation electrodes. Two stimulation electrodes placed in the stratum oriens and the stratum radiatum were used to evoke fEPSPs. In this case, we used two recording electrodes placed within the basal and apical dendritic region of CA1 neurons to faithfully record the synaptic potentials generated on different sides of the cell body.

© Linear regression shows no correlation between potentiation in the reactivated pathway and decay in the test pathway. n, number of slices.


Fourth, we reasoned that if the number of additional tags set on the competing pathway was varied, for instance, by tetanizing the reactivated pathway with successively stronger stimulation, the decay of the test pathway should be enhanced proportionately. Indeed, when we increased the number of pulses in the high-frequency retetanizing train, we found that decay in the test pathway increased accordingly (Figures 5A and 5B) . This is consistent with the view that stronger reactivation tilts the competition for plasticity factors in favor of the reactivated pathway at the expense of the test pathway. Note, however, that more tetanizing pulses do not trigger a stronger potentiation of the reactivated pathway. This is puzzling but might be explained in terms of a dissociation between the potentiation at an individual synapse, which rapidly reaches an asymptote, and the number of tags that can be set at it.

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Figure 5. Competitive Interaction Is a Function of LTP Reactivation Strength

(A) Experiment similar to the one shown in Figure 1A. For clarity, only the relevant 3.5 hr of the experiment are shown (responses 20 min before the last tetanus were normalized to 100%). In contrast to the experiment in Figure 1A, high-frequency trains differing in the number of pulses were used to reactivate the second pathway. The more pulses are applied to the reactivated pathway (the “stronger” the stimulation), the more pronounced is the decay in the test pathway.

(B) Relationship between the number of pulses used for the reactivating tetanus and the subsequent decay produced in the synaptic responses of the test pathway. n, number of slices.


To explore whether the effect of competitive maintenance occurs under more physiological conditions and not only under conditions of protein synthesis blockade, we performed further experiments in which the initial LTP was achieved by associatively combining stimulation with two weak tetani (see diagram and inset in Figure 6A). We reasoned that if the degree of LTP persistence is related to the amount of plasticity factor synthesized, inducing associative LTP by pairing two weakly stimulated pathways would be expected to result in a lower concentration than that induced by strong tetanization and thus stronger competition at the time of reactivation. Figure 6A shows that, indeed, under such conditions and in the absence of anisomycin, stimulation of the RP was associated with depression of the test pathway. There was again a correlation between the amount of potentiation in the RP and the amount of decrease in the TP (Figure 6B).

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Figure 6. Competitive Interaction under Conditions of Prior Weak Associative Tetanization

(A) Experiment similar to the one shown in Figure 1A, but in the absence of anisomycin. Associative LTP was induced by concurrently applying weak tetanus to both pathways (see inset). Four hours later, one of the pathways (P1) received a second weak tetanus, this time in the absence of anisomycin. This results in potentiation of the reactivated pathway, again at the expense of a decay in the test pathway. In the control experiments (open symbols), no second tetanus was applied. For clarity, only the relevant 4 hr of the experiment are shown (responses 20 min before the last tetanus were normalized to 100%). Repeated-measures ANOVA values: F(1,12) = 27.28; p = 0.00021.

(B) Linear regression shows a clear correlation between potentiation in the reactivated pathway and decay in the test pathway. n, number of slices.



Discussion
 
Protein Synthesis Inhibition Uncovers Competition between Potentiated Synapses
Our experiments describe a novel phenomenon—“competitive maintenance”—in which the successful persistence of synaptic potentiation in a reactivated input to a population of neurons is at the expense of sustained potentiation in an independent input. This phenomenon is consistent with there being intracellular competition for plasticity factors responsible for the persistence of synaptic potentiation.

The scenario of competitive interactions between these factors makes a number of strong predictions that we have tested. First, if protein synthesis normally occurs for a sustained period after tetanization, longer application of anisomycin should lead to lower amounts of plasticity factor and thus stronger competition. This is precisely what we observed. Second, a shorter interval between initial potentiation and reactivation should result in a higher abundance of plasticity factors and reduced competition. Third, increased spatial distance between the activation sites should lead to less competition and therefore a smaller competitive maintenance effect. Fourth, stronger reactivation should lead to more tags being set and thus a higher demand for plasticity factors and hence a stronger competition. With respect to this fourth prediction, a distinction should be recognized between the magnitude of LTP and its persistence. At first sight, the findings of Figure 5 are puzzling, but an asymmetry exists between the reactivated and test pathways in that a graded alteration in the availability of new tags on the reactivated pathway will, paradoxically, more rapidly alter the rate of decline of the test pathway than the impact on the magnitude of LTP in the reactivated pathway. Plasticity factor molecules need not augment the magnitude of LTP, only its persistence. Finally, competitive maintenance also occurred when competition was engineered in the absence of anisomycin using weak tetanization. All these predictions were upheld, and the data are therefore consistent with our interpretation that competition for plasticity factors might account for the competitive maintenance effect. While this evidence is indirect as we do not yet know the identity of the tags or plasticity factors (Martin and Kosik, 2002), the predictions are independent of the molecular identities.

Our results are consistent with the view that plasticity factors synthesized upon the activation of relevant signal transduction cascades—presumably proteins, although they could be mRNAs (e.g., Kelleher et al., 2004; Steward and Schuman, 2001)—are a limited resource to be distributed in the cell. They indicate that distribution and synthesis occur over a sustained period of time—at the time of induction and also during the later maintenance phase of LTP expression. The synaptic tagging hypothesis implies that reactivation of one of the potentiated pathways sets new tags at the activated synapses, and these tags serve as a functional sink for plasticity factors. Experiments in which weak tetanization was given before strong tetanization to independent pathways earlier suggested (Frey and Morris, 1998a) that synaptic tags lasted no longer than 1–2 hr (at 32°C). However, these studies were conducted such that tags set on the weak pathway would not have had access to any plasticity factors throughout that time. The present findings suggest that synaptic tags can be maintained for longer times provided that plasticity factors are present, pointing to dynamic tag-plasticity factor interactions over time during the maintenance phase of late LTP. Competitive interactions can be observed in potentiated but not yet stabilized pathways for as long as 4 hr after initial LTP induction.


Can Competitive Maintenance Be a Form of Heterosynaptic Depression?
The effect described here is, at first glance, reminiscent of heterosynaptic depression (Abraham et al., 1985; Abraham and Goddard, 1983; Lynch et al., 1977; Scanziani et al., 1996). There are three reasons to doubt that this could account for our finding. First, the decay in the test pathway was only observed for pathways that had been potentiated previously (e.g., Figure 1E), whereas for “classical” heterosynaptic depression, it makes no difference whether the pathways were initially potentiated or not. Second, we could only observe a competitive effect under conditions where the levels of plasticity proteins were expected to be low—during protein synthesis inhibition or after prior weak associative LTP induction. If the same experiments were performed without applying protein synthesis inhibitors, competition was not observed (control cases in Figures 1A, 2A, 2C, and 3A). Finally, LTD lasting several hours has been reported to be protein synthesis dependent (Kauderer and Kandel, 2000; Sajikumar and Frey, 2003). If the mechanisms underlying competitive maintenance overlapped with those of this form of LTD, it should not occur and be maintained with protein synthesis blocked. The key difference between classical heterosynaptic depression and competitive maintenance is that the former relates to the induction and expression of decreased synaptic strength, whereas we have described an effect that reflects the maintenance of synaptic potentiation.

Competition for Proteins: A Mechanism to Scale Synaptic Potentiation?
We favor and regard as most parsimonious the interpretation that competition for a limited pool of proteins is the basic mechanism underlying competitive maintenance, but there are other possibilities. In particular, as mentioned above and suggested earlier (Martin and Kosik, 2002), mRNAs could well serve as “tags,” and proteins controlling translation could be the “plasticity factors” for which the mRNAs compete. Also, it is conceivable that, instead of competing for strengthening proteins, enhanced synapses release an inhibiting factor that acts on nearby (tagged) synapses to cause a decrement in their strength. In this scenario, however, it is less easy to understand why the effect should only occur under regimes of reduced protein availability (but see Woo and Nguyen, 2003). Importantly, while describing different molecular underpinnings of the effect, all these alternative mechanisms are functionally equivalent in that they cause enhancement of one pathway at the expense of another.

One of the potential functional consequences of competitive maintenance is that it could provide a means for selective information storage when multiple inputs converge. That we could enhance competitive interactions by increasing the number of pulses delivered during reactivation suggests that the number or potency of tags is determined by the strength of input stimulation. Competition could, therefore, be used to scale cellular responses and thereby maintain a balance of overall synaptic strength during the maintenance phase of L-LTP (Turrigiano et al., 1998). Even though competition was initially revealed under artificial circumstances, namely, protein synthesis inhibition, later experiments revealed that the more physiological conditions of prior weak associative LTP enables a similar effect to occur during the reactivation of one pathway. We hypothesize that competition for plasticity factors could provide a means for the selective memory storage of events, even if they have occurred at different times, provided they have taken place within a finite time window. As such circumstances may be common in remembering the events of daily life, one might speculate whether our findings may provide a physiological counterpart of the interference theory of forgetting (Baddeley, 1990).

The phenomenon of competitive maintenance offers further support for the synaptic tagging hypothesis and extends it in an important way. Plasticity factors are shared according to need among synapses whose activity may have played no part in their provenance. However, under circumstances of reduced availability, competition defines which synapses will win. Equitable sharing and ruthless competition are two sides of the tagging coin.



Experimental Procedures

Slice Preparation
Male Wistar rats (3–4 weeks old) were decapitated under halothane anesthesia; the brains were quickly removed and immersed in ice-cold artificial cerebrospinal fluid (ACSF). The ACSF was saturated with 95%O2/5%CO2 and contained 124 mM NaCl, 3 mM KCl, 1.25 mM KH2PO4, 26 mM NaHCO3, 2 mM MgSO4, 2.5 mM CaCl2, and 10 mM Glucose. The hippocampi were isolated and cut into 400 μm thick transverse slices by a custom-made tissue slicer (Katz, 1987). Slices were maintained in ACSF at 20°C for at least 1 hr before recording. They were then transferred to a submersion chamber and perfused continuously (2 ml/min; medium recirculated) with ACSF at 32°C.

Electrophysiological Recordings
Recordings started after a 20 min resting phase in the recording chamber. Schaffer collaterals were stimulated with 0.2 ms pulses using monopolar tungsten electrodes. Field excitatory postsynaptic potentials (fEPSP) were recorded extracellularly in the stratum radiatum of the CA1 region (130 μm below slice surface) using glass microelectrodes filled with 3 M NaCl (tip resistance 5–20 MΩ). Stimulus intensities were set to evoke 50% of the maximal fEPSP slope. LTP was induced after recording a stable 20 min baseline of fEPSPs. The test pulse frequency was 0.1 Hz.

Induction of Long-Term Potentiation
For the induction of associative LTP, two sets of Schaffer collaterals were stimulated. We always checked for pathway independence by applying two pulses with a 25 ms interpulse interval to the two pathways and checking for the absence of paired-pulse facilitation. Arbitrarily chosen, one of the pathways received a weak tetanus (0.2 ms pulse duration, 100 Hz for 0.25 s). After 10 min, the other pathway received a strong tetanus (0.2 ms pulse duration, 100 Hz for 1 s). Associative LTP was induced by concurrent tetani (weak and strong) of both pathways. Although other authors have suggested that multiple stimuli are needed to induce the long-lasting protein synthesis-dependent form of LTP (Huang et al., 1996; Reymann et al., 1985), in our hands the above stimulation protocol was sufficient to achieve L-LTP. LTP was monitored for a period of up to 4 hr, after which the pathway that had received the weak stimulus earlier received another tetanus, in the presence or absence of protein synthesis inhibitors such as anisomycin or emetine. It was verified that the experimental outcome was the same if we selected the initially strongly stimulated pathway to receive the last tetanus (data not shown). The stimulation intensity (in μA) of the single shocks was maintained throughout the experiment. It was also the same for weak and strong stimuli as well as for the test pulses (evoking 50% of the maximal fEPSP slope). See the figures for a schematic timeline of the experimental paradigms.

Drug Treatment
Anisomycin (Sigma) or emetine (Sigma) was dissolved in DMSO and diluted down to achieve a final concentration of 25 μM and 50 μM, respectively (in 0.01% DMSO). Anisomycin and emetine at this concentration reliably block protein synthesis (Frey et al., 1988; Stanton and Sarvey, 1984). D-AP-5 was dissolved in ACSF to achieve a final concentration of 50 μM. All drugs were bath applied for 40 min or 2 hr before and washed out 1 hr after the second tetanus. For the control experiments, only DMSO (0.01%) was added to the ACSF.

Data Analysis
Electrophysiological data were collected using an Axoclamp 2B amplifier (Axon Instruments, Union City, CA) and band-pass filtered (low-pass filter, 1 kHz; high-pass filter, 1 Hz). Data were sampled at 5 kHz using a Lab-PC-1200 data acquisition board (National Instruments, Austin, TX) and stored on a PC. Offline data analysis was performed using a customized LabView-program (National Instruments). As a measure for synaptic strength, the initial slope of the evoked fEPSPs was calculated and expressed as percent changes from the baseline mean. Error bars are always displayed as SEM. To test for group differences between LTP values across conditions, a two-tailed Student's t test was used (green triangles indicate p values). To this end, LTP values were averaged over 20 min data bins.

Further statistical analysis was performed using a repeated-measures analysis of variance (repeated measures ANOVA) (Statistica, StatSoft, Inc., Tulsa, OK). LTP values from the onset of the second potentiation (reactivation) were considered for this analysis. F and p values obtained from this analysis are given in the figure legends for the respective experiments.

The degree of correlation between potentiation in one pathway and decay in the other for individual experiments was calculated using time windows where the effect was largest: potentiation of the reactivated pathway was taken 30 min after the last tetanus, and the decrease of the synaptic responses in the test pathway was measured 5 hr later. These values were taken to produce the correlation plots in the figures. The precise time points did not matter. We tried several other time points and got qualitatively similar results (data not shown). For normalization of LTP values, the 20 min window before reactivation was taken as baseline.



Acknowledgments

We thank Mark Hübener, Martin Korte, and Volker Staiger for comments on the manuscript. Funding was provided by the Max Planck Society (R.F., U.V.N., and T.B.), the Portuguese Foundation for Science under the Gulbenkian PhD Program in Biology and Medicine (R.F.), and the Human Frontier Science Program (R.F., R.G.M.M., and T.B.)


References

Abraham, W.C. and Goddard, G.V. (1983). Asymmetric relationships between homosynaptic long-term potentiation and heterosynaptic long-term depression. Nature 305, 717-719. [Medline]
Abraham, W.C., Bliss, T.V. and Goddard, G.V. (1985). Heterosynaptic changes accompany long-term but not short-term potentiation of the perforant path in the anaesthetized rat. J. Physiol. 363, 335-349. [Medline]

Baddeley, A. (1990). Human Memory: Theory and Practice. (Hove: Lawrence Erlbaum Associates),

Barrionuevo, G. and Brown, T.H. (1983). Associative long-term potentiation in hippocampal slices. Proc. Natl. Acad. Sci. USA 80, 7347-7351. [Medline]

Bear, M.F. and Abraham, W.C. (1996). Long-term depression in hippocampus. Annu. Rev. Neurosci. 19, 437-462. [Medline]

Bliss, T.V., Collingridge, G.L. and Morris, R.G. (2003). Introduction. Long-term potentiation and structure of the issue. Philos. Trans. R. Soc. Lond. B Biol. Sci. 358, 607-611. [Medline]

Deisseroth, K., Bito, H. and Tsien, R.W. (1996). Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron 16, 89-101. [Medline] [Summary] [Full Text]

Dudek, S.M. and Bear, M.F. (1992). Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc. Natl. Acad. Sci. USA 89, 4363-4367. [Medline]

Frey, U. and Morris, R.G. (1997). Synaptic tagging and long-term potentiation. Nature 385, 533-536. [Medline]

Frey, U. and Morris, R.G. (1998). Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci. 21, 181-188. [Medline]

Frey, U. and Morris, R.G. (1998). Weak before strong: dissociating synaptic tagging and plasticity-factor accounts of late-LTP. Neuropharmacology 37, 545-552. [Medline]

Frey, U., Krug, M., Reymann, K.G. and Matthies, H. (1988). Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro. Brain Res. 452, 57-65. [Medline]

Goelet, P., Castellucci, V.F., Schacher, S. and Kandel, E.R. (1986). The long and the short of long-term memory—a molecular framework. Nature 322, 419-422. [Medline]

Huang, Y.Y., Nguyen, P.V., Abel, T. and Kandel, E.R. (1996). Long-lasting forms of synaptic potentiation in the mammalian hippocampus. Learn. Mem. 3, 74-85. [Medline]

Katz, L.C. (1987). Local circuitry of identified projection neurons in cat visual cortex brain slices. J. Neurosci. 7, 1223-1249. [Medline]

Kauderer, B.S. and Kandel, E.R. (2000). Capture of a protein synthesis-dependent component of long-term depression. Proc. Natl. Acad. Sci. USA 97, 13342-13347. [Medline]

Kelleher, R.J.III , Govindarajan, A., Jung, H.Y., Kang, H. and Tonegawa, S. (2004). Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467-479. [Medline] [Summary] [Full Text]

Krug, M., Lossner, B. and Ott, T. (1984). Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats. Brain Res. Bull. 13, 39-42. [Medline]

Lynch, G.S., Dunwiddie, T. and Gribkoff, V. (1977). Heterosynaptic depression: a postsynaptic correlate of long-term potentiation. Nature 266, 737-739. [Medline]

Martin, K.C. and Kosik, K.S. (2002). Synaptic tagging—who's it?. Nat. Rev. Neurosci. 3, 813-820. [Medline]

Martin, K.C., Casadio, A., Zhu, H., Yaping, E., Rose, J.C., Chen, M., Bailey, C.H. and Kandel, E.R. (1997). Synapse-specific, long-term facilitation of Aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91, 927-938. [Medline] [Summary] [Full Text]

Mulkey, R.M. and Malenka, R.C. (1992). Mechanisms underlying induction of homosynaptic long-term depression in area Ca1 of the hippocampus. Neuron 9, 967-975. [Medline]

Reymann, K.G., Malisch, R., Schulzeck, K., Brodemann, R., Ott, T. and Matthies, H. (1985). The duration of long-term potentiation in the CA1 region of the hippocampal slice preparation. Brain Res. Bull. 15, 249-255. [Medline]

Sajikumar, S. and Frey, J.U. (2003). Anisomycin inhibits the late maintenance of long-term depression in rat hippocampal slices in vitro. Neurosci. Lett. 338, 147-150. [Medline]

Scanziani, M., Nicoll, R.A. and Malenka, R.C. (1996). Heterosynaptic long-term depression in the hippocampus. J. Physiol. (Paris) 90, 165-166. [Medline]

Silva, A.J., Kogan, J.H., Frankland, P.W. and Kida, S. (1998). CREB and memory. Annu. Rev. Neurosci. 21, 127-148. [Medline]

Stanton, P.K. and Sarvey, J.M. (1984). Blockade of long-term potentiation in rat hippocampal CA1 region by inhibitors of protein synthesis. J. Neurosci. 4, 3080-3088. [Medline]

Staubli, U. and Lynch, G. (1990). Stable depression of potentiated synaptic responses in the hippocampus with 1–5 Hz stimulation. Brain Res. 513, 113-118. [Medline]

Steward, O. and Schuman, E.M. (2001). Protein synthesis at synaptic sites on dendrites. Annu. Rev. Neurosci. 24, 299-325. [Medline]

Turrigiano, G.G., Leslie, K.R., Desai, N.S., Rutherford, L.C. and Nelson, S.B. (1998). Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391, 892-896. [Medline]

Woo, N.H. and Nguyen, P.V. (2003). Protein synthesis is required for synaptic immunity to depotentiation. J. Neurosci. 23, 1125-1132. [Medline]


Received: July 8, 2004
Revised: September 7, 2004
Accepted: October 20, 2004
Published: December 15, 2004





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