Microglia controls neuron production as brain develops

In a surprise breakthrough, researchers at the UC Davis MIND Institute and their colleagues have found that microglia remove healthy neural progenitor cells (NPCs) through phagocytosis to control neuron production during brain development. This newly discovered mechanism keeps neuron numbers in check, preventing brain overgrowth.

The discovery could open up new avenues for brain research and lead to therapies for a variety of neurological conditions.

The study was published online in the The Journal of Neuroscience.

Microglia are the immune component cell of the central nervous system. Similar to macrophages, microglia provide the brain’s primary defense against pathogens and foreign bodies, clear away dying cells and help repair neural damage. When inactive, they act as sentinels. When a problem is located, they activate and eliminate it. However, until recently, no one had realized the important roles they play in brain development.

"We have known for some time that neurons can undergo apoptosis, a form of cell death, and ultimately be removed by microglia," said Stephen Noctor, assistant professor in the Department of Psychiatry and Behavioral Sciences and the study’s lead author. "But this is new. Microglia are actually eating healthy progenitor cells, thereby regulating the number of neurons produced in the developing brain."

During development, NPCs produce neurons in the brain’s proliferative zones. However, creating too many or too few neurons can have dire consequences.

"If you have too many cells, there’s only so much trophic support (brain infrastructure for cell growth and survival) to keep neurons alive," Noctor said. "All these cells competing for resources could easily throw off connectional properties, altering the way surviving neurons interact. Likewise, having too few cortical cells would have profoundly negative consequences."

(Image: Antoine Triller, Alain Bessis & Serge Marty - Département de Biologie, ENS)

'Network' analysis of the brain may explain features of autism

A look at how the brain processes information finds a distinct pattern in children with autism spectrum disorders. Using EEGs to track the brain’s electrical cross-talk, researchers from Boston Children’s Hospital have found a structural difference in brain connections. Compared with neurotypical children, those with autism have multiple redundant connections between neighboring brain areas at the expense of long-distance links.

The study, using a “network analysis” like that used to study airlines or electrical grids, may help in understanding some classic behaviors in autism. It was published February 27 in BioMed Central’s open access journal BMC Medicine, accompanied by a commentary.

"We examined brain networks as a whole in terms of their capacity to transfer and process information," says Jurriaan Peters, MD, of the Department of Neurology at Boston Children’s Hospital, who is co-first author of the paper with Maxime Taquet, a PhD student in Boston Children’s Computational Radiology Laboratory. "What we found may well change the way we look at the brains of autistic children."

Peters, Taquet and senior authors Simon Warfield, PhD, of the Computational Radiology Laboratory and Mustafa Sahin, MD, PhD, of Neurology, analyzed EEG recordings from two groups of autistic children: 16 children with classic autism, and 14 children whose autism is part of a genetic syndrome known as tuberous sclerosis complex (TSC). They compared these readings with EEGs from two control groups—46 healthy neurotypical children and 29 children with TSC but not autism.

In both groups with autism, there were more short-range connections within different brain region, but fewer connections linking far-flung areas.

A brain network that favors short-range over long-range connections seems to be consistent with autism’s classic cognitive profile—a child who excels at specific, focused tasks like memorizing streets, but who cannot integrate information across different brain areas into higher-order concepts.

"For example, a child with autism may not understand why a face looks really angry, because his visual brain centers and emotional brain centers have less cross-talk," Peters says. "The brain cannot integrate these areas. It’s doing a lot with the information locally, but it’s not sending it out to the rest of the brain."

Discovery on animal memory opens doors to research on memory impairment diseases

If you ask a rat whether it knows how it came to acquire a certain coveted piece of chocolate, Indiana University neuroscientists conclude, the answer is a resounding, “Yes.” A study newly published in the journal Current Biology offers the first evidence of source memory in a nonhuman animal.

The findings have “fascinating implications,” said principal investigator Jonathon Crystal, both in evolutionary terms and for future research into the biological underpinnings of memory, as well as the treatment of diseases marked by memory failure such as Alzheimer’s, Parkinson’s and Huntington’s, or disorders such as schizophrenia, PTSD and depression.

The study further opens up the possibility of creating animal models of memory disorders.

"Researchers can now study in animals what was once thought an exclusively human domain," said Crystal, professor in the Department of Psychological and Brain Sciences in the College of Arts and Sciences. "If you can export types of behaviors such as source memory failures to transgenic animal models, you have the ability to produce preclinical models for the treatment of diseases such as Alzheimer’s."

Of the various forms of memory identified by scientists, some have long been considered distinctively human. Among these is source memory. When someone retells a joke to the person who told it to him, it is an everyday example of source memory failure. The person telling the joke forgot the source of the information — how he acquired it — though not the information he was told. People combine source information to construct memories of discrete events and to distinguish one event or episode from another.

Nonhuman animals, by contrast, have been thought to have limited forms of memory, acquired through conditioning and repetition, habits rather than conscious memories. The kind of memory failures most devastating to those directly affected by Alzheimer’s have typically been considered beyond the scope of nonhuman minds.

The study owes much to another quality these rodents share with humans: They love chocolate. “There’s no amount of chocolate you can give to a rat which will stop it from eating more chocolate,” Crystal said.

Research shows why not everyone learns from their mistakes

Some people do not learn from their mistakes because of the way their brain works, according to research led by an academic at Goldsmiths, University of London.

The research, led by Professor Joydeep Bhattacharya in the Department of Psychology at Goldsmiths, examined what it is about the brain that defines someone as a ‘good learner’ from those who do not learn from their mistakes.

Professor Bhattacharya said: “We are always told how important it is to learn from our errors, our experiences, but is this true? If so, then why do we all not learn from our experiences in the same way? It seems some people rarely do, even when they were informed of their errors in repeated attempts.

"This study presents a first tantalising insight into how our brain processes the performance feedback and what it does with this information, whether to learn from it or to brush it aside."

The study, published in a recent issue of the Journal of Neuroscience, investigated brainwave patterns of 36 healthy human volunteers performing a simple time estimation task. Researchers asked the participants to estimate a time interval of 1.7 seconds and provided feedback on their errors. The participants were then measured to see whether they incorporated the feedback to improve their future performances.

'Good learners', who were successful in incorporating the feedback information in adjusting their future performance, presented increased brain responses as fast as 200 milliseconds after the feedback on their performance was presented on a computer screen.

This brain response was weaker in the poor learners who did not learn the task well and who showed decreased responses to their performance errors. The researchers further found that the good learners showed increased communication between brain areas involved with performance monitoring and sensorimotor processes.

Caroline Di Bernardi Luft, one of the research paper’s co-authors from the Federal University of Santa Catarina, commented: “Good learners used the feedback not only to check their past performance, but also to adjust their next performance accordingly.”

The brain responses correlated highly with how well the volunteers learned this simple task over the course of the experiment, and how good they were at maintaining the learned skill without any guiding feedback.

"Though these results are very encouraging in establishing a correlation between brains responses and learning performance, future studies are needed to identify a causal role of these effects," Professor Bhattacharya added.

Songbirds’ brains coordinate singing with intricate timing

As a bird sings, some neurons in its brain prepare to make the next sounds while others are synchronized with the current notes—a coordination of physical actions and brain activity that is needed to produce complex movements, new research at the University of Chicago shows.

In an article in the current issue of Nature, neuroscientist Daniel Margoliash and colleagues show, for the first time, how the brain is organized to govern skilled performance—a finding that may lead to new ways of understanding human speech production.

The new study shows that birds’ physical movements actually are made up of a multitude of smaller actions. “It is amazing that such small units of movements are encoded, and so precisely, at the level of the forebrain,” said Margoliash, a professor of organismal biology and anatomy and psychology at UChicago.

“This work provides new insight into how the physics of controlling vocal signals are represented in the brain to control vocalizations,” said Howard Nusbaum, a professor of psychology at UChicago and an expert on speech.

By decoding the neural representation of communication, Nusbaum explained, the research may shed light on speech problems such as stuttering or aphasia (a disorder following a stroke). And it offers an unusual window into how the brain and body carry out other kinds of complex movement, from throwing a ball to doing a backflip.

“A big question in muscle control is how the motor system organizes the dynamics of movement,” said Margoliash. Movements like reaching or grasping are difficult to study because they entail many variables, such as the angles of the shoulder, elbow, wrist and fingers; the forces of many muscles; and how these change over time,” he said.

"With all this complexity, it has been difficult to determine which of the many variables that describe movements are represented in the brain, and which of those are used to control movements," he said.

"It’s difficult to find a natural framework with which to analyze the activity of single neurons. The bird study provided us a perfect opportunity,” Margoliash said. Margoliash is a pioneer in the study of brain function in birds, with studies that include how learning occurs when a bird sleeps and recalls singing a song.

The great orchestral work of speech

What goes on inside our heads is similar to an orchestra. For Peter Hagoort, Director at the Max Planck Institute for Psycholinguistics, this image is a very apt one for explaining how speech arises in the human brain. “There are different orchestra members and different instruments, all playing in time with each other, and sounding perfect together.”

When we speak, we transform our thoughts into a linear sequence of sounds. When we understand language, exactly the opposite occurs: we deduce an interpretation from the speech sounds we hear. Closely connected regions of the brain – like the Broca’s area and Wernicke’s area – are involved in both processes, and these form the neurobiological basis of our capacity for language.

The 58-year-old scientist, who has had a strong interest in language and literature since his youth, has been searching for the neurobiological foundations of our communication since the 1990s. Using imaging processes, he observes the brain “in action” and tries to find out how this complex organ controls the way we speak and understand speech.

Making language visible

Hagoort is one of the first researchers to combine psychological theories with neuroscientific methods in his efforts to understand this complex interaction. Because this is not possible without the very latest technology, in 1999, Hagoort established the Nijmegen-based Donders Centre for Cognitive Neuroimaging where an interdisciplinary team of researchers uses state-of-the-art technology, for example MRI and PET scanners, to find out how the brain succeeds in combining functions like memory, speech, observation, attention, feelings and consciousness.

The Dutch scientist is particularly fascinated by the temporal sequence of speech. He discovered, for example, that the brain begins by collecting grammatical information about a word before it compiles information about its sound. This first reliable real-time measurement of speech production in the brain provided researchers with a basis for observing speakers in the act of speaking. They were then able to obtain new insights about why the complex orchestral work of language is impaired, for example, after strokes and in the case of disorders like dyslexia and autism.

“Language is an essential component of human culture, which distinguishes us from other species,” says Hagoort. “Young children understand language before they even start to speak. They master complex grammatical structures before they can add 3 and 13. Our brain is tuned for language at a very early stage,” stresses Hagoort, referring to research findings. The exact composition of the orchestra in our heads and the nature of the score on which the process of speech is based are topics which Hagoort continues to research.

Homer prevents stress-induced cognitive deficits

Before examinations and in critical situations, we need to be particularly receptive and capable of learning. However, acute exam stress and stage fright causes learning blockades and reduced memory function. Scientists from the Max Planck Institute of Psychiatry in Munich have now discovered a mechanism responsible for these cognitive deficits, which functions independently of stress hormones. In animal studies, the researchers show that social stress reduces the volume of Homer-1 in the hippocampus – a region of the brain that plays a central role in learning. This specific protein deficiency leads to altered neuronal activity followed by deterioration in the animals’ learning performance. In the experiments, it was possible to prevent the cognitive deficit by administering additional volumes of the protein to the mice. This suggests that Homer-1 could provide a key molecule for the development of drugs for the treatment of stress-induced cognitive deficits.

Klaus Wagner, a scientist at the Max Planck Institute of Psychiatry, studied the learning behaviour of mice that had been subjected to severe stress. He exposed the animals to social stress – a pressure also frequently experienced by humans today. A male mouse was placed in the cage of an aggressive member of the same species for five minutes. The latter tried to banish the “intruder” by attacking it. Unlike in nature, the test mouse was unable to flee from the cage and was under severe stress, as substantiated by measurements of the stress hormones in its blood.

Following a period of eight hours in which the animal was able to recover in its own cage, its behaviour was examined. While the mouse’s motivation, activity and sensory functions were not impaired at this time, it displayed clear deficits in its learning behaviour. A single five-minute situation of social stress was sufficient, therefore, to impair the animal’s learning performance hours later.

The researchers at the Max Planck Institute then tried to establish which mechanisms were responsible for these cognitive deficits. They identified the protein Homer-1, the concentration of which declines specifically in the hippocampus after exposure to stress. Through its interaction with the neuronal messenger substance glutamate and its receptors, Homer-1 modulates the communication in the neuronal synapses. When the volume of Homer-1 in the hippocampus falls after exposure to stress, the natural receptor activity is severely disrupted and learning capacity declines. The researchers were able to prevent this effect by increasing the Homer-1 concentration again.

Mathias Schmidt, Research Group Leader at the Max Planck Institute of Psychiatry interprets the results as follows: “With our study, we demonstrated the regulation of glutamate-mediated communication in the hippocampus, which directly controls learning behaviour. This mechanism functions independently of stress hormones for the most part. The molecule Homer-1 assumes a key role in this process and will hopefully provide new possibilities in future for targeted pharmaceutical intervention for the avoidance of cognitive deficits.”

Choosing Wisely: AAN Cites Five Things to Question

In 2012, the AAN joined the Choosing Wisely campaign, a project initiated by the American Board of Internal Medicine (ABIM) Foundation to promote appropriate medical decision-making and the stewardship of health care resources. The campaign is designed to help consumers and physicians engage in conversations about the overuse of particular tests, procedures, and treatments and to help patients make smart and effective care choices.

In February 2013, the AAN participated in a news conference with the ABIM Foundation and Consumer Reports, where medical specialties announced their lists of the top five questionable tests and procedures each selected for patients and physicians to consider.

Read AAN’s Five Things Physicians and Patients Should Question

The AAN’s complete recommendations were published online ahead of print in the February 21, 2013, issue of Neurology®.

How Neurology Tests and Procedures Were identified

The AAN established a Choosing Wisely Working Group to develop its list of recommendations. Members of this group were selected to broadly represent varying practice settings and neurological subspecialties. Neurologists with expertise in evidence-based medicine and a broad range of subspecialty disciplines were also included. The working group solicited recommendations from AAN members, which were then rated based upon their judgments of harm and benefit that would result based upon compliance with the recommendation. Based on committee voting and a literature review, candidate recommendations were sent to relevant AAN sections, committees, specialty societies and patient advocacy groups for review and comment. The working group reviewed this feedback and voted on the final top five recommendations, which were approved by the AAN Practice Committee and Board of Directors.

The great illusion of the self

As you wake up each morning, hazy and disoriented, you gradually become aware of the rustling of the sheets, sense their texture and squint at the light. One aspect of your self has reassembled: the first-person observer of reality, inhabiting a human body.

As wakefulness grows, so does your sense of having a past, a personality and motivations. Your self is complete, as both witness of the world and bearer of your consciousness and identity. You.

This intuitive sense of self is an effortless and fundamental human experience. But it is nothing more than an elaborate illusion. Under scrutiny, many common-sense beliefs about selfhood begin to unravel. Some thinkers even go as far as claiming that there is no such thing as the self.

In these articles, discover why “you” aren’t the person you thought you were.

Linking insulin to learning: Important insights in research with worms

Recent work by Harvard researchers demonstrates how the signaling pathway of insulin and insulinlike peptides plays a critical role in helping to regulate learning and memory.

The research, led by Yun Zhang, associate professor of organismic and evolutionary biology, is described in a Feb. 6 paper in Neuron.

“People think of insulin and diabetes, but many metabolic syndromes are associated with some types of cognitive defects and behavioral disorders, like depression or dementia,” Zhang said. “That suggests that insulin and insulinlike peptides may play an important role in neural function, but it’s been very difficult to nail down the underlying mechanism, because these peptides do not have to function through synapses that connect different neurons in the brain.”

To get at that mechanism, Zhang and colleagues turned to an organism whose genome and nervous system are well described and highly accessible by genetics: C. elegans.

Using genetic tools, researchers altered the transparent worms by removing their ability to create individual insulinlike compounds. These new “mutant” worms were then tested to see whether they would learn to avoid eating a particular type of bacteria that is known to infect the worms. Tests showed that although some worms did learn to steer clear of the bacteria, others didn’t — suggesting that removing a specific insulinlike compound halted the worms’ ability to learn.

Researchers were surprised to find, however, that it wasn’t just removing the molecules that could make the animals lose the ability to learn — some peptides were found to inhibit learning.

“We hadn’t predicted that we would find both positive and negative regulators from these peptides,” Zhang said. “Why does the animal need this bidirectional regulation of learning? One possibility is that learning depends on context. There are certain things you want to learn — for example, the worms in these experiments wanted to learn that they shouldn’t eat this type of infectious bacteria. That’s a positive regulation of the learning. But if they needed to eat, even if it is a bad food, to survive, they would need a way to suppress this type of learning.”

Even more surprising for Zhang and her colleagues was evidence that the various insulinlike molecules could regulate each other.

“Many animals, including humans, have multiple insulinlike molecules, and it appears that these molecules can act like a network,” she said. “Each of them may play a slightly different role in the nervous system, and they function together to coordinate the signaling related to learning and memory. By changing the way the molecules interact, the brain can fine-tune learning in a host of different ways.”