Posts tagged memory formation
Articles and news from the latest research reports.
Eye movement rhythm important to eye-tracking diagnoses
Quick eye movements, called saccades, that enable us to scan a visual scene appear to act as a metronome for pushing information about that scene into memory.
Scientists at Yerkes National Primate Research Center, Emory University, have observed that in monkeys exploring images with their eyes, the onset of a saccade resets the rhythms of electrical activity (theta oscillations) in the hippocampus, a region of the brain important for memory formation.
Tracking eye movements is already a promising basis for diagnosing brain disorders such as Alzheimer’s disease and schizophrenia. A deeper understanding of how the rhythm of eye movements orchestrate memories could bolster the accuracy and power of eye-tracking diagnoses.
The findings were published this week in Proceedings of the National Academy of Sciences, Early Edition.
Senior author Elizabeth Buffalo was a researcher at the Yerkes National Primate Research Center and an associate professor of neurology at Emory University School of Medicine and is currently associate professor of physiology and biophysics at Universpity of Washington in Seattle. The first author of the paper is postdoctoral fellow Michael Jutras„ who is now an instructor at the University of Washington.
Theta oscillations are cycles of electrical activity in the brain occurring between 3 to 12 times per second. Scientists have previously seen theta oscillations in the hippocampus in rodents, when the rodents were actively exploring, sniffing or feeling something with their whiskers.
"Both animals and humans seem to take in sensory information at this theta rhythm," Buffalo says. "But one striking difference between rodents and primates is the way they gather information about the external world. Rodents are much more reliant on the senses of smell and touch."
She says the actions that are most comparable to rodents’ sniffing and whiskering in primates are saccades. When our eyes scan text or explore a picture, the eyes’ focus tends to jump from point to point several times per second.
Buffalo and Jutras examined electrical signals in the hippocampi of two rhesus monkeys while the monkeys were looking at a variety of pictures and the researchers tracked their eye movements. The researchers observed that after a saccade, the electrical signals in the hippocampus display a more coherent rhythm.
The rhythm reset a saccade imposes may be a way to ensure the hippocampus is receptive to new sensory information, the researchers propose.
“The eye movements are acting like the conductor of the hippocampal orchestra,” Jutras says, “The phase reset might be a mechanism to ensure the ongoing theta rhythm is in sync with incoming visual information.”
Scientists have previously hypothesized that theta oscillations in the hippocampus set the stage for memory formation. The researchers tested this idea by presenting the monkeys each image twice during a viewing session. Because all primates have an innate preference for novelty, monkeys tend to spend a longer time looking at new images and less time looking at repeated ones. The researchers inferred that the monkeys had a stronger memory of a given picture if, upon second viewing, they looked through it quickly. The theta rhythm reset was more consistent during the viewing of images that the monkeys remembered well.
"Based on this finding, we concluded that this resetting of the theta rhythm is an important part of the memory process," Jutras says.
"This study has given us a better understanding of the function of the hippocampal theta rhythm, which has been well characterized in rodents but isn’t well understood in primates," he says. "A future goal is to investigate the relationship between hippocampal theta and eye movements during memory formation and navigation in humans. This could be possible with epilepsy patients who undergo monitoring of hippocampal activity as part of their treatment."
(Source: news.emory.edu)
Promising Alzheimer’s ‘drug’ halts memory loss
A new class of experimental drug-like small molecules is showing great promise in targeting a brain enzyme to prevent early memory loss in Alzheimer’s disease, according to Northwestern Medicine® research.
Developed in the laboratory of D. Martin Watterson, the molecules halted memory loss and fixed damaged communication among brain cells in a mouse model of Alzheimer’s.
"This is the starting point for the development of a new class of drugs," said Watterson, lead author of a paper on the study and the John G. Searle Professor of Molecular Biology and Biochemistry at Northwestern University Feinberg School of Medicine. "It’s possible someday this class of drugs could be given early on to people to arrest certain aspects of Alzheimer’s."
Changes in the brain start to occur ten to 15 years before serious memory problems become apparent in Alzheimer’s.
"This class of drugs could be beneficial when the nerve cells are just beginning to become impaired," said Linda Van Eldik, a senior author of the paper and director of the University of Kentucky Sanders-Brown Center on Aging.
The study is a collaboration between Northwestern’s Feinberg School, Columbia University Medical Center and the University of Kentucky. It will be published June 26 in the journal PLOS ONE.
The novel drug-like molecule, called MW108, reduces the activity of an enzyme that is over-activated during Alzheimer’s and is considered a contributor to brain inflammation and impaired neuron function. Strong communication between neurons in the brain is an essential process for memory formation.
"I’m not aware of any other drug that has this effect on the central nervous system," Watterson said.
"These exciting results provide new hope for developing drugs against an important molecular target in the brain," said Roderick Corriveau, program director at the National Institute of Neurological Disorders and Stroke, which helped support the research. "They also provide a promising strategy for identifying small molecule drugs designed to treat Alzheimer’s disease and other neurological disorders."
Watterson and his collaborators have a new National Institutes of Health (NIH) award to further refine the compound so it is metabolically stable and safe for use in humans and develop it to the point of starting a phase 1 clinical trial.
(Image: Jay Vollmar)
Psychiatric disorders linked to a protein involved in the formation of long-term memories
Researchers have discovered a pathway by which the brain controls a molecule critical to forming long-term memories and connected with bipolar disorder and schizophrenia.
The discovery was made by a team of scientists led by Alexei Morozov, an assistant professor at the Virginia Tech Carilion Research Institute.
The mechanism – a protein called Rap1 – controls L-type calcium channels, which participate in the formation of long-term memories. Previous studies have also linked alterations in these ion channels to certain psychiatric disorders. The discovery of the channels’ regulation by Rap1 could help scientists understand the physiological genesis of bipolar disorder and schizophrenia.
"People with genetic mutations affecting L-type calcium channels have higher rates of bipolar disorder and schizophrenia," said Morozov. "This suggests that there might be a relationship between the activation of L-type calcium channels and these psychiatric disorders. Understanding how these ion channels are controlled is the first step to determining how their functioning or malfunctioning affects mental health."
A single neuron in the brain can have thousands of synapses, each of which can grow, strengthen, weaken, and change structurally in response to learning new information. Electric signals traveling from neuron to neuron jump across these synapses through chemical neurotransmitters. The release of these chemicals is caused by the flow of electrically charged atoms through a particular subset of ion channels known as voltage-gated calcium channels.
Previous studies have shown that blocking these ion channels inhibits the formation of long-term memories. Although it was known that L-type calcium channels are activated in response to learning, how they are controlled was a mystery.
In the experiment, Morozov and colleagues knocked out the gene responsible for coding the enzyme Rap1, which he suspected played a role in activating L-type calcium channels. The researchers then used live imaging techniques to monitor the release of neurotransmitters and electron microscopy to visualize L-type channels at synapses. They discovered that, without Rap1, the L-type calcium channels were more active and more abundant at synapses all the time, increasing the release of neurotransmitters. The results showed that Rap1 is responsible for suppressing L-type calcium channels, allowing them to activate only at the proper moments, possibly during long-term memory formation.
"Our next step is to determine whether this new signaling pathway is altered in cases of mental disease," said Morozov. "If so, it could help us gain a better understanding of the molecular underpinnings of channel-related psychiatric disorders, such as bipolar disorder and schizophrenia. Such knowledge would go a long way toward developing new therapeutic methods."
(Source: eurekalert.org)
In our interaction with our environment we constantly refer to past experiences stored as memories to guide behavioral decisions. But how memories are formed, stored and then retrieved to assist decision-making remains a mystery. By observing whole-brain activity in live zebrafish, researchers from the RIKEN Brain Science Institute have visualized for the first time how information stored as long-term memory in the cerebral cortex is processed to guide behavioral choices.
The study, published today in the journal Neuron, was carried out by Dr. Tazu Aoki and Dr. Hitoshi Okamoto from the Laboratory for Developmental Gene Regulation, a pioneer in the study of how the brain controls behavior in zebrafish.
The mammalian brain is too large to observe the whole neural circuit in action. But using a technique called calcium imaging, Aoki et al. were able to visualize for the first time the activity of the whole zebrafish brain during memory retrieval.
Calcium imaging takes advantage of the fact that calcium ions enter neurons upon neural activation. By introducing a calcium sensitive fluorescent substance in the neural tissue, it becomes possible to trace the calcium influx in neurons and thus visualize neural activity.
The researchers trained transgenic zebrafish expressing a calcium sensitive protein to avoid a mild electric shock using a red LED as cue. By observing the zebrafish brain activity upon presentation of the red LED they were able to visualize the process of remembering the learned avoidance behavior.
They observe spot-like neural activity in the dorsal part of the fish telencephalon, which corresponds to the human cortex, upon presentation of the red LED 24 hours after the training session. No activity is observed when the cue is presented 30 minutes after training.
In another experiment, Aoki et al. show that if this region of the brain is removed, the fish are able to learn the avoidance behavior, remember it short-term, but cannot form any long-term memory of it.
“This indicates that short-term and long-term memories are formed and stored in different parts of the brain. We think that short-term memories must be transferred to the cortical region to be consolidated into long-term memories,” explains Dr. Aoki.
The team then tested whether memories for the best behavioral choices can be modified by new learning. The fish were trained to learn two opposite avoidance behaviors, each associated with a different LED color, blue or red, as a cue. They find that presentation of the different cues leads to the activation of different groups of neurons in the telencephalon, which indicates that different behavioral programs are stored and retrieved by different populations of neurons.
“Using calcium imaging on zebrafish, we were able to visualize an on-going process of memory consolidation for the first time. This approach opens new avenues for research into memory using zebrafish as model organism,” concludes Dr. Okamoto.
Memory Implants
A maverick neuroscientist believes he has deciphered the code by which the brain forms long-term memories.
Theodore Berger, a biomedical engineer and neuroscientist at the University of Southern California in Los Angeles, envisions a day in the not too distant future when a patient with severe memory loss can get help from an electronic implant. In people whose brains have suffered damage from Alzheimer’s, stroke, or injury, disrupted neuronal networks often prevent long-term memories from forming. For more than two decades, Berger has designed silicon chips to mimic the signal processing that those neurons do when they’re functioning properly—the work that allows us to recall experiences and knowledge for more than a minute. Ultimately, Berger wants to restore the ability to create long-term memories by implanting chips like these in the brain.
The idea is so audacious and so far outside the mainstream of neuroscience that many of his colleagues, says Berger, think of him as being just this side of crazy. “They told me I was nuts a long time ago,” he says with a laugh, sitting in a conference room that abuts one of his labs. But given the success of recent experiments carried out by his group and several close collaborators, Berger is shedding the loony label and increasingly taking on the role of a visionary pioneer.
Berger and his research partners have yet to conduct human tests of their neural prostheses, but their experiments show how a silicon chip externally connected to rat and monkey brains by electrodes can process information just like actual neurons. “We’re not putting individual memories back into the brain,” he says. “We’re putting in the capacity to generate memories.” In an impressive experiment published last fall, Berger and his coworkers demonstrated that they could also help monkeys retrieve long-term memories from a part of the brain that stores them.
If a memory implant sounds farfetched, Berger points to other recent successes in neuroprosthetics. Cochlear implants now help more than 200,000 deaf people hear by converting sound into electrical signals and sending them to the auditory nerve. Meanwhile, early experiments have shown that implanted electrodes can allow paralyzed people to move robotic arms with their thoughts. Other researchers have had preliminary success with artificial retinas in blind people.
Still, restoring a form of cognition in the brain is far more difficult than any of those achievements. Berger has spent much of the past 35 years trying to understand fundamental questions about the behavior of neurons in the hippocampus, a part of the brain known to be involved in forming memory. “It’s very clear,” he says. “The hippocampus makes short-term memories into long-term memories.”
What has been anything but clear is how the hippocampus accomplishes this complicated feat. Berger has developed mathematical theorems that describe how electrical signals move through the neurons of the hippocampus to form a long-term memory, and he has proved that his equations match reality. “You don’t have to do everything the brain does, but can you mimic at least some of the things the real brain does?” he asks. “Can you model it and put it into a device? Can you get that device to work in any brain? It’s those three things that lead people to think I’m crazy. They just think it’s too hard.”
New learning and memory neurons uncovered
A University of Queensland study has identified precisely when new neurons become important for learning.
Lead researcher Dr Jana Vukovic from UQ’s Queensland Brain Institute (QBI) said the study highlighted the importance of new neuron development.
“New neurons are continually produced in the brain, passing through a number of developmental stages before becoming fully mature,” Dr Vukovic said.
“Using a genetic technique to delete immature neurons in animal models, we found they had great difficulty learning a new spatial task.
“There are ways to encourage the production of new neurons – including physical exercise – to improve learning.
“The new neurons appear particularly important for the brain to detect subtle but critical differences in the environment that can impact on the individual.”
The study, performed in QBI Director Professor Perry Bartlett’s laboratory, also demonstrates that immature neurons, born in a region of the brain known as the hippocampus, are required for learning but not for the retrieval of past memories.
“On the other hand, if the animals needed to remember a task they had already mastered in the past, before these immature neurons were deleted, their ability to perform the task was the same – so, they’ve remembered the task they learned earlier,” Dr Vukovic said.
This research allows for better understanding of the processes underlying learning and memory formation.
(Image Caption: Newly generated neurons doublecortin positive in the dentate gyrus of a degenerating hippocampus in mutant mice lacking the transcription factor TIF-IA. Credit: Rosanna Parlato (AG Schütz, DKFZ-ZMBH Alliance)
New mechanism for long-term memory formation discovered
UC Irvine neurobiologists have found a novel molecular mechanism that helps trigger the formation of long-term memory. The researchers believe the discovery of this mechanism adds another piece to the puzzle in the ongoing effort to uncover the mysteries of memory and, potentially, certain intellectual disabilities.
In a study led by Marcelo Wood of UC Irvine’s Center for the Neurobiology of Learning & Memory, the team investigated the role of this mechanism – a gene designated Baf53b – in long-term memory formation. Baf53b is one of several proteins making up a molecular complex called nBAF.
Mutations in the proteins of the nBAF complex have been linked to several intellectual disorders, including Coffin-Siris syndrome, Nicolaides-Baraitser syndrome and sporadic autism. One of the key questions the researchers addressed is how mutations in components of the nBAF complex lead to cognitive impairments.
In their study, Wood and his colleagues used mice bred with mutations in Baf53b. While this genetic modification did not affect the mice’s ability to learn, it did notably inhibit long-term memories from forming and severely impaired synaptic function.
“These findings present a whole new way to look at how long-term memories form,” said Wood, associate professor of neurobiology & behavior. “They also provide a mechanism by which mutations in the proteins of the nBAF complex may underlie the development of intellectual disability disorders characterized by significant cognitive impairments.”
How does this mechanism regulate gene expression required for long-term memory formation? Most genes are tightly packaged by a chromatin structure – chromatin being what compacts DNA so that it fits inside the nucleus of a cell. That compaction mechanism represses gene expression. Baf53b, and the nBAF complex, physically open the chromatin structure so specific genes required for long-term memory formation are turned on. The mutated forms of Baf53b did not allow for this necessary gene expression.
“The results from this study reveal a powerful new mechanism that increases our understanding of how genes are regulated for memory formation,” Wood said. “Our next step is to identify the key genes the nBAF complex regulates. With that information, we can begin to understand what can go wrong in intellectual disability disorders, which paves a path toward possible therapeutics.”
Findings appear online today in Nature Neuroscience.
Study indicates reverse impulses clear useless information, prime brain for learning
When the mind is at rest, the electrical signals by which brain cells communicate appear to travel in reverse, wiping out unimportant information in the process, but sensitizing the cells for future sensory learning, according to a study of rats conducted by researchers at the National Institutes of Health.
The finding has implications not only for studies seeking to help people learn more efficiently, but also for attempts to understand and treat post-traumatic stress disorder—in which the mind has difficulty moving beyond a disturbing experience.
During waking hours, brain cells, or neurons, communicate via high-speed electrical signals that travel the length of the cell. These communications are the foundation for learning. As learning progresses, these signals travel across groups of neurons with increasing rapidity, forming circuits that work together to recall a memory.
It was previously known that, during sleep, these impulses were reversed, arising from waves of electrical activity originating deep within the brain. In the current study, the researchers found that these reverse signals weakened circuits formed during waking hours, apparently so that unimportant information could be erased from the brain. But the reverse signals also appeared to prime the brain to relearn at least some of the forgotten information. If the animals encountered the same information upon awakening, the circuits re-formed much more rapidly than when they originally encountered the information.
"The brain doesn’t store all the information it encounters, so there must be a mechanism for discarding what isn’t important," said senior author R. Douglas Fields, Ph.D., head of the Section on Nervous System Development and Plasticity at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH institute where the research was conducted. "These reverse brain signals appear to be the mechanism by which the brain clears itself of unimportant information."
Their findings appear in the Proceedings of the National Academy of Sciences.
The researchers studied the activity of rats’ brain cells from the hippocampus, a tube-like structure deep in the brain. The hippocampus relays information to and from many other regions of the brain. It plays an important role in memory, orientation, and navigation.
The classic understanding of brain cell activity is that electrical signals travel from dendrites—antenna-like projections at one end of the cell—through the cell body. From the cell body, they then travel the length of the axon, a single long projection at the other end of the cell. This electrical signal stimulates the release of chemicals at the end of the axon, which bind to dendrites on adjacent cells, stimulating these recipient cells to fire electrical signals, and so on. When groups of cells repeatedly fire in this way, the electrical signals increase in intensity.
Dr. Bukalo and her team examined electrical signals that traveled in reverse—from the cell’s axon, to the cell body, and out its many dendrites. This reverse firing happens during sleep and at rest, appearing to reset the cell, the researchers found.
After first stimulating the cells with reverse electrical impulses, the researchers next stimulated the dendrites again with electrical impulses traveling in the forward direction. In response, the neurons generated a stronger signal, with the connections appearing to strengthen with repeated electrical stimulation.
This pattern appears to underlie the formation of new memories. A connection that is reset but never stimulated again may simply fade from use over time, Dr. Bukalo explained. But when a cell is stimulated again, it fires a stronger signal and may be more easily synchronized to the reinforced signals of other brain cells, all of which act in concert over time.
Epigenetics: Neurons remember because they move genes in space
How do neurons store information about past events? In the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw, a mechanism unknown previously of memory traces formation has been discovered. It appears that at least some events are remembered thanks to… geometry.
Neurons are the most important cells of the nervous system. Scientists from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw have shown that during neuron stimulation permanent changes are observed with respect to genes’ arrangement within the cell nucleus. This discovery, reported in the “Journal of Neuroscience”, one of the most prestigious journals in the field of neurobiology, is significant for developing a better understanding of the processes going on in the mind and disorders of the nervous system, especially the brain.
“While conducting experiments on rats after epileptic seizures we have observed that a gene may permanently move deeper into the neuron’s cell nucleus. Since modification of the geometrical structure of the nucleus leads to changes in gene expression, this is how the neuron remembers, what happened”, explains Prof. Grzegorz Wilczyński from the Laboratory of Molecular and Systemic Neuromorphology at the Nencki Institute.
Novel storage mechanism allows command, control of memory
Introductions at a party seemingly go in one ear and out the other. However, if you meet someone two or three times during the party, you are more likely to remember his or her name. Your brain has taken a short-term memory - the introduction - and converted it into a long-term one. The molecular key to this activity is mTORC2 (mammalian target of rapamycin complex 2), according to researchers at Baylor College of Medicine in an article that appeared online in the journal Nature Neuroscience.
"Memory consolidation is a fundamental process," said Dr. Mauro Costa-Mattioli, assistant professor of neuroscience at BCM and corresponding author of the report. "Memories are at the center of our identity. They allow us to remember people, places and events for a long time, even a lifetime. Understanding the precise mechanism by which memories are stored in the brain will lead to the development of new treatments for conditions associated with memory loss".
Actin fibers
For the last five decades, neuroscientists have known that making long-lasting memories is dependent on the ability of brain cells (neurons) to synthesize new proteins. In their studies, Costa-Mattioli and his colleagues found a new mechanism by which memories are stored in the brain. The newly discovered mTORC2 regulates memory formation by modulating actin fibers, an important component of the architectural structure of the neuron.
"These actin fibers allow long-lasting changes in synaptic strength and ultimately long-term memories," said Wei Huang, a BCM graduate student and first author in the study.
Using genetically-engineered mice, the researchers found that turning off mTORC2 in the hippocampus (a crucial region required for memory formation) and surrounding areas allowed the animals to have a normal short-term memory, but prevented them from forming long-term memories. Similar to human patients with injury in the hippocampus, these mutant mice were no longer able to form new long-lasting memories.
According to Costa-Mattioli’s findings, mTORC2’s role is evolutionarily conserved and likely relevant to humans. Like mTORC2-deficient mice, fruit flies lacking TORC2 show defective long-term memory storage.
"Given that flies and mice last shared a common ancestor 500 million years ago, it is quite remarkable and telling that the function of mTORC2 in the regulation of memory is indeed maintained," said Dr. Gregg Roman, director of the Biology of Behavior Institute at the University of Houston, who contributed to the fly experiments.
Form long-term memories
The Holy Grail of memory neuroscience and to a certain extent, of industry efforts to produce a “smart drug,” has been the identification of molecules that promote the formation of long-term memory, said Costa-Mattioli. “We therefore wondered whether by turning on mTORC2 or even actin polymerization itself, we could form long-term memories more easily,” said Dr. Ping Jun Zhu, assistant professor of neuroscience at BCM, co-first author and senior scientist in Costa-Mattioli’s lab.
The team has identified a small molecule (a drug) that by activating mTORC2 and consequently actin polymerization enhances not only the synaptic strength between nerve cells but also long-term memory formation. In addition, the authors found that by directly promoting actin polymerization, with a second drug, long-term memory is generated more easily.
Costa-Mattioli’s team has identified two memory-enhancing drugs, but can they enhance memory in people? It is perhaps too early to say.
Huang said, “mTORC2, as far as we know, is really a new potential target for therapeutic treatments of human disorders. In the next few years, I predict we will see a lot of studies focusing on mTORC2 as a target.”
Memory cocktail
Costa-Mattioli’s short-term goals are to identify human cognitive disorders in which mTORC2 activity is dysfunctional and to see whether its restoration can return to normal impaired memory function in aging or even Alzheimer’s disease. But a small molecule alone might not do the job. Similar to the treatments for HIV or cancer, he believes that a combination of small molecules improving different aspects of memory formation will be required to efficiently treat cognitive disorders.
"We should start thinking about an efficient ‘memory cocktail’ rather than a single ‘memory pill.’ One molecule alone might not be enough. We may be years away from a decisive treatment, but I believe we are definitely on the right path," he said.
Others who took part in this work include Hongyi Zhou, Loredana Stoica and Mauricio Galiano, all of BCM, Krešimir Krnjević of McGill University in Montreal, Canada; and Shixing Zhang of the University of Houston.
(Image: Shutterstock)