Genes for learning, remembering and forgetting

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. 

"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. 

Synapse Plasticity is the Basis of Learning and Memory 

Synapses are the connections between nerve cells (neurons). Nerve signals are transmitted through synapses. Learning and memory concern how these connections are made, broken, strengthened or weakened. Proteins known as receptors are delivered to the synapses or removed from them to strengthen or weaken the connection. 

In the new study, Maricq and colleagues identified a "Wnt signaling pathway" -- a series of genes and the proteins they produce -- that controls the strength of nerve signal transmission from one neuron through a synapse to the next neuron. This allows "plasticity" of synapses -- a key factor in learning, retaining memories and forgetting. 

"The adult nervous system is not a stagnant tissue, but rather dynamic and plastic, with the strength of synapses -- specialized neuron-to-neuron connections -- changing with experience, learning and memory," Maricq says. "It's not a fixed thing, like when you're done making the heart, you're done." 

When synapses and thus incoming nerve signals are strengthened by adding receptors, an organism learns and remembers; when the opposite occurs, the organism forgets, he adds. 

How is that connection strengthened or weakened? When one neuron sends a nerve signal to another neuron, the first neuron releases a chemical known as a neurotransmitter, which moves through the synapse connecting the two cells and attaches or binds to receptors on the surface of the second neuron. 

"You can think of the receptors like amplifiers, like hearing aids," Maricq says. 

The volume of the received nerve signal depends on the number of receptors, which are stored in a supply depot just below the nerve cell's surface. 

The Wnt signaling identified in the new study "tells the depot to put more receptors into the synapse -- or not," says Maricq. 

He emphasizes that the Wnt chemical signal is different than the actual nerve signal carried by a neurotransmitter chemical, which in the new study was acetylcholine. The Wnt signal "is a secondary signal that controls the volume of the neurotransmitter signal," Maricq says. 

Worms Reveal Details of Nerve Signal Volume Control 

By crippling various genes in the worms, the researchers identified the "signaling pathway" by which a Wnt protein in one nerve cell sends a chemical signal to another cell telling it to increase the number of receptors on its surface, thus increasing the strength or volume of nerve signals between the cells. 

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]

The type of nerve-signal receptor in the study is an acetylcholine receptor named ACR-16. When researchers crippled the gene that makes the ACR-16 receptor protein, there were not enough receptors, so nerve signals were disrupted and the worms "had uncoordinated movement," Maricq says. "They were semi-paralyzed." 

The scientists found mutations of other genes that also resulted in inadequate ACR-16 receptors and impaired the worms' movement. They discovered such genes belong to the "Wnt signaling pathway" that puts enough receptors on the cell surface so signals can be received. 

Besides ACR-16, genes in that pathway produced proteins named CWN-2 -- which is a Wnt protein -- LIN-17, CAM-1 and DSH-1. 

Here is how that pathway controls the volume of incoming nerve signals: 

1. A neuron releases CWN-2, which binds onto a receptor protein on the signal-receiving cell. That protein is a newly discovered combination of the LIN-17 and CAM-1 proteins. 

2. The LIN-17/CAM-1 protein sends a signal to a protein called disheveled, or DSH-1. 

3. "DSH-1 somehow sends the volume-control signal" that dispatches more ACR-16 receptors from depots inside the second neuron to that cell's surface, thus boosting the volume of the received nerve signal, Maricq says. 

The researchers used a green jellyfish protein to mark the ACR-16 receptors so they were visible under a microscope. When any of the genes in the Wnt signaling pathway were mutant, the scientists could see the green-labeled receptors accumulate under the surfaces of nerve cells instead of moving to the surface. 

Another experiment recorded electrical currents in worm nerve synapses and found it was smaller when any of the Wnt pathway genes were mutated. The smaller current -- reflecting impaired nerve-signal transmission -- explains why the mutant worms were partially paralyzed. 

Human Version of Worm Receptor Tied to Mental Disorders 

The ACR-16 acetylcholine receptor is the worm version of the alpha-7 nicotinic acetylcholine receptor in humans and other vertebrates. Both are similar in structure and function in animals from worms to fruit flies, mice and people. 

The alpha-7 receptor "is important in schizophrenia and a number of different mental disorders, and may have a role in addiction, but we don't understand how it's regulated," Maricq says. 

Many existing psychiatric drugs modify synapse strength. The new study suggests research should be done to show if the same Wnt signaling genes in worms also control alpha-7 receptor levels on human brain cells. If so, new drugs might be developed to target those genes as a way to treat mental disorders, including addiction. 

"Addiction is like learning at a primitive level," Maricq says. "Addiction means that somewhere in your brain, synapses are too strong. So you want more." 

The study was funded by the National Institutes of Health and the American Heart Association. 

Source: University of Utah [March 29, 2012]

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Why the brain is more reluctant to function as we age

New findings, led by neuroscientists at the University of Bristol and published this week in the journal Neurobiology of Aging, reveal a novel mechanism through which the brain may become more reluctant to function as we grow older. 

It is not fully understood why the brain's cognitive functions such as memory and speech decline as we age. Although work published this year suggests cognitive decline can be detectable before 50 years of age. The research, led by Professor Andy Randall and Dr Jon Brown from the University's School of Physiology and Pharmacology, identified a novel cellular mechanism underpinning changes to the activity of neurones which may underlie cognitive decline during normal healthy aging. 

The brain largely uses electrical signals to encode and convey information. Modifications to this electrical activity are likely to underpin age-dependent changes to cognitive abilities. 

The researchers examined the brain's electrical activity by making recordings of electrical signals in single cells of the hippocampus, a structure with a crucial role in cognitive function. In this way they characterised what is known as "neuronal excitability" — this is a descriptor of how easy it is to produce brief, but very large, electrical signals called action potentials; these occur in practically all nerve cells and are absolutely essential for communication within all the circuits of the nervous system. 

Action potentials are triggered near the neurone's cell body and once produced travel rapidly through the massively branching structure of the nerve cell, along the way activating the synapses the nerve cell makes with the numerous other nerve cells to which it is connected. 

The Bristol group identified that in the aged brain it is more difficult to make hippocampal neurones generate action potentials. Furthermore they demonstrated that this relative reluctance to produce action potential arises from changes to the activation properties of membrane proteins called sodium channels, which mediate the rapid upstroke of the action potential by allowing a flow of sodium ions into neurones. 

Professor Randall, Professor in Applied Neurophysiology said: "Much of our work is about understanding dysfunctional electrical signalling in the diseased brain, in particular Alzheimer's disease. We began to question, however, why even the healthy brain can slow down once you reach my age. Previous investigations elsewhere have described age-related changes in processes that are triggered by action potentials, but our findings are significant because they show that generating the action potential in the first place is harder work in aged brain cells. 

"Also by identifying sodium channels as the likely culprit for this reluctance to produce action potentials, our work even points to ways in which we might be able modify age-related changes to neuronal excitability, and by inference cognitive ability." 

Source: University of Bristol [February 01, 2012]

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Biologists a Step Nearer to Solving the Parkinson's Conundrum

Scientists at the University of York have made a significant step forward in isolating the cause of Parkinson's disease in younger adults. 

Parkinson's disease occurs when some nerve cells in a part of the brain called the substantia nigra die or become impaired. Normally, these cells produce dopamine - a vital chemical that allows smooth, coordinated function of the body's muscles and movements [Credit: iStockphoto/Martí Sáiz]

Research by a team in the University's Department of Biology found evidence that movement disorders, including tremor and slowness of movement (bradykinesia), associated with Parkinson's disease (PD) may be due to a defect in energy production in the nervous system. The advance may help to identify young adults who may be susceptible to the disease. 

Parkinson's, the second most common form of neurodegenerative disease, principally affects people aged over 60, but some forms -- known as juvenile PD -- usually start in the 30-40 age group. One in 20 people diagnosed with Parkinson's are under 40 and such early onset PD is often inherited. Previous research has identified the genes which cause the disease and found them to be linked in a common pathway to failure of the mitochondria -- the power source within each cell. 

In the latest research, part-funded by leading research charity Parkinson's UK and published in Human Molecular Genetics, scientists at York studied the effect that parkin, one of the genes which cause juvenile PD, has on the larva of the fruit fly, Drosophila. 

They discovered that parkin faithfully models the locomotory defects of PD with a marked reduction in speed, and slower muscle contractions, reminiscent of bradykinesia. 

Dr Chris Elliott, who led the study, said: "Our experimental evidence confirmed that this was due to a defect in the nervous system. This was important because previous work had suggested a big impact on the muscles, but PD is associated with neuronal failure." 

The research team, which included undergraduate and postgraduate students, found that oxygen consumption and the production of ATP (the chief supply of energy inside cells) were drastically reduced. In response, lactate was increased. 

The researchers also discovered that parkin larvae showed oxidative stress due to high levels of reactive oxygen species (ROS; also known as free radicals, such as hydrogen peroxide) which have been suggested as a key component of PD. The study suggested that relieving the ROS had only a marginal effect on mitigating slowed locomotion. 

Dr Elliott added: "These findings show drastic failure in energy production by parkin larvae, and suggest that biochemicals related to lactate may be worth investigating as biomarkers for the progress of PD. 

"We believe that the larval bradykinesia is a consequence of neuronal energy deficit, which leads to failure in neural communication. Oxidative stress is a consequence, rather than cause, of PD." 

Dr Kieran Breen, Director of Research and Innovation at Parkinson's UK, comments: "This study shows just how vital models like the fruit fly are in helping us understand what happens to the nerve cells that are affected in Parkinson's. 

"We already knew that mitochondria were important in Parkinson's but this research suggests that mitochondrial problems may be the root cause of the problems that lead to nerve cell death. 

"So finding ways to protect and enhance the mitochondria may be the key to treatments that can slow or even stop Parkinson's in its tracks." 

Source: University of York [January 16, 2012]

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Scientists map the frontiers of vision

There's a 3-D world in our brains. It's a landscape that mimics the outside world, where the objects we see exist as collections of neural circuits and electrical impulses. 

Now, scientists at the Salk Institute for Biological Studies are using new tools they developed to chart that world, a key step in revolutionizing research into the neurological basis of vision. 

For the first time, the scientists have produced neuron-by-neuron maps of the regions of the mouse brain that process different kinds of visual information, laying the groundwork for decoding the circuitry of the brain using cutting-edge, genetic research techniques only possible in mice. 

"In the field of cognitive research, this puts the mouse on the map - by putting the map on the mouse," says James Marshel, a Salk research associate. Marshel and Marina Garrett, a graduate student at University of California San Diego, were lead authors on a paper reporting the advance in the December 22 issue of Neuron. 

To understand the extraordinarily complex computations of the human brain, including those behind visual cognition, scientists have mostly relied on studies on primates, such as monkeys, our closest relatives in the animal kingdom, and the most like us in terms of cognitive ability. 

Researchers have identified what portions of the primate brain process different aspects of the sensory information they gather from the outside world. In particular, a great deal is known about what regions of the primate brain process certain visual information, helping them identify objects and follow their movements in three-dimensional space. 

"We've learned a lot about how our eyes feed information to our brains, and a huge portion of our brain is devoted to processing this information," says Edward Callaway, a professor in Salk's Systems Neurobiology Laboratory, whose laboratory conducted the research. "Vision is a terrific system for understanding how the brain works and, ultimately, for studying mental diseases and consciousness." 

Powerful new scientific tools are emerging that could allow scientists to better understand the human brain by studying the relatively simpler brains of mice. These methods allow scientists to alter genes, the instructions in DNA that control the behavior of cells - including the neurons that form brain circuits. By using genetic methods for mapping brain connections and controlling the activity of cells, scientists hope to generate detailed wiring diagrams of the brain and probe how these circuits function. 

"While mice can not replace the work that is being done in monkeys, these research techniques are much further along in mice than in monkeys," Callaway says. "The ability to modify neural activity using genetic tools and to study the resulting changes in brain and nerve activity is revolutionizing neuroscience." 

Although such genetic engineering techniques in mice offer huge potential, little was known about what areas of the mouse visual cortex - the high-level brain region that computes the meaning of signals from the eyes - were responsible for processing different elements of the visual information. 

To remedy this, Callaway and his colleagues set out to chart a map of the mouse's visual processing system. They injected mice with a calcium-sensitive fluorescent dye that glows when exposed to a certain color of light. The amount of calcium in nerve cells varies depending on the activity level of the neurons, so the scientists could measure the activity of brain cells based on how brightly they glowed. 

The scientists then displayed different types of visual stimulus on a television monitor and recorded what parts of the brain glowed. To make the recordings, they used a high-resolution camera capable of discerning the activity of individual nerve cells. 

They found that a mouse's visual field, the area of three-dimensional space visible through its eyes, is represented by a corresponding collection of neurons in its brain. The researchers precisely recorded which neurons were associated with which area of the animal's visual field. 

The scientists studied seven different areas of the animal's visual cortex containing full neuronal "maps" of the visible outside world, and found that each area has a specialized role in processing visual information. For instance, certain areas were more sensitive to the direction objects move in space, while other areas were focused on distinguishing fine detail. 

With these maps of brain function in hand, the Salk researchers and others now have a baseline against which they can compare the brain function of mice in which circuit function is manipulated using genetic methods. Ultimately, Callaway says, understanding in detail how the mouse brain works will illuminate the workings of the human mind. 

"This gives us new ways to explore the neural underpinnings of consciousness and to identify what goes wrong in neural circuits in the case of diseases such as schizophrenia and autism," Callaway said.  

Source: Salk Institute [January 06, 2012]

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Diet, nutrient levels linked to cognitive ability, brain shrinkage

New research has found that elderly people with higher levels of several vitamins and omega 3 fatty acids in their blood had better performance on mental acuity tests and less of the brain shrinkage typical of Alzheimer's disease – while "junk food" diets produced just the opposite result. 

The study was among the first of its type to specifically measure a wide range of blood nutrient levels instead of basing findings on less precise data such as food questionnaires, and found positive effects of high levels of vitamins B, C, D, E and the healthy oils most commonly found in fish. 

The research was done by scientists from the Oregon Health and Science University in Portland, Ore., and the Linus Pauling Institute at Oregon State University. It was published today in Neurology, the medical journal of the American Academy of Neurology. 

"This approach clearly shows the biological and neurological activity that's associated with actual nutrient levels, both good and bad," said Maret Traber, a principal investigator with the Linus Pauling Institute and co-author on the study. 

"The vitamins and nutrients you get from eating a wide range of fruits, vegetables and fish can be measured in blood biomarkers," Traber said. "I'm a firm believer these nutrients have strong potential to protect your brain and make it work better." 

The study was done with 104 people, at an average age of 87, with no special risk factors for memory or mental acuity. It tested 30 different nutrient biomarkers in their blood, and 42 participants also had MRI scans to measure their brain volume. 

"These findings are based on average people eating average American diets," Traber said. "If anyone right now is considering a New Year's resolution to improve their diet, this would certainly give them another reason to eat more fruits and vegetables." 

Among the findings and observations: 

• The most favorable cognitive outcomes and brain size measurements were associated with two dietary patterns – high levels of marine fatty acids, and high levels of vitamins B, C, D and E. 

• Consistently worse cognitive performance was associated with a higher intake of the type of trans-fats found in baked and fried foods, margarine, fast food and other less-healthy dietary choices. 

• The range of demographic and lifestyle habits examined included age, gender, education, smoking, drinking, blood pressure, body mass index and many others. 

• The use of blood analysis helped to eliminate issues such as people's flawed recollection of what they ate, and personal variability in nutrients absorbed. 

• Much of the variation in mental performance depended on factors such as age or education, but nutrient status accounted for 17 percent of thinking and memory scores and 37 percent of the variation in brain size. 

• Cognitive changes related to different diets may be due both to impacts on brain size and cardiovascular function. 

The epidemiology of Alzheimer's disease has suggested a role for nutrition, the researchers said in their study, but previous research using conventional analysis, and looking in isolation at single nutrients or small groups, have been disappointing. The study of 30 different blood nutrient levels done in this research reflects a wider range of nutrients and adds specificity to the findings. 

The study needs to be confirmed with further research and other variables tested, the scientists said. 

Source: Oregon State University [December 28, 2011]

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Brain size may predict risk for early Alzheimer's disease

New research suggests that, in people who don't currently have memory problems, those with smaller regions of the brain's cortex may be more likely to develop symptoms consistent with very early Alzheimer's disease. The study is published in the December 21, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology. 

"The ability to identify people who are not showing memory problems and other symptoms but may be at a higher risk for cognitive decline is a very important step toward developing new ways for doctors to detect Alzheimer's disease," said Susan Resnick, PhD, with the National Institute on Aging in Baltimore, who wrote an accompanying editorial. 

For the study, researchers used brain scans to measure the thickness of regions of the brain's cortex in 159 people free of dementia with an average age of 76. The brain regions were chosen based on prior studies showing that they shrink in patients with Alzheimer's dementia. Of the 159 people, 19 were classified as at high risk for having early Alzheimer's disease due to smaller size of particular regions known to be vulnerable to Alzheimer's in the brain's cortex, 116 were classified as average risk and 24 as low risk. At the beginning of the study and over the next three years, participants were also given tests that measured memory, problem solving and ability to plan and pay attention. 

The study found that 21 percent of those at high risk experienced cognitive decline during three years of follow-up after the MRI scan, compared to seven percent of those at average risk and none of those at low risk. 

"Further research is needed on how using MRI scans to measure the size of different brain regions in combination with other tests may help identify people at the greatest risk of developing early Alzheimer's as early as possible," said study author Bradford Dickerson, MD, of Massachusetts General Hospital in Boston and a member of the American Academy of Neurology. 

The study also found 60 percent of the group considered most at risk for early Alzheimer's disease had abnormal levels of proteins associated with the disease in cerebrospinal fluid, which is another marker for the disease, compared to 36 percent of those at average risk and 19 percent of those at low risk. 

Source: American Academy of Neurology [December 21, 2011]

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A novel mechanism regulating stress is identified

Neuroscience researchers from Tufts have demonstrated, for the first time, that the physiological response to stress depends on neurosteroids acting on specific receptors in the brain, and they have been able to block that response in mice. This breakthrough suggests that these critical receptors may be drug therapy targets for control of the stress-response pathway. This finding may pave the way for new approaches to manage a wide range of neurological disorders involving stress. 

The stress-control pathway, more technically known as the Hypothalamus-Pituitary-Adrenal (HPA) axis, determines the levels of cortisol and other stress hormones in the human body. In addition to being implicated in the types of emotional and psychological stress that can lead to major depression, disorders of the stress-control pathway are also associated with obesity, premenstrual syndrome, postpartum depression, Cushing's syndrome (hypercortisolism) and diseases including epilepsy and osteoporosis. 

"We have identified a novel mechanism regulating the body's response to stress by determining that neurosteroids are required to mount the physiological response to stress. Moreover, we were able to completely block the physiological response to stress as well as prevent stress-induced anxiety," said author Jamie Maguire, PhD, assistant professor in the department of neuroscience at Tufts University School of Medicine and a member of the Neuroscience and Pharmacology & Experimental Therapeutics program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts. 

Using the brain tissues of adult mice, the research team identified mechanisms controlling the activity of Corticotrophin Releasing Hormone (CRH) neurons involved in the control of the stress pathway. By monitoring the activity of CRH neurons following stress and measuring levels of corticosterone in the blood, they found that the production of stress hormones required the action of neurosteroids on specific receptors on CRH neurons. 

Apart from the finding that stress causes a neurosteroid-induced increase in blood corticosterone levels, the researchers also found that blocking the synthesis of neurosteroids is sufficient to block the stress-induced elevations in corticosterone and prevent stress-induced, anxiety-like behavior in mice. Previous research had identified the presence of specialized CRH-nerve-cell receptors in the HPA axis, but the findings had been controversial because of limited studies showing any connection between these receptors and the regulation of the CRH nerve cells. 

"We have found a definite role of neurosteroids on the receptors regulating CRH nerve cells and the stress response. The data suggest that these receptors may be novel targets for control of the stress-control pathway. Our next work will focus on modulating these receptors to treat disorders associated with stress, including epilepsy and depression-like behaviors," said Maguire. 

Source: Tufts University, Health Sciences Campus [December 13, 2011]

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Multiple Sclerosis Often Starts in Brain's Outer Layers

Multiple sclerosis (MS) may progress from the outermost layers of the brain to its deep parts, and isn't always an "inside-out" process as previously thought, reported a new collaborative study from researchers at the Mayo Clinic and the Cleveland Clinic. 

The traditional understanding is that the disease begins in the white matter that forms the bulk of the brain's inside, and extends to involve the brain's superficial layers, the cortex. Study findings support an opposite, outside-in process: from the cerebrospinal fluid-filled subarachnoid space, that cushions the outside of the brain and the cortex, into the white matter. The new findings will guide researchers as they seek to further understand and treat the disease. The study was published in the New England Journal of Medicine in December, 2011. 

Researchers do not know precisely what causes MS, but it is thought to be an autoimmune disease in which the body's immune system attacks and destroys its own myelin. This fatty substance surrounds and protects axons, nerve cell projections that carry information, and its damage slows down or blocks messages between the brain and body, leading to MS symptoms, which can include blindness, numbness, paralysis, and thinking and memory problems. 

"Our study shows the cortex is involved early in MS and may even be the initial target of disease," says Claudia F. Lucchinetti, M.D., co-lead author of the study and Mayo Clinic neurologist. "Inflammation in the cortex must be considered when investigating the causes and progression of MS," she says. 

Study authors say current therapeutic options may not even address issues associated with the cortex. Understanding how the cortex is involved, therefore, is critical to creating new therapies for MS. "Measures of cortical damage will enhance enormously the power of clinical trials to determine if new medications address tissue changes of MS in all regions of the brain," says co-lead author Richard Ransohoff, M.D., a Cleveland Clinic neurologist. 

These measures are important because disease accumulates in the cortex over time, and inflammation in the cortex is a sign the disease has progressed. 

The research is distinct because it studied brain tissues from patients in the earliest stages of MS. "What's unique about the study is, and the reason the National MS Society funded this international team of researchers, is that it offers a rare view of MS early in the disease," says Timothy Coetzee, Ph.D., Chief Research Officer at the National Multiple Sclerosis Society. "Collaborative studies like this, that deepen our understanding of the sequence of nervous system-damaging events, should offer new opportunities for stopping MS disease progression and improving quality of life for people with MS." 

The findings support the understanding that MS is primarily a disease of inflammation, not neurodegeneration, as some studies have recently suggested. Co-lead authors Drs. Lucchinetti and Ransohoff conclude that it is "overwhelmingly likely" that MS is fundamentally an inflammatory disease, and not a neurodegenerative Alzheimer-like disease. 

How They Did It The research did not at first focus on the 'outside-in' question, says Dr. Lucchinetti. Instead, the team initially wondered what tissue changes in the cortex of MS patients gave rise to indicators of cortical damage. For the last several years, researchers knew from MRI studies that the cortex was damaged very early after onset of MS, and they knew from autopsy studies that the cortex was demyelinated, as was white matter. What researchers were unable to determine, until completion of the present study, was whether findings at autopsy (usually after 30-50 years of disease) accurately reflected the indicators of cortical damage from MRI images taken after only a few months of disease. In autopsy MS tissues, cortical lesions show demyelination, but without inflammation-raising the possibility that MS cortex degenerates due to intrinsic tissue defects. Such a process would not be treatable by current MS therapies and could not be explained by present concepts of the causes of MS. 

Drs. Lucchinetti and Ransohoff determined to see if early-MS cortical lesions were, or were not, inflammatory. To do so, they studied the Mayo resource of white-matter biopsies taken largely from patients with suspected tumors, but eventually proving to have MS. About one-fourth of the biopsies also included tiny fragments of cortex, which formed the focus of study. The primary question was quickly answered: cortical demyelinating lesions of early-MS patients resembled those found at autopsy in every way but one -- the early lesions were highly inflammatory. These findings were reassuring because they indicated that treatments targeting inflammation in the disease may ameliorate MS effects on both the cortex as well as the white matter. 

While investigating the cortical changes in the biopsies, researchers were struck by the high frequency of cortical demyelinating lesions. Furthermore, in the white matter biopsies, which contained miniscule cortical fragments, about 20% showed inflammatory demyelination was contained entirely in the cortex. 

Researchers also noted inflammation was present in the meninges, the protective membranes that cover the surface of the brain and demarcate the subarachnoid space. Meningeal inflammation and cortical demyelination were highly-associated. Looking at implications of their data, Drs. Lucchinetti and Ransohoff could weave together a proposed pathway for lesion initiation, along with known experimental data from MS animal models, and term this pathway the "outside-in" theory. The research findings also lend urgency to efforts to use MRI to "see" more deeply into the cortical lesions of MS, particularly given that cortical damage is an important correlate of progressive disability and cognitive dysfunction in MS. 

Source: Mayo Clinic [December 07, 2011]

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Study Looks at the Nature of Change in Our Aging, Changing Brains

As we get older, our cognitive abilities change, improving when we're younger and declining as we age. Scientists posit a hierarchical structure within which these abilities are organized. There's the "lowest" level -- measured by specific tests, such as story memory or word memory; the second level, which groups various skills involved in a category of cognitive ability, such as memory, perceptual speed, or reasoning; and finally, the "general," or G, factor, a sort of statistical aggregate of all the thinking abilities. 

What happens to this structure as we age? That was the question Timothy A. Salthouse, Brown-Forman professor of psychology at the University of Virginia, investigated in a new study appearing in an upcoming issue of Psychological Science, a journal published by the Association for Psychological Science. His findings advance psychologists' understanding of the complexities of the aging brain. 

"There are three hypotheses about how this works," says Salthouse. "One is that abilities become more strongly integrated with one another as we age." That theory suggests the general factor influences cognitive aging the most. The second -- based on the idea that connectivity among different brain regions lessens with age -- "is almost the opposite: that the changes in cognitive abilities become more rather than less independent with age." The third was Salthouse's hypothesis: The structure remains constant throughout the aging process. 

Using a sample of 1,490 healthy adults ages 18 to 89, Salthouse performed analyses of the scores on 16 tests of five cognitive abilities -- vocabulary, reasoning, spatial relations, memory, and perceptual speed. The primary analyses were on the changes in the test scores across an interval of about two and a half years. 

The findings confirmed Salthouse's hunch: "The effects of aging on memory, on reasoning, on spatial relations, and so on are not necessarily constant. But the structure within which these changes are occurring does not seem to change as a function of age." In normal, healthy people, "the direction and magnitude of change may be different" when we're 18 or 88, he says. "But it appears that the qualitative nature of cognitive change remains the same throughout adulthood." 

The study could inform other research investigating "what allows some people to age more gracefully than others," says Salthouse. That is, do people who stay mentally sharper maintain their ability structures better than those who become more forgetful or less agile at reasoning? And in the future, applying what we know about the structures of change could enhance "interventions that we think will improve cognitive functioning" at any age or stage of life. 

Source: Association for Psychological Science [November 22, 2011]

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Scientists identify defect in brain cell channel that may cause autism-like syndrome

Neuroscientists at Stanford University School of Medicine have homed in on potential differences in autistic people's brain cells by studying brainlike spheres grown in an elaborate process from skin cells. 

The scientists studied cells from patients with Timothy syndrome, a rare genetic condition that is associated with one of the most penetrant forms of autism: In other words, most people with the Timothy syndrome mutation have autism as a symptom, among other problems. 

Autism is a spectrum of developmental disorders of impaired social and verbal interaction. Currently, no medication exists to treat its underlying causes, according to the U.S. National Library of Medicine. Understanding what goes awry in autistic brain development could improve prospects for treating the condition. 

In this study, the scientists suggest that the autism in Timothy syndrome patients is caused by a gene mutation that makes calcium channels in neuron membranes defective, interfering with how those neurons communicate and develop. The flow of calcium into neurons enables them to fire, and the way that the calcium flow is regulated is a pivotal factor in how our brains function. 

The researchers also found brain cells grown from individuals with Timothy syndrome resulted in fewer of the kind of cells that connect both halves of the brain, as well as an overproduction of two of the brain's chemical messengers, dopamine and norepinephrine. Furthermore, they found they could reverse these effects by chemically blocking the faulty channels. 

Postdoctoral scholar Sergiu Pasca, MD, and Ricardo Dolmetsch, PhD, associate professor of neurobiology, led the study, which will be published online Nov. 27 in Nature Medicine. Dolmetsch, a biophysicist, redirected his research to study autism after his son was diagnosed with Timothy syndrome. It's unclear what leads to autism, but its incidence is increasing, he said. 

The gaps in our understanding of the causes of psychiatric disorders such as autism have made them difficult to treat. Perhaps the biggest obstacle to research into autism and other psychiatric and neurological diseases is that scientists can't get living brain cell samples from people with these conditions, for obvious reasons. Dolmetsch and his colleagues figured out a solution to this dilemma, using a novel approach involving what are known as induced pluripotent stem cells, or iPS cells. 

"We developed a way of taking skin cells from humans with Timothy syndrome and converting them into stem cells, then converting those stem cells into neurons," said Dolmetsch. 

The scientists grew these iPS cells as free-floating clumps in a nutrient-rich solution, later transferring the clumps to tissue culture plates. Here, some of them formed three-dimensional, brainlike spheres whose cells later migrated outward and matured into neurons. These neurons formed three distinct layers, a good first approximation of living tissue in the brain. By visualizing these neurons under a microscope and quantifying their gene expression, the scientists were able to characterize at the cellular level abnormalities that may be associated with autism. 

The neurons grown from Timothy-syndrome iPS cells showed larger-than-normal spikes in calcium levels, suggesting the calcium channels lost their ability to shut off. This set off dramatic changes in neuronal signaling, reconfiguring how genes were expressed. 

The cerebral cortex, the outer layer of the brain, has six distinct layers. In Timothy syndrome cell cultures, the proportion of neurons of specific layers differed from that in normal brains — additional biological evidence for the disorder. The neurons grown from the Timothy syndrome cells were less characteristic of lower-level neurons, which include neurons that bridge the left and right halves of the brain via the bundle of fibers known as the corpus callosum. This reinforces the view that autism results from defects in brain connectivity. 

Pasca and Dolmetsch had an "aha" moment when they realized the neurons grown from Timothy syndrome cells were making too much of the enzyme most critical for producing dopamine and norepinephrine, which play an important role in sensory processing and social behavior. The realization may offer important clues about what causes the problems seen in autism. 

To determine whether the enzyme upsurge was reversible, the scientists treated the neurons with a chemical that blocks the defective calcium channels, called roscovitine. They saw a nearly 70 percent reduction in the proportion of cells producing the enzyme, confirming the defective calcium channel was the culprit in producing too much dopamine and norepinephrine. Such reversibility suggests that certain cellular abnormalities in autism may be treatable. 

Dolmetsch warned, however, that roscovitine is not currently approved for use in humans and has never been tested in children. While it is currently in clinical trials for lung cancer, it reportedly causes nausea and other side effects. "The reported side effects are probably due to the fact that, in addition to targeting the channel that is mutated in autism, roscovitine also inhibits kinases that are required for cell proliferation," he said. "We think that roscovitine is a good starting point, but probably has to be optimized before it would be useful for autism." 

In the meantime, the study represents a major achievement with its success in developing a technique to recreate how the neurons of individuals with Timothy syndrome develop in a lab setting. It's the first time it's been possible to study the disorder in human cells rather than mouse cells, so it represents a better clinical model, Dolmetsch said. 

"These results could lead to a very powerful research tool," he said. "It's human psychiatric disease in a petri dish." 

Source: Stanford University Medical Center [November 27, 2011]

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Psychopaths' brains show differences in structure and function

Images of prisoners' brains show important differences between those who are diagnosed as psychopaths and those who aren't, according to a new study led by University of Wisconsin-Madison researchers. 

This study found reduced connectivity between an area of prefrontal cortex (PFC, red) and the amygdala (blue). The white matter pathway connecting the two structures (the uncinate fasciculus) is shown in green [Credit: UWSMPH]

The results could help explain the callous and impulsive anti-social behavior exhibited by some psychopaths. 

The study showed that psychopaths have reduced connections between the ventromedial prefrontal cortex (vmPFC), the part of the brain responsible for sentiments such as empathy and guilt, and the amygdala, which mediates fear and anxiety. Two types of brain images were collected. Diffusion tensor images (DTI) showed reduced structural integrity in the white matter fibers connecting the two areas, while a second type of image that maps brain activity, a functional magnetic resonance image (fMRI), showed less coordinated activity between the vmPFC and the amygdala. 

"This is the first study to show both structural and functional differences in the brains of people diagnosed with psychopathy," says Michael Koenigs, assistant professor of psychiatry in the University of Wisconsin School of Medicine and Public Health. "Those two structures in the brain, which are believed to regulate emotion and social behavior, seem to not be communicating as they should." 

The study, which took place in a medium-security prison in Wisconsin, is a unique collaborative between three laboratories, 

UW-Madison psychology Professor Joseph Newman has had a long term interest in studying and diagnosing those with psychopathy and has worked extensively in the Wisconsin corrections system. Dr. Kent Kiehl, of the University of New Mexico and the MIND Research Network, has a mobile MRI scanner that he brought to the prison and used to scan the prisoners' brains. Koenigs and his graduate student, Julian Motzkin, led the analysis of the brain scans. 

The study compared the brains of 20 prisoners with a diagnosis of psychopathy with the brains of 20 other prisoners who committed similar crimes but were not diagnosed with psychopathy. 

"The combination of structural and functional abnormalities provides compelling evidence that the dysfunction observed in this crucial social-emotional circuitry is a stable characteristic of our psychopathic offenders,'' Newman says. "I am optimistic that our ongoing collaborative work will shed more light on the source of this dysfunction and strategies for treating the problem." 

Newman notes that none of this work would be possible without the extraordinary support provided by the Wisconsin Department of Corrections, which he called "the silent partner in this research." He says the DOC has demonstrated an unprecedented commitment to supporting research designed to facilitate the differential diagnosis and treatment of prisoners. 

The study, published in the most recent Journal of Neuroscience, builds on earlier work by Newman and Koenigs that showed that psychopaths' decision-making mirrors that of patients with known damage to their ventromedial prefrontal cortex (vmPFC). This bolsters evidence that problems in that part of the brain are connected to the disorder. 

"The decision-making study showed indirectly what this study shows directly – that there is a specific brain abnormality associated with criminal psychopathy,'' Koenigs adds. 

Source: University of Wisconsin-Madison [November 22, 2011]

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Nerve cells key to making sense of our senses

The human brain is bombarded with a cacophony of information from the eyes, ears, nose, mouth and skin. Now a team of scientists at the University of Rochester, Washington University in St. Louis, and Baylor College of Medicine has unraveled how the brain manages to process those complex, rapidly changing, and often conflicting sensory signals to make sense of our world. 

The answer lies in a relatively simple computation performed by single nerve cells, an operation that can be described mathematically as a straightforward weighted average. The key is that the neurons have to apply the correct weights to each sensory cue, and the authors reveal how this is done. 

The study, to be published online Nov. 20 in Nature Neuroscience, represents the first direct evidence of how the brain combines multiple sources of sensory information to form as accurate a perception as possible of its environment, the researchers report. 

The discovery may eventually lead to new therapies for people with Alzheimer's disease and other disorders that impair a person's sense of self-motion, says study coauthor Greg DeAngelis, professor and chair of brain and cognitive sciences at the University of Rochester. This deeper understanding of how brain circuits combine different sensory cues could also help scientists and engineers to design more sophisticated artificial nervous systems such as those used in robots, he adds. 

The brain is constantly confronted with changing and conflicting sensory input, says DeAngelis. For example, during IMAX theater footage of an aircraft rolling into a turn "you may find yourself grabbing the seat," he says. The large visual input makes you feel like you are moving, but the balance cues conveyed by sensors in your inner ear indicate that your body is in fact safely glued to the theater seat. So how does your brain decide how to interpret these conflicting inputs?

The study shows that the brain does not have to first "decide" which sensory cue is more reliable. "Indeed, this is what's exciting about what we have shown," says DeAngelis. The study demonstrates that the low-level computations performed by single neurons in the brain, when repeated by millions of neurons performing similar computations, accounts for the brain's complex ability to know which sensory signals to weight as more important. "Thus, the brain essentially can break down a seemingly high-level behavioral task into a set of much simpler operations performed simultaneously by many neurons," explains DeAngelis. 

The study confirms and extends a computational theory developed earlier by brain and cognitive scientist Alexandre Pouget at the University of Rochester and the University of Geneva, Switzerland and a coauthor on the paper. The theory predicted that neurons fire in a manner predicted by a weighted summation rule, which was largely confirmed by the neural data. Surprisingly, however, the weights that the neurons learned were slightly off target from the theoretical predictions, and the difference could explain why behavior also varies slightly from subject to subject, the authors conclude. "Being able to predict these small discrepancies establishes an exciting connection between computations performed at the level of single neurons and detailed aspects of behavior," says DeAngelis. 

To gather the data, the researchers designed a virtual-reality system to present subjects with two directional cues, a visual pattern of moving dots on a computer screen to simulate traveling forward and physical movement of the subject created by a platform. The researchers varied the amount of randomness in the motion of the dots to change how reliable the visual cues were relative to the motion of the platform. At the end of each trial, subjects indicated which direction they were heading, to the right or to the left.  

Source: University of Rochester [November 20, 2011]

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The brain's zoom button

Everybody knows how to zoom in and out on an online map, to get the level of resolution you need to get you where you want to go. Now researchers have discovered a key mechanism that can act like a zoom button in the brain, by controlling the resolution of the brain's internal maps. 

In this week's edition of Cell, Lisa Giocomo and colleagues at the Kavli Icondnstitute for Systems Neuroscience at NTNU describe how they "knocked out", or disabled, ion channels in the grid cells of the mouse brain. Grid cells are equivalent to a longitude and latitude coordinate system in the brain, with the grid cell firing at the cross-point where the longitude and latitude lines meet. This network enables the brain to make internal maps. Ion channels mediate signals between the inside and the outside of the cells. When the researchers knocked out the ion channels, they found that the resolution of the maps created by the mouse brain became coarser, in that the area covered by each grid cell was larger. 

"If grid cells are similar to a longitude and latitude coordinate system, what determines the distance between the coordinate points of this internal map?" Giocomo asks. "When we knocked out the HCN1 ion channel, the scale of the innate coordinate system increased. It's like losing longitude and latitude lines on a map. Suddenly you can't represent a spatial environment at a very fine scale." 

In a normal brain, the ion channels function as they should, and the brain is able to generate the precise resolution for the map that it needs. But if the ion channels don't work – as was the case in the experimental set up – then the map isn't at the right resolution. 

Future research will aim at determining what effect this might have on spatial memory and navigation. Giocomo says her findings could prove useful for future research on Alzheimer's and related diseases, "particularly because the area that is damaged in Alzheimer's is the area that we are investigating. Also, one of the first things to go wrong with Alzheimer's is that you suddenly start to lose your sense of direction. Of course, we don't know if there is any connection yet, but it might be worth looking into." 

The article in Cell is being published simultaneously with a companion article in Neuron, authored by researchers at the Kavli Institute for Brain Science, at Columbia University in New York. The two Kavli Institutes decided to work cooperatively on the topic, says Edvard Moser, director of the Kavli Institute at NTNU. 

"We believe that this is a great example of collaborative research instead of neck-and-neck competition. We got our knock-out mice from (Eric) Kandel's lab (at Columbia), and they sent a post-doc over here to work with us. We discussed and debated our findings of course, gave each other feedback and input," Moser says. 

The collaborative approach enabled the two institutes to publish linked research data from two interconnected areas of the brain, the entorhinal cortex and the hippocampus. Both sets of data show the effect of removing ion channels in grid cells and place cells. Place cells are thought to base their spatial response based on the calculations of the grid cells, so finding this close correspondence in research results is "very rewarding," Moser says. "It's great that we can find two pieces of evidence that show how scale is represented in our brain, and that we can publish these results at the same time. 

Source: Norwegian University of Science and Technology [November 17, 2011]

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