Archive for the ‘Neuroscience’ Category

Just as losing a limb can spare a life, parting with a damaged axon by way of Wallerian degeneration can spare a neuron. A protein called SARM1 acts as the self-destruct button, and now researchers led by Jeffrey Milbrandt of Washington University Medical School in St. Louis believe they have figured out how. They report in the April 24 Science that SARM1 forms dimers that trigger the destruction of NAD+. Basic biochemistry dictates that this enzyme cofactor is essential for cell survival.

ARM1 and NAD+ have emerged as key players in the complex, orderly process underlying Wallerian degeneration. Scientists are still filling in other parts of the pathway. SARM1, short for sterile alpha and TIR motif-containing 1, seems to act as a damage sensor, but researchers are not sure how. Recently, researchers led by Marc Tessier-Lavigne at Rockefeller University, New York, found that SARM1 turns on a mitogen-activated protein (MAP) kinase cascade that is involved. Loss of NAD+ may also contribute to axon degeneration, because its concentration drops in dying axons, and Wlds mutant mice that overproduce an NAD+ synthase have slower Wallerian degeneration.

Now, first author Josiah Gerdts confirms that SARM1 is the self-destruct switch. He engineered a version of the protein with a target sequence for tobacco etch virus (TEV) protease embedded in it. Using a rapamycin-activated form of TEV, he eliminated SARM1 from axons he had sliced off of mouse dorsal root ganglion (DRG) neurons. Without SARM1, the severed axons survived.

SARM1 contains SAM and TIR domains, which promote protein-protein interactions. Previously, Gerdts discovered that the TIR domain was sufficient to induce degeneration, even in healthy axons, but it relied on the SAM region to bring multiple SARM1 molecules together. He hypothesized that axonal SARM1 multimerizes upon axon damage. To test this idea, he used a standard biochemical technique to force the SARM1 TIR domains together. He fused domains to one or another of the rapamycin-binding peptides Frb and Fkbp and expressed them in DRG neurons. When he added rapamycin to the cultures, the Frb and Fkbp snapped the TIR domains together within minutes. As Gerdts had predicted, this destroyed axons, confirming that SARM1 activates via dimerization.

Next, the authors investigated what happens to NAD+ during that process. Using high-performance liquid chromatography, Gerdts measured the concentration of NAD+ in the disembodied axons. Normally, its level dropped by about two-thirds within 15 minutes of severing. In axons from SARM1 knockout mice, however, the NAD+ concentration stayed unchanged. In neurons carrying the forced-dimerization constructs, adding rapamycin was sufficient to knock down NAD+ levels—Gerdts did not even have to cut the axons. Ramping up NAD+ production by overexpressing its synthases, NMNAT and NAMPT, overcame the effects of TIR dimerization, and the axons survived. Gerdts concluded that loss of NAD+ was a crucial, SARM1-controlled step on the way to degeneration.

He still wondered what caused the loss of NAD+. It might be that the axon simply stopped making it, or maybe the Wallerian pathway actively destroyed it. To distinguish between these possibilities, Gerdts added radiolabeled exogenous NAD+ to human embryonic kidney HEK293 cultures expressing the forced-dimerization TIR domains. Rapamycin caused them to rapidly degrade the radioactive NAD+, confirming that the cell actively disposes of it.

Gerdts suspects that with this essential cofactor gone, the axon runs out of energy and can no longer survive. He speculated that the MAP kinase cascade reportedly turned on by SARM1 might lead to NAD+ destruction. Alternatively, SARM1 might induce distinct MAP kinase and NAD+ destruction pathways in parallel, he suggested.

“Demonstrating how NAD+ is actively and locally degraded in the axon is a big advance,” commented Andrew Pieper of the Iowa Carver College of Medicine in Iowa City, who was not involved in the study. Jonathan Gilley and Michael Coleman of the Babraham Institute in Cambridge, U.K., predict that there will be more to the story. They note that a drug called FK866, which prevents NAD+ production, protects axons in some instances. Gerdts suggested that FK866 acts on processes upstream of SARM1, delaying the start of axon degeneration. In contrast, his paper only addressed what happens after SARM1 activates. “It will be fascinating to see how the apparent contradictions raised by this new study will be resolved,” wrote Gilley and Coleman.

Could these findings help researchers looking for ways to prevent neurodegeneration? “The study supports the notion that augmenting NAD+ levels is potentially a valuable approach,” said Pieper. He and his colleagues developed a small molecule that enhances NAD+ synthesis, now under commercial development. It improved symptoms in ALS model mice, and protected neurons in mice mimicking Parkinson’s. NAD+ also activates sirtuin, an enzyme important for longevity and stress resistance as well as learning and memory.

However, both Pieper and Gerdts cautioned that they cannot clearly predict which conditions might benefit from an anti-SARM1 or NAD+-boosting therapy. At this point, Gerdts said, researchers do not fully understand how much axon degeneration contributes to symptoms of diseases like Alzheimer’s and Parkinson’s. He suggested that crossing SARM1 knockout mice with models for various neurodegenerative conditions would indicate how well an anti-Wallerian therapy might work.

—Amber Dance

http://www.alzforum.org/news/research-news/axon-self-destruct-button-triggers-energy-woes

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By Rachel Feltman

If you give a mouse an eating disorder, you might just figure out how to treat the disease in humans. In a new study published Thursday in Cell Press, researchers created mice who lacked a gene associated with disordered eating in humans. Without it, the mice showed behaviors not unlike those seen in humans with eating disorders: They tended to be obsessive compulsive and have trouble socializing, and they were less interested in eating high-fat food than the control mice. The findings could lead to novel drug treatments for some of the 24 million Americans estimated to suffer from eating disorders.

In a 2013 study, the same researchers went looking for genes that might contribute to the risk of an eating disorder. Anorexia nervosa and bulimia nervosa aren’t straightforwardly inherited — there’s definitely more to an eating disorder than your genes — but it does seem like some families might have higher risks than others. Sure enough, the study of two large families, each with several members who had eating disorders, yielded mutations in two interacting genes. In one family, the estrogen-related receptor α (ESRRA) gene was mutated. The other family had a mutation on another gene that seemed to affect how well ESRRA could do its job.

So in the latest study, they created mice that didn’t have ESRRA in the parts of the brain associated with eating disorders.

“You can’t go testing this kind of gene expression in a human,” lead author and University of Iowa neuroscientist Michael Lutter said. “But in mice, you can manipulate the expression of the gene and then look at how it changes their behavior.”

It’s not a perfect analogy to what the gene mutation might do in a human, but the similarities can allow researchers to figure out the mechanism that causes the connection between your DNA and your eating habits.

The mice without ESRRA were tested for several eating-disorder-like behaviors: The researchers tested how hard they were willing to work for high fat food when they were hungry (less, it seemed, so much so that they weighed 15 percent less than their unaltered littermates), how compulsive they were, and how they behaved socially.

In general, the ESRRA-lacking mice were twitchier: They tended to overgroom, a common sign of anxiety in mice, and they were more wary of novelty, growing anxious when researchers put marbles into their cages. They also showed an inability to adapt: When researchers taught the mice how to exit a maze and then changed where the exit was, the mice without ESRRA spent way more time checking out the area where the exit should have been before looking for where it had gone.

The social changes were even more striking: Mice will usually show more interest in a new mouse than one they’ve met before, but in tests the modified mice showed the opposite preference, socializing with a familiar mouse when a new one was also presented.

They were also universally submissive to other mice, something the researchers detected with a sort of scientific game of chicken. Two mice are placed at either end of a tube, and one always plows past the other to get to the opposite side. It’s just the way mice size each other up — someone has to be on top. But every single one of the modified mice let themselves get pushed around.

“100% of the mice lacking this gene were subordinate,” Lutter said. “I’ve never seen an experiment before that produced a 0% verses 100% result.”

The avoidance of fats has an obvious connection to human disorders. But the social anxiety and rigidity are also close analogies to disordered eating in humans.

Now that Lutter and his colleagues know that the gene does something similar in mice, they can start looking for the actual mechanism that’s tripping these switches in the brain. They know that the gene’s pathway is very important for energy metabolism, especially in the breakdown of glucose. It’s possible that mutations in the gene cause some kind of impairment in neurons’ ability to get and process energy, but they can’t be sure yet.

They’ll see if they can pinpoint affected neurons and fix them. They’re also going to test some drugs that are known to affect this gene and its pathways. It’s possible that they’ll land on a treatment that helps calm these negative behaviors in affected mice, leading to treatments for humans with the mutation.

http://www.washingtonpost.com/news/speaking-of-science/wp/2015/04/09/scientists-manage-to-give-mice-eating-disorders-by-knocking-out-one-gene/

Open Access Article here: http://www.cell.com/cell-reports/abstract/S2211-1247(15)00301-0

Sleeping minds: prepare to be hacked. For the first time, conscious memories have been implanted into the minds of mice while they sleep. The same technique could one day be used to alter memories in people who have undergone traumatic events.

When we sleep, our brain replays the day’s activities. The pattern of brain activity exhibited by mice when they explore a new area during the day, for example, will reappear, speeded up, while the animal sleeps. This is thought to be the brain practising an activity – an essential part of learning. People who miss out on sleep do not learn as well as those who get a good night’s rest, and when the replay process is disrupted in mice, so too is their ability to remember what they learned the previous day.

Karim Benchenane and his colleagues at the Industrial Physics and Chemistry Higher Educational Institution in Paris, France, hijacked this process to create new memories in sleeping mice. The team targeted the rodents’ place cells – neurons that fire in response to being in or thinking about a specific place. These cells are thought to help us form internal maps, and their discoverers won a Nobel prize last year.

Benchenane’s team used electrodes to monitor the activity of mice’s place cells as the animals explored an enclosed arena, and in each mouse they identified a cell that fired only in a certain arena location. Later, when the mice were sleeping, the researchers monitored the animals’ brain activity as they replayed the day’s experiences. A computer recognised when the specific place cell fired; each time it did, a separate electrode would stimulate brain areas associated with reward.

When the mice awoke, they made a beeline for the location represented by the place cell that had been linked to a rewarding feeling in their sleep. A brand new memory – linking a place with reward – had been formed.

It is the first time a conscious memory has been created in animals during sleep. In recent years, researchers have been able to form subconscious associations in sleeping minds – smokers keen to quit can learn to associate cigarettes with the smells of rotten eggs and fish in their sleep, for example.

Previous work suggested that if this kind of subconscious learning had occurred in Benchenane’s mice, they would have explored the arena in a random manner, perhaps stopping at the reward-associated location. But these mice headed straight for the location, suggesting a conscious memory. “The mouse develops a goal-directed behaviour to go towards the place,” says Benchenane. “It proves that it’s not an automatic behaviour. What we create is an association between a particular place and a reward that can be consciously accessed by the mouse.”

“The mouse is remembering enough abstract information to think ‘I want to go to a certain place’, and go there when it wakes up,” says neuroscientist Neil Burgess at University College London. “It’s a bigger breakthrough [than previous studies] because it really does show what the man in the street would call a memory – the ability to bring to mind abstract knowledge which can guide behaviour in a directed way.”

Benchenane doesn’t think the technique can be used to implant many other types of memories, such as skills – at least for the time being. Spatial memories are easier to modify because they are among the best understood.

His team’s findings also provide some of the strongest evidence for the way in which place cells work. It is almost impossible to test whether place cells function as an internal map while animals are awake, says Benchenane, because these animals also use external cues, such as landmarks, to navigate. By specifically targeting place cells while the mouse is asleep, the team were able to directly test theories that specific cells represent specific places.

“Even when those place cells fire in sleep, they still convey spatial information,” says Benchenane. “That provides evidence that when you’ve got activation of place cells during the consolidation of memories in sleep, you’ve got consolidation of the spatial information.”

Benchenane hopes that his technique could be developed to help alter people’s memories, perhaps of traumatic events (see “Now it’s our turn”, below).

Loren Frank at the University of California, San Francisco, agrees. “I think this is a really important step towards helping people with memory impairments or depression,” he says. “It is surprising to me how many neurological and psychiatric illnesses have something to do with memory, including schizophrenia and obsessive compulsive disorder.”

“In principle, you could selectively change brain processing during sleep to soften memories or change their emotional content,” he adds.

Journal reference: Nature Neuroscience, doi:10.1038/nn.3970

http://www.newscientist.com/article/dn27115-new-memories-implanted-in-mice-while-they-sleep.html#.VP_L9uOVquD

Thanks to Kebmodee for bringing this to the attention of the It’s Interesting community.

The more scientists study pigeons, the more they learn how their brains—no bigger than the tip of an index finger—operate in ways not so different from our own.

In a new study from the University of Iowa, researchers found that pigeons can categorize and name both natural and manmade objects—and not just a few objects. These birds categorized 128 photographs into 16 categories, and they did so simultaneously.

Ed Wasserman, UI professor of psychology and corresponding author of the study, says the finding suggests a similarity between how pigeons learn the equivalent of words and the way children do.

“Unlike prior attempts to teach words to primates, dogs, and parrots, we used neither elaborate shaping methods nor social cues,” Wasserman says of the study, published online in the journal Cognition. “And our pigeons were trained on all 16 categories simultaneously, a much closer analog of how children learn words and categories.”

For researchers like Wasserman, who has been studying animal intelligence for decades, this latest experiment is further proof that animals—whether primates, birds, or dogs—are smarter than once presumed and have more to teach scientists.

“It is certainly no simple task to investigate animal cognition; But, as our methods have improved, so too have our understanding and appreciation of animal intelligence,” he says. “Differences between humans and animals must indeed exist: many are already known. But, they may be outnumbered by similarities. Our research on categorization in pigeons suggests that those similarities may even extend to how children learn words.”

Wasserman says the pigeon experiment comes from a project published in 1988 and featured in The New York Times in which UI researchers discovered pigeons could distinguish among four categories of objects.

This time, the UI researchers used a computerized version of the “name game” in which three pigeons were shown 128 black-and-white photos of objects from 16 basic categories: baby, bottle, cake, car, cracker, dog, duck, fish, flower, hat, key, pen, phone, plan, shoe, tree. They then had to peck on one of two different symbols: the correct one for that photo and an incorrect one that was randomly chosen from one of the remaining 15 categories. The pigeons not only succeeded in learning the task, but they reliably transferred the learning to four new photos from each of the 16 categories.

Pigeons have long been known to be smarter than your average bird—or many other animals, for that matter. Among their many talents, pigeons have a “homing instinct” that helps them find their way home from hundreds of miles away, even when blindfolded. They have better eyesight than humans and have been trained by the U. S. Coast Guard to spot orange life jackets of people lost at sea. They carried messages for the U.S. Army during World Wars I and II, saving lives and providing vital strategic information.

UI researchers say their expanded experiment represents the first purely associative animal model that captures an essential ingredient of word learning—the many-to-many mapping between stimuli and responses.

“Ours is a computerized task that can be provided to any animal, it doesn’t have to be pigeons,” says UI psychologist Bob McMurray, another author of the study. “These methods can be used with any type of animal that can interact with a computer screen.”

McMurray says the research shows the mechanisms by which children learn words might not be unique to humans.

“Children are confronted with an immense task of learning thousands of words without a lot of background knowledge to go on,” he says. “For a long time, people thought that such learning is special to humans. What this research shows is that the mechanisms by which children solve this huge problem may be mechanisms that are shared with many species.”

Wasserman acknowledges the recent pigeon study is not a direct analogue of word learning in children and more work needs to be done. Nonetheless, the model used in the study could lead to a better understanding of the associative principles involved in children’s word learning.

“That’s the parallel that we’re pursuing,” he says, “but a single project—however innovative it may be—will not suffice to answer such a provocative question.”

http://now.uiowa.edu/2015/02/pigeon-power


Chinese children are lined up in Tiananmen Square in 2003 for photos with the overseas families adopting them. The children in the new study were adopted from China at an average age of 12.8 months and raised in French-speaking families.

You may not recall any memories from the first year of life, but if you were exposed to a different language at the time, your brain will still respond to it at some level, a new study suggests.

Brain scans show that children adopted from China as babies into families that don’t speak Chinese still unconsciously recognize Chinese sounds as language more than a decade later.

“It was amazing to see evidence that such an early experience continued to have a lasting effect,” said Lara Pierce, lead author of the study just published in the journal Proceedings of the National Academy of Sciences, in an email to CBC News.

The adopted children, who were raised in French-speaking Quebec families, had no conscious memory of hearing Chinese.

“If you actually test these people in Chinese, they don’t actually know it,” said Denise Klein, a researcher at McGill University’s Montreal Neurological Institute who co-authored the paper.

But their brains responded to Chinese language sounds the same way as those of bilingual children raised in Chinese-speaking families.


Children exposed to Chinese as babies display similar brain activation patterns as children with continued exposure to Chinese when hearing Chinese words, fMRI scans show.

“In essence, their pattern still looks like people who’ve been exposed to Chinese all their lives.”

Pierce, a PhD candidate in psychology at McGill University, working with Klein and other collaborators, scanned the brains of 48 girls aged nine to 17. Each participant lay inside a functional magnetic resonance imaging machine while she listened to pairs of three-syllable phrases. The phrases contained either:

■Sounds and tones from Mandarin, the official Chinese dialect.
■Hummed versions of the same tones but no actual words.

Participants were asked to tell if the last syllables of each pair were the same or different. The imaging machine measured what parts of the brain were active as the participants were thinking.

“Everybody can do the task — it’s not a difficult task to do,” Klein said. But the sounds are processed differently by people who recognize Chinese words — in that case, they activate the part of the brain that processes language.

Klein said the 21 children adopted from China who participated in the study might have been expected to show patterns similar to those of the 11 monolingual French-speaking children. After all, the adoptees left China at an average age of 12.8 months, an age when most children can only say a few words. On average, those children had not heard Chinese in more than 12 years.

The fact that their brains still recognized Chinese provides some insight into the importance of language learning during the first year of life, Klein suggested.

Effect on ‘relearning’ language not known

But Klein noted that the study is a preliminary one and the researchers don’t yet know what the results mean.

For example, would adopted children exposed to Chinese in infancy have an easier time relearning Chinese later, compared with monolingual French-speaking children who were learning it for the first time?

Pierce said studies trying to figure that out have had mixed results, but she hopes the findings in this study could generate better ways to tackle that question.

She is also interested in whether the traces of the lost language affect how the brain responds to other languages or other kinds of learning. Being able to speak multiple languages has already been shown to have different effects on the way the brain processes languages and other kinds of information.

http://www.cbc.ca/news/technology/adoptees-lost-language-from-infancy-triggers-brain-response-1.2838001

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Talking to yourself used to be a strictly private pastime. That’s no longer the case – researchers have eavesdropped on our internal monologue for the first time. The achievement is a step towards helping people who cannot physically speak communicate with the outside world.

“If you’re reading text in a newspaper or a book, you hear a voice in your own head,” says Brian Pasley at the University of California, Berkeley. “We’re trying to decode the brain activity related to that voice to create a medical prosthesis that can allow someone who is paralysed or locked in to speak.”

When you hear someone speak, sound waves activate sensory neurons in your inner ear. These neurons pass information to areas of the brain where different aspects of the sound are extracted and interpreted as words.

In a previous study, Pasley and his colleagues recorded brain activity in people who already had electrodes implanted in their brain to treat epilepsy, while they listened to speech. The team found that certain neurons in the brain’s temporal lobe were only active in response to certain aspects of sound, such as a specific frequency. One set of neurons might only react to sound waves that had a frequency of 1000 hertz, for example, while another set only cares about those at 2000 hertz. Armed with this knowledge, the team built an algorithm that could decode the words heard based on neural activity alone (PLoS Biology, doi.org/fzv269).

The team hypothesised that hearing speech and thinking to oneself might spark some of the same neural signatures in the brain. They supposed that an algorithm trained to identify speech heard out loud might also be able to identify words that are thought.

Mind-reading

To test the idea, they recorded brain activity in another seven people undergoing epilepsy surgery, while they looked at a screen that displayed text from either the Gettysburg Address, John F. Kennedy’s inaugural address or the nursery rhyme Humpty Dumpty.

Each participant was asked to read the text aloud, read it silently in their head and then do nothing. While they read the text out loud, the team worked out which neurons were reacting to what aspects of speech and generated a personalised decoder to interpret this information. The decoder was used to create a spectrogram – a visual representation of the different frequencies of sound waves heard over time. As each frequency correlates to specific sounds in each word spoken, the spectrogram can be used to recreate what had been said. They then applied the decoder to the brain activity that occurred while the participants read the passages silently to themselves.

Despite the neural activity from imagined or actual speech differing slightly, the decoder was able to reconstruct which words several of the volunteers were thinking, using neural activity alone (Frontiers in Neuroengineering, doi.org/whb).

The algorithm isn’t perfect, says Stephanie Martin, who worked on the study with Pasley. “We got significant results but it’s not good enough yet to build a device.”

In practice, if the decoder is to be used by people who are unable to speak it would have to be trained on what they hear rather than their own speech. “We don’t think it would be an issue to train the decoder on heard speech because they share overlapping brain areas,” says Martin.

The team is now fine-tuning their algorithms, by looking at the neural activity associated with speaking rate and different pronunciations of the same word, for example. “The bar is very high,” says Pasley. “Its preliminary data, and we’re still working on making it better.”

The team have also turned their hand to predicting what songs a person is listening to by playing lots of Pink Floyd to volunteers, and then working out which neurons respond to what aspects of the music. “Sound is sound,” says Pasley. “It all helps us understand different aspects of how the brain processes it.”

“Ultimately, if we understand covert speech well enough, we’ll be able to create a medical prosthesis that could help someone who is paralysed, or locked in and can’t speak,” he says.

Several other researchers are also investigating ways to read the human mind. Some can tell what pictures a person is looking at, others have worked out what neural activity represents certain concepts in the brain, and one team has even produced crude reproductions of movie clips that someone is watching just by analysing their brain activity. So is it possible to put it all together to create one multisensory mind-reading device?

In theory, yes, says Martin, but it would be extraordinarily complicated. She says you would need a huge amount of data for each thing you are trying to predict. “It would be really interesting to look into. It would allow us to predict what people are doing or thinking,” she says. “But we need individual decoders that work really well before combining different senses.”

http://www.newscientist.com/article/mg22429934.000-brain-decoder-can-eavesdrop-on-your-inner-voice.html

Everyone knows it’s easier to learn about a topic you’re curious about. Now, a new study reveals what’s going on in the brain during that process, revealing that such curiosity may give a person a memory boost.

When participants in the study were feeling curious, they were better at remembering information even about unrelated topics, and brain scans showed activity in areas linked to reward and memory.

The results, detailed October 2 in the journal Neuron, hint at ways to improve learning and memory in both healthy people and those with neurological disorders, the researchers said.

“Curiosity may put the brain in a state that allows it to learn and retain any kind of information, like a vortex that sucks in what you are motivated to learn, and also everything around it,” Matthias Gruber, a memory researcher at the University of California, Davis, said in a statement. “These findings suggest ways to enhance learning in the classroom and other settings.”

Gruber and his colleagues put people in a magnetic resonance imaging (MRI) scanner and showed them a series of trivia questions, asking them to rate their curiosity about the answers to those questions. Later, the participants were shown selected trivia questions, then a picture of a neutral face during a 14-second delay, followed by the answer. Afterward, the participants were given a surprise memory test of the faces, and then a memory test of the trivia answers.

Not surprisingly, the study researchers found that people remembered more information about the trivia when they were curious about the trivia answers. But unexpectedly, when the participants were curious, they were also better at remembering the faces, an entirely unrelated task. Participants who were curious were also more likley than others to remember both the trivia information and unrelated faces a day later, the researchers found.

The brain scans showed that, compared with when their curiosity wasn’t piqued, when people were curious, they showed more activation of brain circuits in the nucleus accumbens, an area involved in reward. These same circuits, mediated by the neurochemical messenger dopamine, are involved in forms of external motivation, such as food, sex or drug addiction.

Finally, being curious while learning seemed to produce a spike of activity in the hippocampus, an area involved in forming new memories, and strengthened the link between memory and reward brain circuits.

The study’s findings not only highlight the importance of curiosity for learning in healthy people, but could also give insight into neurological conditions. For example, as people age, their dopamine circuits tend to deteriorate, so understanding how curiosity affects these circuits could help scientists develop treatments for patients with memory disorders, the researchers said.

http://www.livescience.com/48121-curiosity-boosts-memory-learning.html