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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In recognizing faces, the whole is not greater than the sum of its parts

How do we recognize a face? To date, most research has answered "holistically": We look at all the features -- eyes, nose, mouth -- simultaneously and, perceiving the relationships among them, gain an advantage over taking in each feature individually. Now a new study overturns this theory. The researchers -- Jason M. Gold and Patrick J. Mundy of the Indiana University and Bosco S. Tjan of the University of Southern California -- found that people's performance in recognizing a whole face is no better than their performance with each individual feature shown alone. "Surprisingly, the whole was not greater than the sum of its parts," says Gold. 

How do we recognize a face? [Credit: © olly / Fotolia]

The findings appear in the journal Psychological Science, which is published by the Association for Psychological Science. 

To predict each participant's best possible performance in putting together the individual features, the investigators used a theoretical model called an "optimal Bayesian integrator" (OBI). The OBI measures someone's success in perceiving a series of sources of information -- in this case, facial features -- and combines them as if they were using the sources together just as they would when perceiving them one by one. Their score recognizing the combination of features (the whole face) should equal the sum of the individual-feature scores. If the whole-face performance exceeds this sum, it implies that the relationships among the features enhanced the information processing -- that is, "holistic" facial recognition exists. 

In the first experiment participants were shown fuzzy images of three male and three female faces. Then either one feature -- a left or right eye, nose, or mouth -- or all four in proper face-like relationships appeared on the screen. That image would disappear and, if they saw an eye, all six eyes would appear; if a whole face, six whole faces. The participants clicked on the feature or face they'd just seen. In a second experiment, the whole-face images were superimposed on face-shaped ovals -- in case such context helps holistic recognition, as is often claimed. In both experiments, participants' performance with the whole faces was no better than with the isolated features -- and no better than the OBI -- indicating that the facial features were not processed holistically when shown in combination. 

"The OBI offers a clearly defined mathematical framework for studying what historically has been a rather loosely defined set of concepts," says Gold. 

The findings may offer promise in understanding the cognitive disorder prosopagnosia, the inability to recognize faces, and could also help in constructing better face-recognition software for security. But the real value, says Gold, is in basic research. "If you want to understand the complexities of the human mind, then understanding the basic processes that underlie how we perceive patterns and objects is an important part of that puzzle." 

Source: Association for Psychological Science [March 09, 2012]

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Making memories last

Memories in our brains are maintained by connections between neurons called "synapses". But how do these synapses stay strong and keep memories alive for decades? Neuroscientists at the Stowers Institute for Medical Research have discovered a major clue from a study in fruit flies: Hardy, self-copying clusters or oligomers of a synapse protein are an essential ingredient for the formation of long-term memory. 

Drosophila Orb2 plays an important role in the persistence of memory. Upon stimulation, Orb2 (shown in yellow) forms amyloid-like oligomers (shown in red), which are an essential ingredient for the formation of long-term memory [Credit: Illustration: Nicolle Rager Fuller, Sayo-Art]

The finding supports a surprising new theory about memory, and may have a profound impact on explaining other oligomer-linked functions and diseases in the brain, including Alzheimer's disease and prion diseases. 

"Self-sustaining populations of oligomers located at synapses may be the key to the long-term synaptic changes that underlie memory; in fact, our finding hints that oligomers play a wider role in the brain than has been thought," says Kausik Si, Ph.D., an associate investigator at the Stowers Institute, and senior author of the new study, which is published in the January 27, 2012 online issue of the journal Cell. 

Si's investigations in this area began nearly a decade ago during his doctoral research in the Columbia University laboratory of Nobel-winning neuroscientist Eric Kandel. He found that in the sea slug Aplysia californica, which has long been favored by neuroscientists for memory experiments because of its large, easily-studied neurons, a synapse-maintenance protein known as CPEB (Cytoplasmic Polyadenylation Element Binding protein) has an unexpected property. 

A portion of the structure is self-complementary and—much like empty egg cartons—can easily stack up with other copies of itself. CPEB thus exists in neurons partly in the form of oligomers, which increase in number when neuronal synapses strengthen. These oligomers have a hardy resistance to ordinary solvents, and within neurons may be much more stable than single-copy "monomers" of CPEB. They also seem to actively sustain their population by serving as templates for the formation of new oligomers from free monomers in the vicinity. 

CPEB-like proteins exist in all animals, and in brain cells they play a key role in maintaining the production of other synapse-strengthening proteins. Studies by Si and others in the past few years have hinted that CPEB's tendency to oligomerize is not merely incidental, but is indeed essential to its ability to stabilize longer-term memory. "What we've lacked till now are experiments showing this conclusively," Si says. 

In the new study, Si and his colleagues examined a Drosophila fruit fly CPEB protein known as Orb2. Like its counterpart in Aplysia, it forms oligomers within neurons. "We found that these Orb2 oligomers become more numerous in neurons whose synapses are stimulated, and that this increase in oligomers happens near synapses," says lead author Amitabha Majumdar, Ph.D., a postdoctoral researcher in Si's lab. 

The key was to show that the disruption of Orb2 oligomerization on its own impairs Orb2's function in stabilizing memory. Majumdar was able to do this by generating an Orb2 mutant that lacks the normal ability to oligomerize yet maintains a near-normal concentration in neurons. Fruit flies carrying this mutant form of Orb2 lost their ability to form long-term memories. "For the first 24 hours after a memory-forming stimulus, the memory was there, but by 48 hours it was gone, whereas in flies with normal Orb2 the memory persisted," Majumdar says. 

Si and his team are now following up with experiments to determine for how long Orb2 oligomers are needed to keep a memory alive. "We suspect that they need to be continuously present, because they are self-sustaining in a way that Orb2 monomers are not," says Si. 

The team's research also suggests some intriguing possibilities for other areas of neuroscience. This study revealed that Orb2 proteins in the Drosophila nervous system come in a rare, highly oligomerization-prone form (Orb2A) and a much more common, much less oligomerization-prone form (Orb2B). "The rare form seems to be the one that is regulated, and it seems to act like a seed for the initial oligomerization, which pulls in copies of the more abundant form," Si says. "This may turn out to be a basic pattern for functional oligomers." 

The findings may help scientists understand disease-causing oligomers too. Alzheimer's, Parkinson's and Huntington's disease, as well as prion diseases such as Creutzfeldt-Jakob disease, all involve the spread in the brain of apparently toxic oligomers of various proteins. One such protein, strongly implicated in Alzheimer's disease, is amyloid beta; like Orb2 it comes in two forms, the highly oligomerizing amyloid-beta-42 and the relatively inert amyloid-beta-40. Si's work hints at the possibility that oligomer-linked diseases are relatively common in the brain because the brain evolved to be relatively hospitable to CPEB proteins and other functional oligomers, and thus has fewer mechanisms for keeping rogue oligomers under control. 

Source: Stowers Institute for Medical Research [January 27, 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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Alzheimer's vaccine cures memory... of mice

A vaccine that slows the progression of Alzheimer's disease and other types of dementia has been developed by researchers at the University of Sydney's Brain and Mind Research Institute (BMRI). 

The vaccine, which targets a protein known as tau, prevents the ongoing formation of neurofibrillary tangles in the brain of a mouse with Alzheimer's disease. 

This progressive neurodegenerative disease affects more than 35 million people worldwide. The tau protein is also involved in front temporal dementia, the second most common form of dementia in people younger than 65 years. 

The results of the study which led to the production of the vaccine have been published today in the scientific journal PLoS ONE. 

Lead author on the study, Associate Professor Lars Ittner, from the Alzheimer's and Parkinson's Disease Laboratory says: 

"Our study is the first to show that a vaccine targeting the tau protein can be effective once the disease has already set in. 

"The vaccine appears to have a preventative effect: slowing the development of further tangles, rather than clearing existing ones, but the exact mechanism involved is not yet understood," he said. 

According to Associate Professor Ittner, scientists have been working on vaccines targeting the amyloid plaques seen in Alzheimer's for many years with a few currently in clinical trials. 

"Most of the other vaccines targeting tau were tested only before or around the onset of the disease in animal models, but the vast majority of people with Alzheimer's disease are only diagnosed after the symptoms have appeared. 

"We are already collaborating with the US pharmaceutical industry to develop this new vaccine for humans. 

"Although we have a long way to go before the vaccine might be available for human use, these early results are very promising and a great reward for the countless hours spent in the lab by me and my team!" 

Source: The University of Sydney [December 09, 2011]

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Scientists provide potential explanation for mechanisms of associative memory

Researchers from the University of Bristol have discovered that a chemical compound in the brain can weaken the synaptic connections between neurons in a region of the brain important for the formation of long-term memories. The findings, published in the Journal of Neuroscience, may also provide a potential explanation for the loss of memory associated with Alzheimer's. 

Acetylcholine, a neurotransmitter, is released in the brain and is known to play an important role in normal brain functions such as sleep, attention, and learning and memory. Until now the mechanisms by which this transmitter controls such processes were not well understood. 

The findings, led by researchers from the University's MRC Centre for Synaptic Plasticity in the School of Physiology and Pharmacology, highlight the mechanisms by which acetylcholine controls communication between neurons located in the prefrontal cortex and may help in understanding how higher cognitive processing is controlled in this important brain area. 

Professor of Cellular Neuroscience, Zafar Bashir and his team have demonstrated how electrical stimulation of the prefrontal cortex leads to the release of acetylcholine from synaptic terminals and the subsequent weakening of synaptic connections between neurons. 

When acetylcholine is released it binds to specific receptors and starts a molecular cascade which triggers physiological alterations in how prefrontal cortical neurons are 'wired' together. The findings suggest that the persistent weakening of synaptic connections between neurons induced by the endogenous release of acetylcholine in the prefrontal cortex may underlie the formation of new associative memories. 

The authors speculate that the memory impairments associated with Alzheimer's dementia may result, in part, from a loss of synaptic plasticity in the prefrontal cortex related to the depletion of brain acetylcholine that occurs in the disease. 

Dr Douglas Caruana, who carried out the experiments, said: "Disruptions in cholinergic signaling in the prefrontal cortex are known to affect how the brain encodes lasting associations between objects and places, and a depletion of brain acetylcholine levels in the cortex is a classic hallmark of Alzheimer's dementia'." 

Professor Bashir added: "Acetylcholinesterase inhibitors are the most widely used medication to treat individuals with Alzheimer's dementia and the enhancement of synaptic plasticity by acetylcholinesterase inhibition that we now demonstrate may be a way in which these drugs provide clinical efficacy." 

Source: University of Bristol [December 13, 2011]

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Tapping the brain orchestra

Researchers at the Norwegian University of Life Sciences (UMB) and Forschungszentrum Jülich in Germany have developed a new method for detailed analyses of electrical activity in the brain. The method, recently published in Neuron, can help doctors and researchers to better interpret brain cell signals. In turn, this may lead to considerable steps forward in terms of interpreting for example EEG measurements, making diagnoses and treatment of various brain illnesses. 

A forest of neurons [Credit: Hermann Cuntz]

Researchers and doctors have been measuring and interpreting electrical activity generated by brain cells since 1875. Doctors have over the years acquired considerable practical skills in relating signal shapes to different brain illnesses such as epilepsy. However, doctors have so far had little knowledge on how these signals are formed in the network of nerve cells. 

"Based on methods from physics, mathematics and informatics, as well as computational power from the Stallo supercomputer in Tromsø, we have developed detailed mathematical models revealing the connection between nerve cell activity and the electrical signal recorded by an electrode," says Professor Gaute Einevoll at the Department of Mathematical Sciences and Technology (IMT) at UMB. 

Microphone in a crowd 

The problem of interpreting electrical signals measured by electrodes in the brain is similar to that of interpreting sound signals measures by a microphone in a crowd of people. Just like people sometimes all talk at once, nerve cells are also sending signals "on top of each other". 

The electrode records the sounds from the whole orchestra of nerve cells surrounding it and there are numerous contributors. One cubic millimetre can contain as many as 100,000 nerve cells. 

Treble and bass 

Similar to bass and treble in a soundtrack, high and low frequency electrical signals are distinguished in the brain. 

"This project has focused on the bass - the low frequency signals called "local field potential" or simply LFP. We have found that if nerve cells are babbling randomly on top of each other and out of sync, the electrode's reach is narrow so that it can only receive signals from nerve cells less than about 0.3 millimetres away. However, when nerve cells are speaking simultaneously and in sync, the range can be much wider," Einevoll says. 

Large treatment potential 

Better understanding of the electrical brain signals may directly influence diagnosing and treatment of illnesses such as epilepsy. 

"Electrodes are already being used to measure brain cell activity related to seizures in epilepsy patients, as well as planning surgical procedures. In the future, LFP signals measured by implanted electrodes could detect an impending epilepsy seizure and stop it by injecting a suitable electrical current," Einevoll says. 

"A similar technique is being used on many Parkinson's patients, who have had electrodes surgically implanted to prevent trembling," Researcher Klas Pettersen at UMB adds. 

Einevoll and Pettersen also outline treatment of patients paralysed by spinal cord fracture as another potential area where the method can be used. 

"When a patient is paralysed, nerve cells in the cerebral cortex continue to send out signals, but the signals do not reach the muscles, and the patient is thus unable to move arms or legs. By monitoring the right nerve cells and forwarding these signals to for example a robot arm, the patient may be able to steer by his or her thoughts alone," Einevoll says. 

The Computational Neuroscience Group at UMB has already established contacts with clinical research groups in the USA and Europe for further research on using the approach in patient treatment.  

Author: Torunn Moe | Source: Norwegian University of Life Sciences [December 08, 2011]

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Neuroscientists Boost Memory in Mice Using Genetics and a New Memory-Enhancing Drug

When the activity of a molecule that is normally elevated during viral infections is inhibited in the brain, mice learn and remember better, researchers at Baylor College of Medicine reported in a recent article in the journal Cell. 

Laboratory mouse [Credit: impactlab]

"The molecule PKR (the double-stranded RNA-activated protein kinase) was originally described as a sensor of viral infections, but its function in the brain was totally unknown," said Dr. Mauro Costa-Mattioli, assistant professor of neuroscience at BCM and senior author of the paper. Since the activity of PKR is altered in a variety of cognitive disorders, Costa-Mattioli and colleagues decided to take a closer look at its role in the mammalian brain. 

Super memory 

The authors discovered that mice lacking PKR in the brain have a kind of "super" memory. "We found that when we genetically inhibit PKR, we increased the excitability of brain cells and enhanced learning and memory, in a variety of behavioral tests," he said. For instance, when the authors assessed spatial memory (the memory for people, places and events) through a test in which mice use visual cues for finding a hidden platform in a circular pool, they found that normal mice had to repeat the task multiple times over many days in order to remember the platform's location. By contrast, mice lacking PKR learned the task after only one training session. 

Costa-Mattioli and colleagues wanted to know how this molecular process actually works. They found that when PKR is inhibited, the increased synaptic activity (that is, the enhanced communication between neurons) is caused by gamma interferon, another molecule involved in immunity. 

"These data are totally unexpected, and show that two molecules classically known to play a role in viral infection and the immune response regulate the kind of brain activity that leads to the formation of long-term memory in the adult brain," said Costa-Mattioli. 

Drug targets PKR 

Another key finding made by Costa-Mattioli and his team of researchers was the fact that this process could be mimicked by a PKR inhibitor -- a small molecule that blocks PKR activity and thus acts as a "memory-enhancing drug." 

"It is indeed quite amazing that we can also enhance both memory and brain activity with a drug that specifically targets PKR." Definitely then, the next step is to use what we have learned in mice and to try to improve brain function in people suffering from memory loss, said Costa-Mattioli. 

Although Costa-Mattioli's memory pill may be years away from approval by the U.S. Food and Drug Administration, its impact on society and medicine could be very profound. There are roughly 6 million Americans and 35 million people world-wide with Alzheimer's disease and more than 70 million Americans over the age of 60 who may suffer from aged-associated impairment of memory. 

Costa-Mattioli said, "More investigation is undoubtedly necessary to translate these findings to effective therapies but we would be delighted if our scientific studies were to contribute in some way to this ultimate goal." 

"Our identity and uniqueness is made up of our memories," Costa-Mattioli said. "This molecule could hold the key to how we can keep our memories longer, but also how we create new ones." 

Others who contributed to the research include: first author Ping Jun Zhu, Wei Huang, Jong W. Yoo, Loredana Stoica, Hongyi Zhou, Jeffrey Noebels, all at BCM; Andon N. Placzek, currently with Mercer University School of Medicine; Michael J. Friedlander and Djanenkhodja Kalikulov currently with Virginia Tech; Kresimir Krnjevic, McGill University; and John C. Bell, Ottawa Health Research Institute. 

The research was supported through funding from the Searle Scholars Program (award to Costa-Mattioli), the Cynthia and George Mitchell Founds (award to Costa-Mattioli), the National Institute of Neurological Diseases and Stroke, the National Institute for Child Health and Development, the BCM Intellectual and Developmental Disabilities Research Center and the National Eye Institute. 

Source: Baylor College of Medicine [December 08, 2011]

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Drug reverses aging-associated changes in brain cells

Drugs that affect the levels of an important brain protein involved in learning and memory reverse cellular changes in the brain seen during aging, according to an animal study in the December 7 issue of The Journal of Neuroscience. The findings could one day aid in the development of new drugs that enhance cognitive function in older adults. 

Aging-related memory loss is associated with the gradual deterioration of the structure and function of synapses (the connections between brain cells) in brain regions critical to learning and memory, such as the hippocampus. Recent studies suggested that histone acetylation, a chemical process that controls whether genes are turned on, affects this process. Specifically, it affects brain cells' ability to alter the strength and structure of their connections for information storage, a process known as synaptic plasticity, which is a cellular signature of memory. 

In the current study, Cui-Wei Xie, PhD, of the University of California, Los Angeles, and colleagues found that compared with younger rats, hippocampi from older rats have less brain-derived neurotrophic factor (BDNF) -- a protein that promotes synaptic plasticity -- and less histone acetylation of the Bdnf gene. By treating the hippocampal tissue from older animals with a drug that increased histone acetylation, they were able to restore BDNF production and synaptic plasticity to levels found in younger animals. 

"These findings shed light on why synapses become less efficient and more vulnerable to impairment during aging," said Xie, who led the study. "Such knowledge could help develop new drugs for cognitive aging and aging-related neurodegenerative diseases, such as Alzheimer's disease," she added. 

The researchers also found that treating the hippocampal tissue from older animals with a different drug that activates a BDNF receptor also reversed the synaptic plasticity deficit in the older rats. Because histone acetylation is important in many functions throughout the body, these findings offer a potential pathway to treat aging-related synaptic plasticity deficits without interfering with histone acetylation. 

"It appears that lifelong shifts in gene regulation steadily deprive the brain of a key growth factor and cause a collapse of the 'machinery' supporting memory, cognition, and the viability of neurons," said Gary Lynch, PhD, a synaptic plasticity expert at the University of California, Irvine. "The very good news suggested by this study is that it may be possible to reverse these effects." 

Source: Society for Neuroscience [December 07, 2011]

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Why aren't we smarter already? Evolutionary limits on cognition

We put a lot of energy into improving our memory, intelligence, and attention. There are even drugs that make us sharper, such as Ritalin and caffeine. But maybe smarter isn’t really all that better. A new paper published in Current Directions in Psychological Science, a journal of the Association for Psychological Science, warns that there are limits on how smart humans can get, and any increases in thinking ability are likely to come with problems. 

The authors looked to evolution to understand about why humans are only as smart as we are and not any smarter. “A lot of people are interested in drugs that can enhance cognition in various ways,” says Thomas Hills of the University of Warwick, who cowrote the article with Ralph Hertwig of the University of Basel. “But it seems natural to ask, why aren’t we smarter already?” 

Tradeoffs are common in evolution. It might be nice to be eight feet tall, but most hearts couldn’t handle getting blood up that high. So most humans top out under six feet. Just as there are evolutionary tradeoffs for physical traits, Hills says, there are tradeoffs for intelligence. A baby’s brain size is thought to be limited by, among other things, the size of the mother’s pelvis; bigger brains could mean more deaths in childbirth, and the pelvis can’t change substantially without changing the way we stand and walk. 

Drugs like Ritalin and amphetamines help people pay better attention. But they often only help people with lower baseline abilities; people who don’t have trouble paying attention in the first place can actually perform worse when they take attention-enhancing drugs. That suggests there is some kind of upper limit to how much people can or should pay attention. “This makes sense if you think about a focused task like driving,” Hills says, “where you have to pay attention, but to the right things—which may be changing all the time. If your attention is focused on a shiny billboard or changing the channel on the radio, you’re going to have problems.” 

It may seem like a good thing to have a better memory, but people with excessively vivid memories have a difficult life. “Memory is a double-edged sword,” Hills says. In post-traumatic stress disorder, for example, a person can’t stop remembering some awful episode. “If something bad happens, you want to be able to forget it, to move on.” 

Even increasing general intelligence can cause problems. Hills and Hertwig cite a study of Ashkenazi Jews, who have an average IQ much higher than the general European population. This is apparently because of evolutionary selection for intelligence in the last 2,000 years. But, at the same time, Ashkenazi Jews have been plagued by inherited diseases like Tay-Sachs disease that affect the nervous system. It may be that the increase in brain power has caused an increase in disease. 

Given all of these tradeoffs that emerge when you make people better at thinking, Hills says, it’s unlikely that there will ever be a supermind. “If you have a specific task that requires more memory or more speed or more accuracy or whatever, then you could potentially take an enhancer that increases your capacity for that task,” he says. “But it would be wrong to think that this is going to improve your abilities all across the board.” 

Source: Association for Psychological Science [December 06, 2011]

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Where is the accurate memory? The eyes have it

The witness points out the criminal in a police lineup. She swears she’d remember that face forever. Then DNA evidence shows she’s got the wrong guy. It happens so frequently that many courts are looking with extreme skepticism at eyewitness testimony. 

Is there a way to get a more accurate reading of memory? A new study says yes. “Eye movements are drawn quickly to remembered objects,” says Deborah Hannula, assistant professor at the University of Wisconsin Milwaukee, who conducted the study with Carol L. Baym and Neal J. Cohen of the University of Illinois, Urbana-Champaign and David E. Warren of the University of Iowa College of Medicine. Tracking where and for how long a person focuses his or her eyes “can distinguish previously seen from novel materials even when behavioral reports fail to do so.” The findings will appear in an upcoming issue of Psychological Science, a journal published by the Association for Psychological Science. 

The researchers gave university students 36 faces to study. These target faces were also morphed to produce images closely resembling them; the morphed phases were not seen during the study phase. The students were then shown 36 three-face displays, one at a time. Told that the studied faces wouldn’t always be there, the participants had to press a button indicating which face was the studied one, or simply choose a face if they felt none had been studied. They then reported verbally whether the studied target face was present or not. While they looked at the 3-face display, their eye movements were recorded, tracking where the eyes focused first and what proportion of time was spent looking there. For the analysis, the psychologists divided the faces into three groups: studied targets; morphs mistaken for the “target” face; and morphs chosen and known to be incorrect. 

Participants easily identified the target faces most of the time. They also spent more time looking at these faces, and did so soon after the 3-face display had been presented. “The really interesting finding is that before they chose a face and pressed a button, there was disproportionate viewing of the target faces as compared to either type of selected face,” said Hannula. However, “after the response was made, viewing tended to mimic the behavioral endorsement of a face as studied or not, whether that endorsement was correct or incorrect.” In other words, “pre-response viewing seems to reflect actual experience, and post-response viewing seems to reflect the decision making process and whether or not the face will be endorsed as studied.” 

Hannula theorizes as to what is happening: “Early disproportionate viewing of the target face may precede and help give rise to awareness that a particular face has been studied. Subsequently, we begin to think about the choice that we’re making”—we look closely, compare and weigh the options—“these cognitive processes permit us to make a decision, but may also lead us down the wrong path. In this case, leading us to endorse a face as studied despite having never seen it before.” 

Aside from the potential for practical application, says Hannula, eye movement methods could be used to examine memory in individuals—like some psychiatric patients and children – who may have trouble communicating what it is that they remember. “Eye movements might provide us with more information about what exactly these individuals remember than behavioral reports alone.” 

Source: Association for Psychological Science [December 02, 2011]

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Study Looks at the Nature of Change in Our Aging, Changing Brains

As we get older, our cognitive abilities change, improving when we're younger and declining as we age. Scientists posit a hierarchical structure within which these abilities are organized. There's the "lowest" level -- measured by specific tests, such as story memory or word memory; the second level, which groups various skills involved in a category of cognitive ability, such as memory, perceptual speed, or reasoning; and finally, the "general," or G, factor, a sort of statistical aggregate of all the thinking abilities. 

What happens to this structure as we age? That was the question Timothy A. Salthouse, Brown-Forman professor of psychology at the University of Virginia, investigated in a new study appearing in an upcoming issue of Psychological Science, a journal published by the Association for Psychological Science. His findings advance psychologists' understanding of the complexities of the aging brain. 

"There are three hypotheses about how this works," says Salthouse. "One is that abilities become more strongly integrated with one another as we age." That theory suggests the general factor influences cognitive aging the most. The second -- based on the idea that connectivity among different brain regions lessens with age -- "is almost the opposite: that the changes in cognitive abilities become more rather than less independent with age." The third was Salthouse's hypothesis: The structure remains constant throughout the aging process. 

Using a sample of 1,490 healthy adults ages 18 to 89, Salthouse performed analyses of the scores on 16 tests of five cognitive abilities -- vocabulary, reasoning, spatial relations, memory, and perceptual speed. The primary analyses were on the changes in the test scores across an interval of about two and a half years. 

The findings confirmed Salthouse's hunch: "The effects of aging on memory, on reasoning, on spatial relations, and so on are not necessarily constant. But the structure within which these changes are occurring does not seem to change as a function of age." In normal, healthy people, "the direction and magnitude of change may be different" when we're 18 or 88, he says. "But it appears that the qualitative nature of cognitive change remains the same throughout adulthood." 

The study could inform other research investigating "what allows some people to age more gracefully than others," says Salthouse. That is, do people who stay mentally sharper maintain their ability structures better than those who become more forgetful or less agile at reasoning? And in the future, applying what we know about the structures of change could enhance "interventions that we think will improve cognitive functioning" at any age or stage of life. 

Source: Association for Psychological Science [November 22, 2011]

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Walking through doorways causes forgetting, new research shows

We've all experienced it: The frustration of entering a room and forgetting what we were going to do. Or get. Or find. 

New research from University of Notre Dame Psychology Professor Gabriel Radvansky suggests that passing through doorways is the cause of these memory lapses. "Entering or exiting through a doorway serves as an 'event boundary' in the mind, which separates episodes of activity and files them away," Radvansky explains. 

"Recalling the decision or activity that was made in a different room is difficult because it has been compartmentalized." 

The study was published recently in the Quarterly Journal of Experimental Psychology. 

Conducting three experiments in both real and virtual environments, Radvansky's subjects – all college students – performed memory tasks while crossing a room and while exiting a doorway. 

In the first experiment, subjects used a virtual environment and moved from one room to another, selecting an object on a table and exchanging it for an object at a different table. They did the same thing while simply moving across a room but not crossing through a doorway. 

Radvansky found that the subjects forgot more after walking through a doorway compared to moving the same distance across a room, suggesting that the doorway or "event boundary" impedes one's ability to retrieve thoughts or decisions made in a different room. 

The second experiment in a real-world setting required subjects to conceal in boxes the objects chosen from the table and move either across a room or travel the same distance and walk through a doorway. The results in the real-world environment replicated those in the virtual world: walking through a doorway diminished subjects' memories. 

The final experiment was designed to test whether doorways actually served as event boundaries or if one's ability to remember is linked to the environment in which a decision – in this case, the selection of an object – was created. Previous research has shown that environmental factors affect memory and that information learned in one environment is retrieved better when the retrieval occurs in the same context. Subjects in this leg of the study passed through several doorways, leading back to the room in which they started. The results showed no improvements in memory, suggesting that the act of passing through a doorway serves as a way the mind files away memories. 

Source: University of Notre Dame [November 18, 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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