Lost memories might be able to be restored, suggests research into marine snail

New UCLA research indicates that lost memories can be restored. The findings offer some hope for patients in the early stages of Alzheimer's disease.

New UCLA research indicates that lost memories can be restored. The findings offer some hope for patients in the early stages of Alzheimer's disease.

For decades, most neuroscientists have believed that memories are stored at the synapses -- the connections between brain cells, or neurons -- which are destroyed by Alzheimer's disease. The new study provides evidence contradicting the idea that long-term memory is stored at synapses.

"Long-term memory is not stored at the synapse," said David Glanzman, a senior author of the study, and a UCLA professor of integrative biology and physiology and of neurobiology. 

"That's a radical idea, but that's where the evidence leads. The nervous system appears to be able to regenerate lost synaptic connections. If you can restore the synaptic connections, the memory will come back. It won't be easy, but I believe it's possible."

The findings were published recently in eLife.

Glanzman's research team studies a type of marine snail called Aplysia to understand the animal's learning and memory. The Aplysia displays a defensive response to protect its gill from potential harm, and the researchers are especially interested in its withdrawal reflex and the sensory and motor neurons that produce it.

They enhanced the snail's withdrawal reflex by giving it several mild electrical shocks on its tail. The enhancement lasts for days after a series of electrical shocks, which indicates the snail's long-term memory. Glanzman explained that the shock causes the hormone serotonin to be released in the snail's central nervous system.

Long-term memory is a function of the growth of new synaptic connections caused by the serotonin, said Glanzman, a member of UCLA's Brain Research Institute. As long-term memories are formed, the brain creates new proteins that are involved in making new synapses. If that process is disrupted -- for example by a concussion or other injury -- the proteins may not be synthesized and long-term memories cannot form. (This is why people cannot remember what happened moments before a concussion.)

"If you train an animal on a task, inhibit its ability to produce proteins immediately after training, and then test it 24 hours later, the animal doesn't remember the training," 

Glanzman said. "However, if you train an animal, wait 24 hours, and then inject a protein synthesis inhibitor in its brain, the animal shows perfectly good memory 24 hours later. In other words, once memories are formed, if you temporarily disrupt protein synthesis, it doesn't affect long-term memory. That's true in the Aplysia and in human's brains." (This explains why people's older memories typically survive following a concussion.)

Glanzman's team found the same mechanism held true when studying the snail's neurons in a Petri dish. The researchers placed the sensory and motor neurons that mediate the snail's withdrawal reflex in a Petri dish, where the neurons re-formed the synaptic connections that existed when the neurons were inside the snail's body. When serotonin was added to the dish, new synaptic connections formed between the sensory and motor neurons. But if the addition of serotonin was immediately followed by the addition of a substance that inhibits protein synthesis, the new synaptic growth was blocked; long-term memory could not be formed.

The researchers also wanted to understand whether synapses disappeared when memories did. To find out, they counted the number of synapses in the dish and then, 24 hours later, added a protein synthesis inhibitor. One day later, they re-counted the synapses.

What they found was that new synapses had grown and the synaptic connections between the neurons had been strengthened; late treatment with the protein synthesis inhibitor did not disrupt the long-term memory. The phenomenon is extremely similar to what happens in the snail's nervous system during this type of simple learning, Glanzman said.

Next, the scientists added serotonin to a Petri dish containing a sensory neuron and motor neuron, waited 24 hours, and then added another brief pulse of serotonin -- which served to remind the neurons of the original training -- and immediately afterward add the protein synthesis inhibitor. This time, they found that synaptic growth and memory were erased. When they re-counted the synapses, they found that the number had reset to the number before the training, Glanzman said. This suggests that the "reminder" pulse of serotonin triggered a new round of memory consolidation, and that inhibiting protein synthesis during this "reconsolidation" erased the memory in the neurons.

If the prevailing wisdom were true -- that memories are stored in the synapses -- the researchers should have found that the lost synapses were the same ones that had grown in response to the serotonin. But that's not what happened: Instead, they found that some of the new synapses were still present and some were gone, and that some of the original ones were gone, too.

Glanzman said there was no obvious pattern to which synapses stayed and which disappeared, which implied that memory is not stored in synapses.

When the scientists repeated the experiment in the snail, and then gave the animal a modest number of tail shocks -- which do not produce long-term memory in a naive snail -- the memory they thought had been completely erased returned. This implies that synaptic connections that were lost were apparently restored.

"That suggests that the memory is not in the synapses but somewhere else," Glanzman said. 

"We think it's in the nucleus of the neurons. We haven't proved that, though."

Glanzman said the research could have significant implications for people with Alzheimer's disease. Specifically, just because the disease is known to destroy synapses in the brain doesn't mean that memories are destroyed.

"As long as the neurons are still alive, the memory will still be there, which means you may be able to recover some of the lost memories in the early stages of Alzheimer's," he said.

Glanzman added that in the later stages of the disease, neurons die, which likely means that the memories cannot be recovered.

The cellular and molecular processes seem to be very similar between the marine snail and humans, even though the snail has approximately 20,000 neurons and humans have about 1 trillion. Neurons each have several thousand synapses.

Glanzman used to believe that traumatic memories could be erased but he has changed his mind. He now believes that, because memories are stored in the nucleus, it may be much more difficult to modify them. He will continue to study how the marine snail's memories are restored and how synapses re-grow.

Co-authors of the study include Shanping Chen, Diancai Cai and Kaycey Pearce, research associates in Glanzman's laboratory.

The research was funded by the National Institutes of Health's National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health and the National Science Foundation.

Almost all the processes that are involved in memory in the snail also have been shown to be involved in memory in the brains of mammals, Glanzman said.

In a 1997 study published in the journal Science, Glanzman and colleagues identified a cellular mechanism in the Aplysia that plays an important role in learning and memory. A protein called N-methyl D-aspartate, or NMDA, receptor enhances the strength of synaptic connections in the nervous system and plays a vital role in memory and in certain kinds of learning in the mammalian brain as well. Glanzman's demonstration that the NMDA receptor plays a critical role in learning in a simple animal like the marine snail was entirely unexpected at the time.

Source: University of California, Los Angeles

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Bugs life: The nerve cells that make locusts ‘gang up’

Computer reconstruction of nerve cells in a desert locust that produce the neurochemical serotonin. The colors indicate each cell's response to the social stimuli that cause gregarious behavior. The green cells contain less serotonin after a life-time of crowding with other locusts. The blue cells contain more serotonin after a locust has seen and smelled other locusts for just one hour. The yellow cells increase their serotonin content within an hour of exposing a locust to any of the social stimuli that induce gregarious behavior. Credit: University of Leicester

A team of biologists has identified a set of nerve cells in desert locusts that bring about 'gang-like' gregarious behaviour when they are forced into a crowd.

Dr Swidbert Ott from the University of Leicester's Department of Biology, working with Dr Steve Rogers at the University of Sydney, Australia, has published a study that reveals how newly identified nerve cells in locusts produce the neurochemical serotonin to initiate changes in their behaviour and lifestyle.

The findings demonstrate the importance of individual history for understanding how brain chemicals control behaviour, which may apply more broadly to humans also.

Locusts are normally shy, solitary animals that actively avoid the company of other locusts. But when they are forced into contact with other locusts, they undergo a radical change in behaviour -- they enter a 'bolder' gregarious state where they are attracted to the company of other locusts. This is the critical first step towards the formation of the notorious locust swarms.

Dr Ott said: "Locusts only have a small number of nerve cells that can synthesise serotonin. Now we have found that of these, a very select few respond specifically when a locust is first forced to be with other locusts. Within an hour, they produce more serotonin.

"It is these few cells that we think are responsible for the transformation of a loner into a gang member. In the long run, however, many of the other serotonin-cells also change, albeit towards making less serotonin."

When a locust is first forced into contact with other locusts, a specific set of nerve cells that produce the neurochemical serotonin is responsible for reconfiguring its behaviour so that the previously solitary locust becomes a member of the gang, which is known as 'gregarious' behaviour.

An entirely different set of its serotonin-producing nerve cells is then affected by life in the group in the long run.

Dr Ott added: "The key to our success was to look in locusts that have just become gregarious and that had never met another locust until an hour earlier. If we had looked only in solitary locusts and in locusts that had a life-long history of living in crowds, we would have missed the nerve cells that are the key players in the transformation.

"There is an important lesson here for understanding the mechanisms that drive changes in social behaviour in general, both in locusts and in humans. We have shown how important it is to look at what happens when a new social behaviour is first set up, not just at the long-term outcome.

"Research in insects can give us deep insights into how brains work in general, including our own."

Studies have previously shown that the change from solitary to gregarious behaviour is caused by serotonin.

The new study, which was funded by the Leverhulme Trust, the Biotechnology and Biological Sciences Research Council (BBSRC) and the Royal Society, has identified the individual serotonin-producing nerve cells that are responsible for the switch from solitary to gregarious behaviour.

The scientists used a fluorescent stain that reveals the serotonin-producing nerve cells under the microscope. This allowed them to measure the amount of serotonin in individual nerve cells -- the brighter a nerve cell lights up, the more serotonin it contains. The newly identified cells were much brighter in locusts that had just been forcedly crowded with other locusts. Moreover, the same cells were also brighter in locusts that had their hind legs tickled by the researchers for an hour -- which is sufficient to make the locusts behave gregariously.

Serotonin has important roles in the brains of all animals that include the regulation of moods and social interactions.

In humans, there are strong links between changes in serotonin and mental disorders such as depression and anxiety.

Source: University of Leicester

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Colorado's Front Range fire severity not much different than past

A new study indicates present-day forest fires on Colorado's Front Range are not significantly more intense than historical fires. Credit: Glenn Asakawa, University of Colorado

The perception that Colorado's Front Range wildfires are becoming increasingly severe does not hold much water scientifically, according to a massive new study led by the University of Colorado Boulder and Humboldt State University in Arcata, Calif.

The study authors, who looked at 1.3 million acres of ponderosa pine and mixed conifer forest from Teller County west of Colorado Springs through Larimer County west and north of Fort Collins, reconstructed the timing and severity of past fires using fire-scarred trees and tree-ring data going back to the 1600s. Only 16 percent of the study area showed a shift from historically low-severity fires to severe, potential crown fires that can jump from treetop to treetop.

The idea that modern fires are larger and more severe as a result of fire suppression that allowed forest fuels to build up in the past century is still prevalent among some, said CU-Boulder geography Professor Thomas Veblen, a study co-author. "The key point here is that modern fires in these Front Range forests are not radically different from the fire severity of the region prior to any effects of fire suppression," he said.

A paper on the subject was published Sept. 24 in the journal PLOS ONE. The study was led by Associate Professor Rosemary Sherriff of Humboldt State University and involved Research Scientist Tania Schoennagel of CU-Boulder's Institute of Arctic and Alpine Research, CU-Boulder doctoral student Meredith Gartner and Associate Professor Rutherford Platt of Gettysburg College in Gettysburg, Pa.

The study was funded by the National Science Foundation.

"The common assumption is that fires are now more severe and are killing higher percentages of trees," said Sherriff, who completed her doctorate at CU-Boulder under Veblen in 2004. "Our results show that this is not the case on the Front Range except for the lowest elevation forests and woodlands."

One important new finding comes from a comparison of nine large fires that have occurred on the Front Range since 2000 -- including the 2002 Hayman Fire southwest of Denver, the 2010 Fourmile Canyon Fire west of Boulder and the 2012 High Park Fire west of Fort Collins -- with historic fire effects in the region.

"It's true that the Colorado Front Range has experienced a number of large fires recently," said Schoennagel. "While more area has burned recently compared to prior decades -- with more homes coming into the line of fire -- the severity of recent fires is not unprecedented when we look at fire records going back before the 1900s."

In addition, tree-ring evidence from the new study shows there were several years on the Front Range since the 1650s when there were very large, severe fires. The authors looked at more than 1,200 fire-scarred tree samples and nearly 8,000 samples of tree ages at 232 forest sample sites from Teller County to Larimer County.

The study is one of the largest of its kind ever undertaken in the western United States. The team was especially interested in fire records before about 1920, when effective fire suppression in the West began in earnest.

"In relatively dry ponderosa pine forests of the West, a common assumption is that fires were relatively frequent and of low severity, and not lethal to most large trees, prior to fuel build-up in the 20th century," said Veblen. "But our study results showed that about 70 percent of the forest study area experienced a combination of moderate and high-severity fires in which large percentages of the mature trees were killed."

Along the Front Range, especially at higher elevations, homeowners and fire managers should expect a number of high-severity fires unrelated to any kind of fire suppression and fuel build-up, said Schoennagel. "This matters because high-severity fires are dangerous to people, kill more trees and are trickier and more expensive to suppress."

"Severe fires are not new to most forests in this region," said Sherriff. "What is new is the expanded wildland-urban interface hazard to people and property and the high cost of suppressing fires for society."

In addition, a warming Colorado climate -- 2 degrees Fahrenheit since 1977 -- has become a wild card regarding future Front Range fires, according to the team. While fires are dependent on ignition sources and can be dramatically influenced by high winds, the team expects to see a substantial increase in Front Range fire activity in the low and mid-elevations in the coming years as temperatures continue to warm, a result of rising greenhouses gases in Earth's atmosphere.

Source: University of Colorado at Boulder

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