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Scientists use lasers and carbon nanotubes to look inside living brains

Some of the most damaging brain diseases can be traced to irregular blood delivery in the brain. Now, Stanford chemists have employed lasers and carbon nanotubes to capture an unprecedented look at blood flowing through a living brain.

The technique was developed for mice but could one day be applied to humans, potentially providing vital information in the study of stroke and migraines, and perhaps even Alzheimer’s and Parkinson’s diseases. The work is described in the journal Nature Photonics.

Current procedures for exploring the brain in living animals face significant tradeoffs. Surgically removing part of the skull offers a clear view of activity at the cellular level. But the trauma can alter the function or activity of the brain or even stimulate an immune response. Meanwhile, non-invasive techniques such as CT scans or MRI visualize function best at the whole-organ level; they cannot visualize individual vessels or groups of neurons.

The first step of the new technique, called near infrared-IIa imaging, or NIR-IIa, calls for injecting water-soluble carbon nanotubes into a live mouse’s bloodstream. The researchers then shine a near-infrared laser over the rodent’s skull.

The light causes the specially designed nanotubes to fluoresce at wavelengths of 1,300-1,400 nanometers; this range represents a sweet spot for optimal penetration with very little light scattering. The fluorescing nanotubes can then be detected to visualize the blood vessels’ structure.

Amazingly, the technique allows scientists to view about three millimeters underneath the scalp and is fine enough to visualize blood coursing through single capillaries only a few microns across, said senior author Hongjie Dai, a professor of chemistry at Stanford. Furthermore, it does not appear to have any adverse affect on innate brain functions.

"The NIR-IIa light can pass through intact scalp skin and skull and penetrate millimeters into the brain, allowing us to see vasculature in an almost non-invasive way," said first author Guosong Hong, who conducted the research as a graduate student in Dai’s lab and is now a postdoctoral fellow at Harvard. "All we have to remove is some hair."

The technique could eventually be used in human clinical trials, Hong said, but will need to be tweaked. First, the light penetration depth needs to be increased to pass deep into the human brain. Second, injecting carbon nanotubes needs approval for clinical application; the scientists are currently investigating alternative fluorescent agents.

For now, though, the technique provides a new technique for studying human cerebral-vascular diseases, such as stroke and migraines, in animal models. Other research has shown that Alzheimer’s and Parkinson’s diseases might elicit – or be caused in part by – changes in blood flow to certain parts of the brain, Hong said, and NIR-IIa imaging might offer a means of better understanding the role of healthy vasculature in those diseases.

"We could also label different neuron types in the brain with bio-markers and use this to monitor how each neuron performs," Hong said. "Eventually, we might be able to use NIR-IIa to learn how each neuron functions inside of the brain."

(Image caption: Membranes containing monounsaturated (left) and polyunsaturated (right) lipids after adding dynamin and endophilin. In a few seconds membranes rich in polyunsaturated lipids undergo many fissions. Credit: © Mathieu Pinot)

Lipids boost the brain

Consuming oils with high polyunsaturated fatty acid content, in particular those containing omega-3s, is beneficial for the health. But the mechanisms underlying this phenomenon are poorly known. Researchers at the Institut de Pharmacologie Moléculaire et Cellulaire (CNRS/Université Nice Sophia Antipolis), the Unité Compartimentation et Dynamique Cellulaires (CNRS/Institut Curie/UPMC), the INSERM and the Université de Poitiers investigated the effect of lipids bearing polyunsaturated chains when they are integrated into cell membranes. Their work shows that the presence of these lipids makes the membranes more malleable and therefore more sensitive to deformation and fission by proteins. These results, published on August 8, 2014 in Science, could help explain the extraordinary efficacy of endocytosis in neuron cells.

Consuming polyunsaturated fatty acids (such as omega-3 fatty acids) is good for the health. The effects range from neuronal differentiation to protection against cerebral ischemia. However the molecular mechanisms underlying these effects are poorly understood, prompting researchers to focus on the role of these fatty acids in cell membrane function.

For a cell to function properly, the membrane must be able to deform and divide into small vesicles. This phenomenon is called endocytosis. Generally, these vesicles allow the cells to encapsulate molecules and transport them. In neurons, these synaptic vesicles will act as a transmission pathway to the synapse for nerve messages. They are formed inside the cell, then they move to its exterior and fuse with its membrane, to transmit the neurotransmitters that they contain. Then they reform in less than a tenth of a second: this is synaptic recycling.

In the work published in Science, the researchers show that cell-or artificial membranes rich in polyunsaturated lipids are much more sensitive to the action of two proteins, dynamin and endophilin, which facilitate membrane deformation and fission.Other measurements in the study and in simulations suggest that these lipids also make the membranes more malleable. By facilitating the deformation and scission necessary for endocytosis, the presence of polyunsaturated lipids could explain rapid synaptic vesicle recycling. The abundance of these lipids in the brain could then represent a major advantage for cognitive function.

This work partially sheds light on the mode of action of omega-3. Considering that the body cannot synthesize them and that they can only be supplied by a suit able diet (rich in oily fish, etc.), it seems important to continue this work to understand the link between the functions performed by these lipids in the neuronal membrane and their health benefits.

Musical Training Offsets Some Academic Achievement Gaps

Learning to play a musical instrument or to sing can help disadvantaged children strengthen their reading and language skills, according to research presented at the American Psychological Association’s 122nd Annual Convention.

The findings, which involved hundreds of kids participating in musical training programs in Chicago and Los Angeles public schools, highlight the role learning music can have on the brains of youth in impoverished areas, according to presenter Nina Kraus, PhD, a neurobiologist at Northwestern University.

“Research has shown that there are differences in the brains of children raised in impoverished environments that affect their ability to learn,” said Kraus. “While more affluent students do better in school than children from lower income backgrounds, we are finding that musical training can alter the nervous system to create a better learner and help offset this academic gap.” Up until now, research on the impact of musical training has been primarily conducted on middle- to upper-income music students participating in private music lessons, she said.

Kraus’s lab research has concluded that musical training appears to enhance the way children’s nervous systems process sounds in a busy environment, such as a classroom or a playground. This improved neural function may lead to enhanced memory and attention spans which, in turn, allow kids to focus better in the classroom and improve their communication skills, she said.

Many of Kraus’s study participants are part of the Harmony Project in Los Angeles, which was founded by fellow presenter Margaret Martin, DrPH. In her most recent research, Kraus studied children beginning when they were in first and second grade. Half participated in musical training and the other half were randomly selected from the program’s lengthy waiting list and received no musical training during the first year of the study. Children who had no musical training had diminished reading scores while Harmony Project participants’ reading scores remained unchanged over the same time span. 

Kraus’s lab also found that, after two years, neural responses to sound in adolescent music students were faster and more precise than in students in another type of enrichment class. The researchers tested the auditory abilities in adolescents from lower economic backgrounds at three public high schools in Chicago. Over two years, half of the students participated in either band or choir during each school day while the other half were enrolled in Junior Reserve Officer’s Training Corps classes, which teaches character education, achievement, wellness, leadership and diversity. All participants had comparable reading ability and IQs at the start of the study. The researchers recorded the children’s brain waves as they listened to a repeated syllable against soft background sound, which made it harder for the brain to process. The researchers repeated measures after one year and again at the two-year mark. They found music students’ neural responses had strengthened while the JROTC students’ responses had remained the same. Interestingly, the differences in the music students’ brain waves in response to sounds as described above occurred after two years but not at one year, which showed that these programs cannot be used as quick fixes, Kraus said. This is the strongest evidence to date that public school music education in lower-income students can lead to better sound processing in the brain when compared to other types of enrichment education, she added.

Even after the lessons stop, the brain still reaps benefits, according to studies on the long-term benefits of music lessons. In one study, Kraus’s team surveyed college students and asked them how many years they had music training. As they found with the elementary school students, college students who had more than five years of musical training in elementary school or high school had improved neural responses to sound when compared to college students who had had no musical training.

The Harmony Project provides instruments for the students who participate five or more hours a week in musical instruction and ensemble rehearsals. The project is year-round and tuition-free based on income, said Martin. Many of the programs build full-time bands in neighborhoods where the students live and the students agree to commit to the program from elementary school through high school, she said.

“We’re spending millions of dollars on drugs to help kids focus and here we have a non-pharmacologic intervention that thousands of disadvantaged kids devote themselves to in their non-school hours — that works,” Martin said. “Learning to make music appears to remodel our kids’ brains in ways that facilitates and improves their ability to learn.”

The Harmony Project has launched programs in other urban school districts, including Miami, New Orleans, Tulsa, Oklahoma, Kansas City, Missouri and Ventura, California.

(Image: Shutterstock)

How we form habits and change existing ones

Much of our daily lives are taken up by habits that we’ve formed over our lifetime. An important characteristic of a habit is that it’s automatic— we don’t always recognize habits in our own behavior. Studies show that about 40 percent of people’s daily activities are performed each day in almost the same situations. Habits emerge through associative learning. “We find patterns of behavior that allow us to reach goals. We repeat what works, and when actions are repeated in a stable context, we form associations between cues and response,” Wendy Wood explains in her session at the American Psychological Association’s 122nd Annual Convention.

What are habits?

Wood calls attention to the neurology of habits, and how they have a recognizable neural signature. When you are learning a response you engage your associative basal ganglia, which involves the prefrontal cortex and supports working memory so you can make decisions. As you repeat the behavior in the same context, the information is reorganized in your brain. It shifts to the sensory motor loop that supports representations of cue response associations, and no longer retains information on the goal or outcome. This shift from goal directed to context cue response helps to explain why our habits are rigid behaviors.

There is a dual mind at play, Wood explains. When our intentional mind is engaged, we act in ways that meet an outcome we desire and typically we’re aware of our intentions. Intentions can change quickly because we can make conscious decisions about what we want to do in the future that may be different from the past. However, when the habitual mind is engaged, our habits function largely outside of awareness. We can’t easily articulate how we do our habits or why we do them, and they change slowly through repeated experience. “Our minds don’t always integrate in the best way possible. Even when you know the right answer, you can’t make yourself change the habitual behavior,” Wood says.

Participants in a study were asked to taste popcorn, and as expected, fresh popcorn was preferable to stale. But when participants were given popcorn in a movie theater, people who have a habit of eating popcorn at the movies ate just as much stale popcorn as participants in the fresh popcorn group. “The thoughtful intentional mind is easily derailed and people tend to fall back on habitual behaviors. Forty percent of the time we’re not thinking about what we’re doing,” Wood interjects. “Habits allow us to focus on other things…Willpower is a limited resource, and when it runs out you fall back on habits.”

How can we change our habits?

Public service announcements, educational programs, community workshops, and weight-loss programs are all geared toward improving your day-to-day habits. But are they really effective? These standard interventions are very successful at increasing motivation and desire. You will almost always leave feeling like you can change and that you want to change. The programs give you knowledge and goal-setting strategies for implementation, but these programs only address the intentional mind.

In a study on the “Take 5” program, 35 percent of people polled came away believing they should eat 5 fruits and vegetables a day. Looking at that result, it appears that the national program was effective at teaching people that it’s important to have 5 servings of fruits and vegetables every day. But the data changes when you ask what people are actually eating. Only 11 percent of people reported that they met this goal. The program changed people’s intentions, but it did not overrule habitual behavior.

According to Wood, there are three main principles to consider when effectively changing habitual behavior. First, you must derail existing habits and create a window of opportunity to act on new intentions. Someone who moves to a new city or changes jobs has the perfect scenario to disrupt old cues and create new habits. When the cues for existing habits are removed, it’s easier to form a new behavior. If you can’t alter your entire environment by switching cities— make small changes. For instance, if weight-loss or healthy eating is your goal, try moving unhealthy foods to a top shelf out of reach, or to the back of the freezer instead of in front.

The second principle is remembering that repetition is key. Studies have shown it can take anywhere from 15 days to 254 days to truly form a new habit. “There’s no easy formula for how long it takes,” Wood says. Lastly, there must be stable context cues available in order to trigger a new pattern. “It’s easier to maintain the behavior if it’s repeated in a specific context,” Wood emphasizes. Flossing after you brush your teeth allows the act of brushing to be the cue to remember to floss. Reversing the two behaviors is not as successful at creating a new flossing habit. Having an initial cue is a crucial component.

(Image caption: MRI scans showing brain damage in the stroke patients before treatment. Source: Stem Cells Translational Medicine.)

Stem cells show promise for stroke in pilot study

A stroke therapy using stem cells extracted from patients’ bone marrow has shown promising results in the first trial of its kind in humans.

Five patients received the treatment in a pilot study conducted by doctors at Imperial College Healthcare NHS Trust and scientists at Imperial College London.

The therapy was found to be safe, and all the patients showed improvements in clinical measures of disability.

The findings are published in the journal Stem Cells Translational Medicine. It is the first UK human trial of a stem cell treatment for acute stroke to be published.

The therapy uses a type of cell called CD34+ cells, a set of stem cells in the bone marrow that give rise to blood cells and blood vessel lining cells. Previous research has shown that treatment using these cells can significantly improve recovery from stroke in animals. Rather than developing into brain cells themselves, the cells are thought to release chemicals that trigger the growth of new brain tissue and new blood vessels in the area damaged by stroke.

The patients were treated within seven days of a severe stroke, in contrast to several other stem cell trials, most of which have treated patients after six months or later. The Imperial researchers believe early treatment may improve the chances of a better recovery.

A bone marrow sample was taken from each patient. The CD34+ cells were isolated from the sample and then infused into an artery that supplies the brain. No previous trial has selectively used CD34+ cells, so early after the stroke, until now.

Although the trial was mainly designed to assess the safety and tolerability of the treatment, the patients all showed improvements in their condition in clinical tests over a six-month follow-up period.

Four out of five patients had the most severe type of stroke: only four per cent of people who experience this kind of stroke are expected to be alive and independent six months later. In the trial, all four of these patients were alive and three were independent after six months.

Dr Soma Banerjee, a lead author and Consultant in Stroke Medicine at Imperial College Healthcare NHS Trust, said: “This study showed that the treatment appears to be safe and that it’s feasible to treat patients early when they might be more likely to benefit. The improvements we saw in these patients are very encouraging, but it’s too early to draw definitive conclusions about the effectiveness of the therapy. We need to do more tests to work out the best dose and timescale for treatment before starting larger trials.”

Over 150,000 people have a stroke in England every year. Survivors can be affected by a wide range of mental and physical symptoms, and many never recover their independence.

Stem cell therapy is seen as an exciting new potential avenue of treatment for stroke, but its exact role is yet to be clearly defined.

Dr Paul Bentley, also a lead author of the study, from the Department of Medicine at Imperial College London, said: “This is the first trial to isolate stem cells from human bone marrow and inject them directly into the damaged brain area using keyhole techniques. Our group are currently looking at new brain scanning techniques to monitor the effects of cells once they have been injected.”

Professor Nagy Habib, Principal Investigator of the study, from the Department of Surgery and Cancer at Imperial College London, said: “These are early but exciting data worth pursuing. Scientific evidence from our lab further supports the clinical findings and our aim is to develop a drug, based on the factors secreted by stem cells, that could be stored in the hospital pharmacy so that it is administered to the patient immediately following the diagnosis of stroke in the emergency room. This may diminish the minimum time to therapy and therefore optimise outcome. Now the hard work starts to raise funds for this exciting research.”

Discovery of new pathways controlling the serotonergic system

With the aid of new methods, a research team at Karolinska Institutet have developed a detailed map of the networks of the brain that control the neurotransmitter serotonin. The study, published in the scientific journal Neuron, may lead to new knowledge on a number of psychiatric conditions and the development of new pharmaceuticals.

The neurotransmitter serotonin controls impulsivity, mood and our cognitive functions, among other things, and comes from the serotonergic neurons – the neurons that produce serotonin. So that we have good mental health and normal behaviour, it is important that there is correctly regulated activity among these neurons. The activity is governed by other neurons from different regions of the brain via direct links, known as synapses, on the serotonergic neurons. Imbalance in the serotonergic system can lead to depression, Parkinson’s disease, schizophrenia and autism, among other things.

So far it has been impossible to study in detail how different types of nerve cells are interlinked and how the brain’s networks control behaviour. Consequently, there has also been a lack of knowledge of which nerve cells control the activity of the serotonergic neurons. But with the help of new methods, researchers at Karolinska Institutet can now investigate how the various networks of the brain are organised and how they work. The research team, led by Konstantinos Meletis of the Department of Neuroscience, has established which networks of the brain control the serotonergic neurons.

“We have been able to create a new type of map of the neurons’ contacts and discovered new pathways that control the serotonergic system. These networks were previously unknown and are very interesting in terms of how they help us to understand how the serotonergic system works, which could also help us to understand certain mental illnesses,” Konstantinos Meletis explains.

In order to map out which neurons have direct contact with serotonergic neurons, the researchers established a method in which these cells were marked with a rabies virus which produced a fluorescent marker. Via genetic manipulation, the rabies virus was then spread to all of the neurons directly linked to the serotonergic neurons. The researchers thereby gained a very detailed, three-dimensional image of the networks of the brain that control serotonin. Using optogenetics, a method in which light is used to control the activity of neurons, the researchers were then able to manipulate select networks and thus study their effect on the serotonergic neurons.

Via mapping, the researchers discovered a network in the frontal lobe which is associated with cognition and well-being and which controls the serotonergic neurons. Researchers also found that serotonin can be controlled from new types of neurons in the basal ganglia, an area of the cerebrum which among other things controls movement, well-being and decision-making; a discovery which may have significance for conditions such as Parkinson’s disease.

“We are very optimistic that the revolution we are now seeing in brain research could also lead to entirely new and effective medicine in the field of psychiatry,” Konstantinos Meletis explains.

Scientists unravel mystery of brain cell growth

In the developing brain, special proteins that act like molecular tugboats push or pull on growing nerve cells, or neurons, helping them navigate to their assigned places amidst the brain’s wiring.

How a single protein can exert both a push and a pull force to nudge a neuron in the desired direction is a longstanding mystery that has now been solved by scientists from Dana-Farber Cancer Institute and collaborators in Europe and China.

Jia-huai Wang, PhD, who led the work at Dana-Farber and Peking University in Beijing, is a corresponding author of a report published in the August 7 online edition of Neuron that explains how one guidance protein, netrin-1, can either attract or repel a brain cell to steer it along its course. Wang and co-authors at the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, used X-ray crystallography to reveal the three-dimensional atomic structure of netrin-1 as it bound to a docking molecule, called DCC, on the axon of a neuron. The axon is the long, thin extension of a neuron that connects to other neurons or to muscle cells.

As connections between neurons are established – in the developing brain and throughout life – axons grow out from a neuron and extend through the brain until they reach the neuron they are connecting to. To choose its path, a growing axon senses and reacts to different molecules it encounters along the way. One of these molecules, netrin-1, posed an interesting puzzle: an axon can be both attracted to and repelled from this cue. The axon’s behavior is determined by two types of receptors on its tip: DCC drives attraction, while UNC5 in combination with DCC drives repulsion.

“How netrin works at the molecular level has long been a puzzle in neuroscience field,” said Wang, “We now provide structure evidences that reveal a novel mechanism of this important guidance cue molecule.” The structure showed that netrin-1 binds not to one, but to two DCC molecules. And most surprisingly, it binds those two molecules in different ways.

“Normally a receptor and a signal are like lock-and-key, they have evolved to bind each other and are highly specific – and that’s what we see in one netrin site,” said Meijers. “But the second binding site is a very unusual one, which is not specific for DCC.”

Not all of the second binding site connects directly to a receptor. Instead, in a large portion of the binding interface, it requires small molecules that act as middle-men. These intermediary molecules seem to have a preference for UNC5, so if the axon has both UNC5 and DCC receptors, netrin-1 will bind to one copy of UNC5 via those molecules and the other copy of DCC at the DCC-specific site. This triggers a cascade of events inside the cell that ultimately drives the axon away from the source of netrin-1, author Yan Zhang’s lab at Peking University found. The researchers surmised that, if an axon has only DCC receptors, each netrin-1 molecule binds two DCC molecules, which results in the axon being attracted to netrin-1. “By controlling whether or not UNC5 is present on its tip, an axon can switch from moving toward netrin to moving away from it, weaving through the brain to establish the right connection,” said Zhang.

Knowing how neurons switch from being attracted to netrin to being repelled opens the door to devise ways of activating that switch in other cells that respond to netrin cues, too. For instance, many cancer cells produce netrin to attract growing blood vessels that bring them nourishment and allow the tumor to grow, so switching off that attraction could starve the tumor, or at least prevent it from growing.

On the other hand, when cancers metastasize they often stop being responsive to netrin. In fact, the DCC receptor was first identified as a marker for an aggressive form of colon cancer, and DCC stands for “deleted in colorectal cancer.” Since colorectal cancer cells have no DCC, they are ‘immune’ to the programmed cell death that would normally follow once they move away from the lining of the gut and no longer have access to netrin. As a result, these tumor cells continue to move into the bloodstream, and metastasize to other tissues. “Therefore, to understand the molecular mechanism of how netrin works should also have a good impact in cancer biology,” said Wang.

The guidance issue is a very complicated cell biology problem. Meijers, Zhang, Wang and their colleagues are now investigating how other receptors bind to netrin-1, exactly how the intermediary molecules ‘choose’ their preferred receptor, how other guidance molecule binds to DCC, and how the system is regulated. The answers could one day enable researchers to steer a cell’s response to netrin and other guidance cues, ultimately changing its fate.