What Makes Memories Last?

Prions can be notoriously destructive, spurring proteins to misfold and interfere with cellular function as they spread without control. New research, published in the open access journal PLOS Biology on February 11, 2014, from scientists at the Stowers Institute for Medical Research reveals that certain prion-like proteins, however, can be precisely controlled so that they are generated only in a specific time and place. These prion-like proteins are not involved in disease processes; rather, they are essential for creating and maintaining long-term memories.

“This protein is not toxic; it’s important for memory to persist,” says Stowers researcher Kausik Si, Ph.D., who led the study. To ensure that long-lasting memories are created only in the appropriate neural circuits, Si explains, the protein must be tightly regulated so that it adopts its prion-like form only in response to specific stimuli. He and his colleagues report on the biochemical changes that make that precision possible.

Si’s lab is focused on finding the molecular alterations that encode a memory in specific neurons as it endures for the days, months, or years—even as the cells’ proteins are degraded and renewed. Increasingly, their research is pointing toward prion-like proteins as critical regulators of long-term memory.

In 2012, Si’s group demonstrated that prion formation in nerve cells is essential for the persistence of long-term memory in fruit flies. Prions are a fitting candidate for this job because their conversion is self-sustaining: once a prion-forming protein has shifted into its prion shape, additional proteins continue to convert without any additional stimulus.

Si’s team found that in fruit flies, the prion-forming protein Orb2 is necessary for memories to persist. Flies that produce a mutated version of Orb2 that is unable to form prions learn new behaviors, but their memories are short-lived. “Beyond a day, the memories become unstable. By three days, the memory has completely disappeared,” Si explains.

In the new study, Si wanted to find out how this process could be controlled so that memories form at the right time. “We know that all experiences do not form long-term memory—somehow the nervous system has a way to discriminate. So if prion-formation is the biochemical basis of memory, it must be regulated.” Si says. “But prion formation appears to be random for all the cases we know of so far.”

Si and his colleagues knew that Orb2 existed in two forms—Orb2A and Orb2B. Orb2B is widespread throughout the fruit fly’s nervous system, but Orb2A appears only in a few neurons, at extremely low concentrations. What’s more, once it is produced, Orb2A quickly falls apart; the protein has a half-life of only about an hour.

“When Orb2A binds to the more abundant form, it triggers conversion to the prion state, acting as a seed for the conversion. Once conversion begins, it is a self-sustaining process; additional Orb2 continues to convert to the prion state, with or without Orb2A. By altering the abundance of the Orb2A seed”, Si says, “cells might regulate where, when, and how the conversion process is engaged”. But how do nerve cells control the abundance of the Orb2A seed?

Their experiments revealed that when a protein called TOB associates with Orb2A , it becomes much more stable, with a new half-life of 24 hours. This step increases the prevalence of the prion-like state and explains how Orb2’s conversion to the prion state can be confined in both time and space.

The findings raise a host of new questions for Si, who now wants to understand what happens when Orb2 enters its prion-like state, as well as where in the brain the process occurs. While unraveling these mechanisms will likely be more accessible in the fruit fly than in more complex organisms, Si points out that proteins related to Orb2 and TOB have also been found in the brains of mice and humans. He has already shown that in the sea snail Aplysia, conversion to a prion-like state facilitates long-term change in synaptic strength. “This basic mechanism appears to be conserved across species,” he notes.

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."

Take note students: Mice that ‘cram’ for exams remember less

It’s been more than 100 years since German psychologist Hermann Ebbinghaus determined that learning interspersed with rest created longer-lasting memories than so-called cramming, or learning without rest intervals.

Dolphins Have Longest Memories in Animal Kingdom

Marine mammals can remember their friends after 20 years apart, study says.

New experiments show that bottlenose dolphins can remember whistles of other dolphins they’d lived with after 20 years of separation. Each dolphin has a unique whistle that functions like a name, allowing the marine mammals to keep close social bonds.

The new research shows that dolphins have the longest memory yet known in any species other than people. Elephants and chimpanzees are thought to have similar abilities, but they haven’t yet been tested, said study author Jason Bruck, an animal behaviorist at the University of Chicago.

Bruck came up with the idea to study animal memory when his brother’s dog, usually wary of male strangers, remembered and greeted him four years after last seeing him. “That got me thinking: How long do other animals remember each other?”

I Remember You!

Bruck studied dolphins because their social bonds are extremely important and because there are good records for captive dolphins (as opposed to wild ones).

So he collected data from 43 bottlenose dolphins at six facilities in the U.S. and Bermuda, members of a breeding consortium that has swapped dolphins for decades and kept careful records of each animal’s social partners.

He first played recordings of lots of unfamiliar whistles to the dolphins in the study until the subjects got bored and stopped inspecting the underwater speaker making the sounds.

At this point, he played the whistles of the listening dolphins’ old friends.

When the dolphins heard these familiar whistles, they would perk up and approach the speakers, often whistling their own name and listening for a response.

Overall, the dolphins responded more to animals they’d known decades ago than to random animals—suggesting they recognized their former companions, according to the study, published recently in Proceedings of the Royal Society B.

Cheeky Dolphins

Working with animals as intelligent as dolphins was a challenge, Bruck added. The animals loved participating in the experiment so much that they’d often hover over the speaker, blocking the noise.

Others would begin “whistling directly at me as if I could understand them,” he said.

And one set of cheeky young dolphins swam up to Bruck and started whistling the names of the dominant males in their group in order of rank, perhaps suggesting the names they wanted to hear, Bruck said.

Memory Linked to Smarts?

Why dolphins—which live an average of 20 years in the wild—need long-term memory is still unknown. But it may have to do with maintaining relationships, since over time dolphin groups often break up and reorganize into new alliances.

This sort of social system is called “fission-fusion,” and it’s also seen in elephants and chimpanzees—two other highly intelligent and social beings.

Coincidence? Bruck suspects not: “It seems that maybe complex cognition comes from a place of trying to remember who your buddies are,” he said.

Visualizing a memory trace

Whole brain imaging of zebrafish reveals neuronal networks involved in retrieving long-term memories during decision making

In mammals, a neural pathway called the cortico-basal ganglia circuit is thought to play an important role in the choice of behaviors. However, where and how behavioral programs are written, stored and read out as a memory within this circuit remains unclear. A research team led by Hitoshi Okamoto and Tazu Aoki of the RIKEN Brain Science Institute has for the first time visualized in zebrafish the neuronal activity associated with the retrieval of long-term memories during decision making.

The team performed experiments on genetically engineered zebrafish expressing a fluorescent protein that changes its intensity when it binds to calcium ions in neurons and thereby acts as an indicator of neuronal activity. “Neurons in the fish cortical region form a neural circuit similar to the mammalian cortico-basal ganglia circuit,” says Okamoto.

The fish were trained on an avoidance task by placing individual fish into a two-compartment tank and shining a red light for several seconds into the compartment containing the fish. If the fish did not move into the other compartment in response to the light, it was ‘punished’ with a mild electric shock. After several repetitions, the fish learned to avoid the shock by switching compartments as soon as the light came on. 

The researchers then examined the neuronal activity of the fish under the microscope in response to exposure to red light. One day after the learning task, the fish showed specific activity in a discrete region of the telencephalon, which corresponds to the cerebral cortex in mammals, when presented with the red light. However, just 30 minutes after the learning task no activity was observed in this part of the brain. The results suggest that this telencephalonic area encodes the long-term memory for the learned avoidance behavior. Confirming this, removing this part of the telencephalon abolished the long-term memory but did not affect learning or short-term storage of the memory. 

In humans, the ability to choose the correct behavioral programs in response to environmental changes is indispensable for everyday life, and the ability to do so is thought to be impaired in various psychiatric conditions such as depression and schizophrenia. 

“Combining the neural imaging technique with genetics, we will be able to investigate how neurons in the cortico-basal ganglia circuit choose the most suitable behavior in any given situation,” says Okamoto. “Our findings open the way to investigate and understand how these symptoms appear in human psychiatric disorders.”

Researchers Identify “Switch” for Long-term Memory

Calcium signal in neuronal cell nuclei initiates the formation of lasting memories

Neurobiologists at Heidelberg University have identified calcium in the cell nucleus to be a cellular “switch” responsible for the formation of long-term memory. Using the fruit fly “Drosophila melanogaster” as a model, the team led by Prof. Dr. Christoph Schuster and Prof. Dr. Hilmar Bading investigates how the brain learns. The researchers wanted to know which signals in the brain were responsible for building long-term memory and for forming the special proteins involved. The results of the research were published in the journal “Science Signaling”.

The team from the Interdisciplinary Center for Neurosciences (IZN) measured nuclear calcium levels with a fluorescent protein in the association and learning centres of the insect’s brain to investigate any changes that might occur during the learning process. Their work on the fruit fly revealed brief surges in calcium levels in the cell nuclei of certain neurons during learning. It was this calcium signal that researchers identified as the trigger of a genetic programme that controls the production of “memory proteins”. If this nuclear calcium switch is blocked, the flies are unable to form long-term memory.

Prof. Schuster explains that insects and mammals separated evolutionary paths approximately 600 million years ago. In spite of this sizable gap, certain vitally important processes such as memory formation use similar cellular mechanisms in humans, mice and flies, as the researchers’ experiments were able to prove. “These commonalities indicate that the formation of long-term memory is an ancient phenomenon already present in the shared ancestors of insects and vertebrates. Both species probably use similar cellular mechanisms for forming long-term memory, including the nuclear calcium switch”, Schuster continues.

The IZN researchers assume that similar switches based on nuclear calcium signals may have applications in other areas – presumably whenever organisms need to adapt to new conditions over the long term. “Pain memory, for example, or certain protective and survival functions of neurons use this nuclear calcium switch, too”, says Prof. Bading. This cellular switch may no longer work as well in the elderly, which Bading believes may explain the decline in memory typically observed in old age. Thus, the discoveries by the Heidelberg neurobiologists open up new perspectives for the treatment of age- and illness-related changes in brain functions.