Neuroscience

Blood-circulating immune cells can take over the essential immune surveillance of the brain, this is shown by scientists of the German Center for Neurodegenerative Diseases (DZNE) and the Hertie Institute for Clinical Brain Research in Tübingen. Their study, now published in PNAS, might indicate new ways of dealing with diseases of the nervous system.

The immune system is comprised of multiple cell types each capable of specialized functions to protect the body from invading pathogens and promote tissue repair after injury. One cell type, known as monocytes, circulates throughout the organism in the blood and enters tissues to actively phagocytose (eat!) foreign cells and assist in tissue healing. While monocytes can freely enter most bodily tissues, the healthy, normal brain is different as it is sequestered from circulating blood by a tight network of cells known as the blood brain barrier. Thus, the brain must maintain a highly specialized, resident immune cell, known as microglia, to remove harmful invaders and respond to tissue damage.

In certain situations, such as during disease, monocytes can enter the brain and also contribute to tissue repair or disease progression. However, the potential for monocytes to actively replace old or injured microglia is under considerable debate. To address this, Nicholas Varvel, Stefan Grathwohl and colleagues from the German Center for Neurodegenerative Diseases (DZNE) Tübingen and the Hertie Institute for Clinical Brain Research in Tübingen used a transgenic mouse model in which almost all brain microglia cells (>95%) can be removed within two weeks. This was done by introducing a so-called suicide gene into microglia cells and administering a pharmaceutical agent that leads to acute death of the cells. Surprisingly, after the ablation of the microglia, the brain was rapidly repopulated by blood-circulating monocytes. The monocytes appeared similar, but not identical to resident microglia. The newly populated monocytes, evenly dispersed throughout the brain, responded to acute neuronal injury and other stimuli — all activities normally assumed by microglia. Most interestingly, the monocytes were still present in the brain six months - nearly a quarter of the life of a laboratory mouse - after initial colonization.

These studies now published in PNAS provide evidence that blood-circulating monocytes can replace brain resident microglia and take over the essential immune surveillance of the brain. Furthermore, the findings highlight a strong homeostatic mechanism to maintain a resident immune cell within the brain. The observation that the monocytes took up long-term residence in the brain raises the possibility that these cells can be utilized to deliver therapeutic agents into the diseased brain or replace microglia when they become dysfunctional. Can monocytes be exploited to combat the consequences of Alzheimer’s disease and other neurodegenerative diseases? The scientists and their colleagues in the research groups headed by Mathias Jucker are now following exactly this research avenue.

In 1906, when Alois Alzheimer discovered the neurodegenerative disease that would later be named for him, he saw amyloid-beta plaques and neurofibrillary tangles inside the brain. Several decades later, abnormal protein structures called Hirano bodies also were frequently observed in patients with neurodegenerative diseases.

A hundred years and many millions of suffering patients and families later, scientists still don’t know what these structures do. They do know, thanks to new research from the University of Georgia, that Hirano bodies may have a protective role in the brain of Alzheimer’s patients.

Matthew Furgerson, a doctoral candidate in the UGA Franklin College of Arts and Sciences department of biochemistry and molecular biology, used cell culture models to study the role of Hirano bodies in cell death induced by AICD, or a fragment of AICD called c31, that are released inside the cell during cleavage of the amyloid precursor protein. This cleavage also produces amyloid-beta, which forms extracellular plaques.

Furgerson found mixtures of amyloid precursor protein, c31 and tau-the protein that forms the intracellular neurofibrillary tangles-or of AICD and tau cause synergistic cell death that is significantly higher than cell death from amyloid precursor protein, c31, AICD or tau alone.

"This synergistic cell death is very exciting," Furgerson said. "Other groups have shown synergy between extracellular amyloid beta or amyloid precursor protein with tau, but these new results show that there may be an important interaction that occurs inside the cells."

The results of this study were published in the September issue of PLoS One. Ruth Furukawa, associate research scientist, and Marcus Fechheimer, University Professor in cellular biology, are co-authors on the paper.

Furgerson also found cell death is significantly reduced in cells that contain Hirano bodies compared to cells without Hirano bodies. The protective effect of Hirano bodies was observed in cell cultures in both the presence and absence of tau. The findings reveal that Hirano bodies may have a protective role during the progression of Alzheimer’s disease.

While this research offers no cure for the disease, it does offer some understanding about how the disease operates. The lab has been a leader of Hirano body research for more than a decade due to their development of cell culture and mouse model systems.

Before the development of model systems, the only way to study these abnormal structures was in post-mortem brain tissue. The recently developed Hirano body mouse model is currently being used with an Alzheimer’s model mouse to investigate whether cell culture results can translate to a complex animal.

"I feel privileged to lead a team that might be able to contribute knowledge to help us understand Alzheimer’s disease processes," Fechheimer said. "Other groups have focused on plaques and tangles, and we don’t know as much about Hirano bodies. Results from the cell culture studies are exciting and reveal the protective role of Hirano bodies. Our ongoing studies with mouse models are essential to defining the role of Hirano bodies in Alzheimer’s disease progression in a whole animal."

Perceive first, act afterwards. The architecture of most of today’s robots is underpinned by this control strategy. The eSMCs project has set itself the aim of changing the paradigm and generating more dynamic computer models in which action is not a mere consequence of perception but an integral part of the perception process. It is about improving robot behaviour by means of perception models closer to those of humans.

"The concept of how science understands the mind when it comes to building a robot or looking at the brain is that you take a photo, which is then processed as if the mind were a computer, and a recognition of patterns is carried out. There are various types of algorithms and techniques for identifying an object, scenes, etc. However, organic perception, that of human beings, is much more active. The eye, for example, carries out a whole host of saccadic movements -small rapid ocular movements- that we do not see. Seeing is establishing and recognising objects through this visual action, knowing how the relationship and sensation of my body changes with respect to movement," explains Xabier Barandiaran, a PhD-holder in Philosophy and researcher at IAS-Research (UPV/EHU) which under the leadership of Ikerbasque researcher Ezequiel di Paolo is part of the European project eSMCs (Extending Sensorimotor Contingencies to Cognition).

Until now, the belief has been that sensations were processed, and the perception was created, and this in turn then led to reasoning and action. As Barandiaran sees it, action is an integral part of perception:”Our basic idea is that when we perceive, what is there is active exploration, a particular co-ordination with the surroundings, like a kind of invisible dance than makes vision possible.”

The eSMCs project aims to apply this idea to the computer models used in robots, improve their behaviour and thus understand the nature of the animal and human mind. For this purpose, the researchers are working on sensorimotor contingencies: regular relationships existing between actions and changes in the sensory variations associated with these actions.

An example of this kind of contingency is when you drink water and speak at the same time, almost without realising it. Interaction with the surroundings has taken place “without any need to internally represent that this is a glass and then compute needs and plan an action,” explains Barandiaran, “seeing the glass draws one’s attention, it is coordinated with thirst while the presence of the water itself on the table is enough for me to coordinate the visual-motor cycle that ends up with the glass at my lips.”The same thing happens in the robots in the eSMCs project, “they are moving the whole time, they don’t stop to think; they think about the act using the body and the surroundings,” he adds.

The researchers in the eSMCs project maintain that actions play a key role not only in perception, but also in the development of more complex cognitive capacities. That is why they believe that sensorimotor contingencies can be used to specify habits, intentions, tendencies and mental structures, thus providing the robot with a more complex, fluid behaviour.

So one of the experiments involves a robot simulation (developed by Thomas Buhrmann, who is also a member of this team at the UPV/EHU) in which an agent has to discriminate between what we could call an acne pimple and a bite or lump on the skin.”The acne has a tip, the bite doesn’t. Just as people do, our agent stays with the tip and recognises the acne, and when it goes on to touch the lump, it ignores it. What we are seeking to model and explain is that moment of perception that is built with the active exploration of the skin, when you feel ‘ah! I’ve found the acne pimple’ and you go on sliding your finger across it,” says Barandiaran. The model tries to identify what kind of relationship is established between the movement and sensation cycles and the neurodynamic patterns that are simulated in the robot’s “mini brain”.

In another robot, built at the Artificial Intelligence Laboratory of Zürich University, Puppy, a robot dog, is capable of adapting and “feeling” the texture of the terrain on which it is moving (slippery, viscous, rough, etc.) by exploring the sensorimotor contingencies that take place when walking.

The work of the UPV/EHU’s research team is focusing on the theoretical part of the models to be developed.”As philosophers, what we mostly do is define concepts. Our main aim is to be able to define technical concepts like the sensorimotor habitat, or that of the pattern of sensorimotor co-ordination, as well as that of habit or of mental life as a whole. “Defining concepts and giving them a mathematical form is essential so that the scientist can apply it to specific experiments, not only with robots, but also with human beings. The partners at the University Medical Centre Hamburg-Eppendorf, for example, are studying in dialogue with the theoretical development of the UPV/EHU team how the perception of time and space changes in Parkinson’s patients.

Researchers identify brain mechanisms that regulating cocaine-seeking behavior

Researchers from the University of Wisconsin-Milwaukee (UWM) have identified mechanisms in the brain responsible for regulating cocaine-seeking behavior, providing an avenue for drug development that could greatly reduce the high relapse rate in cocaine addiction.

The research reveals that stimulation of certain brain receptors promotes inhibition of cocaine-associated memories, helping addicts to stop drug use. This inhibition is achieved through enhancing a process called “extinction learning,” in which cocaine-associated memories are replaced with associations that have no drug “reward.” This reduces drug-seeking behavior in rats.

The work was presented at the annual meeting of the Society for Neuroscience in New Orleans by Devin Mueller, UWM assistant professor of psychology, and doctoral student James Otis.

There are currently no FDA-approved medications to treat cocaine abuse, only treatments that address withdrawal symptoms, says Mueller. Abuse is maintained, in part, through exposure to environmental cues that trigger cocaine-related memories which lead to craving and relapse in recovering addicts. Currently, exposure therapy is used to help recovering addicts suppress their drug-seeking behavior, but with limited success. In exposure therapy, a patient is repeatedly exposed to stimuli that provoke craving. With repeated exposure, the patient experiences extinction, leading to reduced craving when presented with those stimuli.

If extinction could be strengthened, it would increase the effectiveness of exposure therapies in preventing relapse.

Isolating the receptor

The team found that a specific variant of the NMDA receptor, those which contain the NR2B subunit, are critical for extinction learning. They also discovered that drugs known to enhance NR2B function strengthened extinction because they act specifically in a region of the brain that regulates learned behaviors. In their investigation, researchers conditioned rats to associate one distinct chamber, but not another, with cocaine. Following conditioning, the rats were tested for a place preference by allowing drug-free access to both chambers. Rats demonstrating cocaine-seeking behavior spent significantly more time in the previously cocaine-associated chamber. Over several cocaine-free test sessions, addicted rats lost their place preference through extinction learning.

To examine the neural mechanisms of extinction, the researchers administered ifenprodil, which blocks NR2B-containing NMDA receptors, immediately after an extinction test. Ifenprodil-treated rats continued to spend more time in the cocaine-associated chamber even in the absence of cocaine, while saline-treated rats did not. These results were also replicated through specific infusion of ifenprodil into the brain’s infralimbic cortex, localizing a key brain structure in arresting cocaine-seeking.

Other avenues

The results indicate that enhancing NR2B function would boost the effectiveness of extinction-based exposure therapies. Although there are currently no NR2B-enhancing drugs, the NR2B containing receptor can be stimulated using other molecular pathways, says Mueller.

An example is the brain derived neurotrophic factor (BDNF) signaling cascade, which is implicated in neuron survival and growth. The authors targeted this cascade by directly administering BDNF into the infralimbic cortex. In extinction tests, administration of BDNF caused rats to lose their preference for the cocaine-associated chamber faster than rats given a placebo.

Mueller and Otis took these findings even further toward possible therapeutic intervention for addicts.

One issue with giving BDNF to humans is that it is unable to reach the brain through the bloodstream. Therefore, researchers next targeted the TrkB receptor, which is where BDNF normally binds. They did so with a newly synthesized drug that is able to reach the brain due to its small molecular size. This TrkB receptor agonist, known as 7,8 dihydroxyflavone, also strengthened extinction when given to rats during extinction training. The authors conclude that combining TrKB receptor stimulation simultaneously with exposure therapy could be an effective treatment for cocaine abuse, reducing craving and the potential for relapse.

You glimpse a stranger standing in the street. The light is hazy and the person’s face and clothing are indistinct. Who is it? Chances are you will think it is a man—and the reason for this is a survival reflex, according to an unusual study published on Wednesday.

Psychologists at the University of California at Los Angeles delved into our quest for visual clues when we assess other people.

They asked male and female students to look at 21 human silhouettes, all of them the same height, but with a progressively changing waist-to-hip ratio. The figures began with an obviously female “hourglass” figure and, after incremental changes, ended with an obviously male “hunk” figure. The volunteers were asked to say whether each of the 21 silhouettes was male or female, the idea being to identify the point where they saw a shift in gender.

What was striking, said researcher Kerri Johnson, was a preference for the volunteers to deem a shape to be a man whenever it was ambiguous—or could readily have been taken for a woman. “I was surprised by the size of the effect. It was a much stronger effect than I ever imagined,” Johnson said in a phone interview.

In the natural world, the demarcation between a woman’s shape and man’s shape comes when the ratio of the waist and hip circumferences is 0.8. But the volunteers, on average, placed the boundary at 0.68. In other words, an identifiable female shape for them was close to the idealised curves of a pinup.

Johnson’s team carried out three further studies, using a slightly different methods to see whether their approach had been skewed, and found that the bias in favour of men was unchanged. Are these errors in perception? Not so, said Johnson, who believes it to be an ancestral survival mechanism.

A man is likelier than a woman to be a bigger physical threat and our default perception is to prepare for risk: it’s better to be safe than sorry. “We suspect that this might be for a self-protective reason,” she said. “If you are walking down a dark alley at night, a woman poses no great physical threat to you in general, but if you encounter an unknown man, he’s more likely to have a physical formidability that could pose some risks.”

Johnson conceded that there could be cultural or ethnic factors which influence judgement but argued that the same kind of bias would prevail anywhere. “I think it’s entirely likely that if we were to test this in different populations we would probably have the same basic effect, the same pattern of judgement, although the strength of the judgement might vary,” she said.

The findings show how gender stereotypes can be reinforced, sometimes dangerously so, said the study. A woman could struggle if she has a body shape that is perceived as masculine and thus unattractive. “Consistent with other research, this is likely to produce preferences for extreme body shapes, particularly for women,” said the study.

The paper appears in the British journal Proceedings of the Royal Society B

Electrical stimulation of the visual cortex may one day give image perception to blind people.

Work presented at the Society for Neuroscience meeting in New Orleans today suggests a way to create a completely new kind of visual prosthetic—one that restores vision by directly activating the brain.

In a poster session, researchers presented results showing how electrical stimulation of the visual cortex can evoke the sensation of simple flashes of light—including spatial information about those flashes.

While other researchers are trying to develop artificial retinas that feed visual signals into existing sensory pathways (see “A Retinal Prosthetic Powered by Light" and "Now I See You" for instance), the team behind the new work, from the Baylor College of Medicine and the University of Texas Health Science Center in Houston, is exploring the possibility of bypassing those routes all together. This could be vital for those whose retinas are unable to receive retinal stimulation.

The researchers used electrodes to stimulate the brains of three patients who were already undergoing brian surgery to treat epilepsy. All three were able to detect bright spots of light, called phosphenes, when certain regions of their brains were stimulated. And, in seven out of eight trials, the patients were able to correctly see the orientation of a phosphene—in one of two orientations, depending on the stimulation they received. 

The work builds upon a study published by the same team in Nature Neuroscience this summer. In that study, the researchers defined which areas of the brain produce phosphene perception when patients’ brains were electrically stimulated.

A press release related to the earlier work says that the researchers “plan to conduct a larger patient study and create multiple flashes of light at the same time. Twenty-seven or so simultaneous flashes might allow participants to see the outline of a letter.”

There’s a reason genius and solitude seem to go hand in hand, a new study says. Social rejection leads to creative problem solving.

Don’t let rejection get you down—it might be the ticket to creativity, science says. That’s right: If regular rejection doesn’t cause you to lose all self-confidence and withdraw from the world entirely, it just might boost your ability to think outside of the mainstream and draw upon a unique worldview, suggesting that the kind of people society considers “geniuses” might tend to have a go-it-alone, loner mentality.

Research conducted by Cornell and Johns Hopkins University researchers has shown that people who are able to handle rejection in the proper manner—by shrugging it off and blazing their own, independent trails—can experience heightened creativity and even commercial success through an ability to eschew mainstream thought and groupthink and instead pursue their own creative solutions to problems. They tested their hypothesis through a series of experiments in which they manipulated the experience of social rejection; subjects in the study were led to believe that everyone in a group exercise could choose whom to work with on a team project, only to be told later that no one had selected them for a team.

For people with an independent mindset, this rejection inspired them to go on and complete the exercise in a way that was deemed more creative (we’re not exactly sure how “creativity” was measured). For people without an independent mindset—well, we’re not really sure what kind of impact this exclusion had on them (hopefully someone later told them it was just an experiment, it was all in good fun, and really, everyone here thinks you’re great).

The researchers acknowledge that for some, the consequences of rejection can be quite negative. Their research is only intended to show that for those of a certain mindset, social rejection can have a silver lining, driving home something that we more or less already knew: it’s not easy being a genius.

The idea that an individual might suffer from a sexual addiction is great fodder for radio talk shows, comedians and late night TV. But a sex addiction is no laughing matter. Relationships are destroyed, jobs are lost, lives ruined.

Yet psychiatrists have been reluctant to accept the idea of out-of-control sexual behavior as a mental health disorder because of the lack of scientific evidence.

Now a UCLA-led team of experts has tested a proposed set of criteria to define “hypersexual disorder,” also known as sexual addiction, as a new mental health condition.

Rory Reid, a research psychologist and assistant professor of psychiatry at the Semel Institute of Neuroscience and Human Behavior at UCLA, led a team of psychiatrists, psychologists, social workers, and marriage and family therapists that found the proposed criteria to be reliable and valid in helping mental health professionals accurately diagnose hypersexual disorder.

The results of this study — reported in the current edition of the Journal of Sexual Medicine — will influence whether hypersexual disorder should be included in the forthcoming revised fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), considered the “bible” of psychiatry.

The importance of the study, Reid said, is that it suggests evidence in support of hypersexual disorder as a legitimate mental health condition.

"The criteria for hypersexual disorder that have been proposed, and now tested, will allow researchers and clinicians to study, treat and develop prevention strategies for individuals at risk for developing hypersexual behavior," he said.

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The Who asked “who are you?” but Dartmouth neurobiologist Jeffrey Taube asks “where are you?” and “where are you going?” Taube is not asking philosophical or theological questions. Rather, he is investigating nerve cells in the brain that function in establishing one’s location and direction.

Taube, a professor in the Department of Psychological and Brain Sciences, is using microelectrodes to record the activity of cells in a rat’s brain that make possible spatial navigation — how the rat gets from one place to another — from “here” to “there.” But before embarking to go “there,” you must first define “here.”

Survival Value

"Knowing what direction you are facing, where you are, and how to navigate are really fundamental to your survival," says Taube. "For any animal that is preyed upon, you’d better know where your hole in the ground is and how you are going to get there quickly. And you also need to know direction and location to find food resources, water resources, and the like."

Not only is this information fundamental to your survival, but knowing your spatial orientation at a given moment is important in other ways, as well. Taube points out that it is a sense or skill that you tend to take for granted, which you subconsciously keep track of. “It only comes to your attention when something goes wrong, like when you look for your car at the end of the day and you can’t find it in the parking lot,” says Taube.

Perhaps this is a momentary lapse, a minor navigational error, but it might also be the result of brain damage due to trauma or a stroke, or it might even be attributable to the onset of a disease such as Alzheimer’s. Understanding the process of spatial navigation and knowing its relevant areas in the brain may be crucial to dealing with such situations.

The Cells Themselves

One critical component involved in this process is the set of neurons called “head direction cells.” These cells act like a compass based on the direction your head is facing. They are located in the thalamus, a structure that sits on top of the brainstem, near the center of the brain.

He is also studying neurons he calls “place cells.” These cells work to establish your location relative to some landmarks or cues in the environment. The place cells are found in the hippocampus, part of the brain’s temporal lobe. They fire based not on the direction you are facing, but on where you are located.

Studies were conducted using implanted microelectrodes that enabled the monitoring of electrical activity as these different cell types fired.

Taube explains that the two populations — the head direction cells and the place cells — talk to one another. “They put that information together to give you an overall sense of ‘here,’ location wise and direction wise,” he says. “That is the first ingredient for being able to ask the question, ‘How am I going to get to point B if I am at point A?’ It is the starting point on the cognitive map.”

The Latest Research

Taube and Stephane Valerio, his postdoctoral associate for the last four years, have just published a paper in the journal Nature Neuroscience, highlighting the head direction cells. Valerio has since returned to the Université Bordeaux in France.

The studies described in Nature Neuroscience discuss the responses of the spatial navigation system when an animal makes an error and arrives at a destination other than the one targeted — its home refuge, in this case. The authors describe two error-correction processes that may be called into play — resetting and remapping — differentiating them based on the size of error the animal makes when performing the task.

When the animal makes a small error and misses the target by a little, the cells will reset to their original setting, fixing on landmarks it can identify in its landscape. “We concluded that this was an active behavioral correction process, an adjustment in performance,” Taube says. “However, if the animal becomes disoriented and makes a large error in its quest for home, it will construct an entirely new cognitive map with a permanent shift in the directional firing pattern of the head direction cells.” This is the “remapping.”

Taube acknowledges that others have talked about remapping and resetting, but they have always regarded them as if they were the same process. “What we are trying to argue in this paper is that they are really two different, separate brain processes, and we demonstrated it empirically,” he says. “To continue to study spatial navigation, in particular how you correct for errors, you have to distinguish between these two qualitatively different responses.”

Taube says other investigators will use this distinction as a basis for further studies, particularly in understanding how people correct their orientation when making navigational errors.

A research team from Stanford University has found that injecting the blood of young mice into older mice can cause new neural development and improved memory. Team lead Saul Villeda presented the groups’ findings at this year’s Society for Neuroscience conference.

The researchers were following up on work by another team also led by Villeda that last year found that when younger mice were given transfusions of blood from older mice, their mental faculties aged more quickly than non transfused young mice. In their paper published in the journal Nature, the team also noted that the reverse appeared to be true as well, namely that the older mice derived a degree of mental benefit from the transfusions.

In this new research, the team connected the bloodstreams of an older mouse and a younger mouse, allowing their blood to comingle. Subsequent brain scans found that the number of neural stem cells in the brains of the older mice increased by 20 percent after just a few days, indicating that new neural connections were being made – a necessary occurrence for increased memory retention.

To find out if such differences could be measured in a behavioral sense, the team gave transfusions of blood plasma from young mice to older mice and then tested them in a standard water maze; one that requires strong memory skills. The team found that the transfused mice were able to perform as well as much younger mice, while a similar group of older mice that did not get transfusions were much less successful at solving the maze.

Villeda pointed out in his talk that his team’s findings don’t indicate that older people should try to obtain transfusions from younger people to stave off dementia or Alzheimer’s disease, as it’s not yet known if the same results might be had. What needs to happen, he said, is for researchers to look more closely at young mouse blood compared to the blood of older mice to discover what differences in it might account for the increased neural buildup it offers to older mice.

Neurobiologists at the Research Institute of Molecular Pathology (IMP) in Vienna investigated how the brain is able to group external stimuli into stable categories. They found the answer in the discrete dynamics of neuronal circuits. The journal Neuron publishes the results in its current issue.

How do we manage to recognize a friend’s face, regardless of the light conditions, the person’s hairstyle or make-up? Why do we always hear the same words, whether they are spoken by a man or woman, in a loud or soft voice? It is due to the amazing skill of our brain to turn a wealth of sensory information into a number of defined categories and objects. The ability to create constants in a changing world feels natural and effortless to a human, but it is extremely difficult to train a computer to perform the task.

At the IMP in Vienna, neurobiologist Simon Rumpel and his post-doc Brice Bathellier have been able to show that certain properties of neuronal networks in the brain are responsible for the formation of categories. In experiments with mice, the researchers produced an array of sounds and monitored the activity of nerve cell-clusters in the auditory cortex. They found that groups of 50 to 100 neurons displayed only a limited number of different activity-patterns in response to the different sounds.

The scientists then selected two basis sounds that produced different response patterns and constructed linear mixtures from them. When the mixture ratio was varied continuously, the answer was not a continuous change in the activity patters of the nerve cells, but rather an abrupt transition. Such dynamic behavior is reminiscent of the behavior of artificial attractor-networks that have been suggested by computer scientists as a solution to the categorization problem.

The findings in the activity patters of neurons were backed up by behavioral experiments with mice. The animals were trained to discriminate between two sounds. They were then exposed to a third sound and their reaction was tracked. Whether the answer to the third tone was more like the reaction to the first or the second one, was used as an indicator of the similarity of perception. By looking at the activity patters in the auditory cortex, the scientists were able to predict the reaction of the mice.

The new findings that are published in the current issue of the journal Neuron, demonstrate that discrete network states provide a substrate for category formation in brain circuits. The authors suggest that the hierarchical structure of discrete representations might be essential for elaborate cognitive functions such as language processing.

Chronic alcohol abuse can severely damage the nervous system, particularly cognitive functions, cerebral metabolism, and brain morphology. Building upon previous findings that alcoholics can experience brain volume recovery with abstinence, this study found that recovery of cerebral gray matter (GM) can take place within the first two weeks of abstinence, but may vary between brain regions.

Results will be published in the January 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"Shrinkage of brain matter, and an accompanying increase of cerebrospinal fluid, which acts as a cushion or buffer for the brain, are well-known degradations caused by alcohol abuse," explained Gabriele Ende, professor of medical physics in the Department of Neuroimaging at the Central Institute of Mental Health. 
 "This volume loss has previously been associated with neuropsychological deficits such as memory loss, concentration deficits, and increased impulsivity."

"Several processes likely account for changes in brain tissue volume observed through bouts of drinking and abstinence over the course of alcoholism," added Natalie May Zahr, a research scientist in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine. "One process likely reflects true, irreversible neuronal cell death, while another process likely reflects shrinkage, a mechanism that would allow for volume changes in both negative and positive directions, and could account for brain volume recovery with abstinence."

"Gray matter (GM) and white matter (WM) are the main components of the brain that can be distinguished with magnetic resonance imaging (MRI)," explained Ende. "GM consists of neuronal cell bodies, neuropil, glial cells, and capillaries. WM mostly contains myelinated axon tracts."

"Myelin forms an insulating sheath around axons that increases the speed at which they are able to conduct electrical activity," added Zahr. "Because myelin is composed primarily of fat, it gives white matter its color. Cerebrospinal fluid (CSF) is a clear fluid that surrounds and thereby cushions the brain in the skull. Conventional brain structural MRI produces images of protons, with contributions primarily from water and some from fat. Tissue contrast is possible because of the fundamental differences in water content in the primary tissues of the brain: WM consists of about 70 percent water, GM 80 percent, and CSF 99 percent."

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Decreased activity of a group of genes may explain why in young children the “fear center” of the anxious brain can’t learn to distinguish real threats from the imaginary, according to a new University of Wisconsin study.

The study, published this week in the Proceedings of the National Academy of Sciences (PNAS), lays out evidence that young primates with highly anxious temperaments have decreased activity of specific genes within the amygdala, the brain’s fear center.

The authors hypothesize that this may result in over activity of the brain circuit that leads to higher risk for developing disabling anxiety and depression.

This may be particularly important since the genes involved play a major role in forming the brain connections needed for learning about fears. While all children have fears and anxieties, the authors suggest that children with low levels of activity of these genes develop anxious dispositions because they fail to learn to cope by overcoming their early childhood fears.

“Working with my close collaborator and graduate student, Drew Fox, we focused on understanding the function of genes that promote learning and plasticity in the amygdala,” says Dr. Ned H. Kalin, chair of psychiatry at the University of Wisconsin School of Medicine and Public Health, who led the research. “We found reduced activity in key genes that could impair the ability to sculpt the brain, resulting in a failure to develop the capacity to discriminate between real and imaginary fears.”

Kalin says the study helps support the need for early intervention in children identified as excessively shy and anxious. It may also point a way to better treatments aimed at decreasing the likelihood of children developing more severe psychiatric problems. Anxiety in children is quite common and can lead to anxiety and depression in adolescence and often precedes anxiety disorders, depression and substance abuse in adults.

Most small children go through a phase when they’re frightened of many things, including monsters or new social situations, Kalin says, but their maturing brains soon learn to distinguish real threats from the imaginary. But some children do not adapt, generalize their fears to numerous situations, and may later develop serious anxiety and mood disorders. These children tend to be more sensitive to stress, produce more stress hormones and have heightened nervous-system activity.

Kalin, Fox and co-authors wondered whether some differences in the developing amygdala prevent it from learning how to regulate and adapt to anxiety. Kalin’s earlier work identified a subset of young monkeys, similar to extremely shy children, with an inherited anxious disposition. Using brain imaging, the authors showed that high levels of amygdala activity predicted trait-like anxiety in anxious young primates. Like their stable and enduring anxious dispositions, these individuals also had chronically elevated levels of amygdala activity.

“We believe that this pinpoints a critical region in the brain that determines an individual’s level of trait anxiety,’’ Kalin explains.

In examining a specific part of the amygdala, the central nucleus, the researchers analyzed gene expression, which reflects both environmental and inherited influences. Within the central nucleus of the amygdala the authors found that anxious individuals tended to have decreased expression of a gene called neurotrophic tyrosine kinase, receptor, type 3 (NTRK3). Low levels of this gene that encodes for a brain cell surface receptor may be why the amygdala of an anxious monkey or child is chronically overactive and unable to overcome anxiety and fears.

“This is the first demonstration that the early risk to develop anxiety and depression may be related to the underactivity of particular genes in the developing primate amygdala,’’ Kalin says. “These findings have provided the basis for our hypothesis that can explain the early childhood risk to develop anxiety and depression. It also suggests some creative ways to help children with extreme anxiety by developing new treatments focused on increasing the activity of specific genes involved in facilitating the brain development that underlies fear learning and coping.”

A diverse team of biologists has shown using induced pluripotent stem cells (iPSCs) that a gene mutation that causes malformations in the structure of the nuclear envelope of neural cells, is associated with Parkinson’s disease. In their paper published in the journal Nature, they describe how they found iPSC cells taken from Parkinson’s patients over time demonstrated the same cell disruption found in neural cells taken from other deceased patient’s with the disease. They also found that by introducing a compound known to disrupt the gene mutation, that they could reverse the cell malformation.

Parkinson’s disease is a degenerative disorder of the nervous system characterized by shaking, slowness of movement and difficulty walking. Over time most patients succumb to dementia and eventually die. Much research has centered on the disruption and death of dopamine-generating cells as the root cause of the disorder despite evidence that such a disruption would not result in all of the symptoms Parkinson’s patient’s exhibit. For that reason, researchers have looked to other causes.

In this new effort, the researchers looked at possible reasons for disruption to the nuclear envelope, the thin film that separates the nucleus from the cytoplasm in neural cells. Such disruptions have been associated with Parkinson’s but no definitive correlation has been found, until now.

To gain a better understanding of what might be causing such disruptions, the research team obtained samples of induced iPSCs from Parkinson’s patients and allowed them to grow in an external environment. They noted that the same disruptions occurred as the iPSCs grew into neural cells, suggesting a genetic cause. Prior research had indicated that a mutation of the LRRK2 gene was connected to Parkinson’s disease but no clear indication of the mechanism involved had been found. Testing the cells derived from the iPSCs showed the same mutation, implicating it as a possible cause of the disorder. The researchers also induced the mutation in human embryo stem cells and found that they too developed the same disruption as they grew into neural cells as was found with the iPSCs.

Next the researchers generated a line of iPSCs minus the mutation and found that the cells did not develop the disruptions. They followed that up by adding a chemical compound known to disrupt the mutation to already affected cells and discovered that it prevented them from being disrupted as well.

The researchers don’t know why the mutation occurs but believe a new therapy for treating Parkinson’s patients might be on the horizon as a result of their research.

A study led by researchers at Boston University School of Medicine (BUSM) provides novel insight into the impact that Huntington’s disease has on the brain. The findings, published online in Neurology, pinpoint areas of the brain most affected by the disease and opens the door to examine why some people experience milder forms of the disease than others.

Richard Myers, PhD, professor of neurology at BUSM, is the study’s lead/corresponding author. This study, which is the largest to date of brains specific to Huntington’s disease, is the product of nearly 30 years of collaboration between the lead investigators at BUSM and their colleagues at the McLean Brain Tissue Resource Center, Massachusetts General Hospital and Columbia University.

Huntington’s disease (HD) is an inherited and fatal neurological disorder that typically is diagnosed when a person is approximately 40 years old. The gene responsible for the disease was identified in 1993, but the reason why certain neurons or brain cells die remains unknown.

The investigators examined 664 autopsy brain samples with HD that were donated to the McLean Brain Bank. They evaluated and scored more than 50 areas of the brain for the effects of HD on neurons and other brain cell types. This information was combined with a genetic study to characterize variations in the Huntington gene. They also gathered the clinical neurological information on the patients’ age when HD symptoms presented and how long the patient survived with the disease.

Based on this analysis, the investigators discovered that HD primarily damages the brain in two areas. The striatum, which is located deep within the brain and is involved in motor control and involuntary movement, was the area most severely impacted by HD. The outer cortical regions, which are involved in cognitive function and thought processing, also showed damage from HD, but it was less severe than in the striatum.

The investigators identified extraordinary variation in the extent of cell death in different brain regions. For example, some individuals had extremely severe outer cortical degeneration while others appeared virtually normal. Also, the extent of involvement for these two regions was remarkably unrelated, where some people demonstrated heavy involvement in the striatum but very little involvement in the cortex, and vice versa.

“There are tremendous differences in how people with Huntington’s disease are affected,” Myers said. “Some people with the disease have more difficulty with motor control than with their cognitive function while others suffer more from cognitive disability than motor control issues.”

When studying these differences, the investigators noted that the cell death in the striatum is heavily driven by the effects of variations in the Huntington gene itself, while effects on the cortex were minimally affected by the HD gene and are thus likely to be a consequence of other unidentified causes. Importantly, the study showed that some people with HD experienced remarkably less neuronal cell death than others.

“While there is just one genetic defect that causes Huntington’s disease, the disease affects different parts of the brain in very different ways in different people,” said Myers. “For the first time, we can measure these differences with a very fine level of detail and hopefully identify what is preventing brain cell death in some individuals with HD.”

The investigators have initiated extensive studies into what genes and other factors are associated with the protection of neurons in HD, and they hope these protective factors will point to possible novel treatments.

At ‘rest,’ right hemisphere of the brain ‘talks’ more than the left hemisphere does

People who like to nap say it helps them focus their minds post a little shut eye. Now, a study from Georgetown University Medical Center may have found evidence to support that notion.

The research, presented at Neuroscience 2012, the annual meeting of the Society for Neuroscience, found that when participants in a study rested, the right hemisphere of their brains talked more to itself and to the left hemisphere than the left hemisphere communicated within itself and to the right hemisphere – no matter which of the participants’ hands was dominant. (Neuroscientists say right-handed people use their left hemisphere to a greater degree, and vice versa.)

Results of this study, the first known to look at activity in the two different hemispheres during rest, suggests that the right hemisphere “is doing important things in the resting state that we don’t yet understand,” says Andrei Medvedev, Ph.D., an assistant professor in the Center for Functional and Molecular Imaging at Georgetown. The activities being processed by the right hemisphere, which is known to be involved in creative tasks, could be daydreaming or processing and storing previously acquired information. “The brain could be doing some helpful housecleaning, classifying data, consolidating memories,” Medvedev says. “That could explain the power of napping. But we just don’t know yet the relative roles of both hemispheres in those processes and whether the power nap might benefit righties more then lefties.”

To find out what happens in the resting state, the research team connected 15 study participants to near-infrared spectroscopy (NIRS) equipment. This technology, which is low cost and portable, uses light to measure changes in oxygenated hemoglobin inside the body.

The study participants wore a cap adorned with optical fibers that delivers infrared light to the outermost layers of the brain and then measures the light that bounces back. In this way, the device can “see” which parts of the brain are most active and communicating at a higher level based on increased use of oxygen in the blood and heightened synchronicity of their activities.

"The device can help delineate global networks inside the brain — how the components all work together," Medvedev says. "The better integrated they are, the better cognitive tasks are performed."

To their surprise, the researchers found that left and right hemispheres behaved differently during the resting state. “That was true no matter which hand a participant used. The right hemisphere was more integrated in right-handed participants, and even stronger in the left-handed,” he says.

Medvedev is exploring the findings for an explanation. And he suggests that brain scientists should start focusing more of their attention on the right hemisphere. “Most brain theories emphasize the dominance of the left hemisphere especially in right handed individuals, and that describes the population of participants in these studies,” Medvedev says. “Our study suggests that looking at only the left hemisphere prevents us from a truer understanding of brain function.”