Posts Tagged ‘memory’

The majority of the cells in the brain are no neurons, but Glia (from “glue”) cells, that support the structure and function of the brain. Astrocytes (“start cells”) are star-shaped glial cells providing many supportive functions for the neurons surrounding them, such as the provision of nutrients and the regulation of their chemical environment. Newer studies showed that astrocytes also monitor and modulate neuronal activity. For example, these studies have shown that astrocytes are necessary for the ability of neurons to change the strength of the connections between them, the process underlying learning and memory, and indeed astrocytes are also necessary for normal cognitive function. However, it is still unknown whether astrocytic activity is only necessary, or is it may also be sufficient to induce synaptic potentiation and enhance cognitive performance.

In a new study published in Cell, two graduate students, Adar Adamsky and Adi Kol, from Inbal Goshen’s lab, employed chemogenetic and optogenetic tools that allow specific activation of astrocytes in behaving mice, to explore their role in synaptic activity and memory performance. They found that astrocytic activation in the hippocampus, a brain region that plays an important role in memory acquisition and consolidation, potentiated the synaptic connections in this region, measured in brain slices. Moreover, in the intact brain, astrocytic activation enhanced hippocampal neuronal activity in a task-dependent way: i.e. only during when it was combined with memory acquisition, but not when mice were at their home cage with no meaningful stimuli. The ability of astrocytes to increase neuronal activity during memory acquisition had a significant effect on cognitive function: Specifically, astrocytic activation during learning resulted in enhanced memory in two memory tests. In contrast, direct neuronal activation in the hippocampus induced a non-selective increase in activity (during learning or in the home cage), and thus resulted in drastic memory impairment.

The results suggest that the memory enhancement induced by astrocytic activation during learning is not simply a result of a general increase in hippocampal neuronal activity. Rather, the astrocytes, which sense and respond to changes in the surrounding neuronal activity, can detect and specifically enhance only the neuronal activity involved in learning, without affecting the general activity. This may explain why general astrocytic activation improves memory performance, whereas a similar activation of neurons impairs it.

Memory is not a binary process (remember/don’t remember); the strength of a memory can vary greatly, either for the same memory or between different memories. Here, we show that activating astrocytes in mice with intact cognition improves their memory performance. This finding has important clinical implications for cognitive augmentation treatments. Furthermore, the ability of astrocytes to strengthen neuronal communication and improve memory performance supports the claim that astrocytes are able to take an active part in the neuronal processes underlying cognitive function. This perspective expands the definition of the role of astrocytes, from passive support cells to active cells that can modulate neural activity and thus shape behavior.



by Nicolas Scherger

Dr. Thomas Hainmüller and Prof. Dr. Marlene Bartos of the Institute of Physiology of the University of Freiburg have established a new model to explain how the brain stores memories of tangible events. The model is based on an experiment that involved mice seeking a place where they received rewards in a virtual environment. The scientific journal “Nature” has published the study.

In the world of the mouse’s video game, the walls that depict a corridor four meters long are made up of green and blue patterned blocks. The floor is marked with turquoise dots. A short distance away, there’s a brown disc on the floor that looks like a cookie. That’s the symbol for the reward location. The mouse heads for it, gets there, and the symbol disappears. The next cookie promptly appears a bit further down the corridor. The mouse is surrounded by monitors and is standing on a styrofoam ball that is floating on compressed air and turns beneath the mouse when it runs. The ball makes it possible to transfer of the mouse’s movements to the virtual environment. If the mouse reaches the reward symbol, a straw is used to give it a drop of soy milk and stimulate it to form memories of its experiences in the virtual world. The mouse learns when, and at which location, it will receive a reward. It also learns how to locate itself and discriminate between different corridors in the video game.

Viewing the brain with a special microscope

“As the mouse is getting to know its environment, we use a special microscope to look from the outside into its brain and we record the activities of its nerve cells on video,” explains Thomas Hainmüller, a physician and doctoral candidate in the MD/PhD program of the Spemann Graduate School of Biology and Medicine (SGBM) of the University of Freiburg. He says that works because, in reality, the head of the mouse remains relatively still under the microscope as it runs through the virtual world of the video game. On the recordings, the mice’s genetically-manipulated nerve cells flash as soon as they become active. Hainmüller and Marlene Bartos, a Professor of Systemic and Cellular Neurobiology are using this method to investigate how memories are sorted and retrieved. “We repeatedly place the mouse in the virtual world on consecutive days,” says Hainmüller. “In that way, we can observe and compare the activity of the nerve cells in different stages of memory formation,” he explains.

Nerve cells encode places

The region of the brain called the hippocampus plays a decisive role in the formation of memory episodes – or memories of tangible experiences. Hainmüller and Bartos published that the nerve cells in the hippocampus create a map of the virtual world in which single neurons code for actual places in the video game. Earlier studies done at the Freiburg University Medical Center showed that nerve cells in the human hippocampus code video games in the same way. The cells become activated and flash when the mouse is at the respective place, otherwise they remain dark. “To our surprise, we found very different maps inside the hippocampus,” reports Hainmüller. In part, they provide an approximate overview of the position of the mouse in the corridor, yet they also consider time and context factors, and above all, information about in which of the corridors the mouse is located. The maps are also updated during the days of the experiment and as a result can be recognized as a learning process.

Better understanding of memory formation

The research team summarizes, saying that their observations provide a model that explains how activity of the nerve cells in the hippocampus can map the space, time and and context of memory episodes. The findings allow for better understanding of the biological processes that effect the formation of memory in the brain. Hainmüller says, “In the long term, we would like to use our results to contribute to the development of treatments to help people with neurological and psychiatric illnesses.”

Original publication
Thomas Hainmüller and Marlene Bartos (2018): Parallel emergence of stable and dynamic memory engrams in the hippocampus. In: Nature. doi: 10.1038/s41586-018-0191-2

By Hilary Hurd Anyaso

Leading theories propose that sleep presents an opportune time for important, new memories to become stabilized. And it’s long been known which brain waves are produced during sleep. But in a new study, researchers set out to better understand the brain mechanisms that secure memory storage.

The team from Northwestern and Princeton universities set out to find more direct and precisely timed evidence for the involvement of one particular sleep wave — known as the “sleep spindle.”

In the study, sleep spindles, described as bursts of brain activity typically lasting around one second, were linked to memory reactivation. The paper, “Sleep spindle refractoriness segregates periods of memory reactivation,” published today in the journal Current Biology.

“The most novel aspect of our study is that we found these spindles occur rhythmically — about every three to six seconds — and this rhythm is related to memory,” said James W. Antony, first author of the study and a postdoctoral fellow in Princeton’s Computational Memory Lab.

Three experiments explored how recent memories are reactivated during sleep. While volunteers took an afternoon nap, sound cues were surreptitiously played. Each was linked to a specific memory. The researchers’ final experiment showed that if cues were presented at opportune times such that spindles could follow them, the linked memories were more likely to be retained. If they were presented when a spindle was unlikely to follow, the linked memories were more likely to be forgotten.

“One particularly remarkable aspect of the study was that we were able to monitor spindles moment by moment while people slept,” said Ken A. Paller, senior author of the study and professor of psychology at Northwestern’s Weinberg College of Arts and Sciences. “Therefore, we could know when the brain was most ready for us to prompt memory reactivation.”
If the researchers reminded people of a recently learned fact, a spindle would likely be evident in the cerebral cortex, and memory for that information would be improved, added Paller, also director of Northwestern’s Cognitive Neuroscience Program.

“In memory research, we know it’s important to segregate experiences while you’re awake so that everything doesn’t just blend together,” said Antony, who worked in Paller’s lab at Northwestern as a doctoral student. “If that happens, you may have difficulty retrieving information because so many things will come to mind at once. We believe the spindle rhythmicity shown here might play a role in segregating successive memory reactivations from each other, preventing overlap that might cause later interference between memories.”

Ultimately, the researchers’ goal is to understand how sleep affects memory under natural conditions and how aging or disease can impact these functions.

“With that goal in mind, we’ve helped elucidate the importance of sleep spindles more generally,” Antony said.

Paller said they are on the trail of the physiology of memory reactivation.

“Future work will be needed to see how spindles fit together with other aspects of the physiology of memory and will involve other types of memory testing and other species,” Paller said.

In addition to Antony and Paller, co-authors are Luis Piloto, Margaret Wang, Paula Pacheco and Kenneth A. Norman, all of Princeton.

By Rachael Rettner

Many people tend to look back on the past with rose-colored glasses, remembering the good times and the good feelings…while forgetting the bad.

But a new study suggests that heavy marijuana users may have some trouble letting go of negative emotions tied to memories — a phenomenon that’s also seen in people with depression. Earlier research has also linked marijuana use with depression.

Although the new results are very preliminary, the findings, presented here on Friday (May 25) at the annual meeting of the Association for Psychological Science, may offer clues about the link between marijuana use and depression.

Rose-colored memories

The study explored a psychological phenomenon called “fading affect bias,” in which people tend to hold on to positive feelings tied to their memories more than they hold on to negative feelings. In other words, negative feelings related to our memories fade faster than positive ones.

Psychologists have hypothesized that this phenomenon, which is generally seen in people without mental health conditions, may serve as a sort of “psychological immune system,” said study lead author Daniel Pillersdorf, a graduate student in psychology at the University of Windsor in Ontario. This may be “so that we think more pleasantly in general, and don’t have that cognitive burden of holding on to negative emotions associated with memories,” Pillersdorf said.

Some previous studies have suggested that this fading affect bias may be different for people who use drugs, but no studies have looked at whether marijuana use could affect this phenomenon.

In the new study, the researchers analyzed information from 46 heavy marijuana users — most of whom used the drug at least four times a week — and 51 people who didn’t use marijuana. Participants were asked to recall, and provide written descriptions of, three pleasant memories and three unpleasant memories from the past year. The participants were then asked to rate the intensity of emotion tied to those memories, on a scale of negative 10, meaning extremely unpleasant, to positive 10, or extremely pleasant. They rated their emotions both at the time the memory was made, and at the current time. (Marijuana users were not under the influence at the time the researchers asked them the questions.)

The researchers found that both marijuana users and non-users showed fading affect bias, but for marijuana users, the fading was a lot less.

“They were hanging on to that unpleasant affect over time, much more” than non-users, Pillersdorf told Live Science. “They were less able … to shed that unpleasantness associated with their memories.”

The study also found that marijuana users tended to recall life events in more general terms than specific ones. For example, when asked about a happy event in the past year, marijuana users were more likely to respond with general or broad answers such as “I went on vacation,” rather than recalling a specific event or day, such as “I attended my college graduation.” This phenomenon is known as over-general autobiographical memory, and it’s also linked with depression, Pillersdorf said.

It’s important to note that the new study found only an association and cannot determine why marijuana users show less fading affect bias, and more overgeneral memory, than non-users.

Link with depression?

Even so, the new findings agree with previous research that has found a link between heavy marijuana use and depression. However, researchers don’t know why marijuana and depression are linked — it could be that marijuana use plays a role in developing depression, or that people who are already depressed are more likely to use the drug. [7 Ways Marijuana May Affect the Brain]

Based on the new findings, one hypothesis is that the decreased “fading” of negative memories in marijuana users could be contributing to the development or continuing of depression, Pillersdorf said. “It may be that, chronic or frequent cannabis use is putting [a person] more at risk for the development or continuing of depression,” he said. However, Pillersdorf stressed that this is just a hypothesis that would need to be investigated with future research.

To further investigate the link, researchers will need to study marijuana users and non-users over long periods of time. For example, researchers could start with people in their late teens or early 20s, who don’t have depression, and see if those who use marijuana frequently are more likely to eventually develop depression than non-users.

Additional studies could also investigate whether other substances have an effect on fading affect bias, Pillersdorf said.

The study has not yet been published in a peer-reviewed journal.

Scientists have just discovered that a small region of a cellular protein that helps long-term memories form also drives the neurodegeneration seen in motor neuron disease (MND). This small part of the Ataxin-2 protein thus works for good and for bad. When a version of the protein lacking this region was substituted for the normal form in fruit flies (model organisms), the animals could not form long-term memories – but, surprisingly, the same flies showed a remarkable resistance to neurodegeneration.

The popular “ice bucket challenge” highlighted the social significance of MND, as well as the need to better understand and treat neurodegenerative conditions. This new research identifies a very specific basic mechanism that facilitates progression of neuronal loss in an animal model of MND, and, by shedding light on a potential way to protect against cell death in MND, it should inform strategies for the development of therapeutics to treat or manage these devastating conditions, which are currently incurable.

The Science Foundation Ireland-funded research, involving scientists from the Trinity College Institute of Neuroscience, NCBS Bangalore and HMMI, University of Colorado, Boulder, has just been published in the leading international journal Neuron.

Professor of Neurogenetics at Trinity College Dublin, Mani Ramaswami, said: “This work, by collaborating young researchers based in Irish, Indian and American laboratories, provides a great example of the ability of fundamental research in model organisms to produce biologically and clinically interesting information.”

A common feature of neurodegenerative diseases is the presence of specific protein aggregates in nerve cells, which accumulate and clump together — usually as protein fibres called amyloid filaments. Such aggregates are believed to trigger processes that cause the neuronal death associated with these debilitating diseases. For example, amyloid-beta (Aβ) aggregates are associated with Alzheimer’s disease, while TDP-43, FUS and Ataxin-2 proteins are commonly found in MND patients.

The scientists behind the current study set out to test this “amyloid hypothesis” to see whether it may explain how MND develops. The scientists genetically engineered fruit flies with mutations designed to reduce Ataxin-2 protein assembly into aggregates without affecting other functions of the protein.

Arnas Petrauskas, Trinity, said: “The flies with this altered, non-aggregating version of the protein showed a striking resistance to neurodegeneration. This suggests the normal Ataxin-2 protein and its ability to form aggregates is required for the progression of at least some forms of MND, which means these results provide support for the amyloid hypothesis.”

“What really surprised us though was that this same protein region seems to be required for the flies to develop long-term memory, as those with the altered version of Ataxin-2 showed normal short-term but defective long-term memories.”

Fruit flies normally respond strongly to new odorants, but weakly to familiar odorants through a process called habituation. This memory of the familiar can be of the short-term kind – to an odorant encountered for half-an-hour, or of the long-term kind, to odorants encountered for days (think of it as remembering a phone number of a new acquaintance versus remembering your own phone number). Flies lacking this small domain of Ataxin-2 showed greatly reduced long-term memory.

So how is long-term memory formation and disease progression connected? It turns out that proteins like the TDP-43, FUS and Ataxin-2 found in MND are also involved in the natural control and management of protein expression in the cell. The very same region of Ataxin-2 is needed to form RNP granules that store RNAs (essentially blueprints, or recipes for specific proteins) in a silent form until they are unpackaged by a signal and used to produce molecules when they are required. This local control of RNAs is required for long-term changes at neuronal synapses that underlie long-term memory.

The new discovery shows that Ataxin-2 concentrates several RNA-binding proteins used in the process of memory storing, but in doing so, it creates a biological environment that can help these proteins aggregate into disease-causing amyloids. A “trade-off” therefore exists in nature where the Ataxin-2 gene increases the danger of neurodegeneration, but helps our cells control RNA and form long-term memories.

In a commentary on the research published in the same issue of the journal Neuron, Aaron Gitler, Professor of Genetics in the Stanford Neuroscience Institute, an independent expert in MND research said: “This data suggest that manipulating RNP granule formation by genetically manipulating ataxin-2’s IDRs, or by other means could be therapeutic in ALS. Beyond ataxin-2, the race is now on to discover additional proteins that help build RNP granules.”

By Ashley Yeager

Researchers have transferred a memory from one snail to another via RNA, they report today (May 14) in eNeuro. If confirmed in other species, the finding may lead to a shift in scientists’ thinking about how memories are made—rather than cemented in nerve-cell connections, they may be spurred on by RNA-induced epigenetic changes.

“The study suggests that RNA populations are the missing link in the search for memory,” Bridget Queenan, a neuroscientist at the University of California, Santa Barbara, who was not involved in the study, writes in an email to The Scientist. “If circulating neural RNAs can transfer behavioral states and tendencies, orchestrating both the transient feeling and the more permanent memory, it suggests that human memory—just like mood—will only be explained by exploring the interplay between bodies and brains.”

For decades, researchers have tried to pinpoint how, when, and where memories form. In the 1940s, Canadian psychologist Donald Hebb proposed memories are made in the connections between neurons, called synapses, and stored as those connections grow stronger and more abundant. Experiments in the 1960s, however, suggested RNA could play a role in making memories, though the work was largely written off as irreproducible.

Study coauthor David Glanzman of the University of California, Los Angeles, has been working on the cell biology of learning and memory for nearly 40 years, and says for the majority of that time he believed memory was stored at synapses. Several years ago, though, he and his colleagues began replicating memory-erasing research done in rodents in California sea hares (Aplysia californica), a type of marine snail also called a sea slug. The team found that the snail synapses built to “store” a memory weren’t necessarily the synapses that were removed from the neural circuits in the memory-erasing experiments.

“It was completely arbitrary which synaptic connections got erased,” Glanzman says. “That suggested maybe the memory wasn’t stored at the synapse but somewhere else.”

Glanzman turned his attention to RNA because of those earlier hints it was related to memory, and also because of recent experiments suggesting long-term memory was stored in the cell bodies of neurons, not synapses. He picked Aplysia because it has been a longtime model organism for memory studies. Like all mollusks, these snails have groups of neurons called ganglia, rather than brains. Their nervous systems comprise about 20,000 neurons, and the cells are some of the biggest and easily identifiable among nerve cells in all animals. In the snail’s gut, for example, are specific sensory and motor neurons that control the withdrawal of a fleshy, spout-like organ on the snail’s back called a siphon and the contraction of a caterpillar-looking gill, which the animal uses to breathe.

When touched lightly on the siphon, the neurons fire, retract the tissue, and contract the gill within the body cavity for a few seconds to protect it against attack. Sticking electrodes in the snail’s tail and shocking it makes this defensive response last longer, tens of seconds, and sometimes up to almost a minute. By repeatedly shocking the snail’s tail, the animal learns to stay in that defensive position when touched on the siphon, even weeks after the shocks end.

In his team’s latest experiments, Glanzman and his colleagues zapped snails’ tails, then pulled the abdominal neurons from the shocked snails, extracted their RNA, dissolved the RNA into deionized water, and injected the solution into the necks of snails that had never been shocked. (For a control, the team also took RNA from non-shocked snails and injected into naive snails.) When tapped on the siphon 24 hours later, snails that got RNA from shocked snails withdrew their siphon and gill for significantly longer (almost 40 seconds) than did snails that got RNA from non-shocked animals (less than 10 seconds).

DNA methylation appeared to be essential for the transfer of the memory among snails. When Glanzman and his colleagues blocked DNA methylation in snails getting RNA from shocked ones, the injected snails withdrew their siphons for only a few seconds when tapped on the siphon.

Glanzman wanted to know if the RNA from shocked snails actually affected the neuronal connections of the snails receiving the injections any differently than RNA from nonshocked snails. So, in a third test, he and his team removed sensory neurons from nonshocked snails, cultured the cells in a dish, and then exposed the cells to RNA from shocked snails. Zapping the culture with a bit of current excited the sensory neurons much more than neurons treated with RNA from nonshocked snails. RNA from shocked snails also enhanced a subset of synapses between sensory and motor neurons in vitro, suggesting it was indeed the RNA that transported the memory, Glanzman explains.

The idea “seems quite radical as we don’t have a specific mechanism for how it works in a non-synaptic manner,” Bong-Kiun Kaang, a neuroscientist at Seoul National University who was not involved in the study, writes in an email to The Scientist. Kaang notes there are “many critical questions that need to be addressed to further validate the author’s argument,” such as what kinds of noncoding RNAs are specifically involved, how are the RNAs transferred among neurons, and how much do RNAs at the synapse play a role? The experiments should also be replicated in organisms other than snails, he says.

Glanzman says that in his next experiments he will attempt to identify the RNAs involved, and he has an idea for the mechanism, too. The memory is not stored in the RNA itself, he speculates—instead, noncoding RNA produces epigenetic changes in the nucleus of neurons, thereby storing the memory.

“This idea is probably going to strike most of my colleagues as extremely improbable,” Glanzman says. “But if we’re right, we’re just at the beginning of understanding how memory works.”

A. Bédécarrats et al., “RNA from trained Aplysia can induce an epigenetic engram for long-term sensitization in untrained Aplysia,” eNeuro,, 2018.

Neuroscientists at Indiana University have reported the first evidence that non-human animals can mentally replay past events from memory. The discovery could help advance the development of new drugs to treat Alzheimer’s disease.

The study, led by IU professor Jonathon Crystal, appears today in the journal Current Biology.

“The reason we’re interested in animal memory isn’t only to understand animals, but rather to develop new models of memory that match up with the types of memory impaired in human diseases such as Alzheimer’s disease,” said Crystal, a professor in the IU Bloomington College of Arts and Sciences’ Department of Psychological and Brain Sciences and director of the IU Bloomington Program in Neuroscience.

Under the current paradigm, Crystal said most preclinical studies on potential new Alzheimer’s drugs examine how these compounds affect spatial memory, one of the easiest types of memory to assess in animals. But spatial memory is not the type of memory whose loss causes the most debilitating effects of Alzheimer’s disease.

“If your grandmother is suffering from Alzheimer’s, one of the most heartbreaking aspects of the disease is that she can’t remember what you told her about what’s happening in your life the last time you saw her,” said Danielle Panoz-Brown, an IU Ph.D. student who is the first author on the study. “We’re interested in episodic memory — and episodic memory replay — because it declines in Alzheimer’s disease, and in aging in general.”

Episodic memory is the ability to remember specific events. For example, if a person loses their car keys, they might try to recall every single step — or “episode” — in their trip from the car to their current location. The ability to replay these events in order is known as “episodic memory replay.” People wouldn’t be able to make sense of most scenarios if they couldn’t remember the order in which they occurred, Crystal said.

To assess animals’ ability to replay past events from memory, Crystal’s lab spent nearly a year working with 13 rats, which they trained to memorize a list of up to 12 different odors. The rats were placed inside an “arena” with different odors and rewarded when they identified the second-to-last odor or fourth-to-last odor in the list.

The team changed the number of odors in the list before each test to confirm the odors were identified based upon their position in the list, not by scent alone, proving the animals were relying on their ability to recall the whole list in order. Arenas with different patterns were used to communicate to the rats which of the two options was sought.

After their training, Crystal said, the animals successfully completed their task about 87 percent of the time across all trials. The results are strong evidence the animals were employing episodic memory replay.

Additional experiments confirmed the rats’ memories were long-lasting and resistant to “interference” from other memories, both hallmarks of episodic memory. They also ran tests that temporarily suppressed activity in the hippocampus — the site of episodic memory — to confirm the rats were using this part of their brain to perform their tasks.

Crystal said the need to find reliable ways to test episodic memory replay in rats is urgent since new genetic tools are enabling scientists to create rats with neurological conditions similar to Alzheimer’s disease. Until recently, only mice were available with the genetic modifications needed to study the effect of new drugs on these symptoms.

“We’re really trying push the boundaries of animal models of memory to something that’s increasingly similar to how these memories work in people,” he said. “If we want to eliminate Alzheimer’s disease, we really need to make sure we’re trying to protect the right type of memory.”