Genes for learning, remembering and forgetting

Certain genes and proteins that promote growth and development of embryos also play a surprising role in sending chemical signals that help adults learn, remember, forget and perhaps become addicted, University of Utah biologists have discovered. 

"We found that these molecules and signaling pathways [named Wnt] do not retire after development of the organism, but have a new and surprising role in the adult. They are called back to action to change the properties of the nervous system in response to experience," says biology Professor Andres Villu Maricq, senior author of the new study in the March 30 issue of the journal Cell. 

The study was performed in C. elegans -- the millimeter-long roundworm or nematode -- which has a nervous system that serves as a model for those of vertebrate animals, including humans. 

Because other Wnt pathways in worms are known to work in humans too, the researchers believe that Wnt genes, the Wnt proteins they produce and so-called "Wnt signaling" also are involved in human learning, memory and forgetting. 

"Almost certainly what we have discovered is going on in our brain as well," Maricq says. And because a worm nerve-signal "receptor" in the study is analogous to a human nicotine receptor involved in addiction, schizophrenia and some other mental disorders, some of the genes identified in the worm study "represent possible new targets for treatment of schizophrenia and perhaps addiction," he adds. 

Wnt genes and their proteins already were known to "pattern the development and distribution of organs in the body" during embryo development, and to be responsible for various cancers and developmental defects when mutated, he says. 

Maricq conducted the study with these Utah biologists: doctoral students Michael Jensen and Dane Maxfield; postdoctoral researchers Michael M. Francis, Frederic Hoerndli and Rui Wang; undergraduate Erica Johnson; Penelope Brockie, a research associate professor; and David M. Madsen, a senior research specialist. 

Synapse Plasticity is the Basis of Learning and Memory 

Synapses are the connections between nerve cells (neurons). Nerve signals are transmitted through synapses. Learning and memory concern how these connections are made, broken, strengthened or weakened. Proteins known as receptors are delivered to the synapses or removed from them to strengthen or weaken the connection. 

In the new study, Maricq and colleagues identified a "Wnt signaling pathway" -- a series of genes and the proteins they produce -- that controls the strength of nerve signal transmission from one neuron through a synapse to the next neuron. This allows "plasticity" of synapses -- a key factor in learning, retaining memories and forgetting. 

"The adult nervous system is not a stagnant tissue, but rather dynamic and plastic, with the strength of synapses -- specialized neuron-to-neuron connections -- changing with experience, learning and memory," Maricq says. "It's not a fixed thing, like when you're done making the heart, you're done." 

When synapses and thus incoming nerve signals are strengthened by adding receptors, an organism learns and remembers; when the opposite occurs, the organism forgets, he adds. 

How is that connection strengthened or weakened? When one neuron sends a nerve signal to another neuron, the first neuron releases a chemical known as a neurotransmitter, which moves through the synapse connecting the two cells and attaches or binds to receptors on the surface of the second neuron. 

"You can think of the receptors like amplifiers, like hearing aids," Maricq says. 

The volume of the received nerve signal depends on the number of receptors, which are stored in a supply depot just below the nerve cell's surface. 

The Wnt signaling identified in the new study "tells the depot to put more receptors into the synapse -- or not," says Maricq. 

He emphasizes that the Wnt chemical signal is different than the actual nerve signal carried by a neurotransmitter chemical, which in the new study was acetylcholine. The Wnt signal "is a secondary signal that controls the volume of the neurotransmitter signal," Maricq says. 

Worms Reveal Details of Nerve Signal Volume Control 

By crippling various genes in the worms, the researchers identified the "signaling pathway" by which a Wnt protein in one nerve cell sends a chemical signal to another cell telling it to increase the number of receptors on its surface, thus increasing the strength or volume of nerve signals between the cells. 

This is a microscope image of the roundworm or nematode C. elegans with its nervous system glowing green due to labeling with a green jellyfish protein [Credit: Penelope Brockie, University of Utah]

The type of nerve-signal receptor in the study is an acetylcholine receptor named ACR-16. When researchers crippled the gene that makes the ACR-16 receptor protein, there were not enough receptors, so nerve signals were disrupted and the worms "had uncoordinated movement," Maricq says. "They were semi-paralyzed." 

The scientists found mutations of other genes that also resulted in inadequate ACR-16 receptors and impaired the worms' movement. They discovered such genes belong to the "Wnt signaling pathway" that puts enough receptors on the cell surface so signals can be received. 

Besides ACR-16, genes in that pathway produced proteins named CWN-2 -- which is a Wnt protein -- LIN-17, CAM-1 and DSH-1. 

Here is how that pathway controls the volume of incoming nerve signals: 

1. A neuron releases CWN-2, which binds onto a receptor protein on the signal-receiving cell. That protein is a newly discovered combination of the LIN-17 and CAM-1 proteins. 

2. The LIN-17/CAM-1 protein sends a signal to a protein called disheveled, or DSH-1. 

3. "DSH-1 somehow sends the volume-control signal" that dispatches more ACR-16 receptors from depots inside the second neuron to that cell's surface, thus boosting the volume of the received nerve signal, Maricq says. 

The researchers used a green jellyfish protein to mark the ACR-16 receptors so they were visible under a microscope. When any of the genes in the Wnt signaling pathway were mutant, the scientists could see the green-labeled receptors accumulate under the surfaces of nerve cells instead of moving to the surface. 

Another experiment recorded electrical currents in worm nerve synapses and found it was smaller when any of the Wnt pathway genes were mutated. The smaller current -- reflecting impaired nerve-signal transmission -- explains why the mutant worms were partially paralyzed. 

Human Version of Worm Receptor Tied to Mental Disorders 

The ACR-16 acetylcholine receptor is the worm version of the alpha-7 nicotinic acetylcholine receptor in humans and other vertebrates. Both are similar in structure and function in animals from worms to fruit flies, mice and people. 

The alpha-7 receptor "is important in schizophrenia and a number of different mental disorders, and may have a role in addiction, but we don't understand how it's regulated," Maricq says. 

Many existing psychiatric drugs modify synapse strength. The new study suggests research should be done to show if the same Wnt signaling genes in worms also control alpha-7 receptor levels on human brain cells. If so, new drugs might be developed to target those genes as a way to treat mental disorders, including addiction. 

"Addiction is like learning at a primitive level," Maricq says. "Addiction means that somewhere in your brain, synapses are too strong. So you want more." 

The study was funded by the National Institutes of Health and the American Heart Association. 

Source: University of Utah [March 29, 2012]

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Sea snails help scientists explore a possible way to enhance memory

Efforts to help people with learning impairments are being aided by a species of sea snail known as Aplysia californica. The mollusk, which is used by researchers to study the brain, has much in common with other species including humans. Research involving the snail has contributed to the understanding of learning and memory. 

At The University of Texas Health Science Center at Houston (UTHealth), neuroscientists used this animal model to test an innovative learning strategy designed to help improve the brain's memory and the results were encouraging. It could ultimately benefit people who have impairments resulting from aging, stroke, traumatic brain injury or congenital cognitive impairments. 

The proof-of-principle study was published on the Nature Neuroscience website on Dec. 25. The next steps in the research may involve tests in other animal models and eventually humans. 

The strategy was used to identify times when the brain was primed for learning, which in turn facilitated the scheduling of learning sessions during these peak periods. The result was a significant increase in memory. 

"We found that memory could be enhanced appreciably," said John H. "Jack" Byrne, Ph.D., senior author and chair of the Department of Neurobiology and Anatomy at the UTHealth Medical School. 

Building on earlier research that identified proteins linked to memory, the investigators created a mathematical model that tells researchers when the timing of the activity of these proteins is aligned for the best learning experience. 

Right now, the scheduling of learning sessions is based on trial and error and is somewhat arbitrary. If the model proves effective in follow-up studies, it could be used to identify those periods when learning potential is highest. 

"When you give a training session, you are starting several different chemical reactions. If you give another session, you get additional effects. The idea is to get the sessions in sync," Byrne said. "We have developed a way to adjust the training sessions so they are tuned to the dynamics of the biochemical processes." 

Two groups of snails received five learning sessions. One group received learning sessions at irregular intervals as predicted by a mathematical model. Another group received training sessions in regular 20-minute intervals. 

Five days after the learning sessions were completed, a significant increase in memory was detected in the group that was trained with a schedule predicted by a computer. But, no increase was detected in the group with the regular 20-minute intervals. 

The computer sorted through 10,000 different permutations in order to determine a schedule that would enhance memory. 

To confirm their findings, researchers analyzed nerve cells in the brain of snails and found greater activity in the ones receiving the enhanced training schedule, said Byrne, the June and Virgil Waggoner Chair of Neurobiology and Anatomy at UTHealth. 

"This study shows the feasibility of using computational methods to assist in the design of training schedules that enhance memory," Byrne said.  

Source: University of Texas Health Science Center at Houston [December 25, 2011]

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Learning Matrix Style: Vision Scientists Demonstrate Innovative Learning Method

New research published December 8 in the journal Science suggests it may be possible to use brain technology to learn to play a piano, reduce mental stress or hit a curve ball with little or no conscious effort. It's the kind of thing seen in Hollywood's "Matrix" franchise. 

In the future, a person may be able to watch a computer screen and have his or her brain patterns modified to improve physical or mental performance. Researchers say an innovative learning method that uses decoded functional magnetic resonance imaging could modify brain activities to help people recuperate from an accident or disease, learn a new language or even fly a plane [Credit: Nicolle Rager Fuller, National Science Foundation]

Experiments conducted at Boston University (BU) and ATR Computational Neuroscience Laboratories in Kyoto, Japan, recently demonstrated that through a person's visual cortex, researchers could use decoded functional magnetic resonance imaging (fMRI) to induce brain activity patterns to match a previously known target state and thereby improve performance on visual tasks. 

Think of a person watching a computer screen and having his or her brain patterns modified to match those of a high-performing athlete or modified to recuperate from an accident or disease. Though preliminary, researchers say such possibilities may exist in the future. 

"Adult early visual areas are sufficiently plastic to cause visual perceptual learning," said lead author and BU neuroscientist Takeo Watanabe of the part of the brain analyzed in the study. 

Neuroscientists have found that pictures gradually build up inside a person's brain, appearing first as lines, edges, shapes, colors and motion in early visual areas. The brain then fills in greater detail to make a red ball appear as a red ball, for example. 

Researchers studied the early visual areas for their ability to cause improvements in visual performance and learning. 

"Some previous research confirmed a correlation between improving visual performance and changes in early visual areas, while other researchers found correlations in higher visual and decision areas," said Watanabe, director of BU's Visual Science Laboratory. "However, none of these studies directly addressed the question of whether early visual areas are sufficiently plastic to cause visual perceptual learning." Until now. 

Boston University post-doctoral fellow Kazuhisa Shibata designed and implemented a method using decoded fMRI neurofeedback to induce a particular activation pattern in targeted early visual areas that corresponded to a pattern evoked by a specific visual feature in a brain region of interest. The researchers then tested whether repetitions of the activation pattern caused visual performance improvement on that visual feature. 

The result, say researchers, is a novel learning approach sufficient to cause long-lasting improvement in tasks that require visual performance. 

What's more, the approached worked even when test subjects were not aware of what they were learning. 

"The most surprising thing in this study is that mere inductions of neural activation patterns corresponding to a specific visual feature led to visual performance improvement on the visual feature, without presenting the feature or subjects' awareness of what was to be learned," said Watanabe, who developed the idea for the research project along with Mitsuo Kawato, director of ATR lab and Yuka Sasaki, an assistant in neuroscience at Massachusetts General Hospital. 

"We found that subjects were not aware of what was to be learned while behavioral data obtained before and after the neurofeedback training showed that subjects' visual performance improved specifically for the target orientation, which was used in the neurofeedback training," he said. 

The finding brings up an inevitable question. Is hypnosis or a type of automated learning a potential outcome of the research? 

"In theory, hypnosis or a type of automated learning is a potential outcome," said Kawato. "However, in this study we confirmed the validity of our method only in visual perceptual learning. So we have to test if the method works in other types of learning in the future. At the same time, we have to be careful so that this method is not used in an unethical way." 

At present, the decoded neurofeedback method might be used for various types of learning, including memory, motor and rehabilitation. 

The National Science Foundation, the National Institutes of Health and the Ministry of Education, Culture, Sports, Science and Technology in Japan supported the research. 

Source: National Science Foundation [December 08, 2011]

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Roles of conscious and sub-conscious awareness distinguished by new research

What distinguishes information processing with conscious awareness from processing occurring without awareness? And, is there any role for conscious awareness in information processing, or is it just a byproduct, like the steam from the chimney of a train engine, which is significant, but has no functional role? 

These questions - which have long puzzled psychologists, philosophers, and neurobiologists - were recently addressed in a study by Hebrew University of Jerusalem researchers and published by the journal Psychological Science. 

The study was headed by Prof. Leon Deouell from the Hebrew University’s Edmond and Lily Safra Center for Brain Sciences (ELSC) and Department of Psychology and Prof. Dominique Lamy from the Department of Psychology at Tel Aviv University, and conducted by research student Liad Mudirk of Tel Aviv University with collaboration of research student Assaf Breska from the Hebrew University. 

We are not consciously aware of most of the input that hits upon our sensory systems.  Yet subjectively, conscious awareness dominates our mental activity. “One of the dominant theories in cognitive sciences and psychology posits that parts of the information perceived without awareness may be processed to a certain extent,” says Prof. Deouell. “Yet to bind the different parts of a complex input into something meaningful and coherent requires conscious awareness. 

To test this theory, the research team ran a study in which they presented participants with pictures of natural scenes including some human action, like a picture of basketball players jumping to reach a ball. 

In other tests, the same scenes were presented -- except that the central object was replaced by another, unlikely object. For example, the basketball was replaced by a watermelon. 

The participants viewed the pictures through a mirror stereoscope, a simple device that allowed the research team to present the pictures to only one eye. At the same time, the other eye viewed rapidly flickering patterns of colors which drew the subjects' attention, so that the participants were not aware for many seconds that anything was presented to their other eye. This allowed the researchers to measure how long it takes normal and unusual scenes to “win the competition” against the flickering pattern and break into awareness. 

"We found that participants became aware of the unusual scenes earlier than to the usual scenes," commented Deouell. "The conclusion was that even before the participants were aware of the existence of the picture, the semantic relationships between parts of the scene were interpreted." 

The study shows that, counter to previous theories, integration is not the prerogative of conscious awareness but is achieved even without awareness. When and why then do we need conscious awareness? 

The findings of this research suggest that when the results of the integration between parts of the input are incompatible with expectations or prior knowledge, awareness is required in order to account for the conundrum. Thus, the study expands the realm of unaware processes, yet shows that conscious awareness is not a meaningful luxury - it allows us to deal with novel and unexpected situations. 

Source: Hebrew University of Jerusalem via AlphaGalileo [November 30, 2011]

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Nerve protein linked to learning and memory

Can the nerve signaling inhibitor tomosyn help retain long-term memory? A new study by two University of Illinois at Chicago biologists points to the link. 

Nerve fibres in the brain

Findings by Janet Richmond and David Featherstone, both professors of biological sciences at UIC, are reported in the Oct. 31 online early edition of the Proceedings of the National Academy of Sciences. 

"This is the first really comprehensive effort to look at the role of tomosyn in fly learning," said Richmond, who until now studied the protein in an even simpler organism, the lowly nematode, or roundworm. 

Several studies have shown that learning behavior in fruit flies requires many of the same proteins used in higher animals, including mammals. 

The UIC biologists found that tomosyn plays an important role in regulating the amount of neurotransmitter in the synapse, the junction where messages are relayed between nerve cells. Tomosyn can limit this signaling; eliminating tomosyn strengthens the signaling. 

"When synapses get stronger, we learn. When they get weaker, we forget," said Featherstone. "We discovered that tomosyn is a mechanism that can control whether synapses get stronger or weaker, and this seems to be important for memory formation." 

Tomosyn interacts with a group of proteins known by the acronym SNARE, and that interaction is in turn regulated by an enzyme called PKA, which has been shown to be important for learning. 

Knowing this, Richmond and Featherstone ran experiments on fruit flies to see whether tomosyn might play a role in learning and memory. 

Their experiments involved the fly's ability to learn to associate a particular odor with an electrical shock. Flies remember the association and will avoid the odor for hours afterwards. But by knocking out tomosyn, "the flies were unable to retain that memory," said Richmond. 

The UIC biologists demonstrated how tomosyn can affect both synaptic signaling and learning and memory. 

Richmond and Featherstone hope their findings will provide valuable clues that pharmacologists might use in creating new drug therapies for various forms of human memory loss. Richmond said tomosyn is a good protein to experiment with. 

"Tomosyn regulates the way synapses work, but it's not essential for life," she said. "We hope that by understanding how it functions in memory formation, our research will provide useful insights that may help us better address the issue of severe memory loss." 

Source: University of Illinois at Chicago [October 31, 2011]

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