Category: Memory

 so-called reward center of the brain may need a new name, say scientists who have shown it responds to good and bad experiences. The finding, published in PLoS One, may help explain the "thrill" of thrill-seeking behavior or maybe just the thrill of surviving it, according to scientists at Georgia Health Sciences University and East China Normal University.

Eating chocolate or falling off a building — or just the thought of either — can evoke production of dopamine, a neurotransmitter that can make the heart race and motivate behavior, said Dr. Joe Z. Tsien, Co-Director of GHSU's Brain & Behavior Discovery Institute.

Scientists looked at dopamine neurons in the ventral tegmental area of the mouse brain, widely studied for its role in reward-related motivation or drug addiction. They found essentially all the cells had some response to good or bad experiences while a fearful event excited about 25 percent of the neurons, spurring more dopamine production.

Interestingly neuronal response lasted as long as the event and context was important, Tsien said. Scientists used a conditioned tone to correlate a certain setting with a good or bad event and later, all it took was the tone in that setting to evoke the same response from the dopamine neurons of mice.

"We have believed that dopamine was always engaged in reward and processing the hedonic feeling," Tsien said. "What we have found is that dopamine neurons also are stimulated or respond to negative events."

Just how eating chocolate or jumping off a building induces dopamine production remains a mystery. "That is just the way the brain is wired," Tsien said. He notes that genetics can impact the number of cells activated by bad events — and while interpretation of the findings needs more work — they could help explain inappropriate behaviors such as drug addiction or other risky habits.

In a second paper in PLoS One, Tsien and his colleagues at Boston University have provided more insight into how brains decide how much to remember good or bad. Inside the hippocampus, where memory and knowledge are believe to be formed, recordings from hundreds of mouse brain cells in a region called CA1 showed all are involved in sensing what happens, but not in the same way.

They found among most cells a big event, such as a major earthquake, evoked a bigger sensory response than a mild earthquake. But slightly less than half the cells involved logged a more consistent neural response to all events big and small. These are called invariant cells because of their consistent firing regardless of event intensity. Tsien said these cells are critical in helping the brain remember those events.

The initial muted sensory response was followed by the cells replaying what they just experienced. It's that reverberation that corresponds with learning and memory. "If they play it over and over, you can remember it for a long time," Tsien said of these memory makers.

But these invariant cells vary in that some keep replaying specific memories while the majority focus on more general features of what occurred. "The general-knowledge cells have the 'highest volume,'" Tsien said. "So we walk away with general knowledge that will guide your life, which is more important than the details."

As with the number of dopamine cells that respond to bad or risky behavior, genetics likely plays a role in an individual's specific ratio of cells involved in encoding general versus more detailed memories, Tsien said. A person with a photographic memory likely has more of the specific memory makers while those with autism or schizophrenia, who have difficulty coping in society, may have fewer of the general memory makers that help provide correct context and understanding of complex relationships.

Journal References:

1. Dong V. Wang, Joe Z. Tsien. Convergent Processing of Both Positive and Negative Motivational Signals by the VTA Dopamine Neuronal Populations. PLoS ONE, 2011; 6 (2): e17047 DOI: 10.1371/journal.pone.0017047
2. Remus Oşan, Guifen Chen, Ruiben Feng, Joe Z. Tsien. Differential Consolidation and Pattern Reverberations within Episodic Cell Assemblies in the Mouse Hippocampus. PLoS ONE, 2011; 6 (2): e16507 DOI: 10.1371/journal.pone.0016507

— Usually, we associate rhythms with dance and music. But they also play an important role in the brain. When billions of neurons communicate with each other, certain rhythmic activity patterns arise. The proper metre in this interplay is provided by nerve cells that do not excite other cells, but inhibit their activity instead.

One type of these inhibiting cells acts in a particularly fast and efficient way and is therefore thought to be crucial for memory formation and information processing in neuronal networks. Scientists from Freiburg and the UK were able to specifically switch off this cell type and to observe the consequences for memory formation. Surprisingly, they found that working memory is highly dependent on fast inhibitory cells, whereas spatial reference memory can operate without these neuronal metronomes.

In the journal Nature Neuroscience, Marlene Bartos from the Institute for Physiology I and the Bernstein Center of the University of Freiburg and her colleagues Peer Wulff from the University of Aberdeen and William Wisden from the Imperial College London describe how they were able to specifically switch off these fast inhibiting "interneurons" in the hippocampus of mice. This part of the brain is central to the formation of spatial memories. When the interneurons' output was switched off, the mice behaved completely normal.

Only when the scientists presented the animals with an orientation task that required a functional working memory, impairments became obvious. The mice had to learn to reach a goal within a Y-shaped maze. Animals with deactivated interneurons made significantly more mistakes than their peers from the untreated control group, turning more often into the wrong arm of the maze although they had been there before. This indicated that the working memory was affected by the missing fast inhibitory cells. Remarkably, the spatial reference memory, which had been formed during several days of training, showed no such decrease in performance.

Up to now, impairment of the working memory, common in schizophrenia, had been attributed to dysfunctional inhibitory neurons in the prefrontal cortex. The new results by Bartos, Wisden and Wulff show that this disease can be partly traced back to a change in the function of fast inhibitory cells in the hippocampus.

Journal Reference:

1. Andrew J Murray, Jonas-Frederic Sauer, Gernot Riedel, Christina McClure, Laura Ansel, Lesley Cheyne, Marlene Bartos, William Wisden, Peer Wulff. Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory. Nature Neuroscience, 2011; DOI: 10.1038/nn.2751

 — Amyloid-beta and tau protein deposits in the brain are characteristic features of Alzheimer disease. The effect on the hippocampus, the area of the brain that plays a central role in learning and memory, is particularly severe. However, it appears that the toxic effect of tau protein is largely eliminated when the corresponding tau gene is switched off. Researchers from the Max Planck Research Unit for Structural Molecular Biology at DESY in Hamburg have succeeded in demonstrating that once the gene is deactivated, mice with a human tau gene, which previously presented symptoms of dementia, regain their ability to learn and remember, and that the synapses of the mice also reappear in part. The scientists are now testing active substances to prevent the formation of tau deposits in mice. This may help to reverse memory loss in the early stages of Alzheimer disease — in part, at least.

Whereas aggregated amyloid-beta protein forms insoluble clumps between the neurons, the tau protein accumulates inside them. Tau protein stabilises the tube-shaped fibers of the cytoskeleton, known as microtubules, which provide the "rails" for cellular transport. In Alzheimer disease, excess phosphate groups cause the tau protein to malfunction and form clumps (the 'neurofibrillary tangles'). As a result, nutrient transport breaks down and the neurons and their synapses die off. This process is accompanied by the initial stage of memory loss.

Together with colleagues from Leuven, Hamburg and Erlangen, Eva and Eckhard Mandelkow's team from the Max Planck Research Unit for Structural Molecular Biology generated regulatable transgenic mice with two different human tau gene variants that can be switched on and off again: one group was given a form of the protein that cannot become entangled (anti-aggregant), and a second was provided with the code for the strongly aggregating protein variant (pro-aggregant). The mice with the first form developed no Alzheimer symptoms; the rodents that were given the pro-aggregant tau developed the disease.

The scientists measured the mice's memory loss with the help of a swimming test: the healthy mice quickly learn how to find a life-saving platform located under the surface of the water in a water basin. In contrast, the transgenic animals, which have the additional pro-aggregant tau gene paddle aimlessly around the basin until they accidentally stumble on the platform; they require over four times more time to do this than their healthy counterparts. However, if the mutated toxic tau gene is switched off again, the mice learn to reach "dry land" with ease just a few weeks later. As a control, the mice with the anti-aggregant form of tau have no defects in learning, just as normal non-transgenic mice.

Surprising tissue results

Tissue tests showed that, as expected, no tau clumps had formed in the brains of the first group of mice expressing anti-aggregant tau. In the second group — the mice suffering from Alzheimer's — co-aggregates from human tau and "mouse tau" were formed — against expectations, because tau protein from mice does not usually aggregate. "Even more astonishingly, weeks after the additional gene had been switched off, the aggregated human tau had dissolved again. However, the 'mouse tau' remained clumped. Despite this, the mice were able to learn and remember again," says Eckhard Mandelkow. More precise tests revealed that new synapses had actually formed in their brains.

The scientists concluded from this that mutated or pathological tau can alter healthy tau. It appears that pro-aggregant tau can act similar to a crystal nucleus — once it has started to clump up, it drags neighboring "healthy" tau into the clumps as well. This is what makes the process so toxic to the neurons. "The really important discovery here, however, is that the progression of Alzheimer's disease can be reversed in principle — at least at an early stage of the illness before too many neurons have been destroyed," explains Eva Mandelkow who, together with her husband, will be awarded the Potamkin Prize 2011 for Alzheimer's disease research, which is sponsored by the American Academy of Neurology.

The aggregation of tau proteins, however, cannot simply be switched off in humans the way it can in the transgenic mice. Nevertheless, special substances exist that could dissolve the tau aggregates. By screening 200,000 substances, the Hamburg researchers have already identified several classes of active substances that could re-convert the tau aggregates into soluble tau. These are now being tested on animals.

Journal Reference:

1. Astrid Sydow, Ann Van der Jeugd, Fang Zheng, Tariq Ahmed, Detlef Balschun, Olga Petrova, Dagmar Drexler, Lepu Zhou, Gabriele Rune, Eckhard Mandelkow, Rudi D'Hooge, Christian Alzheimer, and Eva-Maria Mandelkow. Tau-induced Defects in Synaptic Plasticity, Learning and Memory are reversible in Transgenic Mice after Switching off the Toxic Tau Mutant. Journal of Neuroscience, 2011; DOI: 10.1523/JNEUROSCI.5245-10.2011

 Scientists at Duke University Medical Center have uncovered clues to memory and learning by exploring the function of a single gene that governs how neurons form new connections. The finding may also provide insights into a form of human mental retardation.

In a study published in the Journal of Neuroscience, the scientists explored the gene WRP's functions in the brain cell (neuron) and then demonstrated how acutely memory and learning are affected when WRP is missing in mice.

"Human genomics studies have opened the floodgates of information that will benefit people with many different diseases," said Scott Soderling, an assistant professor in the Duke department of cell biology. "But it is impossible to correct something without knowing what the exact underlying problem is."

The researchers knew from earlier human research into the genetics of one individual that when WRP is disrupted, there might be a possible link with severe mental retardation.

The group conducted experiments using neuronal cells in a lab dish which showed that cells enriched with WRP went on to form many filopodia, finger-like protrusions that neurons use to connect with one another.

Without WRP, neurons ultimately were defective in making filopodia,which meant they could not make the correct number of connections, called synapses.

In studies on mice with and without the WRP gene, the researchers were able to see behavior differences.

In one experiment, they tested normal and WRP-deleted mice for their behavior in recognizing a previously unseen toy versus a familiar toy.

A mouse with the gene will typically spend less time investigating a toy it has seen before, but the knockout mice spent the same amount of time each toy, suggesting they don't remember the toy they saw yesterday.

"There was a striking difference between the groups of mice," said Soderling, who is part of the Neonatal Perinatal Research Institute. "The mice without WRP had difficulty learning and didn't display typical memory ability in several experiments."

"Because the excitatory synapses that we are studying form their connections right after birth in humans, we think these specific pathways may even provide an opportunity for early intervention after birth," Soderling said. "Abnormalities in these types of synapses have been linked to mental retardation, and also to schizophrenia and fetal alcohol syndrome, where there are abnormalities that could later affect learning and memory."

"What surprised me most is that we had a preconceived notion that WRP would be part of a process that helped the neuronal cell surface fold inward," said lead author Benjamin Carlson, a graduate student in the Soderling lab. "Eventually we figured out it was just the opposite. When we placed the WRP protein on the inside of the neurons, we could see these buds forming out of the neurons, which then became the longer filopodia and synapses. It is rewarding when you finally think through the possibilities and take a different approach that turns out to yield something valuable."

Soderling credits his collaborators in the Duke Transgenic Mouse and Bacterial Recombineering Core Facility, which helped to produce the right type of mouse for the research.

Other authors include Krissey E. Lloyd, Allison Kruszewski, Il-Hwan Kim, Clifford Heindel and William C. Wetsel of the Duke Departments of Cell Biology and Neurobiology and the Neonatal Perinatal Research Institute; and Wetsel, Ramona M. Rodriguiz and Marika Faytell of Duke Psychiatry and Behavioral Sciences. Faytell is also with the Mouse Behavioral and Neuroendocrine Analysis Core Facility at Duke. Serena M. Dudek is with the National Institute of Environmental Health Sciences in Research Triangle Park, N.C.

This work was supported by National Institutes of Health Grant, March of Dimes Grant Basil O' Connor Starter Scholar Research Grant, Dana Foundation Grant, and by the Intramural Research Program of the National Institute of Environmental Health Sciences Grant.

Journal Reference:

1. Benjamin R. Carlson, Krissey E. Lloyd, Allison Kruszewski, Il-Hwan Kim, Ramona M. Rodriguiz, Clifford Heindel, Marika Faytell, Serena M. Dudek, William C. Wetsel, and Scott H. Soderling. WRP/srGAP3 Facilitates the Initiation of Spine Development by an Inverse F-BAR Domain, and Its Loss Impairs Long-Term Memory. Journal of Neuroscience, 2011; DOI: 10.1523/JNEUROSCI.4433-10.2011

Although many human factors/ergonomics studies conducted over the past few years indicate that drivers who talk on the phone fail to attend to the road and increase the likelihood of an accident, the monotony of driving may also pose an accident risk. New research by HF/E researchers at the University of Kansas, Lawrence, published in Human Factors, suggests that drivers who lose focus on the road because of boredom may actually increase their attention by engaging in a secondary task, particularly during the last leg of their journey.

In a driving simulator, 45 participants drove for 30 minutes while talking on the phone. Researchers Paul Atchley and Mark Chan tested their attentiveness and short-term memory by introducing various obstacles, such as a car suddenly pulling in front of them or a popular fast food restaurant billboard flashing by. Some drivers were given a secondary task throughout the drive, some performed an additional task at the end of the trip, and some had no concurrent task.

Drivers' level of attention was gauged by their ability to stay in their lane, react in time to avoid an intruder car, avoid radical steering maneuvers to maintain a steady course, and accurately remember the signs that they passed.

Results from the study indicate that drivers who had to perform a concurrent task in the latter portion of the trip were more likely to stay in their lane and were less likely to commit road infractions, compared with drivers who had either a continuous or no additional task. These findings suggest that as driving becomes monotonous and drivers' minds drift from the road, strategically introducing an additional task, such as a talking on the phone or listening to the radio, might improve driver attention and stability.

The authors caution that "although these results suggest improvements in driving performance, there is still a degree of risk involved" when drivers perform a secondary task.

Journal Reference:

1. P. Atchley, M. Chan. Potential Benefits and Costs of Concurrent Task Engagement to Maintain Vigilance: A Driving Simulator Investigation. Human Factors: The Journal of the Human Factors and Ergonomics Society, 2010; DOI: 10.1177/0018720810391215

Last week, the Orlando Sentinel newspaper reported that Palm Beach County, Fla., law enforcement is working to develop a consistent set of rules for eyewitnesses, hoping it will help prevent false convictions. And a new Iowa State University study published in the Journal of Experimental Psychology finds that there may be good reason to question the recall of some eyewitnesses.

The study summarizes two experiments conducted by Jason Chan, an ISU assistant professor of psychology; and Moses Langley, a former Iowa State graduate student who is now a psychology faculty member at the University of Wisconsin-Parkside. Both experiments found that subjects who witnessed a criminal event and were tested about it immediately afterward were more susceptible to having misinformation — or false information — instilled in their later recall of the event than non-tested subjects. The researchers call that effect "retrieval-enhanced suggestibility," or RES.

Applying to criminal cases, Chan theorizes that an eyewitness who is asked to make a police statement about a crime may have his or her memory clouded by misinformation — possibly introduced unknowingly by law enforcement, or through erroneous online accounts or news reports — by the time the witness is asked to provide testimony in court.

"There are many cases in which misinformation is introduced unknowingly to people," said Chan, an assistant professor of psychology at Iowa State. "It could be police, or through friends, or a number of sources. And people can confuse their memories, even if it's information not specifically pertaining to that witnessed case. For example, if you saw a bank robbery and later saw a movie depicting bank robberies, whatever you remember from that movie — which has nothing to do with the real-life case — can interfere with your ability to recall the real-life case.

"So misinformation comes from all sorts of sources, especially nowadays with TV news reports trying to compete with people's accounts on Twitter with what they just saw," he continued. "Outlets are trying to compete with these Twitter feeds all the time, so they report something and don't verify the source of the information."

Summarizing two experiments

In the study's first experiment, 78 Iowa State undergraduates viewed a 43-minute pilot episode of the FOX television program "24" that they had not seen before. Half of the subjects then took a 24-question recall test, while the remaining subjects played the video game Tetris. All participants then listened to an eight-minute audio narrative that summarized the video and contained some misinformation about the crime they witnessed in the video. All the subjects returned a week later to take the same recall test. The researchers found that the tested subjects were more likely to recall the misinformation than the non-tested participants.

The researchers duplicated the experiment with 60 undergraduates, with the only difference being a one-week delay in the presentation of the misinformation prior to the second recall test. They found an even more powerful RES effect in the tested subjects, who reported the misinformation much more frequently than their non-tested counterparts.

"The most surprising finding from this line of research was that taking the immediate test, or initially recalling that event, somehow increased your susceptibility to misleading information later," Chan said. "That was definitely not expected. In fact, my collaborators and I expected the opposite based on what we know from the burgeoning cognitive psychology literature on the testing effect."

Initial testing can reinforce memory too

In both experiments, the researchers also found that the subjects who were initially tested and not provided the misinformation recalled the event's details more accurately than the non-tested subjects one week later. So the initial test reinforced their memory of the event.

"One really great thing about testing for memory is that not only does it enhance memory for the original information, it also lets you learn new information better," Chan said. "But because of this dual mechanism, under a situation when you present people with new information that is misleading, it can enhance their learning of that misleading information. The misinformation is more likely to be recalled if people don't question the accuracy of that new information."

This is the latest of three studies Chan has published on RES, with the other two published in Psychological Science (2009) and the Journal of Memory and Language (2010). He plans to continue his work on the influences of eyewitness memory.

"I think that because of all this new misinformation that's floating around, research in this area has even more real world relevance nowadays," he said.

NewsPsychology (Feb. 9, 2011) — People who have memory problems or other declines in their mental abilities may be at higher risk for stroke, according to a study released February 9 that will be presented at the American Academy of Neurology’s 63rd Annual Meeting in Honolulu April 9 to April 16, 2011.

“Finding ways to prevent stroke and identify people at risk for stroke are important public health problems,” said study author Abraham J. Letter of the University of Alabama at Birmingham. “This study shows we might get a better idea of who is at high risk of stroke by including a couple simple tests when we are evaluating people who already have some stroke risk.”

For the study, researchers gave tests to people age 45 and older who had never had a stroke, then contacted them twice a year by phone for up to 4.5 years to determine whether they had suffered a stroke. The average age of the participants was 67. Strokes were then confirmed by medical records. A total of 14,842 people took a verbal fluency test, measuring the brain’s executive functioning skills, and 17,851 people took a word recall memory test.

The study was part of a larger study called the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. During the study, 123 participants who had taken the verbal fluency test and 129 participants who had taken the memory test experienced a stroke.

Those who scored in the bottom 20 percent for verbal fluency were 3.6 times more likely to develop a stroke than those who scored in the top 20 percent. For the memory test, those who scored in the bottom 20 percent were 3.5 times more likely to have a stroke than those in the top 20 percent. The difference in stroke incidence rates between those with the bottom and top 20 percent of scores was 3.3 strokes per thousand person-years. In general, the differences remained after researchers adjusted for age, education, race and where participants lived.

At age 50, those who scored in the bottom 20 percent of the memory test were 9.4 times more likely to later have a stroke than those in the top 20 percent, but the difference was not as large at older ages.

The study was supported by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke.

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— When people think unpleasant events are over, they remember them as being less painful or annoying than when they expect them to happen again, pointing to the power of expectation to help people brace for the worst, according to studies published by the American Psychological Association.

In a series of eight studies exposing people to annoying noise, subjecting them to tedious computer tasks, or asking them about menstrual pain, participants recalled such events as being significantly more negative if they expected them to happen again soon.

This reaction might be adaptive: People may keep their equilibrium by using memory to steel themselves against future harm, said co-authors Jeff Galak, PhD, of Carnegie Mellon University, and Tom Meyvis, PhD, of New York University. Their findings appear in the February issue of the Journal of Experimental Psychology: General.

The laboratory studies (of 30, 44, 112, 154, 174, 160 and 51 subjects) exposed people to five seconds of vacuum cleaner noise. People who were told they would have to listen to more vacuum cleaner noise said it was significantly more irritating than people who were told the noise was over.

Subsequent studies replicated this finding using larger samples and boring, repetitive tasks — such as dragging circles from the left to the right side of a computer screen 50 times. Again, people who were told they would have to do it again said the task was significantly more irritating, boring and annoying than people told when they were done.

Other studies varied the method to allow researchers to understand what subjects were experiencing emotionally. For example, the researchers found evidence that people used more intensely negative memories to steel themselves against the future. Also, not having time to reflect on the first experience, or having their resources drained by a demanding "filler" task, reduced the power of expectation.

Also, people recalled fun activities, such as playing video games, as equally enjoyable whether they thought they would play again or not. The authors concluded that emotions negatively shape memory's judgment of unpleasant experiences, but positively shape the recollected quality of pleasant experiences.

In the culminating field study of 180 women (average age 29), those whose menstrual periods had ended fewer than three days earlier or who expected their periods within three days remembered their last period as significantly more painful than women in the middle of their cycle (none were currently menstruating).

"The prospect of repeating an experience can, in fact, change how people remember it," the authors concluded. Bracing for the worst may actually help people to reduce their discomfort if a bad experience should happen, and allow them to be pleasantly surprised if it does not, they added.

Journal Reference:

1. Jeff Galak, Tom Meyvis. The Pain Was Greater If It Will Happen Again: The Effect of Anticipated Continuation on Retrospective Discomfort. Journal of Experimental Psychology: General, 2011; 140 (12): 63-75 DOI: 10.1037/a0021447

— A new study shows that one year of moderate physical exercise can increase the size of the brain's hippocampus in older adults, leading to an improvement in spatial memory.

The project — conducted by researchers at the University of Pittsburgh, University of Illinois, Rice University, and Ohio State University — is considered the first study of its kind focusing on older adults who are already experiencing atrophy of the hippocampus, the brain structure involved in all forms of memory formation. 

The scientists recruited 120 sedentary older people without dementia and randomly placed them in one of two groups — those who began an exercise regimen of walking around a track for 40 minutes a day, three days a week, or those limited to stretching and toning exercises. Magnetic resonance images were collected before the intervention, after six months, and at the end of the one-year study.

The aerobic exercise group demonstrated an increase in volume of the left and right hippocampus of 2.12 percent and 1.97 percent, respectively. The same regions of the brain in those who did stretching exercises decreased in volume by 1.40 and 1.43 percent, respectively.

Spatial memory tests were conducted for all participants at the three intervals. Those in the aerobic exercise group showed improved memory function, when measured against their performance at the start of the study, an improvement associated with the increased size of the hippocampus. The authors also examined several biomarkers associated with brain health, including brain-derived neurotrophic factor (BDNF), a small molecule that is involved in learning and memory. They found that the increases in hippocampal size were associated with increased amounts of BDNF.

"We think of the atrophy of the hippocampus in later life as almost inevitable," said Kirk Erickson, professor of psychology at the University of Pittsburgh and the paper's lead author. "But we've shown that even moderate exercise for one year can increase the size of that structure. The brain at that stage remains modifiable."

"The results of our study are particularly interesting in that they suggest that even modest amounts of exercise by sedentary older adults can lead to substantial improvements in memory and brain health," said Art Kramer, director of the Beckman Institute at the University of Illinois and the senior author.

"Such improvements have important implications for the health of our citizens and the expanding population of older adults worldwide."

The study, funded through the National Institute on Aging, appears in the Jan. 31 Proceedings of the National Academy of Sciences (PNAS).

Journal Reference:

1. Kirk I. Erickson, Michelle W. Voss, Ruchika Shaurya Prakash, Chandramallika Basak, Amanda Szabo, Laura Chaddock, Jennifer S. Kim, Susie Heo, Heloisa Alves, Siobhan M. White, Thomas R. Wojcicki, Emily Mailey, Victoria J. Vieira, Stephen A. Martin, Brandt D. Pence, Jeffrey A. Woods, Edward Mcauley, and Arthur F. Kramer. Exercise training increases size of hippocampus and improves memory. PNAS, Jan. 31, 2011 DOI: 10.1073/pnas.1015950108

 A naturally occurring growth factor significantly boosted retention and prevented forgetting of a fear memory when injected into rats' memory circuitry during time-limited windows when memories become fragile and changeable. In the study funded by the National Institutes of Health, animals treated with insulin-like growth factor (IGF-II) excelled at remembering to avoid a location where they had previously experienced a mild shock.

"To our knowledge, this is the first demonstration of potent memory enhancement via a naturally occurring factor that readily passes through the blood-brain barrier — and thus may hold promise for treatment development," explained Cristina Alberini, Ph.D., of Mount Sinai School of Medicine, New York, a grantee of the NIH's National Institute of Mental Health (NIMH).

Alberini and colleagues say IGF-II could become a potential drug target for boosting memory. They report on their discovery in the Jan. 27, 2011 issue of Nature.

"As we learn more about such mechanisms of fear memory formation and extinction, we hope to apply this knowledge to address clinical problems, including post-traumatic stress disorder," said NIMH Director Thomas R. Insel, M.D.

The staying power of a memory depends on the synthesis of new proteins and structural changes in the connections between brain cells. These memory-strengthening changes occur within time-limited windows right after learning, when memories undergo consolidation, and also right after a memory is retrieved, a process called reconsolidation.

Hints from other studies led the researchers to suspect that IGF-II plays a role in these processes within the brain's memory center, the hippocampus, where it is relatively highly concentrated. The little-known growth factor is part of the brain's machinery for tissue repair and regeneration; it is important during development and declines with age.

To find out how it might work in memory, Alberini's team employed a standard test of fear memory called inhibitory avoidance training. They tracked the movement of rats in an environment where the animals learned to associate a dark area with mild foot shocks. The more an animal avoided the dark area, the better its fear memory.

This kind of learning boosted the expression of naturally occurring IGF-II in the hippocampus. So the researchers injected synthetic IGF-II directly into the hippocampus during windows of consolidation or reconsolidation, when memories are malleable. Remarkably, the rats' memory markedly improved — with the effects lasting at least a few weeks. An examination of the animals' brains revealed that IGF-II had strengthened the cellular connections and mechanisms underlying long-term memory — a process called long-term potentiation.

So IGF-II both strengthened a memory and delayed its normal decay — forgetting, noted Alberini.

The researchers had previously discovered that the fragility induced by memory retrieval requires new protein synthesis in the brain's fear area, the amygdala — but only if the memory is less than two weeks old. In the new study, they found that memory enhancement triggered by IGF-II during this reconsolidation window depended on new protein synthesis in the hippocampus during the same time period. They suggest that these time-limited effects might be explained by a gradual shift in the site where a memory is stored as it grows older, from the hippocampus to the brain's outer mantle, or cortex.

The study showed that the growth factor works through its own — also little known — IGF-II receptor and depends on activation of an enzyme (GSK3 beta), and AMPA receptors for the chemical messenger glutamate, both of which are implicated in memory. Evidence suggests that rather than activating new neurons, it appears to work through already activated connections between cells — or synapses — that are regulated by the enzyme and receptor.

Among future directions, researchers could explore whether IGF-II might enhance other types of memory, such as extinction learning, in which a fear memory is replaced by a memory of safety, said Alberini. If so, it might provide clues to new treatments for anxiety disorders like PTSD.

In addition to NIMH, the research was also funded by NIH's National Institute on Drug Abuse and National Institute of General Medical Sciences, among other funders

Journal Reference:

1. Dillon Y. Chen, Sarah A. Stern, Ana Garcia-Osta, Bernadette Saunier-Rebori, Gabriella Pollonini, Dhananjay Bambah-Mukku, Robert D. Blitzer, Cristina M. Alberini. A critical role for IGF-II in memory consolidation and enhancement. Nature, 2011; 469 (7331): 491 DOI: 10.1038/nature09667