Research gives unprecedented 3-D view of important brain receptor

Researchers with Oregon Health & Science University’s Vollum Institute have given science a new and unprecedented 3-D view of one of the most important receptors in the brain — a receptor that allows us to learn and remember, and whose dysfunction is involved in a wide range of neurological diseases and conditions, including Alzheimer’s, Parkinson’s, schizophrenia and depression.

The unprecedented view provided by the OHSU research, published online June 22 in the journal Nature, gives scientists new insight into how the receptor — called the NMDA receptor — is structured. And importantly, the new detailed view gives vital clues to developing drugs to combat the neurological diseases and conditions.

"This is the most exciting moment of my career," said Eric Gouaux, a senior scientist at the Vollum Institute and a Howard Hughes Medical Institute investigator. "The NMDA receptor is one of the most essential, and still sometimes mysterious, receptors in our brain. Now, with this work, we can see it in fascinating detail."

Receptors facilitate chemical and electrical signals between neurons in the brain, allowing those neurons to communicate with each other. The NMDA (N-methyl-D-aspartate) receptor is one of the most important brain receptors, as it facilitates neuron communication that is the foundation of memory, learning and thought. Malfunction of the NMDA receptor occurs when it is increasingly or decreasingly active and is associated with a wide range of neurological disorders and diseases. Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia and epilepsy are, in many instances, linked to problems with NMDA activity.

Scientists across the world study the NMDA receptor; some of the most notable discoveries about the receptor during the past three decades have been made by OHSU Vollum scientists.

The NMDA receptor makeup includes receptor “subunits” — all of which have distinct properties and act in distinct ways in the brain, sometimes causing neurological problems. Prior to Gouaux’s study, scientists had only a limited view of how those subtypes were arranged in the NMDA receptor complex and how they interacted to carry out specific functions within the brain and central nervous system.

Gouaux’s team of scientists – Chia-Hsueh Lee, Wei Lu, Jennifer Michel, April Goehring, Juan Du and Xianqiang Song – created a 3-D model of the NMDA receptor through a process called X-ray crystallography. This process throws x-ray beams at crystals of the receptor; a computer calibrates the makeup of the structure based on how those x-ray beams bounce off the crystals. The resulting 3-D model of the receptor, which looks something like a bouquet of flowers, shows where the receptor subunits are located, and gives unprecedented insight into their actions.

"This new detailed view will be invaluable as we try to develop drugs that might work on specific subunits and therefore help fight or cure some of these neurological diseases and conditions," Gouaux said. "Seeing the structure in more detail can unlock some of its secrets — and may help a lot of people."

Researchers find clue to stopping Alzheimer’s-like diseases

Tiny differences in mice that make them peculiarly resistant to a family of conditions that includes Alzheimer’s, Parkinson’s and Creutzfeldt-Jakob Disease may provide clues for treatments in humans.

Amyloid diseases are often incurable because drug designers cannot identify the events that cause them to start.

Professor Sheena Radford, Astbury Professor of Biophysics at the University of Leeds, said: “Amyloid diseases are associated with the build-up of fibrous plaques out of long strings of ‘misfolding’ proteins, but it is not clear what kicks the process off. That means the normal approach of designing a drug to destroy or disable the species that start the disease process does not work.

“We have to take a completely different tack: instead of targeting the cause of the disease, we need to disrupt the plaque building process.”

The University of Leeds-led team’s study, published in the journal Molecular Cell, looked to mice for a way forward.

“We already knew that mice were not prone to the build up of some of these plaques. This study, for the first time, observed the building happening and saw the differences between the mice proteins and their almost identical human equivalents,” Professor Radford said.

She added: “We mixed the mice and human proteins and found that the mice protein actually stopped the formation of the plaque-forming fibrils by the human protein.”

The research was conducted completely in the test-tube using human and mice beta-2 microglobulin proteins produced in the laboratory. Plaques made up of beta-2 microglobulin are associated with Dialysis Related Amyloidosis (DRA). Instead of being a neurodegenerative condition like Alzheimer’s or Parkinson’s, DRA primarily affects the joints of people on kidney dialysis.

The team observed differences in the formation of the plaque-forming fibrils in samples containing only mice protein, samples with only the human protein and samples containing mixtures of the two.

The lead researcher, Dr Theodoros Karamanos, said: “These two versions of the proteins are almost exactly the same, with very slight differences in structure, but the outcomes are completely different. If I put a misfolding-prone protein in the human sample, I see the formation of fibrils in two days in the right conditions. If I do the same in the mouse sample, I can leave it for weeks and there are no fibrils.

Dr Karamanos added: “The exciting thing is that if you mix the proteins—with only one mouse protein for every five human proteins—you see a significant disruption of the formation of fibrils.”

The study used Nuclear Magnetic Resonance spectroscopy to look at a molecular level at the interactions of the different proteins and identified tiny differences in the physical and chemical properties of the surfaces that made a great difference to whether plaques are formed.

The results showed that the mouse protein binds to the human protein more tightly than the human protein binds to its misfolded form. Interestingly, subtle differences in the driving forces of binding (i.e. the balance of hydrophobic and charge-charge interactions) in the binding interface govern the outcome of assembly.

Dr Karamanos said: “We can’t just load up a syringe and inject mouse protein into patients. But if we know the properties of the interface between the two proteins that are responsible for the inhibition effect, we can ask the chemists to design small molecule drugs which mimic what the mouse protein does to the human protein. That may be a key insight into how to stop the plaque building process.”

Controlling movement with light

For the first time, MIT neuroscientists have shown they can control muscle movement by applying optogenetics — a technique that allows scientists to control neurons’ electrical impulses with light — to the spinal cords of animals that are awake and alert.  

Led by MIT Institute Professor Emilio Bizzi, the researchers studied mice in which a light-sensitive protein that promotes neural activity was inserted into a subset of spinal neurons. When the researchers shone blue light on the animals’ spinal cords, their hind legs were completely but reversibly immobilized. The findings, described in the June 25 issue of PLoS One, offer a new approach to studying the complex spinal circuits that coordinate movement and sensory processing, the researchers say.

In this study, Bizzi and Vittorio Caggiano, a postdoc at MIT’s McGovern Institute for Brain Research, used optogenetics to explore the function of inhibitory interneurons, which form circuits with many other neurons in the spinal cord. These circuits execute commands from the brain, with additional input from sensory information from the limbs.

Previously, neuroscientists have used electrical stimulation or pharmacological intervention to control neurons’ activity and try to tease out their function. Those approaches have revealed a great deal of information about spinal control, but they do not offer precise enough control to study specific subsets of neurons.

Optogenetics, on the other hand, allows scientists to control specific types of neurons by genetically programming them to express light-sensitive proteins. These proteins, called opsins, act as ion channels or pumps that regulate neurons’ electrical activity. Some opsins suppress activity when light shines on them, while others stimulate it.

“With optogenetics, you are attacking a system of cells that have certain characteristics similar to each other. It’s a big shift in terms of our ability to understand how the system works,” says Bizzi, who is a member of MIT’s McGovern Institute.

Muscle control

Inhibitory neurons in the spinal cord suppress muscle contractions, which is critical for maintaining balance and for coordinating movement. For example, when you raise an apple to your mouth, the biceps contract while the triceps relax. Inhibitory neurons are also thought to be involved in the state of muscle inhibition that occurs during the rapid eye movement (REM) stage of sleep.

To study the function of inhibitory neurons in more detail, the researchers used mice developed by Guoping Feng, the Poitras Professor of Neuroscience at MIT, in which all inhibitory spinal neurons were engineered to express an opsin called channelrhodopsin 2. This opsin stimulates neural activity when exposed to blue light. They then shone light at different points along the spine to observe the effects of neuron activation.

When inhibitory neurons in a small section of the thoracic spine were activated in freely moving mice, all hind-leg movement ceased. This suggests that inhibitory neurons in the thoracic spine relay the inhibition all the way to the end of the spine, Caggiano says. The researchers also found that activating inhibitory neurons had no effect on the transmission of sensory information from the limbs to the brain, or on normal reflexes.

“The spinal location where we found this complete suppression was completely new,” Caggiano says. “It has not been shown by any other scientists that there is this front-to-back suppression that affects only motor behavior without affecting sensory behavior.”

“It’s a compelling use of optogenetics that raises a lot of very interesting questions,” says Simon Giszter, a professor of neurobiology and anatomy at Drexel University who was not part of the research team. Among those questions is whether this mechanism behaves as a global “kill switch,” or if the inhibitory neurons form modules that allow for more selective suppression of movement patterns.

Now that they have demonstrated the usefulness of optogenetics for this type of study, the MIT team hopes to explore the roles of other types of spinal cord neurons. They also plan to investigate how input from the brain influences these spinal circuits.

“There’s huge interest in trying to extend these studies and dissect these circuits because we tackled only the inhibitory system in a very global way,” Caggiano says. “Further studies will highlight the contribution of single populations of neurons in the spinal cord for the control of limbs and control of movement.”

Gestures that speak

When you gesticulate you don’t just add a “note of colour” that makes your speech more pleasant: you convey information on sentence structure and make your meanings clearer. A study carried out at SISSA in Trieste demonstrates that gestures and “prosody” (the intonation and rhythm of spoken language) form  a  single “communication system” at the cognitive level, and that we speak using our “whole  body” and not only our vocal tract.

Have you ever found yourself gesticulating and felt a bit stupid for it while talking on the phone?

You’re not alone: it happens very often that people accompany their speech with hand gestures, sometimes even when no one can see them. Why can’t we keep still while speaking? “Because gestures and words very probably form a single “communication system”, which ultimately serves to enhance expression intended as the ability to make oneself understood”, explains Marina Nespor, a neuroscientist at the International School for Advanced Studies (SISSA) of Trieste. Nespor, together with Alan Langus, a SISSA research fellow, and Bahia Guellai from the Université Paris Ouest Nanterre La Défence, who conducted the investigation at SISSA, has just published a study in Frontiers in Psychology which demonstrates the role of gestures in speech “prosody”.

Linguists define prosody as the intonation and rhythm of spoken language, features that help to highlight sentence structure and therefore make the message easier to understand. For example, without prosody, nothing would distinguish the declarative statement “this is an apple” from the surprise question “this is an apple?” (in this case the difference lies in the intonation).

According to Nespor and colleagues, even hand gestures are part of prosody: “the prosody that accompanies speech is not ‘modality specific” explains Langus. “Prosodic information, for the person receiving the message, is a combination of auditory and visual cues. The ‘superior’ aspects (at the cognitive processing level) of spoken language are mapped to the motor‐programs responsible for the production of both speech sounds and accompanying hand gestures”.

Nespor, Langus and Guellai had 20 Italian speakers listen to a series of “ambiguous” utterances, which could be said with different prosodies corresponding to two different meanings. Examples of utterances were “come sicuramente hai visto la vecchia sbarra la porta” where, depending on meaning, “vecchia” can be the subject of the main verb (sbarrare, to block) or an adjective qualifying the subject (sbarra, bar) (‘As you for sure have seen the old lady blocks the door’ versus ‘As you for sure have seen the old bar carries it’). The utterances could be simply listened to (“audio only” modality) or be presented in a video, where the participants could both listen to the sentences and see the accompanying gestures. In the “video” stimuli, the condition could be “matched” (gestures corresponding to the meaning conveyed by speech prosody) or “mismatched” (gestures matching the alternative meaning).

“In the matched conditions there was no improvement ascribable to gestures: the  participants’ performance was very good both in the video and in the “audio only” sessions. It’s in the mismatched condition that the effect of hand gestures became apparent”, explains Langus. “With these stimuli the subjects were much more likely to make the wrong choice (that is, they’d choose the meaning indicated in the gestures rather than in the speech) compared to matched or audio only conditions. This means that gestures affect how meaning is interpreted, and we believe this points to the existence of a common cognitive system for gestures, intonation and rhythm of spoken language”.

“In human communication, voice is not sufficient: even the torso and in particular hand movements are involved, as are facial expressions”, concludes Nespor.

To Advance Care for Patients with Brain Metastases: Reject Five Myths

A blue-ribbon team of national experts on brain cancer says that professional pessimism and out-of-date “myths,” rather than current science, are guiding — and compromising — the care of patients with cancers that spread to the brain.

In a special article published in the July issue of Neurosurgery, the team, led by an NYU Langone Medical Center neurosurgeon, argues that many past, key clinical trials were designed with out-of-date assumptions and the tendency of some physicians to “lump together” brain metastases of diverse kinds of cancer, often results in less than optimal care for individual patients. Furthermore, payers question the best care when it deviates from these misconceptions, the authors conclude.

“It’s time to abandon this unjustifiable nihilism and think carefully about more individualized care,” says lead author of the article, Douglas S. Kondziolka, M.D., MSc, FRCSC, Vice Chair of Clinical Research and Director of the Gamma Knife Program in the Department of Neurosurgery at NYU Langone.

The authors — who also say medical insurers help perpetuate the myths by denying coverage that deviates from them — identify five leading misconceptions that often lead to poorer care:

1. All tumor cell types act the same way once they spread to the brain. This oversimplification means that doctors assume that histologically diverse cancers respond the same way to chemotherapy and are equally sensitive (or insensitive) to radiation. It also means that patients are all assumed to be at the same risk of subsequent brain cancer relapses, and development of additional metastatic lesions; and that survival rates are similar as well. The authors point out that this type of thinking overlooks important biological differences in brain metastases resulting from different types of cancer, such as those originating in the lung, breast or skin.
2. The number of brain metastases is the best indicator for guiding management of the disease. Such strict adherence to quantity, the authors say, can wrongly limit treatment options. Physicians should look at total tumor burden, including the size and scope of metastases, rather than just how many metastases occur.
3. All cancers detectable in the brain already reflect the presence of micrometastases, or  smaller, newly formed tumors too miniscule to detect. Evidence, the authors say, suggests otherwise, and aggressively monitoring for, and treating, individual brain metastases can, in fact, improve tumor control and patient survival.
4. Whole brain radiation (WBR) is generally unjustified because it will cause disabling cognitive dysfunction if a patient lives long enough. Dr. Kondziolka and his co-authors say the risks and benefits of WBR should be evaluated for each patient, and that new studies examining the cognitive impact of WBR on thinking and learning are underway.
5. Most brain metastases cause obvious symptoms, making regular screening for them unnecessary, and unlikely to affect survival. The authors counter that advances in screening allow metastases to be detected earlier, and treated sooner, before symptoms occur.

“We are in an era of personalized medicine,” Dr. Kondziolka says, “and we need to begin thinking that way.” The authors further write: “It is time for fresh thinking and new critical analyses,” urging consideration of updated clinical trial designs that include comparison of matched cohorts and cost effectiveness factors. In addition to research that pays more attention to specific cell types and overall tumor burden, investigators should focus on tools available from advances in molecular biology and genetic subtyping and on efforts to learn “why some patients with a given primary cancer develop brain tumors and others do not.”

Ultimately, the authors hope better stratifying patients will improve care for patients with diverse brain metastases.

Study shows puzzle games can improve mental flexibility

A recent study by Nanyang Technological University (NTU) scientists showed that adults who played the physics-based puzzle video game Cut the Rope regularly, for as little as an hour a day, had improved executive functions.

The executive functions in your brain are important for making decisions in everyday life when you have to deal with sudden changes in your environment – better known as thinking on your feet. An example would be when the traffic light turns amber and a driver has to decide in an instant if he will be able to brake in time or if it is safer to travel across the junction/intersection.

The video game study by Assistant Professor Michael D. Patterson and his PhD student Mr Adam Oei, tested four different games for the mobile platform, as their previous research had shown that different games trained different skills.

The games varied in their genres, which included a first person shooter (Modern Combat); arcade (Fruit Ninja); real-time strategy (StarFront Collision); and a complex puzzle (Cut the Rope).

NTU undergraduates, who were non-gamers, were then selected to play an hour a day, 5 days a week on their iPhone or iPod Touch. This video game training lasted for 4 weeks, a total of 20 hours.

Prof Patterson said students who played Cut the Rope, showed significant improvement on executive function tasks while no significant improvements were observed in those playing the other three games.

“This finding is important because previously, no video games have demonstrated this type of broad improvement to executive functions, which are important for general intelligence, dealing with new situations and managing multitasking,” said Prof Patterson, an expert in the psychology of video games.

“This indicates that while some games may help to improve mental abilities, not all games give you the same effect. To improve the specific ability you are looking for, you need to play the right game,” added Mr Oei.

The abilities tested in this study included how fast the players can switch tasks (an indicator of mental flexibility); how fast can the players adapt to a new situation instead of relying on the same strategy (the ability to inhibit prepotent or predominant responses); and how well they can focus on information while blocking out distractors or inappropriate responses (also known as the Flanker task in cognitive psychology).

Prof Patterson said the reason Cut the Rope improved executive function in their players was probably due to the game’s unique puzzle design. Strategies which worked for earlier levels would not work in later levels, and regularly forced the players to think creatively and try alternate solutions. This is unlike most other video games which keep the same general mechanics and goals, and just speed up or increase the number of items to keep track of. 

After 20 hours of game play, players of Cut the Rope could switch between tasks 33 per cent faster, were 30 per cent faster in adapting to new situations, and 60 per cent better in blocking out distractions and focusing on the tasks at hand than before training.

All three tests were done one week after the 52 students had finished playing their assigned game, to ensure that these were not temporary gains due to motivation or arousal effects.

The study will be published in the academic journal, Computers in Human Behavior, this August, but is available currently online. This is the first study that showed broad transfer to several different executive functions, further providing evidence the video games can be effective in training human cognition.

“This result could have implications in many areas such as educational, occupational and rehabilitative settings,” Prof Patterson said.

“In future, with more studies, we will be able to know what type of games improves specific abilities, and prescribe games that will benefit people aside from just being entertainment.”

In their previous study published last year in PloS One, a top academic journal, Prof Patterson and Mr Oei studied the effects mobile gaming had on 75 NTU undergraduates.

The non-gamers were instructed to play one of the following games: “match three” game Bejeweled, virtual life simulation game The Sims, and action shooter Modern Combat.

The study findings showed that adults who play action games improved their ability to track multiple objects in a short span of time, useful when driving during a busy rush hour; while other games improved the participants’ ability for visual search tasks, useful when picking out an item from a large supermarket.

Moving forward, the Prof Patterson is keen to look at whether there is any improvement from playing such games in experienced adult gamers and how much improvement one can make through playing games.

How the brain processes visual information

MSU’s Behrad Noudoost was a co-author with Marc Zirnsak and other neuroscientists from the Tirin Moore Lab at Stanford University in publishing a recent paper on the research in Nature, an international weekly journal for natural sciences.

Noudoost and the team studied saccadic eye movements—those movements where the eye jumps from one point of focus to another—in an effort to determine exactly how this happens without us being overcome by our brains processing too much visual information.

To introduce the study, Noudoost first gets his audience to think about eye movements at the most basic level. “Look in the mirror and stare at one eye,” Noudoost said. “Then look at the other eye. We are essentially blind during eye movement as we cannot see our eyes move, even though we know they did.”

According to Noudoost, scientists have been trying to learn exactly how the brain processes these visual stimuli during saccadic eye movement and this research offers new evidence that the prefrontal cortex of the brain is responsible for visual stability.

"Visual stability is what keeps our vision stable in spite of changing input. It is similar to the stabilizer button on a video camera," Noudoost said.

"We wanted to know what causes the brain to filter out un-necessary information when we shift our vision from one focal target to another," Noudoost said. "Without that filter the visual information would overwhelm us."

According to the scientists, the study offers evidence neurons in the prefrontal cortex of the brain start processing information in anticipation of where we are going to look before we ever do it, suggesting that selective processing might be the mechanism for visual stability.

Noudoost said this new information can help scientists better understand the underlying causes of problems such as dyslexia and attention deficit disorders.

According to Frances Lefcort, the head of the Department of Cell Biology and Neuroscience, the team’s basic research may have implications for understanding a myriad of mental health issues.

"Schizophrenia and attention deficit disorders have been linked to visual stability, so the work Behrad is doing offers valuable knowledge to other scientists working in cognitive neuroscience," Lefcort said.

"Understanding how a healthy brain works is important in terms of knowing its impact on cognitive functions such as memory, learning and in this case attention," Noudoost said. "By exploring normal brain function, we can better understand what happens in someone with a mental illness."

According to Lefcort, Noudoost and neuroscience professor Charles Gray are strengthening MSU’s contribution to the field of cognitive neuroscience.

"Behrad is an exquisitely trained neuroscientist. He offers students a viewpoint as both scientist and a physician," Lefcort said. "We are thrilled to have him and he has already brought new energy and is bolstering our impact on the growing field of brain research."

Noudoost joined MSU’s Department of Cell Biology and Neuroscience last summer from Stanford University and has already been awarded a $225,000 Whitehall Foundation grant for neuroscience. Whitehall Foundation grants are awarded to established scientists working in neurobiology.

"I am colorblind and I wanted to see the world as others could see it," Noudoost said explaining why he was first drawn into this type of research. "Although I still don’t see the world in the same colors as everyone else, I am more amazed everyday by the brain."