Posts tagged LTM
Articles and news from the latest research reports.
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 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.
You may need a cup of coffee to kick start the day but it seems honeybees also get their buzz from drinking flower nectar containing caffeine.
Publishing in Science, researchers have shown that caffeine improves a honeybee’s memory and could help the plant recruit more bees to spread its pollen.
In tests honeybees feeding on a sugar solution containing caffeine, which occurs naturally in the nectar of coffee and citrus flowers, were three times more likely to remember a flower’s scent than those feeding on just sugar.
Study leader Dr Geraldine Wright, Reader in Neuroethology at Newcastle University, explained that the effect of caffeine benefits both the honeybee and the plant: “Remembering floral traits is difficult for bees to perform at a fast pace as they fly from flower to flower and we have found that caffeine helps the bee remember where the flowers are.
“In turn, bees that have fed on caffeine-laced nectar are laden with coffee pollen and these bees search for other coffee plants to find more nectar, leading to better pollination.
“So, caffeine in nectar is likely to improve the bee’s foraging prowess while providing the plant with a more faithful pollinator.”
In the study, researchers found that the nectar of Citrus and Coffea species often contained low doses of caffeine. They included ‘robusta’ coffee species mainly used to produce freeze-dried coffee and ‘arabica’ used for espresso and filter coffee. Grapefruit, lemons, pomelo and oranges were also sampled and all contained caffeine.
Co-author Professor Phil Stevenson from the Royal Botanic Gardens, Kew and the University of Greenwich’s Natural Resources Institute said: “Caffeine is a defence chemical in plants and tastes bitter to many insects including bees so we were surprised to find it in the nectar. However, it occurs at a dose that’s too low for the bees to taste but high enough to affect bee behaviour.”
The effect of caffeine on the bees’ long-term memory was profound with three times as many bees remembering the floral scent 24 hours later and twice as many bees remembering the scent after three days.
Typically, the nectar in the flower of a coffee plant contains almost as much caffeine as a cup of instant coffee. Just as black coffee has a strong bitter taste to us, high concentrations of caffeine are repellent to honeybees.
Dr Wright added: “This work helps us understand the basic mechanisms of how caffeine affects our brains. What we see in bees could explain why people prefer to drink coffee when studying.”
Dr Julie Mustard, a contributor to the study from Arizona State University, explains further: “Although human and honeybee brains obviously have lots of differences, when you look at the level of cells, proteins and genes, human and bee brains function very similarly. Thus, we can use the honeybee to investigate how caffeine affects our own brains and behaviours.”
This project was funded in part by the Insect Pollinators Initiative which supports projects aimed at researching the causes and consequences of threats to insect pollinators and to inform the development of appropriate mitigation strategies.
Population declines among bees have serious consequences for natural ecosystems and agriculture since bees are essential pollinators for many crops and wild flowering species. If declines are allowed to continue there is a risk to our natural biodiversity and on some crop production.
Professor Stevenson said: “Understanding how bees choose to forage and return to some flowers over others will help inform how landscapes could be better managed. Understanding a honeybee’s habits and preferences could help find ways to reinvigorate the species to protect our farming industry and countryside.”
Pannexins are abundant in the central nervous system of vertebrates
Pannexins traverse the cell membrane of vertebrate animals and form large pored channels. They are permeable for certain signalling molecules, such as the energy storage molecule ATP (adenosine triphosphate). The best known representative is Pannexin1, which occurs in abundance in the brain and spinal cord and among others in the hippocampus - a brain structure that is critical for long-term memory. Malfunctions of the pannexins play a role in the development of epilepsy and strokes.
No more scope in long-term potentiation
The research team studied mice in which the gene for Pannexin1 was lacking. Using cell recordings carried out on isolated brain sections, they analysed the long-term potentiation in the hippocampus. Long-term potentiation usually occurs when new memory content is built - the contacts between nerve cells are strengthened; they communicate more effectively with each other. In mice without Pannexin1, the long-term potentiation occurred earlier and was more prolonged than in mice with Pannexin1. “It looks at first glance like a gain in long-term memory”, says Nora Prochnow. “But precise analysis shows that there was no more scope for upward development.” Due to the lack of Pannexin1, the cell communication in general was increased to such an extent that a further increase through the learning of new knowledge was no longer possible. The synaptic plasticity was thus extremely restricted. “The plasticity is essential for learning processes in the brain”, Nora Prochnow explains. “It helps you to organise, keep or even to forget contents in a positive sense, to gain room for new inputs.”
Autistic-like behaviour without Pannexin1
The absence of Pannexin1 also had an impact on behaviour: when solving simple problems, the animals were quickly overwhelmed in terms of content. Their spatial orientation was limited, their attention impaired and an increased probability for seizure generation occurred. “The behavioural patterns are reminiscent of autism. We should therefore consider the Pannexin1 channel more closely with regard to the treatment of such diseases”, says the neurobiologist from Bochum.
Theory: feedback regulation gets out of hand without Pannexin1
According to the scientists’ theory, nerve cells lack a feedback mechanism without Pannexin1. Normally the channel protein releases ATP, which binds to specific receptors and thus reduces the release of the neurotransmitter glutamate. Without Pannexin1 more glutamate is released, which leads to increased long-term potentiation. This causes the cell to lose its dynamic equilibrium, which is needed for an efficient learning process.
Study Refutes Accepted Model of Memory Formation
A study by Johns Hopkins researchers has shown that a widely accepted model of long-term memory formation — that it hinges on a single enzyme in the brain — is flawed. The new study, published in the Jan. 2 issue of Nature, found that mice lacking the enzyme that purportedly builds memory were in fact still able to form long-term memories as well as normal mice could.
“The prevailing theory is that when you learn something, you strengthen connections between your brain cells called synapses,” explains Richard Huganir, Ph.D., a professor and director of the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience. “The question is, how exactly does this strengthening happen?”
A research group at SUNY Downstate, led by Todd Sacktor, Ph.D., has suggested that key to the process is an enzyme they discovered, known as PKM-zeta. In 2006, Sacktor’s group made waves when it created a molecule that seemed to block the action of PKM-zeta — and only PKM-zeta. When the molecule, dubbed ZIP, was given to mice, it erased existing long-term memories. The molecule caught the attention of reporters and bloggers, who mused on the social and ethical implications of memory erasure.
But for researchers, ZIP was exciting primarily as a means for studying PKM-zeta. “Since 2006, many papers have been published on PKM-zeta and ZIP, but no one knew what PKM-zeta was acting on,” says Lenora Volk, Ph.D., a member of Huganir’s team. “We thought that learning the enzyme’s target could tell us a lot about how memories are stored and maintained.”
For the current study, Volk and fellow team member Julia Bachman made mice that lacked working PKM-zeta, so-called genetic “knockouts.” The goal was to compare the synapses of the modified mice with those of normal mice, and find clues about how the enzyme works.
But, says Volk, “what we got was not at all what we expected. We thought the strengthening capacity of the synapses would be impaired, but it wasn’t.” The brains of the mice without PKM-zeta were indistinguishable from those of other mice, she says. Additionally, the synapses of the PKM-zeta-less mice responded to the memory-erasing ZIP molecule just as the synapses of normal mice do.
The team then considered whether, in the absence of PKM-zeta, the mouse brains had honed a substitute synapse-building pathway, much in the way that a blind person learns to glean more information from her other senses. So the researchers made mice whose PKM-zeta genes functioned normally until they were given a drug that would suddenly shut the gene down. This allowed them to study PKM-zeta-less adult mice that had had no opportunity to develop a way around the loss of the gene. Still, the synapses of the so-called conditional knockout mice responded to stimuli just as synapses in normal mice did.
What this means, the researchers say, is that PKM-zeta is not the key long-term memory molecule previous studies had suggested, although it may have some role in memory. “We don’t know what this ZIP peptide is really acting on,” says Volk. “Finding out what its target is will be quite important, because then we can begin to understand at the molecular level how synapses strengthen and how memories form in response to stimuli.”
Neural interaction in periods of silence
While in deep dreamless sleep, our hippocampus sends messages to our cortex and changes its plasticity, possibly transferring recently acquired knowledge to long-term memory. But how exactly is this done? Scientists from the Max Planck Institute for Biological Cybernetics have now developed a novel multimodal methodology called “neural event-triggered functional magnetic resonance imaging” (NET-fMRI) and presented the very first results obtained using it in experiments with both anesthetized and awake, behaving monkeys. The new methodology uses multiple-contact electrodes in combination with functional magnetic resonance imaging (fMRI) of the entire brain to map widespread networks of neurons that are activated by local, structure-specific neural events.
The Fabric for Weaving Memory
The details of memory formation are still largely unknown. It has, however, been established that the two kinds of memory – long term and short term – use different mechanisms. When short-term memory is formed, certain proteins in the nerve cells (neurons) of the brain are transiently modified. To establish long-term memory, the cells have to synthesize new protein molecules. This has been shown in experiments with animals. When drugs were used to block protein synthesis, the treated animals were not able to form long-term memory.
The precise mechanism by which the newly synthesized proteins regulate memory formation is still poorly understood. They are thought to strengthen existing connections between neurons, as well as establish new connections. Both processes are required for long-term memory formation.
A nerve cell in the brain makes connections with tens of thousands of other nerve cells through so-called synapses. When memory is formed, only specific synapses, which are activated by a specific experience are modified. The mechanism of how the synthesis of new proteins can be restricted to these activated synapses has been unclear. Neurobiologists have postulated the existence of “synaptic tags”. One of the candidates is a family of proteins known to regulate local protein synthesis, the CPEB family of proteins. These proteins have been known for some time to perform important tasks during embryonic development, and recently have been identified in neuronal synapses.
In 2007, Krystyna Keleman, a neuroscientist at the Research Institute of Molecular Pathology (IMP) in Vienna, was able to show that fruit flies require CPEB proteins for long-term memory formation.
To study memory formation, the researchers at the IMP looked at the sexual behavior of flies. After copulation, female flies loose interest in the courtship advances of males. Male flies must learn – by trial and error – that only virgin females are receptive. The key to telling them apart is their smell.
How does one’s experience of an event get translated into a memory that can be accessed months, even years later?
A team led by University of Pennsylvania scientists has come closer to answering that question, identifying key molecules that help convert short-term memories into long-term ones. These proteins may offer a target for drugs that can enhance memory, alleviating some of the cognitive symptoms that characterize conditions including schizophrenia, depression and Parkinson’s and Alzheimer’s diseases.
“There are many drugs available to treat some of the symptoms of diseases like schizophrenia,” Abel -Penn’s Brush Family Professor of Biology- said, “but they don’t treat the cognitive deficits that patients have, which can include difficulties with memory. This study looks for more specific targets to treat deficits in cognition.”
Published in the Journal of Clinical Investigation, the study focused on a group of proteins called nuclear receptors, which have been implicated in the regulation of a variety of biological functions, including memory formation.