Posts tagged memory consolidation
Articles and news from the latest research reports.
Learning to play the piano? Sleep on it!
According to researchers at the University of Montreal, the regions of the brain below the cortex play an important role as we train our bodies’ movements and, critically, they interact more effectively after a night of sleep. While researchers knew that sleep helped us the learn sequences of movements (motor learning), it was not known why. “The subcortical regions are important in information consolidation, especially information linked to a motor memory trace. When consolidation level is measured after a period of sleep, the brain network of these areas functions with greater synchrony, that is, we observe that communication between the various regions of this network is better optimized. The opposite is true when there has been no period of sleep,” said Karen Debas, neuropsychologist at the University of Montreal and leader author of the study. A network refers to multiple brain areas that are activated simultaneously.
To achieve these results, the researchers, led by Dr. Julien Doyon, Scientific Director of the Functional Neuroimaging Unit of the Institut universitaire de gériatrie de Montréal Research Centre, taught a group of subjects a new sequence of piano-type finger movements on a box. The brains of the subjects were observed using functional magnetic resonance imaging during their performance of the task before and after a period of sleep. Meanwhile, the same test was performed by a control group at the beginning and end of the day, without a period of sleep.
The researchers had already shown that the putamen, a central part of the brain, was more active in subjects who had slept. Furthermore, they had observed improved performance of the task after a night of sleep and not the simple passage of daytime. Using a brain connectivity analysis technique, which identifies brain networks and measures their integration levels, they found that one network emerged from the others—the cortico-striatal network—composed of cortical and subcortical areas, including the putaman and associated cortical regions. “After a night of sleep, we found that this network was more integrated than the others, that is, interaction among these regions was greater when consolidation had occurred. A night of sleep seems to provide active protection of this network, which the passage of daytime does not provide. Moreover, only a night of sleep results in better performance of the task,” Debas said.
These results provide insight into the role of sleep in learning motor skills requiring new movement sequences and reveal, for the first time, greater interaction within the cortico-striatal system after a consolidation phase following sleep. “Our findings open the door to other research opportunities, which could lead us to better understand the mechanisms that take place during sleep and ensure better interaction between key regions of the brain. Indeed, several other studies in my laboratory are examining the role of sleep spindles—brief physiological events during non-rapid eye movement sleep—in the process of motor memory trace consolidation,” Doyon said. “Ultimately, we believe that we will better be able to explain and act on memory difficulties presented by certain clinical populations who have sleeping problems and help patients who are relearning motor sequences in rehabilitation centres,” Debas said.
(Source: nouvelles.umontreal.ca)
Notch Developmental Pathway Regulates Fear Memory Formation
Nature is thrifty. The same signals that embryonic cells use to decide whether to become nerves, skin or bone come into play again when adult animals are learning whether to become afraid.
Researchers at Yerkes National Primate Research Center, Emory University, have learned that the molecule Notch, critical in many processes during embryonic development, is also involved in fear memory formation. Understanding fear memory formation is critical to developing more effective treatments and preventions for anxiety disorders such as post-traumatic stress disorder (PTSD). The results are scheduled for publication online this week by the journal Neuron.
"We are finding that developmental pathways that appear to be quiescent during adulthood are transiently reactivated to allow new memory formation to occur," says Kerry Ressler, MD, PhD, professor of psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center, and senior author of the paper.
The first author of the paper is postdoctoral fellow Brian Dias, PhD, and co-authors include undergraduates Jared Goodman, Ranbir Ahluwalia and Audrey Easton, and post-doctoral researcher Raul Andero, PhD.
The Notch signaling pathway, present in insects, worms and vertebrates, is involved in embryonic patterning as well as nervous system and cardiovascular development. It’s a way for cells to communicate and coordinate which cells are going to become what types of tissues.
Dias and Ressler probed the Notch pathway because they were examining many genes that are activated in the brains of mice after they learn to become afraid of a sound paired with a mild foot-shock. They were looking for changes in the amygdala, a region of the brain known to regulate fear learning.
The researchers were particularly interested in micro RNAs. MicroRNAs do not encode proteins but can inhibit other genes, often several at once in a coordinated way. Dias and Ressler found that levels of miRNA-34a are increased in the amygdala after fear learning occurs. A day after fear training, animals whose brains were injected with a virus engineered to carry a “sponge” against miRNA-34a froze less often than control animals.
The researchers found that miRNA-34a regulated several genes that encode components of the Notch pathway. They believe their study is the first to link miRNA-34a and Notch signaling to a role in memory consolidation.
Notch is under investigation as a target in the treatment of various cancers and some drugs that target Notch have been well-tolerated by humans.
"From a therapeutic perspective, our data suggest that relevant drugs that regulate Notch signaling could potentially be a starting point for preventing or treating PTSD," Dias says.
(Source: yerkes.emory.edu)
When you have learned words in another language, it may be worth listening to them again in your sleep. A study funded by the Swiss National Science Foundation (SNSF) has now shown that this method reinforces memory.
Reluctant students and sleepyheads take note: a study conducted at the universities of Zurich and Fribourg has shown that German-speaking students are better at remembering the meaning of newly learned Dutch words when they hear the words again in their sleep. “Our method is easy to use in daily life and can be adopted by anyone,” says study director and biopsychologist Björn Rasch. However, the results were obtained in strictly controlled laboratory conditions. It remains to be seen whether they can be successfully transferred to everyday situations.
Quiet playback
In their trial, which has been published in the journal “Cerebral Cortex”, Thomas Schreiner and Björn Rasch asked 60 volunteers to learn pairs of Dutch and German words at ten o’clock in the evening. Half of the volunteers then went to bed. While they slept, some of the Dutch words they had learned before going to bed were played back quietly enough not to awaken them. The remaining volunteers stayed awake to listen to the Dutch words on the playback.
The scientists awoke the sleeping volunteers at two in the morning, then tested everyone’s knowledge of the new words a little later. The group that had been asleep were better at remembering the German translations of the Dutch words they had heard in their sleep. The volunteers who had remained awake were unable to remember words they had heard on the playback any better than those they had not.
Reinforcement of spontaneous activation
Schreiner and Rasch believe that their results provide further evidence that sleep helps memory, probably because the sleeping brain spontaneously activates previously learned subject matter. Playing this subject matter back during sleep can reinforce this activation process and thus improve recall. For example, a person who plays a memory card game to the scent of roses, and is then re-exposed to the same scent while asleep, is subsequently better at remembering where a particular card is in the stack, as Rasch was able to show in another study a few years ago.
Schreiner and Rasch have now observed the beneficial effect of sleep on learning foreign words. A certain amount of swotting is still needed, though. “You can only successfully activate words that you have learned before you go to sleep. Playing back words you don’t know while you’re asleep has no effect,” says Schreiner.
Study finds that learning by repetition impairs recall of details
When learning, practice doesn’t always make perfect.
UC Irvine neurobiologists Zachariah Reagh and Michael Yassa have found that while repetition enhances the factual content of memories, it can reduce the amount of detail stored with those memories. This means that with repeated recall, nuanced aspects may fade away.
In the study, which appears this month in Learning & Memory, student participants were asked to look at pictures either once or three times. They were then tested on their memories of those images. The researchers found that multiple views increased factual recall but actually hindered subjects’ ability to reject similar “imposter” pictures. This suggests that the details of those memories may have been shaken loose by repetition.
This discovery supports Reagh’s and Yassa’s Competitive Trace Theory – published last year in Frontiers in Behavioral Neuroscience – which posits that the details of a memory become more subjective the more they’re recalled and can compete with bits of other similar memories. The scientists hypothesize that this may even lead to false memories, akin to a brain version of the telephone game.
Yassa, an assistant professor of neurobiology & behavior, said that these findings do not discredit the practice of repetitive learning. However, he noted, pure repetition alone has limitations. For a more enriching and lasting learning experience through which nuance and detail are readily recalled, other memory techniques should be used to complement repetition.
Scientists explain how memories stick together
Scientists at the Salk Institute have created a new model of memory that explains how neurons retain select memories a few hours after an event.
This new framework provides a more complete picture of how memory works, which can inform research into disorders liked Parkinson’s, Alzheimer’s, post-traumatic stress and learning disabilities.
"Previous models of memory were based on fast activity patterns," says Terrence Sejnowski, holder of Salk’s Francis Crick Chair and a Howard Hughes Medical Institute Investigator. "Our new model of memory makes it possible to integrate experiences over hours rather than moments."
Over the past few decades, neuroscientists have revealed much about how long-term memories are stored. For significant events—for example, being bit by a dog—a number of proteins are quickly made in activated brain cells to create the new memories. Some of these proteins linger for a few hours at specific places on specific neurons before breaking down.
This series of biochemical events allow us to remember important details about that event—such as, in the case of the dog bite, which dog, where it was located and so on.
One problem scientists have had with modeling memory storage is explaining why only selective details and not everything in that 1-2 hour window is strongly remembered. By incorporating data from previous literature, Sejnowski and first author Cian O’Donnell, a Salk postdoctoral researcher, developed a model that bridges findings from both molecular and systems observations of memory to explain how this 1-2 hour memory window works. The work is detailed in the latest issue of Neuron.
Using computational modeling, O’Donnell and Sejnowski show that, despite the proteins being available to a number of neurons in a given circuit, memories are retained when subsequent events activate the same neurons as the original event. The scientists found that the spatial positioning of proteins at both specific neurons and at specific areas around these neurons predicts which memories are recorded. This spatial patterning framework successfully predicts memory retention as a mathematical function of time and location overlap.
"One thing this study does is link what’s happing in memory formation at the cellular level to the systems level," says O’Donnell. "That the time window is important was already established; we worked out how the content could also determine whether memories were remembered or not. We prove that a set of ideas are consistent and sufficient to explain something in the real world."
The new model also provides a potential framework for understanding how generalizations from memories are processed during dreams.
While much is still unknown about sleep, research suggests that important memories from the day are often cycled through the brain, shuttled from temporary storage in the hippocampus to more long-term storage in the cortex. Researchers observed most of this memory formation in non-dreaming sleep. Little is known about if and how memory packaging or consolidation is done during dreams. However, O’Donnell and Sejnowski’s model suggests that some memory retention does happen during dreams.
"During sleep there’s a reorganizing of memory—you strengthen some memories and lose ones you don’t need anymore," says O’Donnell. "In addition, people learn abstractions as they sleep, but there was no idea how generalization processes happen at a neural level."
By applying their theoretical findings on overlap activity within the 1-2 hour window, they came up with a theoretical model for how the memory abstraction process might work during sleep.
(Source: salk.edu)
Sleep-dependent memory consolidation and accelerated forgetting
Accelerated long-term forgetting (ALF) is a form of memory impairment in which learning and initial retention of information appear normal but subsequent forgetting is excessively rapid. ALF is most commonly associated with epilepsy and, in particular, a form of late-onset epilepsy called transient epileptic amnesia (TEA). ALF provides a novel opportunity to investigate post-encoding memory processes, such as consolidation. Sleep is implicated in the consolidation of memory in healthy people and a deficit in sleep-dependent memory consolidation has been proposed as an explanation for ALF. If this proposal were correct, then sleep would not benefit memory retention in people with ALF as much as in healthy people, and ALF might only be apparent when the retention interval contains sleep. To test this theory, we compared performance on a sleep-sensitive memory task over a night of sleep and a day of wakefulness. We found, contrary to the hypothesis, that sleep benefits memory retention in TEA patients with ALF and that this benefit is no smaller in magnitude than that seen in healthy controls. Indeed, the patients performed significantly more poorly than the controls only in the wake condition and not the sleep condition. Patients were matched to controls on learning rate, initial retention, and the effect of time of day on cognitive performance. These results indicate that ALF is not caused by a disruption of sleep-dependent memory consolidation. Instead, ALF may be due to an encoding abnormality that goes undetected on behavioural assessments of learning, or by a deficit in memory consolidation processes that are not sleep-dependent.
(Image: Courtney Icenhour)
Caffeine has positive effect on memory
Whether it’s a mug full of fresh-brewed coffee, a cup of hot tea, or a can of soda, consuming caffeine is the energy boost of choice for millions who want to wake up or stay up.
Now, researchers at Johns Hopkins University have found another use for the popular stimulant: memory enhancer.
Michael Yassa, an assistant professor of psychological and brain sciences at Johns Hopkins, and his team of scientists found that caffeine has a positive effect on our long-term memory. Their research, published by the journal Nature Neuroscience, shows that caffeine enhances certain memories at least up to 24 hours after it is consumed.
"We’ve always known that caffeine has cognitive-enhancing effects, but its particular effects on strengthening memories and making them resistant to forgetting has never been examined in detail in humans," said Yassa, senior author of the paper. "We report for the first time a specific effect of caffeine on reducing forgetting over 24 hours."
The Johns Hopkins researchers conducted a double-blind trial in which participants who did not regularly eat or drink caffeinated products received either a placebo or a 200-milligram caffeine tablet five minutes after studying a series of images. Salivary samples were taken from the participants before they took the tablets to measure their caffeine levels. Samples were taken again one, three, and 24 hours afterwards.
The next day, both groups were tested on their ability to recognize images from the previous day’s study session. On the test, some of the visuals were the same as those from the day before, some were new additions, and some were similar but not the same.
More members of the caffeine group were able to correctly identify the new images as “similar” to previously viewed images rather than erroneously citing them as the same.
The brain’s ability to recognize the difference between two similar but not identical items, called pattern separation, reflects a deeper level of memory retention, the researchers said.
"If we used a standard recognition memory task without these tricky similar items, we would have found no effect of caffeine," Yassa said. "However, using these items requires the brain to make a more difficult discrimination—what we call pattern separation, which seems to be the process that is enhanced by caffeine in our case."
The memory center in the human brain is the hippocampus, a seahorse-shaped area in the medial temporal lobe of the brain. The hippocampus is the switchbox for all short- and long-term memories. Most research done on memory—the effects of concussions in athletes, of war-related head injuries, and of dementia in the aging population—focuses on this area of the brain.
Until now, caffeine’s effects on long-term memory had not been examined in detail. Of the few studies done, the general consensus was that caffeine has little or no effect on long-term memory retention.
The research is different from prior experiments because the subjects took the caffeine tablets only after they had viewed and attempted to memorize the images.
"Almost all prior studies administered caffeine before the study session, so if there is an enhancement, it’s not clear if it’s due to caffeine’s effects on attention, vigilance, focus, or other factors," Yassa said. "By administering caffeine after the experiment, we rule out all of these effects and make sure that if there is an enhancement, it’s due to memory and nothing else."
According to the U.S. Food and Drug Administration, 90 percent of people worldwide consume caffeine in one form or another. In the United States, 80 percent of adults consume caffeine every day. The average adult has an intake of about 200 milligrams—the same amount used in the Yassa study—or roughly one cup of strong coffee per day.
Yassa’s team completed the research at Johns Hopkins before his lab moved to the University of California, Irvine, at the start of this year.
"The next step for us is to figure out the brain mechanisms underlying this enhancement," Yassa said. "We can use brain-imaging techniques to address these questions. We also know that caffeine is associated with healthy longevity and may have some protective effects from cognitive decline like Alzheimer’s disease. These are certainly important questions for the future."
Recurring memory traces boost long-lasting memories
While the human brain is in a resting state, patterns of neuronal activity which are associated to specific memories may spontaneously reappear. Such recurrences contribute to memory consolidation – i.e. to the stabilization of memory contents. Scientists of the DZNE and the University of Bonn are reporting these findings in the current issue of The Journal of Neuroscience. The researchers headed by Nikolai Axmacher performed a memory test on a series of persons while monitoring their brain activity by functional magnetic resonance imaging (fMRI). The experimental setup comprised several resting states including a nap inside a neuroimaging scanner. The study indicates that resting periods can generally promote memory performance.
Depending on one’s mood and activity different regions are active in the human brain. Perceptions and thoughts also influence this condition and this results in a pattern of neuronal activity which is linked to the experienced situation. When it is recalled, similar patterns, which are slumbering in the brain, are reactivated. How this happens, is still largely unknown.
The prevalent theory of memory formation assumes that memories are stored in a gradual manner. At first, the brain stores new information only temporarily. For memories to remain in the long term, a further step is required. „We call it consolidation“, Dr. Nikolai Axmacher explains, who is a researcher at the Department of Epileptology of the University of Bonn and at the Bonn site of the DZNE. “We do not know exactly how this happens. However, studies suggest that a process we call reactivation is of importance. When this occurs, the brain replays activity patterns associated with a particular memory. In principle, this is a familiar concept. It is a fact that things that are actively repeated and practiced are better memorized. However, we assume that a reactivation of memory contents may also happen spontaneously without there being an external trigger.”
A memory test inside the scanner
Axmacher and his team tested this hypothesis in an experiment that involved ten healthy participants with an average age of 24 years. They were shown a series of pictures, which displayed – among other things – frogs, trees, airplanes and people. Each of these pictures was associated with a white square as a label at a different location. The subjects were asked to memorize the position of the square. At the end of the experiment all images were shown again, but this time without the label. The study participants were then asked to indicate with a mouse cursor where the missing mark was originally located. Memory performance was measured as the distance between the correct and the indicated position.
“This is an associative task. Visual and spatial perceptions have to be linked together”, the researcher explains. “Such tasks involve several brain regions. These include the visual cortex and the hippocampus, which takes part in many memory processes.”
Brain activity was recorded by fMRI during the entire experiment, which lasted several hours and included resting periods and a nap inside the neuroimaging scanner.
Recurrent brain patterns increased the accuracy
For data processing a pattern recognition algorithm was trained to look for similarities between neuronal patterns observed during initial encoding and patterns appearing at later occasions. “This method is complex, but quite effective”, Axmacher says. “Analysis showed that neuronal activity associated with images that were shown initially did reappear during subsequent resting periods and in the sleeping phase.”
Memory performance correlated with the replay of neuronal activity patterns. “The more frequently a pattern had reappeared, the more accurate test participants could label the corresponding image”, Axmacher summarizes the findings. “These results support our assumption that neural patterns can spontaneously reappear and that they promote the formation of long-lasting memory contents. There was already evidence for this from animal studies. Our experiment shows that this phenomenon also happens in humans.”
Memory performance benefits from resting periods
The study indicates that resting periods can generally foster memory performance. “Though, our data did not show whether sleeping had a particular effect. This may be due to the experimental setup, which only allowed for a comparatively short nap”, Axmacher reckons. “By contrast, night sleep is considered to be beneficial for the consolidation of memory contents. But it usually takes many hours and includes multiple transitions between different stages of sleep. However, other studies suggest that even short naps may positively affect memory consolidation.”
An objective look at memory contents
It is up to speculation whether the recurring brain patterns triggered conscious memories or whether they remained below the threshold of perception. “I think it is reasonable to assume that during resting periods the test participants let their mind wander and that they recalled images they had just seen before. But this is a matter of subjective perception of the test participants. That’s something we did not look at because it is not essential for our investigation“, Axmacher says. “The strength of our approach lies rather in the fact that we look at memory contents from the outside, in an objective manner. And that we can evaluate them by pattern recognition. This opens ways to many questions of research. For example, brain patterns that reoccur spontaneously are also of interest in the context of experimental dream research.”
(Source: dzne.de)
Russell Foster is a circadian neuroscientist: He studies the sleep cycles of the brain. And he asks: What do we know about sleep? Not a lot, it turns out, for something we do with one-third of our lives. In this talk, Foster shares three popular theories about why we sleep, busts some myths about how much sleep we need at different ages — and hints at some bold new uses of sleep as a predictor of mental health.
Russell Foster studies sleep and its role in our lives, examining how our perception of light influences our sleep-wake rhythms.
![Memory-Boosting Chemical Is Identified in Mice
Memory improved in mice injected with a small, drug-like molecule discovered by UCSF San Francisco researchers studying how cells respond to biological stress.
The same biochemical pathway the molecule acts on might one day be targeted in humans to improve memory, according to the senior author of the study, Peter Walter, PhD, UCSF professor of biochemistry and biophysics and a Howard Hughes Investigator.
The discovery of the molecule and the results of the subsequent memory tests in mice were published in eLife, an online scientific open-access journal, on May 28, 2013.
In one memory test included in the study, normal mice were able to relocate a submerged platform about three times faster after receiving injections of the potent chemical than mice that received sham injections.
The mice that received the chemical also better remembered cues associated with unpleasant stimuli – the sort of fear conditioning that could help a mouse avoid being preyed upon.
Notably, the findings suggest that despite what would seem to be the importance of having the best biochemical mechanisms to maximize the power of memory, evolution does not seem to have provided them, Walter said.
“It appears that the process of evolution has not optimized memory consolidation; otherwise I don’t think we could have improved upon it the way we did in our study with normal, healthy mice,” Walter said.
The memory-boosting chemical was singled out from among 100,000 chemicals screened at the Small Molecule Discovery Center at UCSF for their potential to perturb a protective biochemical pathway within cells that is activated when cells are unable to keep up with the need to fold proteins into their working forms.
However, UCSF postdoctoral fellow Carmela Sidrauski, PhD, discovered that the chemical acts within the cell beyond the biochemical pathway that activates this unfolded protein response, to more broadly impact what’s known as the integrated stress response. In this response, several biochemical pathways converge on a single molecular lynchpin, a protein called eIF2 alpha.
Scientists have known that in organisms ranging in complexity from yeast to humans different kinds of cellular stress — a backlog of unfolded proteins, DNA-damaging UV light, a shortage of the amino acid building blocks needed to make protein, viral infection, iron deficiency — trigger different enzymes to act downstream to switch off eIF2 alpha.
“Among other things, the inactivation of eIF2 alpha is a brake on memory consolidation,” Walter said, perhaps an evolutionary consequence of a cell or organism becoming better able to adapt in other ways.
Turning off eIF2 alpha dials down production of most proteins, some of which may be needed for memory formation, Walter said. But eIF2 alpha inactivation also ramps up production of a few key proteins that help cells cope with stress.
Study co-author Nahum Sonenberg, PhD, of McGill University previously linked memory and eIF2 alpha in genetic studies of mice, and his lab group also conducted the memory tests for the current study.
The chemical identified by the UCSF researchers is called ISRIB, which stands for integrated stress response inhibitor. ISRIB counters the effects of eIF2 alpha inactivation inside cells, the researchers found.
“ISRIB shows good pharmacokinetic properties [how a drug is absorbed, distributed and eliminated], readily crosses the blood-brain barrier, and exhibits no overt toxicity in mice, which makes it very useful for studies in mice,” Walter said. These properties also indicate that ISRIB might serve as a good starting point for human drug development, according to Walter.
Walter said he is looking for scientists to collaborate with in new studies of cognition and memory in mouse models of neurodegenerative diseases and aging, using ISRIB or related molecules.
In addition, chemicals such as ISRIB could play a role in fighting cancers, which take advantage of stress responses to fuel their own growth, Walter said. Walter already is exploring ways to manipulate the unfolded protein response to inhibit tumor growth, based on his earlier discoveries.
At a more basic level, Walter said, he and other scientists can now use ISRIB to learn more about the role of the unfolded protein response and the integrated stress response in disease and normal physiology.](http://41.media.tumblr.com/11ebbfd04cfa4f78a2b3f00de596c905/tumblr_mofkpwCqOn1rog5d1o1_500.jpg)
Memory-Boosting Chemical Is Identified in Mice
Memory improved in mice injected with a small, drug-like molecule discovered by UCSF San Francisco researchers studying how cells respond to biological stress.
The same biochemical pathway the molecule acts on might one day be targeted in humans to improve memory, according to the senior author of the study, Peter Walter, PhD, UCSF professor of biochemistry and biophysics and a Howard Hughes Investigator.
The discovery of the molecule and the results of the subsequent memory tests in mice were published in eLife, an online scientific open-access journal, on May 28, 2013.
In one memory test included in the study, normal mice were able to relocate a submerged platform about three times faster after receiving injections of the potent chemical than mice that received sham injections.
The mice that received the chemical also better remembered cues associated with unpleasant stimuli – the sort of fear conditioning that could help a mouse avoid being preyed upon.
Notably, the findings suggest that despite what would seem to be the importance of having the best biochemical mechanisms to maximize the power of memory, evolution does not seem to have provided them, Walter said.
“It appears that the process of evolution has not optimized memory consolidation; otherwise I don’t think we could have improved upon it the way we did in our study with normal, healthy mice,” Walter said.
The memory-boosting chemical was singled out from among 100,000 chemicals screened at the Small Molecule Discovery Center at UCSF for their potential to perturb a protective biochemical pathway within cells that is activated when cells are unable to keep up with the need to fold proteins into their working forms.
However, UCSF postdoctoral fellow Carmela Sidrauski, PhD, discovered that the chemical acts within the cell beyond the biochemical pathway that activates this unfolded protein response, to more broadly impact what’s known as the integrated stress response. In this response, several biochemical pathways converge on a single molecular lynchpin, a protein called eIF2 alpha.
Scientists have known that in organisms ranging in complexity from yeast to humans different kinds of cellular stress — a backlog of unfolded proteins, DNA-damaging UV light, a shortage of the amino acid building blocks needed to make protein, viral infection, iron deficiency — trigger different enzymes to act downstream to switch off eIF2 alpha.
“Among other things, the inactivation of eIF2 alpha is a brake on memory consolidation,” Walter said, perhaps an evolutionary consequence of a cell or organism becoming better able to adapt in other ways.
Turning off eIF2 alpha dials down production of most proteins, some of which may be needed for memory formation, Walter said. But eIF2 alpha inactivation also ramps up production of a few key proteins that help cells cope with stress.
Study co-author Nahum Sonenberg, PhD, of McGill University previously linked memory and eIF2 alpha in genetic studies of mice, and his lab group also conducted the memory tests for the current study.
The chemical identified by the UCSF researchers is called ISRIB, which stands for integrated stress response inhibitor. ISRIB counters the effects of eIF2 alpha inactivation inside cells, the researchers found.
“ISRIB shows good pharmacokinetic properties [how a drug is absorbed, distributed and eliminated], readily crosses the blood-brain barrier, and exhibits no overt toxicity in mice, which makes it very useful for studies in mice,” Walter said. These properties also indicate that ISRIB might serve as a good starting point for human drug development, according to Walter.
Walter said he is looking for scientists to collaborate with in new studies of cognition and memory in mouse models of neurodegenerative diseases and aging, using ISRIB or related molecules.
In addition, chemicals such as ISRIB could play a role in fighting cancers, which take advantage of stress responses to fuel their own growth, Walter said. Walter already is exploring ways to manipulate the unfolded protein response to inhibit tumor growth, based on his earlier discoveries.
At a more basic level, Walter said, he and other scientists can now use ISRIB to learn more about the role of the unfolded protein response and the integrated stress response in disease and normal physiology.