Depression Stems from Miscommunication Between Brain Cells; Study Challenges Role of Serotonin in Depression

A new study from the University of Maryland School of Medicine suggests that depression results from a disturbance in the ability of brain cells to communicate with each other. 

Credit: © Artur Golbert / Fotolia

A new study from the University of Maryland School of Medicine suggests that depression results from a disturbance in the ability of brain cells to communicate with each other.

The study indicates a major shift in our understanding of how depression is caused and how it should be treated. Instead of focusing on the levels of hormone-like chemicals in the brain, such as serotonin, the scientists found that the transmission of excitatory signals between cells becomes abnormal in depression.

Scott M. Thompson

The research, by senior author Scott M. Thompson, Ph.D., Professor and Interim Chair of the Department of Physiology at the University of Maryland School of Medicine, was published online in the March 17 issue of Nature Neuroscience.

According to the Centers for Disease Control and Prevention, between 2005 and 2008, approximately one in 10 Americans were treated for depression, with women more than twice as likely as men to become depressed.

The most common antidepressant medications, such as Prozac (Fluoxetine), Zoloft (Setraline) and Celexa (Citalopram), work by preventing brain cells from absorbing serotonin, resulting in an increase in its concentration in the brain.

Unfortunately, these medications are effective in only about half of patients. Because elevation of serotonin makes some depressed patients feel better, it has been thought for over 50 years that the cause of depression must therefore be an insufficient level of serotonin.

The new University of Maryland study challenges that long-standing explanation.

"Dr. Thompson's groundbreaking research could alter the field of psychiatric medicine, changing how we understand the crippling public health problem of depression and other mental illness," says E. Albert Reece, M.D., Ph.D., M.B.A., Vice President for Medical Affairs at the University of Maryland and John Z. and Akiko K. Bowers Distinguished Professor and Dean at the University of Maryland School of Medicine.

"This is the type of cutting-edge science that we strive toward at the University of Maryland, where discoveries made in the laboratory can impact the clinical practice of medicine."

Depression affects more than a quarter of all U.S. adults at some point in their lives, and the World Health Organization (WHO) predicts that by 2020 it will be the second leading cause of disability worldwide.

Depression is also the leading risk factor for suicide, which causes twice as many deaths as murder, and is the third leading cause of death for 15-24 year olds.

The first major finding of the study was the discovery that serotonin has a previously unknown ability to strengthen the communication between brain cells.

"Like speaking louder to your companion at a noisy cocktail party, serotonin amplifies excitatory interactions in brain regions important for emotional and cognitive function and apparently helps to make sure that crucial conversations between neurons get heard," says Dr. Thompson.

"Then we asked, does this action of serotonin play any role in the therapeutic action of drugs like Prozac?"

To understand what might be wrong in the brains of patients with depression and how elevating serotonin might relieve their symptoms, the study team examined the brains of rats and mice that had been repeatedly exposed to various mildly stressful conditions, comparable to the types of psychological stressors that can trigger depression in people.

The researchers could tell that their animals became depressed because they lost their preference for things that are normally pleasurable.

For example, normal animals given a choice of drinking plain water or sugar water strongly prefer the sugary solution. Study animals exposed to repeated stress, however, lost their preference for the sugar water, indicating that they no longer found it rewarding.

This depression-like behaviour strongly mimics one hallmark of human depression, called anhedonia, in which patients no longer feel rewarded by the pleasures of a nice meal or a good movie, the love of their friends and family, and countless other daily interactions.

A comparison of the activity of the animals' brain cells in normal and stressed rats revealed that stress had no effect on the levels of serotonin in the 'depressed' brains.

Instead, it was the excitatory connections that responded to serotonin in strikingly different manner. These changes could be reversed by treating the stressed animals with antidepressants until their normal behaviour was restored.

"In the depressed brain, serotonin appears to be trying hard to amplify that cocktail party conversation, but the message still doesn't get through," says Dr. Thompson.

Using specially engineered mice created by collaborators at Johns Hopkins University School of Medicine, the study also revealed that the ability of serotonin to strengthen excitatory connections was required for drugs like antidepressants to work.

Sustained enhancement of communication between brain cells is considered one of the major processes underlying memory and learning.

The team's observations that excitatory brain cell function is altered in models of depression could explain why people with depression often have difficulty concentrating, remembering details, or making decisions.

Additionally, the findings suggest that the search for new and better antidepressant compounds should be shifted from drugs that elevate serotonin to drugs that strengthen excitatory connections.

"Although more work is needed, we believe that a malfunction of excitatory connections is fundamental to the origins of depression and that restoring normal communication in the brain, something that serotonin apparently does in successfully treated patients, is critical to relieving the symptoms of this devastating disease," Dr. Thompson explains.

The above story is reprinted from materials provided by University of Maryland Medical Center.

Fluorescent Neural Cells from Monkey Skin Mature Into Several Types of Brain Cells in Monkeys

This neuron, created in the Su-Chun Zhang lab at the University of Wisconsin–Madison, makes dopamine, a neurotransmitter involved in normal movement. 

The cell originated in an induced pluripotent stem cell, which derive from adult tissues. Similar neurons survived and integrated normally after transplant into monkey brains—as a proof of principle that personalized medicine may one day treat Parkinson's disease. 

Credit: Image courtesy Yan Liu and Su-Chun Zhang, Waisman Center, University of Wisconsin–Madison

For the first time, scientists have transplanted neural cells derived from a monkey's skin into its brain and watched the cells develop into several types of mature brain cells, according to the authors of a new study in Cell Reports.

After six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein.

Because the cells were derived from adult cells in each monkey's skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual, and since the skin cells were not "foreign" tissue, there were no signs of immune rejection -- potentially a major problem with cell transplants.

"When you look at the brain, you cannot tell that it is a graft," says senior author Su-Chun Zhang, a professor of neuroscience at the University of Wisconsin-Madison.

"Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope." Marina Emborg, an associate professor of medical physics at UW-Madison and the lead co-author of the study, says,

"This is the first time I saw, in a nonhuman primate, that the transplanted cells were so well integrated, with such a minimal reaction. and after six months, to see no scar, that was the best part."

The cells were implanted in the monkeys "using a state-of-the-art surgical procedure" guided by an MRI image, says Emborg.

The three rhesus monkeys used in the study at the Wisconsin National Primate Research Center had a lesion in a brain region that causes the movement disorder Parkinson's disease, which afflicts up to 1 million Americans.

Parkinson's is caused by the death of a small number of neurons that make dopamine, a signaling chemical used in the brain.

The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos.

In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions.

This final stage of maturation occurred inside the monkey. Zhang, who was the first in the world to derive neural cells from embryonic stem cells and then iPS cells, says one key to success was precise control over the development process.

"We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells."

"By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine. ...

Now we want to move ahead and see if this leads to a real treatment for this awful disease." Another positive sign was the absence of any signs of cancer, says Zhang -- a worrisome potential outcome of stem cell transplants.

"Their appearance is normal, and we also used antibodies that mark cells that are dividing rapidly, as cancer cells are, and we do not see that, and when you look at what the cells have become, they become neurons with long axons [conducting fibers], as we'd expect.

They also produce oligodendrocytes that are helping build insulating myelin sheaths for neurons, as they should. That means they have matured correctly, and are not cancerous."

The experiment was designed as a proof of principle, says Zhang, who leads a group pioneering the use of iPS cells at the Waisman Center on the UW-Madison campus. The researchers did not transplant enough neurons to replace the dopamine-making cells in the brain, and the animal's behavior did not improve.

Although promising, the transplant technique is a long way from the clinic, Zhang adds. "Unfortunately, this technique cannot be used to help patients until a number of questions are answered: Can this transplant improve the symptoms? Is it safe? Six months is not long enough… And what are the side effects? You may improve some symptoms, but if that leads to something else, then you have not solved the problem."

Nonetheless, the new study represents a real step forward that may benefit human patients suffering from several diseases, says Emborg. "By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine."

The need for treatment is incessant, says Emborg, noting that each year, Parkinson's is diagnosed in 60,000 patients. "I'm gratified that the Parkinson's Disease Foundation took a risk as the primary funder for this small study. Now we want to move ahead and see if this leads to a real treatment for this awful disease."

"It's really the first-ever transplant of iPS cells from a non-human primate back into the same animal, not just in the brain," says Zhang.

"I have not seen anybody transplanting reprogrammed iPS cells into the blood, the pancreas or anywhere else, into the same primate. This proof-of-principle study in primates presents hopes for personalized regenerative medicine."

The above story is reprinted from materials provided by University of Wisconsin-Madison.

Building brains: toward a do-it-yourself guide

With an estimated 100 billion neurons chattering to one another through perhaps a quadrillion synaptic connections, the human brain has the most intricately complicated structure and function of any object in the known universe.

How do you build something like that? In fact, how does something so ferociously complex start off as a single cell and then create itself?

The problem might at first seem impossible to fathom, even with the knowledge that genetics, natural selection, and a half billion years of evolution can accomplish amazing things. But complexity does not have to be born of complexity, as mathematics and computer programs routinely demonstrate.

Very simple equations can give rise to the stunning complexity of fractals, for example.

Several recent neuroscience studies may be illuminating some of the structural and development principles that organize the brain. Those principles include:

• Co-opting older, simpler genetic programs and elaborating on them to new effect.
• Maintaining geometric order.
• Relying on hierarchies of control.

True, science is still very far from knowing enough to define confidently how a brain takes shape (let alone how one works). Yet it’s still fascinating to see how much structure may be determined by relatively simple rules of thumb.

Rule 1: Elaborate on older genetic mechanisms
In the earliest stages of embryonic development, the nervous systems of vertebrate animals are much like those of simpler invertebrates such as worms and starfish.

The big differences start to appear as a result of actions by certain parts of the vertebrate embryo’s body called signaling centers.

These centers release proteins that tell portions of the embryo’s exterior layer of tissue (the neuroectoderm) to organize themselves into major divisions of what will eventually become brain and spinal cord.

The standing inference has been that the genes for those signaling proteins emerged as part of whatever evolutionary changes first split the vertebrate and invertebrate lines.

New work by Ariel M. Pani of the University of Chicago and others, recently published in Nature, suggests that is not the case, however.

The acorn worm Saccoglossus kowaleskii. (Credit: Ariel Pani)

Pani and her colleagues have identified a highly similar set of genes active in the acorn worm (Saccoglossus kowalevskii), a tiny aquatic invertebrate.

According to their studies, not only do these genes have sequences that echo those of the vertebrates but they also express themselves in a similar pattern and in corresponding parts of the body.

They also help to organize the formation of features in the worms’ ectodermal tissue layer.

What’s most curious about Pani’s findings — and makes them controversial — is that the acorn worms fall into the hemichordate branch of the invertebrate family, and as such are much more distant cousins to vertebrates than are many other creatures (such as sea squirts) that seem to lack these signaling center genes.

The implication is that the genes were present in some common wormy ancestor from about 500 million years ago but that the other lines of related invertebrates subsequently lost them during evolution.

Yet some biologists question both whether the genes are truly missing from the other invertebrates and whether they really serve to organize the acorn worms’ ectoderm to the sophisticated degree claimed. (Katherine Harmon at Scientific American reviews these disagreements.)

In either case, though, it seems likely that vertebrate evolution co-opted those ancient body-patterning genes and elaborated on their function to help kick off the formation of the vastly more complicated structures of the brain and spinal cord.

Rule 2: Stay on the grid

Diffusion spectrum MR image of human brain showing curvature of two-dimensional sheets of parallel neuronal fibers that cross each other at right angles. (Credit: Van Wedeen, M.D., Martinos Center for Biomedical Imaging, Massachusetts General Hospital)

Divvying the nascent nervous systems into segments is only the start, however.

Far trickier is the challenge of directing nerve cells to knit themselves into a networked structure complex enough to support all the capabilities we expect of a brain yet orderly enough to be compressed into a heritable developmental program.

An international research team led by Van J. Wedeen of Massachusetts General Hospital has now produced evidence that the overwhelming tangle of crisscrossing nerve fibers in the brain may obscure an underlying principle of organization that is surprisingly simple — and gridlike.

As Wedeen and his colleagues reported in the March 30 issue of Science, they mapped in detail the paths and intersections of major nerve tracts interconnecting different brain areas in humans and four other primates (rhesus monkeys, owl monkeys, marmosets, and galagos).

To do so, they used a technique called diffusion spectrum magnetic resonance imaging (DSI), which can track the movement of water molecules flowing through the neurons.

Image of rhesus monkey brain showing the sheet-like, three-dimensional structure of neural pathways that cross each other at right angles. (Credit: Van Wedeen, M.D., Martinos Center for Biomedical Imaging, Massachusetts General Hospital)

What they observed was that adjacent fibers running in parallel tended to be arranged into flattened, curving sheets, rather like the ribbon cables found in electronic devices.

Adding to the orderliness, these sheets of fibers crossed one another only at right angles. In effect, the fibers stayed aligned with the front-back, right-left, and top-bottom axes that frame the brain’s anatomical organization. (See Rose Eveleth’s news story about this work for Smart Planet.)

Wedeen’s work, too, has its skeptics. For instance, if the DSI technique happens to detect nerve fibers at right angles more easily than ones crossing more obliquely (which Wedeen seems to rule out), the exclusively orthogonal arrangement of the fiber sheets might be an illusion. (Ed Yong’s “Not Exactly Rocket Science” blog at Discover.com has an excellent rundown of the technical discussion.)

Nevertheless, the possibility of a gridlike design seems exciting. The discovery by Wedeen et al. doesn’t immediately explain how brain cells wire themselves together properly.

But it does suggest that some of the organizational principles in the spinal cord and brainstem, where fibers are very clearly arranged along those front-back, right-left, top-bottom axes, may extend forward into the forebrain, too.

Moreover, the findings hint at a system of “longitude and latitude for the brain,” as Wedeen says, about which some other scientists have previously speculated.

Orderly pathways and an implicit system of coordinates might make it much easier for neurons to navigate to their targets in specific brain areas.

Step 3: Respect the hierarchy!
The roughly 2.6 square feet of cortex covering the human brain is a folded quilt of specialized neural structures that each enable some of our capacities for thought, perception, decision making, and motor control.

Any anatomy student can spot the four major cortical lobes, but for a century and a half, since the time of psychiatrist Theodor Meynert, neuroscientists have been subdividing the cortex still further on the basis of cellular architecture.

Today, the number of subdivisions in the human cortex is more than a hundred, and the variations presumably reflect fine-grained differences in those areas’ functions.

The genetic controls for the development of those areas have nonetheless been obscure.

Chi-Hua Chen of the University of California, San Diego, and a group of collaborators have uncovered an interesting clue, however, as reported in last week’s issue of Science (alongside the Wedeen paper, in fact).

They looked at MRI scans of the brains of 406 adult twins enrolled in the Vietnam Era Twin Registry, an ongoing long-term study of cognitive aging.

From that data, they correlated how closely the size of various cortical surface areas corresponded to the degree of genetic similarity among the participants to find how much shared genetic influence there might be.

Genetic clustering map of the left human brain hemisphere, from Chen et al. (Credit: UC San Diego School of Medicine)

The result was what the scientists are calling the first “brain atlas of human cortical surface area that was based on genetic correlations, rather than a priori structural or functional information.”

Chen’s team identified 12 genetic subdivisions. The most exciting part, however, was that these genetic subdivisions corresponded very closely (though not always identically) to some of the traditional subdivisions neuroanatomists have recognized on the basis of function.

The pattern suggests that specific clusters of genes — all still to be identified — help to direct the formation of each of these specialized cortical areas.

The genetic program shaping the brain would thus be hierarchical, not unlike many computer programs.

That is, some general developmental program may guide overall cortical development up to a point, but then control is handed off to more specialized genetic routines within each area, which would sharpen that cortical region’s usefulness for one job.

Very possibly, within each of the genetic subdivisions that Chen’s group saw, further sets of genetic instructions kick in, too, and further refine smaller regions within the larger ones.

Such a scheme isn’t revolutionary: it’s what most biologists would probably tend to assume must take place, given hints of similarly nested control structures in other aspects of brain development.

Nevertheless, it’s reassuring to have some further direct evidence of it. As the German neuroscientists Karl Zilles and Katrin Amunts observed in their published commentary on the Chen and Wedeen papers in Science, “Hierarchical organization of the cortex is thus the unifying rule, which encompasses all scales from the molecular to the systems level.”

A future Rule 4? Mind the connections
The ultimate detail of structure within the brain that neuroscientists can seek is the precise pattern of synaptic connections among all the individual neurons.

Neuroscientists have started referring to a comprehensive catalog of all such linkages as the connectome.

As Carl Zimmer describes in his April column for Discover, the pursuit of the connectome is a stunningly audacious ambition. Current techniques for tabulating what connects with what in the brain are still slow and painstaking.

The data-keeping challenge alone might beggar belief: a map of all the synaptic connections within just a cubic millimeter of human brain tissue could fill a petabyte of storage.

Then again, perhaps as the connectome studies progress, some organizing principles for the distribution of synaptic connections will start to emerge, as they seem to be for some of the higher levels of structure.

Scientists like Sebastian Seung of M.I.T. are determined to go after the connectome in any case. For them, it is an unavoidable mystery, because that synaptic information could be the key to understanding how memory works, why people differ in intelligence, or what goes wrong in certain mental disorders.
Unless it isn’t.

Clearly, synaptic connections must be important to all neurological phenomena because synapses are what neurons use to send signals to one another. But maybe the ultrafine structure of precise synaptic connections will overshoot the level of structural detail needed to resolve those problems adequately, in the same way that doctors don’t need to know the precise position of every cell in your body to treat cancer.

Maybe the best and most useful answers about memory, intelligence, neurological disease and more will turn out to reside at a slightly higher (and more easily accessible) level of structure.

Toxoplasma Gondii: How your cat could be making you ‘crazy’

It’s long been known that a microbe found in cat's can harm people with weakened immune systems, such as people with AIDS.

It’s also been known that pregnant women should avoid cat litter so they don’t catch the microbe, lest they pass it on to their babies, causing brain damage in the infants or even death.

The microbe in question is Toxoplasma gondii (T. gondii or Toxo for short).

New research from an unconventional scientist is showing that in certain circumstances, the microbe can alter our basic personalities, making us more or less outgoing, trusting and fearful, and even making us more prone to schizophrenia, car crashes and suicides.

The circumstances that create this possibility are as follows;

• We have to be infected by the microbe
• Our bodies will eventually overcome it, 
• But the parasite can lay dormant,
• and the danger lies in whether it lodges or travels to our brain cells

The researcher, the Czech evolutionary biologist Jaroslav Flegr, claims that when you consider all its impacts, “Toxoplasma might even kill as many people as malaria, or at least a million people a year.”

Read more of this article here: How your cat could be making you ‘crazy’

Short-term memory is based on synchronized brain oscillations

In each of the two brain regions (IPF and V4) brain activity shows strong oscillations in a certain set of frequencies called the theta-band.

Credit: Stefanie Liebe, MPI for Biological Cybernetics

Holding information within one's memory for a short while is a seemingly simple and everyday task.

We use our short-term memory when remembering a new telephone number if there is nothing to write at hand, or to find the beautiful dress inside the store that we were just admiring in the shopping window.

Yet, despite the apparent simplicity of these actions, short-term memory is a complex cognitive act that entails the participation of multiple brain regions.

However, whether and how different brain regions cooperate during memory has remained elusive.

A group of researchers from the Max Planck Institute for Biological Cybernetics in Tübingen, Germany have now come closer to answering this question.

They discovered that oscillations between different brain regions are crucial in visually remembering things over a short period of time.

It has long been known that brain regions in the frontal part of the brain are involved in short-term memory, while processing of visual information occurs primarily at the back of the brain.

However, to successfully remember visual information over a short period of time, these distant regions need to coordinate and integrate information.

To better understand how this occurs, scientists from the Max Planck Institute of Biological Cybernetics in the department of Nikos Logothetis recorded electrical activity both in a visual area and in the frontal part of the brain in monkeys.

The scientists showed the animals identical or different images within short intervals while recording their brain activity. The animals then had to indicate whether the second image was the same as the first one.

The scientists observed that, in each of the two brain regions, brain activity showed strong oscillations in a certain set of frequencies called the theta-band.

Importantly, these oscillations did not occur independently of each other, but synchronized their activity temporarily: "It is as if you have two revolving doors in each of the two areas.

During working memory, they get in sync, thereby allowing information to pass through them much more efficiently than if they were out of sync," explains Stefanie Liebe, the first author of the study, conducted in the team of Gregor Rainer in cooperation with Gregor Hörzer from the Technical University Graz.

The more synchronized the activity was, the better could the animals remember the initial image. Thus, the authors were able to establish a direct relationship between what they observed in the brain and the performance of the animal. 

Multiple Sclerosis research links brain activity to steep Cognitive decline

When it comes to communication in the brain, more is usually better but now scientists have linked increased communication in a network of brain regions to more severe mental impairment in patients with early-stage multiple sclerosis (MS).

“Measuring how well this network’s connections are working may provide a way to look beyond the wide-ranging symptoms of MS to help us quantify the disorder’s effects on the brain,” says co-author Maurizio Corbetta, MD, the Norman J. Stupp Professor of Neurology at Washington University School of Medicine in St. Louis.

“This assessment could be very useful in diagnosing the disease and tracking the effectiveness of new treatments.”

Scientists at Washington University and the University Medical Center at Hamburg-Eppendorf and the University of Tübingen, both in Germany, published the results in the Proceedings of the National Academy of Sciences.

MS damages brain cell branches, impairing the cells’ ability to communicate. The disease is highly unpredictable and produces a hodgepodge of symptoms that vary from patient to patient. These include fatigue, numbness, dizziness, pain, bowel and bladder dysfunction, visual impairments, speech disorders, headache, depression and problems with balance, coordination and walking.

The brain can redirect energy and resources to make it possible for more signals to flow through damaged circuits. But in MS, the researchers speculate, that redirection may lead to a decrease in the brain’s ability to reconfigure itself for different cognitive tasks, such as speaking, processing sensory information, controlling movement, regulating mood and creating and accessing memory.

The current study focused on whether correlations could be made between the structural damage caused by MS, the cognitive problems experienced by patients and changes in brain networking, which refers to the ability of various regions in the brain to work with each other.

The study involved 16 patients who had been diagnosed with MS in the previous four years. For comparison, scientists also included 16 healthy individuals. All participants were given an extensive battery of behavioral and cognitive tests, as well as brain scans to look for structural damage. Researchers also evaluated the connectedness of brain regions that often work together in networks.

Brain function - A new way to measure the burden of aging

Cognitive function may be a better indicator of the impact of aging on an economy than age-distribution, with chronological age imposing less of a social and economic burden if the population is "functionally" younger, according to a study published today in the Proceedings of the National Academy of Sciences.

The study finds that one standardized indicator of cognitive ability - memory recall - is better in countries where education, nutrition, and health standards are generally higher.

Aging populations are of concern to many countries as it is often assumed that aging necessarily implies a greater cost to society in terms of aged care, age related disease, and reduced capacity to contribute to society.

However this research suggests that the effects of chronological aging are uneven across nations and that in some countries, particularly more affluent ones that are able to invest in early and sustained education and health programs, cognitive function and thus the ability to live healthy, productive lives, is maintained longer.

"Demographic indicators of the economic impact of an aging population typically rely on measures based on populations' age-distribution, expressed as the Old Age Dependency Ratio (OADR).

Whilst this is helpful measurement it does not include information on individual characteristics, other than age," says lead author Vegard Skirbekk from the International Institute for Applied Systems Analysis (IIASA).

"We believe cognitive function can provide a new and comparable measure of how a region or a nation's population may age. Such information can inform early intervention in the education and health systems to try and improve cognitive performance, ultimately reducing the burden of aging."

"For example, in northern Europe or the United States where there is a relatively large population over the age of 65, we found that cognitive function is higher for this age group than for the same age group in Mexico, India and China. Overall, even though Europe and the US may be chronologically older they are 'functionally' younger."

Cognitive ability levels are also good indicators of individual productivity and this has direct relevance to the economic and business activities within a country.

The authors suggest that the difference in cognitive function may be explained by the fact that seniors in some regions of the world experience better conditions during their childhood and adult life; including nutrition, duration and quality of schooling, exposure to disease, and physical and social activity.

Thinking on your feet - Brain Size

Smithsonian researchers report that the brains of tiny spiders are so large that they fill their body cavities and overflow into their legs. 

As part of ongoing research to understand how miniaturization affects brain size and behaviour, researchers measured the central nervous systems of nine species of spiders, from rainforest giants to spiders smaller than the head of a pin.

As the spiders get smaller, their brains get proportionally bigger, filling up more and more of their body cavities.

A whole new meaning for thinking on your feet

Speaking and Understanding Speech Share the Same Parts of the Brain

The brain has two big tasks related to speech: making it and understanding it.

Psychologists and others who study the brain have debated whether these are really two separate tasks or whether they both use the same regions of the brain.

Now, a new study, published in the August issue of Psychological Science, a journal of the Association for Psychological Science, finds that speaking and understanding speech share the same parts of the brain, with one difference: we don't need the brain regions that control the movements of lips, teeth, and so on to understand speech.

Most studies of how speech works in the brain focuses on comprehension. That's mostly because it's easier to image the brains of people who are listening quietly; talking makes the head move, which is a problem when you're measuring the brain.

But now, the Donders Institute at the Radboud University Nijmegen, where the study was conducted, has developed technology that allows recording from a moving brain.

Laura Menenti, a Postdoctoral Research Associate at the University of Glasgow, co-wrote the paper along with Peter Hagoort of Radboud University Nijmegen and the Max Planck Institute for Psycholinguistics, Sarah Gierhan and Katrien Segaert.

Menenti was initially interested in how the brain produces grammatical sentences and wanted to track the process of producing a sentence in its entirety; looking not only at its grammatical structure but also at its meaning.

"What made this particularly exciting to us was that no one had managed to perform such a study before, meaning that we could explore an almost completely new topic," says Menenti.

The authors used functional MRI technology to measure brain activity in people who were either listening to sentences or speaking sentences.

The other problem with measuring brain activity in people who are speaking is that you have to get them to say the right kind of sentence.

The authors accomplished this with a picture of an action -- a man strangling a woman, say -- with one person coloured green and one coloured red to indicate their order in the sentence.

This prompted people to say either "The man is strangling the woman" or "The woman is strangled by the man." (The experiments were all carried out in Dutch.)

From this, the researchers were able to tell where in the brain three different speech tasks (computing meaning, coming up with the words, and building a grammatical sentence) -- were taking place.

They found that the same areas were activated for each of these tasks in people who were speaking and people who were listening to sentences.

However, although some studies have suggested that while people are listening to speech, they silently articulate the words in order to understand them, the authors found no involvement of motor regions when people were listening.

According to Menenti, though the study was largely designed to answer a specific theoretical question, it also points towards some useful avenues for treatment of people with language-related problems.

It suggests that while it sometimes seems that people with comprehension problems may have intact production, and vice versa, this may not necessarily be the case. According to Menenti, "Our data suggest that these problems would be expected to always at least partly coincide.

On the other, our data confirm the idea that many different processes in the language system, such as understanding meaning or grammar, can at least partly, be damaged independently of each other."

How memory is lost — and re-found

A new study published July 27 in the journal Nature shows that the neural networks in the brains of the middle-aged and elderly have weaker connections and fire less robustly than in youthful ones.

Intriguingly, note the scientists, the research suggests that this condition is reversible.

“Age-related cognitive deficits can have a serious impact on our lives in the Information Age, as people often need higher cognitive functions to meet even basic needs, such as paying bills or accessing medical care,” says Amy Arnsten, professor of neurobiology and psychology and a member of the Kavli Institute for Neuroscience.

“These abilities are critical for maintaining demanding careers and being able to live independently as we grow older.”

Arnsten and her team studied the firing of prefrontal cortical neurons in young, middle-aged and old animals as they performed a working memory task. Neurons in the prefrontal cortex of the young animals were able to maintain firing at a high rate during working memory, while neurons in older animals showed slower firing rates.

However, when the researchers adjusted the neurochemical environment around the neurons to be more similar to that of a younger subject, the neuronal firing rates were restored to more youthful levels.

Arnsten says that the aging prefrontal cortex appears to accumulate excessive levels of a signaling molecule called cAMP, which can open ion channels and weaken prefrontal neuronal firing. Agents that either inhibited cAMP or blocked cAMP-sensitive ion channels were able to restore more youthful firing patterns in the aged neurons.

One of the compounds that enhanced neuronal firing was guanfacine, a medication that is already approved for treating hypertension in adults and prefrontal deficits in children, suggesting that it may be helpful in the elderly as well, note the researchers.

Arnsten’s finding is already moving to the clinical setting. Christopher vn Dyck of the Yale School of Medicine is enrolling subjects in a clinical trial testing guanfacine’s ability to improve working memory and executive functions in elderly subjects who do not have Alzheimer’s disease or other dementias.

Information about the clinical trial can be found online,

Repeated Head Blows may cause Premature Dementia disease in athlete brain

Professional athletes who suffer repeated blows to the head are at risk for developing a brain disease that years later manifests as memory loss, mood disorders, and even early dementia.

The pattern of protein tangles and plaques associated with the disease, known as chronic traumatic encephalopathy (CTE), is distinct from those in Alzheimer’s patients, according to new research reported in the journal Neurosurgery.

“The first thing is to identify the disease, give it a name, and identify its pathology. We’ve done that,” says Bennet Omalu, associate clinical professor of pathology at University of California, Davis. Omalu was the first to describe CTE in 2002, after examining the brain of former Pittsburgh Steelers football player Mike Webster
“We’re seeing CTE in any activity that subjects your brain to repeated acceleration and deceleration.”

In the current study, Omalu and colleagues detailed histological examinations of the brains of 17 athletes who played contact sports, including eight professional football players, four professional wrestlers, and three high school football players. All had died suddenly from suicide, drug abuse, or in accidents.

The researchers diagnosed CTE in 10 of the 14 professional athletes, and one high school football player.

Important differences exist between CTE and Alzheimer’s disease, Omalu says.

Subjects with CTE have tangles of tau proteins in their brains that were similar to those seen in later-stage Alzheimer’s patients, but they occurred in a very different pattern. While the tangles in Alzheimer’s patients are scattered throughout the brain, those in the athletes exhibited a “skip phenomenon.”

The tangles occurred in some areas of the cerebral cortex but were absent in others within the same lobe. In addition, the brains of the athletes did not show the classic neuritic amyloid plaques or the widespread cerebral atrophy characteristic of Alzheimer’s disease.

Finally, the subjects diagnosed with CTE ranged from 18 to 52 years old, whereas Alzheimer’s disease typically does not occur until after age 60.

The study also questions the connection between CTE and a variant of the apolipoprotein E gene. Previous researchers have linked the ApoE4 allele to a predisposition for Alzheimer’s disease and the behaviour changes of CTE, but the CTE-positive subjects in this study were more likely to have the ApoE3 genotype, which is associated with tangle-only dementia. The CTE also produces tangle-only brain abnormalities.

Identifying the genotypes associated with CTE could help patients evaluate the risks they face when playing high contact sports.

“Although we do not have the capability now, it may one day be possible to develop a battery of genetic tests to identify individuals at high, medium or low risk for CTE. Knowing whether you had these certain types of genes, you may be advised not to play football,” Omalu says.

Currently, CTE can only be diagnosed during autopsy. Omalu and his colleagues are now focusing their research on ways to identify the disease in the living and to develop potential drug treatments.

In the meantime, “parents need to be aware of the dangers of repeated blows to the head sustained by children in football, wrestling, and hockey. The younger you are when you start playing, the greater risk you have of permanent brain damage,” says Omalu.

“We need to embark on an aggressive education of physicians and parents, so people are able to make informed judgments before they decide to play or not to play.”

The research received funding from the West Virginia University Foundation, the Hazel Ruby McQuain Charitable Trust, and Robert Fitzsimmons.

More news from UC Davis: http://www.news.ucdavis.edu/

Gardening in the Brain: Cells Called Microglia Prune the Connections Between Neurons

Microglia (green) in a mouse brain. The nuclei of all cells in the brain are labelled blue. (Credit: EMBL/R. Paolicelli)

Gardeners know that some trees require regular pruning: some of their branches have to be cut so that others can grow stronger.

The same is true of the developing brain: cells called microglia prune the connections between neurons, shaping how the brain is wired, scientists at the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, discovered. Published online in Science, the findings could one day help understand neurodevelopmental disorders like autism.

"We're very excited, because our data shows microglia are critical to get the connectivity right in the brain," says Cornelius Gross, who led the work: "they 'eat up' synapses to make space for the most effective contacts between neurons to grow strong."

Microglia are related to the white blood cells that engulf pathogens and cellular debris, and scientists knew already that microglia perform that same clean-up task when the brain is injured, 'swallowing up' dead and dying neurons.

Looking at the developing mouse brain under the microscope, Gross and colleagues found proteins from synapses -- the connections between neurons -- inside microglia, indicating that microglia are able to engulf synapses too.

To probe further, the scientists introduced a mutation that reduced the number of microglia in the developing mouse brain.

"What we saw was similar to what others have seen in at least some cases of autism in humans: many more connections between neurons," Gross says. "So we should be aware that changes in how microglia work might be a major factor in neurodevelopmental disorders that have altered brain wiring."

The microglia-limiting mutation the EMBL scientists used has only temporary effects, so eventually the number of microglia increases and the mouse brain establishes the right connections.

However, this happens later in development than it normally would, and Gross and colleagues would now like to find out if that delay has long-term consequences.

Does it affect the behaviour of the mice behaviour, for example? At the same time, Gross and colleagues plan to investigate what microglia do in the healthy adult brain, where their role is essentially unknown.

Fear boosts activation of young, immature brain cells

Fear burns memories into our brain, and new research by University of California, Berkeley, neuroscientists explains how.

Scientists have long known that fear and other highly emotional experiences lead to incredibly strong memories.

In a study appearing online today (Tuesday, June 14) in advance of publication in the journal Molecular Psychiatry, UC Berkeley’s Daniela Kaufer and colleagues report a new way for emotions to affect memory: The brain’s emotional center, the amygdala, induces the hippocampus, a relay hub for memory, to generate new neurons.

In a fearful situation, these newborn neurons get activated by the amygdala and may provide a “blank slate” to strongly imprint the new fearful memory, she said. In evolutionary terms, it means new neurons are likely helping you to remember the lion that nearly killed you.

“We remember emotional events much more strongly than daily experiences, and for a long time we have known that connections between the amygdala and hippocampus help to encode this emotional information,” said Kaufer, an assistant professor of integrative biology and a member of UC Berkeley’s Wills Neuroscience Institute.

“Our research shows that amygdala input actually pushes the hippocampus to make new neurons from a unique population of neural stem cells. This provides completely new cells that get activated in response to emotional input.”

The finding has implications for post traumatic stress disorder (PTSD) and other problems caused by faulty regulation of emotional memory.

“Many affective disorders involve disordered emotional memories like PTSD, depression and anxiety. We think that newborn neurons may play a role in creating these emotional memories,” she said.

The finding comes a year after brain researcher Fred Gage at the Salk Institute for Biological Studies in La Jolla, Calif., showed that the formation of new memories is associated with increased activation of two-week-old newborn nerve cells in the hippocampus that are derived from adult neural stem cells.

Adult stem cells appear to differentiate continually into new nerve cells – nearly 100 each day – yet half of those newborn neurons are slated for death within four weeks after their birth.

If they are highly activated, however – such as in learning new complex information – many more of them will survive and presumably help in establishing new memories in the brain.

Kaufer, who conducts research on the effects of stress on the brain, knew that many types of positive and negative experiences, such as exercise and stress, affect the rate of neurogenesis in the hippocampus.

Along with graduate students Elizabeth Kirby, the lead author of the study, and Aaron Friedman, she was intrigued by the idea that emotions might affect neurogenesis in the hippocampus, since the brain’s clearinghouse for emotions, the amygdala, is connected to the hippocampus via multiple neural circuits.

To test this, Kirby focused on the basolateral amygdala, the region of the almond-shaped structure that handles negative emotions, including stress, anxiety and fear.

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Schizophrenia cells grown in petrie jar

For a century, the mechanisms that underlie the neuropsychiatric condition schizophrenia have elude scientists. It’s hard to understand the cellular and molecular abnormalities when you only have postmortem brain samples to work with.

But alas, using skin cells from schizophrenic patients, researchers have created schizophrenia in a dish!

“This is the first time that a complex mental disease has been modeled in live human cells,” says study leader Fred Gage of Salk Institute for Biological Studies.

Schizophrenia combines paranoid delusions, auditory hallucinations, and diminished cognitive function. It affects about 3 million people in the US, and now, researchers can look at live neurons from schizophrenia patients and screen for drugs that may reverse it.

“Nobody knows how much the environment contributes to the disease,” explains Kristen Brennand of Salk. “By growing neurons in a dish, we can take the environment out of the equation, and start focusing on the underlying biological problems.”

1. The team took skin cells from 4 schizophrenic patients and reprogrammed those into stem cells, which differentiated into neurons (pictured).
2. They saw that these neurons displayed some of the same types of cellular abnormalities seen in neurons from schizophrenic patients, including fewer connections between neurons and some altered gene expression.
3. The researchers also performed an analysis of gene activity in the cells, and they identified nearly 600 genes that have activity different from cells taken from people without schizophrenia. Only about a quarter of these have been previously identified with postmortem tissue.
4. The team also tested the brain cells with 5 antipsychotic drugs: clozapine, loxapine, olanzapine, risperidone and thioridazine. They discovered that only loxapine increased the neurons’ ability to reach out and connect with their neighbors.

“For many years, mental illness has been thought of as a social or environmental disease, and many thought that if affected people just worked through their problems, they could overcome them,” says Gage. “What we are showing are real biological dysfunctions in neurons that are independent of the environment.”

The study was published in Nature last week, and it was partly funded by Sanofi-Aventis.

Image: Kristen Brennand / Salk Institute for Biological Studies

Fewer Synapses, More Efficient Learning: Molecular Glue Wires the Brain

Yale University researchers have found that a single molecule not only connects brain cells but also changes how we learn. The findings, reported in the December 9 issue of the journal Neuron, may help researchers discover ways to improve memory and could lead to new therapies to correct neurological disorders.


The junctions between brain cells over which nerve pulses pass -- called synapses -- are crucial for regulating learning and memory and how we think. Aberrations in the structure and function of synapses have been linked to mental retardation and autism, while synapses are lost in the aging brains of Alzheimer's patients.

However, the mechanisms that organize synapses in the living brain remain a puzzle. Yale scientists identified one critical piece of this puzzle, a molecule called SynCAM 1 that spans across synaptic junctions.

"We hypothesized that this molecule might promote new synapses in the developing brain, but were surprised that it also impacts the maintenance and function of these structures," said Thomas Biederer, associate professor of molecular biophysics and biochemistry and senior author of the study. "We can now define how this molecule supports the brain's ability to wire itself."

The Yale team focused on SynCAM 1, an adhesion molecule that helps to hold synaptic junctions together. They found that when the SynCAM 1 gene was activated in mice, more synaptic connections formed. Mice without the molecule produced fewer synapses.

When we learn, new synapses can form. However, the strength of synaptic connections also changes during learning, based on the amount of stimuli received -- a quality scientists termed "plasticity." Together with a group in Germany led by Valentin Stein, the team was surprised to find that SynCAM 1 controls an important form of synaptic plasticity.

Unexpectedly, Biederer and colleagues also found that mice with high amounts of SynCAM 1 are unable to learn while mice lacking SynCAM 1 -- and having fewer synapses -- learn better. Apparently an excess of the molecule can be damaging. This builds on recent theories suggesting that having too many connections isn't always better and that the balance of synaptic activity is crucial for proper learning and memory.

"Synapses are dynamic structures. It appears that SynCAM 1 ties synapses together; some of this molecule is needed to promote contact but too much glues down the synapse and inhibits its function. It may act a bit like a sculptor who helps give synapses their shape." Biederer also said that the molecule is almost identical in mice and man, and likely has the same roles in human brains.

Journal Reference:

1. Elissa M. Robbins, Alexander J. Krupp, Karen Perez De Arce, Ananda K. Ghosh, Adam I. Fogel, Antony Boucard, Thomas C. Südhof, Valentin Stein, Thomas Biederer. SynCAM 1 adhesion dynamically regulates synapse number and impacts plasticity and learning. Neuron, 2010; 68 (5): 894-906 DOI: 10.1016/j.neuron.2010.11.003

Blood bubbles promise new treatments for brain disease

(Image: Eleanor Stride)

SCUBA divers are all too aware of the danger of bubbles of air forming in the blood.  

The bends can be lethal. But bubbles in the bloodstream are not always a bad thing. 

Much smaller bubbles can be used to deliver drugs, help prevent damage from stroke and even open up the blood-brain barrier, a discovery that could lead to new treatments for diseases of the brain.

A few decades ago, researchers discovered by chance that "microbubbles" of air in the blood made ultrasound images clearer and brighter. Now a group of researchers who call themselves "the bubble community" are finding new roles for these bubbles.

Ultrasound applied to microbubbles in the blood causes them to oscillate, which appears to boost the uptake of drugs and gene therapies into nearby cells, though how this works is unclear.

"The theory is that the bubbles are stimulating natural uptake mechanisms," says Eleanor Stride at University College London. "Exactly which mechanisms, we're not sure."

Stride's team has enhanced this effect by adding magnetic nanoparticles to the microbubbles. The group injected mice with a solution containing a gene for bioluminescence, and a suspension of bubbles, before magnetically dragging the bubbles to one lung and applying ultrasound there.

Three days later, the team found bioluminescence only in the target lung, confirming that the gene hadn't been expressed elsewhere. The findings were presented at the Institute of Electrical and Electronics Engineers Ultrasonics Conference in San Diego, California, last month.

Robot to be controlled by human brain cells

A robot controlled by human brain cells could soon be trundling around a British lab, New Scientist has learned.

Kevin Warwick and Ben Whalley at the University of Reading, UK, have already used rat brain cells to control a simple wheeled robotMovie Camera.

Some 300,000 rat neurons grown in a nutrient broth and producing spikes of electrical activity were connected to the output of the robot's distance sensors. The neurons proved capable of steering the robot around a small enclosure.

Disease insights
The team say that observing how their neuron culture responds to stimulation could improve our understanding of neurological conditions such as epilepsy. For instance, the way large numbers of neurons sometimes spike in unison – a phenomenon known as "bursting" – may be similar to what happens during an epileptic seizure. If that behaviour can be altered by changing the culture chemically, electrically or physically, it might hint at potential therapies.

To make the system a better model of human disease, a culture of human neurons will be connected to the robot once the current work with rat cells is completed. This will be the first instance of human cells being used to control a robot.

One aim is to investigate any differences in the behaviour of robots controlled by rat and human neurons. "We'll be trying to find out if the learning aspects and memory appear to be similar," says Warwick.

Warwick and colleagues can proceed as soon as they are ready, as they won't need specific ethical approval to use a human neuron cell line. That's because the cultures are available to buy and "the ethical side of sourcing is done by the company from whom they are purchased", Whalley says.