ScienceDaily (Mar. 29, 2012) — A type of cell plentiful in the brain, long considered mainly the stuff that holds the brain together and oft-overlooked by scientists more interested in flashier cells known as neurons, wields more power in the brain than has been realized, according to new research published March 29 in Science Signaling.

Human astrocytes. (Credit: Image courtesy of University of Rochester Medical Center)

Neuroscientists at the University of Rochester Medical Center report that astrocytes are crucial for creating the proper environment for our brains to work. The team found that the cells play a key role in reducing or stopping the electrical signals that are considered brain activity, playing an active role in determining when cells called neurons fire and when they don’t.

That is a big step forward from what scientists have long considered the role of astrocytes — to nurture neurons and keep them healthy.

"Astrocytes have long been called housekeeping cells — tending to neurons, nurturing them, and cleaning up after them," said Maiken Nedergaard, M.D., D.M.Sc., professor of Neurosurgery and leader of the study. "It turns out that they can influence the actions of neurons in ways that have not been realized."

Proper brain function relies on billions of electrical signals — tiny molecular explosions, really — happening remarkably in sync. Recalling the face of a loved one, swinging a baseball bat, walking down the street — all those actions rely on electrical signals passed instantly along our nerves like a molecular hot potato from one brain cell to another.

For that to happen, the molecular brew of chemicals like sodium, calcium and potassium that brain cells reside in must be just right — and astrocytes help to maintain that balanced environment. For instance, when a neuron sends an impulse, or fires, levels of potassium surrounding the cell jump dramatically, and those levels must come down immediately for the brain to work properly. Scientists have long known that that’s a job for astrocytes — sopping up excess potassium, ending the nerve pulse, and restoring the cells so they can fire again immediately.

In the paper in Science Signaling, Nedergaard’s team discovered an expanded role for astrocytes. The team learned that in addition to simply absorbing excess potassium, astrocytes themselves can cause potassium levels around the neuron to drop, putting neuronal signaling to a stop.

"Far from only playing a passive role, astrocytes can initiate the uptake of potassium in a way that affects neuronal activity," said Nedergaard. "It’s a simple, yet powerful mechanism for astrocytes to rapidly modulate neuronal activity."

Nedergaard has investigated the secret lives of astrocytes for more than two decades. She has shown how the cells communicate using calcium to signal. Nearly 20 years ago in a paper in Science, she pioneered the idea that glial cells like astrocytes communicate with neurons and affect them. Since then, has been a lot of speculation by other scientists that chemicals call gliotransmitters, such as glutamate and ATP, are key to this process.

In contrast, in the latest research Nedergaard’s team found that another signaling system involving potassium is at work. By sucking up potassium, astrocytes quell the firing of neurons, increasing what scientists call “synaptic fidelity.” Important brain signals are crisper and clearer because there is less unwanted activity or “chatter” among neurons that should not be firing. Such errant neuronal activity is linked to a plethora of disorders, including epilepsy, schizophrenia, and attention-deficit disorder.

"This gives us a new target for a disease like epilepsy, where signaling among brain cells is not as controlled as it should be," said Nedergaard, whose team is based in the Division of Glia Disease and Therapeutics of the Center for Translational Neuromedicine. of the Department of Neurosurgery

The first authors of the paper are Fushun Wang, Ph.D., research assistant professor of Neurosurgery; and graduate student Nathan Anthony Smith. They did much of the work by using a sophisticated laser-based system to monitor the activity of astrocytes in the living brain of rats and mice. The work by Smith, a graduate student in the University’s neuroscience program, was supported by a Kirschstein National Research Service Award from the National Institute of Neurological Disorders and Stroke (NINDS).

Other authors from Rochester include Takumi Fujita, Ph.D., post-doctoral associate; Takahiro Takano, Ph.D., assistant professor; Qiwu Xu, technical associate; and Lane Bekar, Ph.D., formerly research assistant professor, now at the University of Saskatchewan. Also contributing were Akemichi Baba of Hyogo University of Health Sciences in Japan, and Toshio Matsuda of Osaka University in Japan.

Nedergaard notes that the complexity and size of our astrocytes is one of few characteristics that differentiate our brains from rodents. Our astrocytes are bigger, faster, and much more complex in both structure and function. She has found that astrocytes contribute to conditions like stroke, Alzheimer’s, epilepsy, and spinal cord injury.

"Astrocytes are integral to the most sophisticated brain processes," she added.

Source: Science Daily

ScienceDaily (Mar. 29, 2012) — Certain genes and proteins that promote growth and development of embryos also play a surprising role in sending chemical signals that help adults learn, remember, forget and perhaps become addicted, University of Utah biologists have discovered.

This is a microscope image of the roundworm or nematode C. elegans with its nervous system glowing green due to labeling with a green jellyfish protein. (Credit: Penelope Brockie, University of Utah.)

"We found that these molecules and signaling pathways [named Wnt] do not retire after development of the organism, but have a new and surprising role in the adult. They are called back to action to change the properties of the nervous system in response to experience," says biology Professor Andres Villu Maricq, senior author of the new study in the March 30 issue of the journal Cell.

The study was performed in C. elegans — the millimeter-long roundworm or nematode — which has a nervous system that serves as a model for those of vertebrate animals, including humans.

Because other Wnt pathways in worms are known to work in humans too, the researchers believe that Wnt genes, the Wnt proteins they produce and so-called “Wnt signaling” also are involved in human learning, memory and forgetting.

"Almost certainly what we have discovered is going on in our brain as well," Maricq says. And because a worm nerve-signal "receptor" in the study is analogous to a human nicotine receptor involved in addiction, schizophrenia and some other mental disorders, some of the genes identified in the worm study "represent possible new targets for treatment of schizophrenia and perhaps addiction," he adds.

Wnt genes and their proteins already were known to “pattern the development and distribution of organs in the body” during embryo development, and to be responsible for various cancers and developmental defects when mutated, he says.

Maricq conducted the study with these Utah biologists: doctoral students Michael Jensen and Dane Maxfield; postdoctoral researchers Michael M. Francis, Frederic Hoerndli and Rui Wang; undergraduate Erica Johnson; Penelope Brockie, a research associate professor; and David M. Madsen, a senior research specialist.

Read more …

March 29, 2012

(Medical Xpress) — Brain stimulation can markedly improve people’s ability to solve highly complex problems, a recent University of Sydney study suggests.

(L-R) Professor Allan Snyder and Richard Chi found brain stimulation helped people solve a puzzle.

The findings by Professor Allan Snyder and Richard Chi, from the University of Sydney, are published in Neuroscience Letters.

"The results suggest non-invasive brain stimulation could assist people in solving tasks that appear straightforward but are inherently difficult," said Professor Snyder.

Our minds have evolved to solve certain problems effortlessly, yet we struggle to solve others that appear simple but require us to apply an unfamiliar paradigm, to ‘think outside the box’.

The famous ‘nine dots puzzle’. Can you join them using only four straight lines without taking your pen off the page?

"As an example we have taken the famous nine dots problem, where you are asked to join all the dots with four straight lines without taking the pen off the page," Professor Snyder said.

"Surprisingly, investigations over the last century show that almost no one can do this."

Now the researchers have shown that more than 40 percent of the people they tested were able to solve the nine dots problem after receiving 10 minutes of safe, non-invasive brain stimulation.

Specifically the left anterior temporal lobe of the brain is inhibited while simultaneously the right anterior temporal lobe is excited, employing a technique known as transcranial direct current stimulation.

Using the same procedure the researchers have previously reported success in amplifying insight and memory.

Chi and Snyder suggest that their unique brain stimulation protocol could ultimately enable people to “escape the tricks our minds impose on us,” as Professor Snyder describes it, and solve tasks that appear deceptively simple.

Provided by University of Sydney

Source: medicalxpress.com

March 29, 2012

The first atlas of the surface of the human brain based upon genetic information has been produced by a national team of scientists, led by researchers at the University of California, San Diego School of Medicine and the VA San Diego Healthcare System. The work is published in the March 30 issue of the journal Science.

This is a genetic clustering map of the brain, left lateral view. Credit: UC San Diego School of Medicine

The atlas reveals that the cerebral cortex – the sheet of neural tissue enveloping the brain – is roughly divided into genetic divisions that differ from other brain maps based on physiology or function. The genetic atlas provides scientists with a new tool for studying and explaining how the brain works, particularly the involvement of genes.

"Genetics are important to understanding all kinds of biological phenomena," said William S. Kremen, PhD, professor of psychiatry at the UC San Diego School of Medicine and co-senior author with Anders M. Dale, PhD, professor of radiology, neurosciences, and psychiatry, also at the UC San Diego School of Medicine.

According to Chi-Hua Chen, PhD, first author and a postdoctoral fellow in the UC San Diego Department of Psychiatry, “If we can understand the genetic underpinnings of the brain, we can get a better idea of how it develops and works, information we can then use to ultimately improve treatments for diseases and disorders.”

The human cerebral cortex, characterized by distinctive twisting folds and fissures called sulci, is just 0.08 to 0.16 inches thick, but contains multiple layers of interconnected neurons with key roles in memory, attention, language, cognition and consciousness.

Other atlases have mapped the brain by cytoarchitecture – differences in tissues or function. The new map is based entirely upon genetic information derived from magnetic resonance imaging (MRI) of 406 adult twins participating in the Vietnam Era Twin Registry (VETSA), an ongoing longitudinal study of cognitive aging supported in part by grants from the National Institutes of Health (NIH). It follows a related study published last year by Kremen, Dale and colleagues that affirmed the human cortical regionalization is similar to and consistent with patterns found in other mammals, evidence of a common conservation mechanism in evolution.

"We are excited by the development of this new atlas, which we hope will help us understand aging-related changes in brain structure and cognitive function now occurring in the VETSA participants," said Jonathan W. King, PhD, of the National Institute on Aging, part of the NIH.

The atlas plots genetic correlations between different points on the cortical surface of the twins’ brains. The correlations represent shared genetic influences and reveal that genetic brain divisions do not map one-to-one with traditional brain divisions that are based on structure and function. “Yet, the pattern of this genetic map still suggests that it is neuroanatomically meaningful,” said Kremen.

Kremen said the genetic brain atlas may be especially useful for scientists who employ genome-wide association studies, a relatively new tool that looks for common genetic variants in people that may be associated with a particular trait, condition or disease.

Provided by University of California - San Diego

Source: medicalxpress.com

March 29, 2012

The brain appears to be wired more like the checkerboard streets of New York City than the curvy lanes of Columbia, Md., suggests a new brain imaging study. The most detailed images, to date, reveal a pervasive 3D grid structure with no diagonals, say scientists funded by the National Institutes of Health.

Curvature in this DSI image of a whole human brain turns out to be folding of 2-D sheets of parallel neuronal fibers that cross paths at right angles. This picture came from the new Connectom scanner. Credit: Van Wedeen, M.D., Martinos Center and Dept. of Radiology, Massachusetts General Hospital and Harvard University Medical School

"Far from being just a tangle of wires, the brain’s connections turn out to be more like ribbon cables — folding 2D sheets of parallel neuronal fibers that cross paths at right angles, like the warp and weft of a fabric," explained Van Wedeen, M.D., of Massachusetts General Hospital (MGH), A.A. Martinos Center for Biomedical Imaging and the Harvard Medical School. "This grid structure is continuous and consistent at all scales and across humans and other primate species."

Wedeen and colleagues report new evidence of the brain’s elegant simplicity March 30, 2012 in the journal Science. The study was funded, in part, by the NIH’s National Institute of Mental Health (NIMH), the Human Connectome Project of the NIH Blueprint for Neuroscience Research, and other NIH components.

"Getting a high resolution wiring diagram of our brains is a landmark in human neuroanatomy," said NIMH Director Thomas R. Insel, M.D. "This new technology may reveal individual differences in brain connections that could aid diagnosis and treatment of brain disorders."

Read more …

March 28, 2012 By Kimm Fesenmaier

(Medical Xpress) — When jurors sentencing convicted criminals are instructed to weigh not only facts but also tricky emotional factors, they rely on parts of the brain associated with sympathy and making moral judgments, according to a new paper by a team of neuroscientists. Using brain-imaging techniques, the researchers, including Caltech’s Colin Camerer, found that the most lenient jurors show heightened levels of activity in the insula, a brain region associated with discomfort and pain and with imagining the pain that others feel.

The findings provide insight into the role that emotion plays in jurors’ decision-making processes, indicating a close relationship between sympathy and mitigation.

In the study, the researchers, led by Makiko Yamada of National Institute of Radiological Sciences in Japan, considered cases where juries were given the option to lessen the sentences for convicted murderers. In such cases with “mitigating circumstances,” jurors are instructed to consider factors, sometimes including emotional elements, that might cause them to have sympathy for the criminal and, therefore, shorten the sentence. An example would be a case in which a man killed his wife to spare her from a more painful death, say, from a terminal illness. 

"Finding out if jurors are weighing sympathy reasonably is difficult to do, objectively," says Colin Camerer, the Robert Kirby Professor of Behavioral Finance and Economics at Caltech. "Instead of asking the jurors, we asked their brains."

The researchers scanned the brains of citizens (potential jurors) while the participants read scenarios adapted from actual murder cases with mitigating circumstances. In some cases, the circumstances were sympathy-inducing; in others, where, for example, a man became enraged when an ex-girlfriend refused him, they were not. The scientists used functional magnetic resonance imaging (fMRI), a type of brain scanning that tracks increases in oxygenated blood flow, indicating heightened brain activity. The participants also had their brains scanned when they determined whether to lessen the sentences, and by how much.  

The team found that sympathy activated the dorsomedial prefrontal cortex, precuneus, and temporo-parietal junction—brain regions associated with moral conflict and thinking about the feelings of others. Similarly, the jurors had increased activity in these regions during sentencing when the mitigating circumstances earned their sympathy. In those cases, they also delivered shorter hypothetical sentences.

In addition to Camerer and Yamada, coauthors on the new paper, “Neural circuits in the brain that are activated when mitigating criminal sentences,” are Saori Fujie, Harumasa Takano, Hiroshi Ito, Tetsuya Suhara, and Hidehiko Takahashi of the National Institute of Radiological Sciences; Motoichiro Kato of the Keio University of Medicine; and Tetsuya Matsuda of Tamagawa University Brain Science Institute. Yamada is also affiliated with Tamagawa University Brain Science Institute and Kyoto University School of Medicine; she and Takahashi are additionally affiliated with the Japan Science and Technology Agency.

More information: Neural circuits in the brain that are activated when mitigating criminal sentences 

Provided by California Institute of Technology

Source: medicalxpress.com

March 28, 2012 by Stuart Mason Dambrot

(Medical Xpress) — College and cramming – often where’s there’s one, the other is not far behind. That said, however, it has been recognized since the late 1800s that repeated periodic exposure to the same material leads to better retention than does a single en masse session. Nevertheless, the phenomenon’s neurobiological processes have remained poorly understood, although activity-dependent synaptic plasticity – notably long-term potentiation (LTP) of glutamatergic transmission – is believed to enable rapid storage of new information. Recently, researchers at the University of California in Irvine and the Scripps Research Institute in Jupiter, Florida determined that hippocampal activity can enhance LTP through theta burst stimulation (TBS) – but only when the affected synapses receive, after a long delay, a secondary TBS. The researchers describe mechanisms that maximize synaptic changes that optimally encode new memory by requiring long delays learning-related TBS activity.

A second theta burst train expands the pool of F-actin-enriched spines. (A) Fluorescent phalloidin labeling in CA1 stratum radiatum. (Scale bar = 10 μm). (B) Counts of densely phalloidin-positive spines in slices collected 15 or 75 min after TBS1 (gray bars) or 15 min after TBS2 delayed by 60 min (black bar). (C) Traces show responses to two successive bursts separated by 200 ms (red for second response). (D) Counts of TBS1-induced phalloidin labeling for vehicle (gray) and CX614-treated (blue) slices. (E) Pretreatment with CX614 (blue line) caused a 70% increase in the magnitude of LTP induced by TBS1; this was accompanied by a loss of TBS2-induced potentiation. Image Copyright © 2012 PNAS, doi: 10.1073/pnas.1120700109

Gavin Rumbaugh (Scripps Research Institute) discussed the challenges he, Gary Lynch (University of California) and their team encountered in the study. “The field is trying to understand the neurobiology of new learning, and in particular, how learning induces an even more complex biology to keep new information in our neural circuits,” Rumbaugh tells Medical Xpress. “Over the recent decade, it has become clear that plasticity at individual synapses is a way that neural circuits store information. However, it remains unclear how properties of synapses influence key aspects of learning and memory.”

Read more …

March 28, 2012

Recent clinical studies have shown that general anesthesia can be harmful to infants, presenting a dilemma for both doctors and parents. But new research at Wake Forest Baptist Medical Center may point the way to treatment options that protect very young children against the adverse effects of anesthesia.

As detailed in a study published in the March 23 online edition of the journal Neuroscience, Wake Forest Baptist scientists explored a number of strategies designed to prevent anesthesia-induced damage to the brain in infants.

Using an animal model, the researchers tested the effectiveness of a fragment of a neuroprotective protein called ADNP, as well as vitamin D3, a low-level dose of anesthetic and aspirin. They found that three of the four strategies tested protected the brain from injury induced by 20 mg ketamine, a commonly used general anesthetic.

"What didn’t work was aspirin, which was a surprise because aspirin is known to protect the brain from injury," said Christopher P. Turner, Ph.D., assistant professor of neurobiology and anatomy at Wake Forest Baptist and lead author of the study. "In fact, in our study aspirin actually increased the severity of injury from the anesthesia, possibly because it prevents the generation of substances that may be neuroprotective."

Turner and his team studied rats at ages equivalent to children from birth to age 4.

In separate tests, the rodents were injected with: NAP, a peptide fragment of activity-dependent neuroprotective protein (ADNP), 15 minutes before ketamine was administered; two 20-mg doses of vitamin D3, at 24 hours and at 15 minutes before 20 mg ketamine; a non-toxic (5 mg) doses of ketamine 24 hours before a toxic dose of 20 mg ketamine was administered; and a 30-mg dose of aspirin 15 minutes before exposure to ketamine.

The Turner lab found that NAP, vitamin D3 and prior exposure to low (non-toxic) ketamine could all prevent injury from exposure to a toxic (20 mg) level of ketamine. However, aspirin appeared to enhance ketamine-induced injury.

"We designed our studies to give doctors several possible treatment options because not all of these strategies may work in clinical applications," Turner said. "However, because vitamin D3 is already in clinical use, our findings show that it is quite promising with few risks. Further, NAP is currently in clinical trials to diminish the severity of other types of brain injury, so we feel this discovery represents a breakthrough for anesthesia-induced neurotoxicity. However, there may be a critical window of efficacy for NAP, which we need to explore further.

"Of all the approaches that our team studied, using a low dose of ketamine may be both the simplest and most cost-effective, as it suggests children can be pre-treated with the same anesthesia that will be used when they undergo general surgery," Turner added. "In essence, a low-level dose of ketamine primes the child’s brain so that the second, higher dose is not as lethal, much like an inoculation."

Provided by Wake Forest Baptist Medical Center

Source: medicalxpress.com

March 28, 2012

(Medical Xpress) — While stimulants may improve unengaged workers’ performance, a new University of British Columbia study suggests that for others, caffeine and amphetamines can have the opposite effect, causing workers with higher motivation levels to slack off.

The study – published online today by Nature’s Neuropsychopharmacology – explored the impacts of stimulants on “slacker” rats and “worker” rats, and sheds important light on why stimulants might affect people differently, a question that has long been unclear. It also suggests that patients being treated with stimulants for a range of illnesses may benefit from more personalized treatment programs.

“Every day, millions of people use stimulants to wake up, stay alert and increase their productivity – from truckers driving all night to students cramming for exams,” says Jay Hosking, a PhD candidate in UBC’s Dept. of Psychology, who led the study. “These findings suggest that some stimulants may actually have an opposite effect for people who naturally favour the difficult tasks of life that come with greater rewards.”

Hosking says some individuals are more willing to concentrate and exert effort to achieve their goals than others. However, little is known about the brain mechanisms determining how much cognitive effort one will expend in decision-making for accomplishing tasks.

Hosking and study co-author Catharine Winstanley, a professor in UBC’s Dept. of Psychology, found that rats – like humans – show varying levels of willingness to expend high or low degrees of mental effort to obtain food rewards. When presented with stimulants, the “slacker” rats that typically avoided challenges worked significantly harder when given amphetamines, while “worker” rats that typically embraced challenges were less motivated by caffeine or amphetamine.

While more research is needed to understand the brain mechanisms at work, the study suggests that the amount of mental attention people devote to achieving their goals may play a role in determining how stimulants drugs affect them, Hosking says.

Winstanley, a Michael Smith Foundation for Health Research scholar, says people with psychiatric illnesses, brain injuries and Attention Deficit Hyperactivity Disorder (ADHD) may benefit from treatment programs with greater personalization, noting that patients often use stimulants to counter drowsiness and fatigue from their conditions and treatments, with mixed results.

Provided by University of British Columbia

Source: medicalxpress.com

ScienceDaily (Mar. 27, 2012) — Just as the familiar sugar in food can be bad for the teeth and waistline, another sugar has been implicated as a health menace and blocking its action may have benefits that include improving long-term memory in older people and treating cancer.

Blocking the action of a sugar could boost memory and even fight cancer. The neuron on the left has CREB with O-GlcNAc and is short. The neuron on the right does not have that form of CREB and is long. (Credit: Linda Hsieh-Wilson, Ph.D.)

Progress toward finding such a blocker for the sugar — with the appropriately malicious-sounding name “oh-glick-nack” — was the topic of a report presented at the 243rd National Meeting & Exposition of the American Chemical Society (ACS) in San Diego on March 27.

Linda Hsieh-Wilson, Ph.D., explained that the sugar is not table sugar (sucrose), but one of many other substances produced in the body’s cells that qualify as sugars from a chemical standpoint. Named O-linked beta-N-acetylglucosamine — or “O-GlcNAc” — it helps in orchestrating health and disease at their origins, inside the billions of cells that make up the body. O-GlcNAc does so by attaching to proteins that allow substances to pass in and out of the nucleus of cells, for instance, and helping decide whether certain genes are turned on or off. In doing so, O-GlcNAc sends signals that may be at the basis of cancer, diabetes, Alzheimer’s disease and other disorders. Research suggests, for instance, that proteins loaded up with too much O-GlcNAc can’t function normally.

At the ACS meeting, Hsieh-Wilson described how research in her lab at the California Institute of Technology and Howard Hughes Medical Institute implicate O-GlcNAc in memory loss and cancer. The research emerged from Hsieh-Wilson’s use of advanced lab tools for probing a body process that involves attachment of sugars like O-GlcNAc to proteins. Called protein glycosylation, it helps nerves and other cells communicate with each other in ways that keep the body coordinated and healthy. When O-GlcNAc is attached to a protein, that binding process is known as O-GlcNAc glycosylation.

Hsieh-Wilson’s team screened the entire mammalian brain for all O-GlcNAc-glycosylated proteins, using a new process that her laboratory developed. They identified more than 200 proteins bearing O-GlcNAc attachments or tags, many for the first time. The research was done in mice, stand-ins for humans in research that cannot be done on people. Some of the proteins carrying O-GlcNAc were involved in regulating processes like drug addiction and securing long-term storage of memories.

O-GlcNAc’s effects on one particular protein, CREB, got the scientists’ attention. CREB is a key substance that turns on and regulates the activity of genes. Many of the genes in cells are inactive at any given moment. Substances like CREB, termed transcription factors, turn genes on. Hsieh-Wilson found that when O-GlcNAc attached to CREB, CREB’s ability to turn on genes was impaired. When the researchers blocked O-GlcNAc from binding CREB, the mice developed long-term memories faster than normal mice.

Could blocking O-GlcNAc boost long-term memory in humans?

"We’re far from understanding what happens in humans," Hsieh-Wilson emphasized. "Completely blocking O-GlcNAc might not be desirable. Do you really want to sustain all memories long-term, even of events that are best forgotten? How would blocking the sugar from binding to other proteins affect other body processes? There are a lot of unanswered questions. Nevertheless, this research could eventually lead to ways to improve memory."

In a related study, Hsieh-Wilson found that O-GlcNAc interacted with another protein in ways that encourage the growth of cancer cells, suggesting that blocking its attachment might protect against cancer or slow the growth of cancer. And indeed, in mouse experiments, blocking O-GlcNAc resulted in much smaller tumors.

Again, a treatment for humans based on this discovery is far in the future, but the study singles out O-GlcNAc as a potential new target for developing anti-cancer drugs.

Source: Science Daily