To flexibly deal with our ever-changing world, we need to learn from both the negative and positive consequences of our behaviour. In other words, from punishment and reward. Hanneke den Ouden from the Donders Institute in Nijmegen demonstrated that serotonin and dopamine related genes influence how we base our choices on past punishments or rewards. This influence depends on which gene variant you inherited from your parents. These results were published in Neuron on 20 November.

The brain chemicals dopamine and serotonin partly determine our sensitivity to reward and punishment. At least, this was a common assumption. Hanneke den Ouden and Roshan Cools investigated this assumption together with colleagues from the Donders Institute and New York University. Den Ouden explains: ‘We used a simple computer game to test the genetic influence of the genes DAT1 and SERT, as these genes influence dopamine and serotonin. We discovered that the dopamine gene affects how we learn from the long-term consequences of our choices, while the serotonin gene affects our choices in the short term.’

Online game

‘In nearly 700 people we analysed which variant of the SERT and the DAT1 genes they had’, Den Ouden describes. ‘Using an online game, we investigated how well people are able to adjust their choice strategy after receiving a reward or a punishment.’ The players would repeatedly choose one of two symbols. Symbol A usually resulted in a reward whereas symbol B usually resulted in punishment. Halfway through the game, these rules were reversed. The game allowed the researchers to measure how flexible people are in adjusting their choices when the rules change. But it also showed whether people impulsively change their choice when the computer happened to give misleading feedback.

Different genes, different strategies

Den Ouden: ‘Different players use different strategies, which depend on their genetic material. People’s tendency to change their choice immediately after receiving a punishment depends on which serotonin gene variant they inherited from their parents. The dopamine gene variant, on the other hand, exerts influence on whether people can stop themselves making the choice that was previously rewarded, but no longer is.’

This study shows that dopamine and serotonin are important for different forms of flexibility associated with receiving reward and punishment. Many neuropsychiatric disorders caused by abnormal dopamine and/or serotonin levels are associated with forms of inflexibility, for example addiction, anxiety, or Parkinson’s disease. So this study not only tells us more about the heritability of our choice behaviour; a better understanding of the relationship between brain chemicals and behaviour in healthy people will ultimately help to provide us with better insight into these neuropsychiatric disorders.

(Source: ru.nl)

Alexander disease is a devastating brain disease that almost nobody has heard of — unless someone in the family is afflicted with it. Alexander disease strikes young or old, and in children destroys white matter in the front of the brain. Many patients, especially those with early onset, have significant intellectual disabilities.

(Image: A mutant gene that causes the deadly Alexander disease creates an overgrowth of the protein GFAP in mouse brain cells called astrocytes (right) compared to normal brain cells (left))

Regardless of the age when it begins, Alexander disease is always fatal. It typically results from mutations in a gene known as GFAP (glial fibrillary acidic protein), leading to the formation of fibrous clumps of protein inside brain cells called astrocytes.

Classically, astrocytes and other glial cells were considered “helpers” that nourish and protect the neurons that do the actual communication. But in recent years, it’s become clear that glial cells are much more than passive bystanders, and may be active culprits in many neurological diseases.

Now, in a report in the Journal of Neuroscience, researchers at UW-Madison show that Alexander disease also affects neurons, and in a way that impacts several measures of learning and memory.

Mice were engineered to contain the same mutation in GFAP that is found in human patients. Their astrocytes spontaneously increased production of GFAP, the same response found after many types of injury or disease in the brain. In Alexander disease, the result is an increase in mutant GFAP that is “toxic to the cell, and unfortunately astrocytes respond by making more GFAP,” says first author Tracy Hagemann, an associate scientist with the university’s Waisman Center.

While GFAP is usually found in astrocytes, it also occurs in neural stem cells, a population of cells that persist in some areas of the brain to continually spawn new neurons throughout adulthood. In the mouse versions of Alexander disease, neural stem cells are present, but they fail to develop into neurons, Hagemann says. “Think of a garden where your green beans never sprouted. Was it too cold for them to sprout, or was there another problem? Something similar is happening with these neural stem cells. They are present, but inert, and we’re not sure why.”

The shortage of new neurons could explain why the mice with excess GFAP failed a test that required them to remember the location of a submerged platform in a tub of water.

The report is “the first to suggest that the problems in Alexander disease extend beyond just the white matter and astrocytes, and may provide a clue to the problems with learning and memory that are such prominent features in the human disease,” says lab leader Albee Messing, a professor of comparative biosciences in the UW School of Veterinary Medicine.

One immediate question that the team will try to answer is whether the same defect in stem cells can be found in autopsy samples stored over many years to allow just this kind of investigation.

Still to be clarified is whether the mutation affects the neural stem cells directly, or whether it acts through other astrocytes that are nearby. “We do know that the astrocytes become activated with this GFAP mutation,” Hagemann says. “That activation — a kind of inflammation — could be making the environment hostile to young neurons. Or the mutation could be changing the neural stem cells themselves in some other way.

"Medicine advances by teasing things apart," says Hagemann. "A single mutation can work in different ways — through different chains of cause and effect leading to different symptoms of a disease. In this case it’s like the old question of nature versus nurture. Was the stem cell born bad — was it genetically doomed? Or were the reactive astrocytes in the neighborhood a toxic influence? Or both? This is an important question for Alexander disease and other brain deteriorating disorders, especially with the current focus on stem cells as a source for new neurons and therapy."

Already, the Waisman group is screening drugs that might slow GFAP production. Eventually, Hagemann says, the work may illuminate the role of astrocyte dysfunction in other neural diseases featuring aggregates of misformed proteins, including ALS, Parkinson’s, and Alzheimer’s disease.

(Source: news.wisc.edu)

Studies have shown that resveratrol, a natural compound found in colored vegetables, fruits and especially grapes, may minimize the impact of Parkinson’s disease, stroke and Alzheimer’s disease in those who maintain healthy diets or who regularly take resveratrol supplements. Now, researchers at the University of Missouri have found that resveratrol may also block the effects of the highly addictive drug, methamphetamine.

(Image: Wikipedia)

Dennis Miller, associate professor in the Department of Psychological Sciences in the College of Arts & Science and an investigator with the Bond Life Sciences Center, and researchers in the Center for Translational Neuroscience at MU, study therapies for drug addiction and neurodegenerative disorders. Their research targets treatments for methamphetamine abuse and has focused on the role of the neurotransmitter dopamine in drug addiction. Dopamine levels in the brain surge after methamphetamine use; this increase is associated with the motivation to continue using the drug, despite its adverse consequences. However, with repeated methamphetamine use, dopamine neurons may degenerate causing neurological and behavioral impairments, similar to those observed in people with Parkinson’s disease.

“Dopamine is critical to the development of methamphetamine addiction—the transition from using a drug because one likes or enjoys it to using the drug because one craves or compulsively uses it,” Miller said. “Resveratrol has been shown to regulate these dopamine neurons and to be protective in Parkinson’s disease, a disorder where dopamine neurons degenerate; therefore, we sought to determine if resveratrol could affect methamphetamine-induced changes in the brain.”

Using procedures established by Parkinson’s and Alzheimer’s disease research, rats received resveratrol once a day for seven days in about the same concentration as a human would receive from a healthy diet. After a week of resveratrol, researchers measured how much dopamine was released by methamphetamine. Researchers found that resveratrol significantly diminished methamphetamine’s ability to increase dopamine levels in the brain. Furthermore, resveratrol diminished methamphetamine’s ability to increase activity in mice, a behavior that models the hyperactivity observed in people that use the stimulant.

“People are encouraged by physicians and dieticians to include resveratrol-containing products in their diet and protection against methamphetamine’s harmful effects may be an added bonus,” Miller said. “Additionally, there are no consistently effective treatments to help people who are dependent on methamphetamine. Our initial research suggests that resveratrol could be included in a treatment regimen for those addicted to methamphetamine and it has potential to decrease the craving and desire for the drug. Resveratrol is found in good, colorful foods, and has few side effects. We all ought to consume resveratrol for good brain health; our research suggests it may also prevent the changes in the brain that occur with the development of drug addiction.”

(Source: munews.missouri.edu)

A vision is to implant nerve precursor cells in the diseased brains of patients with Parkinson’s and Huntington’s diseases, whereby these cells are to assume the function of the cells that have died off. However, the implanted nerve cells frequently do not migrate as hoped, rather they hardly move from the site. Scientists at the Institute for Reconstructive Neurobiology at Bonn University have now discovered an important cause of this: Attractants secreted by the precursor cells prevent the maturing nerve cells from migrating into the brain. The results are presented in the journal “Nature Neuroscience.”

One approach for treating patients with Parkinson’s or Huntington’s disease is to replace defective brain cells with fresh cells. To do this, immature precursor cells from neurons are implanted into the diseased brains; these cells are to then mature on-site and take over the function of the defective cells. “However, it has been shown again and again that the nerve cells generated by the transplant barely migrate into the brain but remain largely confined to the implant site,” says Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology at Bonn University. Scientists have believed for a long time that this effect is associated with the fact that in the mature brain, there are unfavorable conditions for the uptake of additional nerve cells.

Immature and more mature nerve cells attract each other like magnets

The researchers from the Institute for Reconstructive Neurobiology of Bonn University have now discovered a fully unexpected mechanism to which the deficient migratory behavior of the graft-derived neurons can be attributed. The implanted cells mature at different rates and thus there is a mixture of the two stages. “Like magnets, the precursor cells which are still largely immature attract the nerve cells which have already matured further, which is why there is a sort of agglomeration,” says lead author Dr. Julia Ladewig, who was recently awarded a research prize of 1.25 million Euro by the North Rhine-Westphalian Stem Cell Network, which is supported by State Ministry of Science and Research.

The cause of the attractive force which has remained hidden to date involves chemical attractants which are secreted by the precursor cells. “In this way, the nerve precursor cells prevent the mature brain cells from penetrating further into the tissue,” says Dr. Philipp Koch, who performed the primary work for the study as an additional lead author, together with Dr. Ladewig.

The scientists had initially observed that, the more precursor cells contained in the transplant, the worse the migration of nerve cells is. In a second step, the researchers from the Institute for Reconstructive Neurobiology at Bonn University were able to decode and inactivate the attractants responsible for the agglomeration of mature and immature neurons. When the scientists deactivated the receptor tyrosine kinase ligands FGF2 and VEGF with inhibitors, mature nerve cells migrated better into the animal brains and dispersed over much larger areas.

Promising universal approach for transplants

“This is a promising new approach to solve an old problem in neurotransplantation,” Prof. Brüstle summarizes. Through the inhibition of attractants, the migration of implanted nerve precursor cells into the brain can be significantly improved. As the researchers have shown in various models with precursor cells from animals and humans, the mechanism is a fundamental principle which also functions across species. “However, more research is still needed to transfer the principle into clinical application,” says Prof. Brüstle.

(Source: www3.uni-bonn.de)

A computer program called the Never Ending Image Learner (NEIL) is running 24 hours a day at Carnegie Mellon University, searching the Web for images, doing its best to understand them on its own and, as it builds a growing visual database, gathering common sense on a massive scale.

NEIL leverages recent advances in computer vision that enable computer programs to identify and label objects in images, to characterize scenes and to recognize attributes, such as colors, lighting and materials, all with a minimum of human supervision. In turn, the data it generates will further enhance the ability of computers to understand the visual world.

But NEIL also makes associations between these things to obtain common sense information that people just seem to know without ever saying — that cars often are found on roads, that buildings tend to be vertical and that ducks look sort of like geese. Based on text references, it might seem that the color associated with sheep is black, but people — and NEIL — nevertheless know that sheep typically are white.

"Images are the best way to learn visual properties," said Abhinav Gupta, assistant research professor in Carnegie Mellon’s Robotics Institute. "Images also include a lot of common sense information about the world. People learn this by themselves and, with NEIL, we hope that computers will do so as well."

A computer cluster has been running the NEIL program since late July and already has analyzed three million images, identifying 1,500 types of objects in half a million images and 1,200 types of scenes in hundreds of thousands of images. It has connected the dots to learn 2,500 associations from thousands of instances.

The public can now view NEIL’s findings at the project website, www.neil-kb.com.

The research team, including Xinlei Chen, a Ph.D. student in CMU’s Language Technologies Institute, and Abhinav Shrivastava, a Ph.D. student in robotics, will present its findings on Dec. 4 at the IEEE International Conference on Computer Vision in Sydney, Australia.

One motivation for the NEIL project is to create the world’s largest visual structured knowledge base, where objects, scenes, actions, attributes and contextual relationships are labeled and catalogued.

"What we have learned in the last 5-10 years of computer vision research is that the more data you have, the better computer vision becomes," Gupta said.

Some projects, such as ImageNet and Visipedia, have tried to compile this structured data with human assistance. But the scale of the Internet is so vast — Facebook alone holds more than 200 billion images — that the only hope to analyze it all is to teach computers to do it largely by themselves.

Shrivastava said NEIL can sometimes make erroneous assumptions that compound mistakes, so people need to be part of the process. A Google Image search, for instance, might convince NEIL that “pink” is just the name of a singer, rather than a color.

"People don’t always know how or what to teach computers," he observed. "But humans are good at telling computers when they are wrong."

People also tell NEIL what categories of objects, scenes, etc., to search and analyze. But sometimes, what NEIL finds can surprise even the researchers. It can be anticipated, for instance, that a search for “apple” might return images of fruit as well as laptop computers. But Gupta and his landlubbing team had no idea that a search for F-18 would identify not only images of a fighter jet, but also of F18-class catamarans.

As its search proceeds, NEIL develops subcategories of objects — tricycles can be for kids, for adults and can be motorized, or cars come in a variety of brands and models. And it begins to notice associations — that zebras tend to be found in savannahs, for instance, and that stock trading floors are typically crowded.

NEIL is computationally intensive, the research team noted. The program runs on two clusters of computers that include 200 processing cores.

This research is supported by the Office of Naval Research and Google Inc.

A genetic defect that profoundly affects speech in humans also disrupts the ability of songbirds to sing effective courtship tunes. This defect in a gene called FoxP2 renders the brain circuitry insensitive to feel-good chemicals that serve as a reward for speaking the correct syllable or hitting the right note, a recent study shows. 

The research, which was conducted in adult zebrafinches, gives insight into how this genetic mutation impairs a network of nerve cells to cause the stuttering and stammering typical of people with FoxP2 mutations. It appears Nov. 21 in an early online edition of the journal Neuron.

"Our results integrate a lot of different observations that have accrued on the FoxP2 mutation and cast a different perspective on what this mutation is doing," said Richard Mooney, Ph.D., the George Barth Geller professor of neurobiology at Duke University School of Medicine and a member of the Duke Institute for Brain Sciences. "FoxP2 mutations do not simply result in a cognitive or learning deficit, but also produce an ongoing motor deficit. Individuals with these mutations can still learn and can still improve; it is just harder for them to reliably hit the right mark." 

About 15 years ago, researchers discovered a British family with many members suffering from severe speech and language deficits. Geneticists eventually pinned down the culprit — a gene called forkhead box transcription factor or FoxP2 — that was mutated in all the affected individuals. The discovery led many to believe FoxP2 was a “language gene” that granted humans the ability to speak. But further studies showed that the gene wasn’t unique to humans, and in fact was conserved among all vertebrates, including songbirds. 

Though the gene is present in every cell, it is “active,” or turned on, mostly in brain cells, particularly ones residing in a region deep within the brain known as the basal ganglia. This region is dysfunctional in Tourette syndrome, known for its vocal tics and outbursts, and is also shrunk in individuals with FoxP2 mutations. 

To explore the complex circuitry involved in these deficits, Mooney and his former graduate student Malavika Murugan, Ph.D., decided to replicate the human mutation in this region of the brain in songbirds. Zebrafinches start learning how to sing 30 days after they hatch, listening to a male tutor and then practicing thousands of times a day until, 60 days later, they are able to make a very good copy of the tutor’s song. As good as that copy is at day 90, the male finch’s song gets even more precise when he “directs” it to a female as part of courtship. 

To investigate the role of FoxP2 in the generation of this directed song, Murugan introduced specifically targeted sequences of RNA to suppress FoxP2 activity in the basal ganglia of male zebrafinches. The birds were placed in a glass cage that revealed a female sitting on the other side. Murugan then recorded sonograms of their song to capture the subtle vocal variations indistinguishable to the human ear when they produced directed songs at the female. 

Murugan found that though the genetically manipulated males had already learned how to sing, their ability to hit the right note repeatedly in the presence of a female — a behavior critical to attracting a mate — was subpar. This indicates that in songbirds, FoxP2 has an ongoing role in vocal control separate from a role in learning, a distinction that has not been possible to make in humans with FOXP2 mutations. 

Having deduced the behavior associated with this genetic mutation, the researchers then identified underlying neural deficits by recording brain activity in birds with normal and altered FoxP2 genes. In one set of experiments, Murugan sent an electrical signal into the input side of the basal ganglia pathway and then used an electrode on the output side to measure how quickly the signal traveled from one side to the other. Surprisingly, the signal moved more quickly through the basal ganglia of FoxP2 mutant songbirds than it did in songbirds with the functional gene. 

Murugan also found that dopamine, an important brain chemical involved in brain signaling and the reinforcement of learned behaviors like singing or playing sports, could influence how fast basal ganglia signals propagated in birds with normal but not mutant forms of FoxP2.  

"This switch between undirected and directed song is actually dependent on the influx of this neurotransmitter called dopamine," said Murugan, first author of the study. "So what we think is happening is knocking down FoxP2 makes the male incapable of reducing song variability in the presence of a female. An adult male sees the female, there is an influx of dopamine, but because the system is insensitive, the dopamine has no effect and the adult male continues to sing a variable tune." In juveniles, the inability to constrain variability and to respond to dopamine could also account for poor learning.

Though the researchers are cautious not to draw too many parallels between their findings in birds and the deficits in humans, they think their study does highlight the value of songbirds in studying human behaviors and disease.

"Birds are one of the few non-human animals that learn to vocalize," said Mooney. "They produce songs for courtship that they culturally transmit from one generation to the next. Their brains might be a thousandth the size of ours, but in this one dimension, vocal learning, they are our equal."

(Source: today.duke.edu)