ScienceDaily (June 12, 2012) — UCC scientists have shown that brain levels of serotonin, the ‘happy hormone’ are regulated by the amount of bacteria in the gut during early life. Their research is being published June 12 in the international psychiatry journal, Molecular Psychiatry.

Happy children. UCC scientists have shown that brain levels of serotonin, the ‘happy hormone’ are regulated by the amount of bacteria in the gut during early life. (Credit: © Marzanna Syncerz / Fotolia)

This research shows that normal adult brain function depends on the presence of gut microbes during development. Serotonin, the major chemical involved in the regulation of mood and emotion, is altered in times of stress, anxiety and depression and most clinically effective antidepressant drugs work by targeting this neurochemical.

Scientists at the Alimentary Pharmabiotic Centre in UCC used a germ-free mouse model to show that the absence of bacteria during early life significantly affected serotonin concentrations in the brain in adulthood. The research also highlighted that the influence is sex dependent, with more marked effects in male compared with female animals. Finally, when the scientists colonized the animals with bacteria prior to adulthood, they found that many of the central nervous system changes, especially those related to serotonin, could not be reversed indicating a permanent imprinting of the effects of absence of gut flora on brain function.

This builds on earlier work, from the Cork group and others, showing that a microbiome-gut-brain axis exists that is essential for maintaining normal health which can affect brain and behavior. The research was carried out by Dr Gerard Clarke, Professor Fergus Shanahan, Professor Ted Dinan and Professor John F Cryan and colleagues at the Alimentary Pharmabiotic Centre in UCC.

"As a neuroscientist these findings are fascinating as they highlight the important role that gut bacteria play in the bidirectional communication between the gut and the brain, and opens up the intriguing opportunity of developing unique microbial-based strategies for treatment for brain disorders," said Professor John F Cryan, senior author on the publication and Head of the Department of Anatomy & Neuroscience at UCC.

This research has multiple health implications as it shows that manipulations of the microbiota (e.g. by antibiotics, diet, or infection) can have profound knock-on effects on brain function. “We’re really excited by these findings” said lead author Dr Gerard Clarke. “Although we always believed that the microbiota was essential for our general health, our results also highlight how important our tiny friends are for our mental wellbeing.”

Source: Science Daily

ScienceDaily (June 12, 2012) — In a study published June 12 in the journal Molecular Psychiatry, researchers from the Twins Early Development Study at King’s College London’s Institute of Psychiatry studied data from more than 6700 families relating to 45 childhood characteristics, from IQ and hyperactivity to height and weight. They found that genetic and environmental contributions to these characteristics vary geographically in the UK and have published their results online as a series of nature-nurture maps.

Newborn twins. (Credit: © pojoslaw / Fotolia)

Our development, health and behaviour are determined by complex interactions between our genetic make-up and the environment in which we live. For example, we may carry genes that increase our risk of developing type 2 diabetes, but if we eat a healthy diet and get sufficient exercise, we may not develop the disease. Similarly, someone may carry genes that reduce his or her risk of developing lung cancer, but heavy smoking may still lead to the disease.

The UK-based Twins Early Development Study follows more than 13,000 pairs of twins, both identical and non-identical, born between 1994 and 1996. When the twins were age 12, the researchers carried out a broad survey to assess a wide range of cognitive abilities, behavioural (and other) traits, environments and academic achievement in 6759 twin pairs. The researchers then designed an analysis that reveals the UK’s genetic and environmental hotspots, something which had never been done before.

"These days we’re used to the idea that it’s not a question of nature or nurture; everything, including our behaviour, is a little of both," explains Dr Oliver Davis, a Sir Henry Wellcome Postdoctoral Fellow at King’s College London’s Institute of Psychiatry. "But when we saw the maps, the first thing that struck us was how much the balance of genes and environments can vary from region to region."

"Take a trait like classroom behaviour problems. From our maps we can tell that in most of the UK around 60 per cent of the difference between people is explained by genes. However, in the South East genes aren’t as important: they explain less than half of the variation. For classroom behaviour, London is an ‘environmental hotspot’."

The maps give the researchers a global overview of how the environment interacts with our genomes, without homing in on particular genes or environments. However, the patterns have given them important clues about which environments to explore in more detail.

"The nature-nurture maps help us to spot patterns in the complex data and to try to work out what’s causing these patterns," says Dr Davis. "For our classroom behaviour example, we realised that one thing that varies more in London is household income. When we compare maps of income inequality to our nature-nurture map for classroom behaviour, we find income inequality may account for some of the pattern.

"Of course, this is just one example. There are any number of environments that vary geographically in the UK, from social environments like healthcare or education provision to physical environments like altitude, the weather or pollution. Our approach is all about tracking down those environments that you wouldn’t necessarily think of at first."

It may be relatively easy to explain environmental hotspots, but what about the genetic hotspots that appear on the maps: do people’s genomes vary more in those regions? The researchers believe this is not the case; rather, genetic hotspots are areas where the environment exposes the effects of genetic variation.

For example, researchers searching for gene variants that increase the risk of hay fever may study populations from two regions. In the first region people live among fields of wind-pollinated crops, whereas the second region is miles away from those fields. In this second region, where no one is exposed to pollen, no one develops hay fever; hence any genetic differences between people living in this region would be invisible.

By contrast, in the first region, where people live among the fields of crops, they will all be exposed to pollen and differences between the people with a genetic susceptibility to hay fever and the people without will stand out. That would make the region a genetic hotspot for hay fever.

"The message that these maps really drive home is that your genes aren’t your destiny. There are plenty of things that can affect how your particular human genome expresses itself, and one of those things is where you grow up," says Dr Davis.

Source: Science Daily

June 12, 2012

Financial loss can lead to irrational behavior. Now, research by Weizmann Institute scientists reveals that the effects of loss go even deeper: Loss can compromise our early perception and interfere with our grasp of the true situation. The findings, which recently appeared in the Journal of Neuroscience, may also have implications for our understanding of the neurological mechanisms underlying post-traumatic stress disorder.

The experiment was conducted by Dr. Rony Paz and research student Offir Laufer of the Neurobiology Department. Subjects underwent a learning process based on classic conditioning and involving money. They were asked to listen to a series of tones composed of three different notes. After hearing one note, they were told they had earned a certain sum; after a second note, they were informed that they had lost some of their money; and a third note was followed by the message that their bankroll would remain the same. According to the findings, when a note was tied to gain, or at least to no loss, the subjects improved over time in a learned task – distinguishing that note from other, similar notes. But when they heard the “lose money” note, they actually got worse at telling one from the other.

Functional MRI (fMRI) scans of the brain areas involved in the learning process revealed an emotional aspect: The amygdala, which is tied to emotions and reward, was strongly involved. The researchers also noted activity in another area in the front of the brain, which functions to moderate the emotional response. Subjects who exhibited stronger activity in this area showed less of a drop in their abilities to distinguish between tones.

Paz: “The evolutionary origins of that blurring of our ability to discriminate are positive: If the best response to the growl of a lion is to run quickly, it would be counterproductive to distinguish between different pitches of growl. Any similar sound should make us flee without thinking. Unfortunately, that same blurring mechanism can be activated today in stress-inducing situations that are not life-threatening – like losing money – and this can harm us.”

That harm may even be quite serious: For instance, it may be involved in post-traumatic stress disorder. If sufferers are unable to distinguish between a stimulus that should cause a panic response and similar, but non-threatening, stimuli, they may experience strong emotional reactions in inappropriate situations.

This perceptional blurring may even expand over time to encompass a larger range of stimuli. Paz intends to investigate this possibility in future research.

Provided by Weizmann Institute of Science

Source: medicalxpress.com

June 12, 2012

You pick up your cell phone and dial the new number of a friend. Ten numbers. One. Number. At. A. Time. Because you haven’t actually typed the number before, your brain handles each button press separately, as a sequence of distinct movements.

This image shows identified brain regions linked to the parsing (left) and concatenation (right) processes involved in motor chunking. Trials with greater parsing showed increased activation of the left prefrontal and parietal cortex and trials with greater concatenation showed increased activation of the putamen. Credit: Photo by Nicholas Wymbs

After dialing the number a few more times, you find yourself typing it out as a series of three successive bursts of movement: the area code, the first three numbers, the last four numbers. Those three separate chunks allow you to type the number faster, and with greater precision. Eventually, dialed often enough, the number is stored in your brain as one chunk. Who needs speed dial?

"You can think about a chunk as a rhythm," said Nicholas Wymbs, a postdoctoral researcher in UC Santa Barbara’s Department of Psychological and Brain Sciences, and the lead author of a new study on motor chunking in the journal Neuron, published by Cell Press. “We highlight the two-part process that seems to occur when we are chunking. This is demonstrated by the rhythm we use when typing the phone number: rapid bursts of finger movements that are interspersed by pauses.”

The rhythm is the human brain taking information and processing it in an efficient way, according to Wymbs. “On one level, the brain is going to try to divide up, or parse, long sequences of movement,” he said. “This parsing process functions to group or cluster movements in the most efficient way possible.”

But it is also in our brain’s best interest to assemble single or short strings of movements into longer, integrated sequences so that a complex behavior can be made with as little effort as possible. “The motor system in the brain wants to output movement in the most computational, low-cost way as possible,” Wymbs said. “With this integrative process, it’s going to try to bind as many individual motor movements into a fluid, uniform movement as it possibly can.”

This diagram illustrates how the subjects in the experiment used their left hands to respond to the “notes” on a button box. Credit: Illustration by Nicholas Wymbs

The two processes are at odds with each other, and it’s how the brain reconciles this struggle during motor learning that intrigues Wymbs and the study’s other authors, including Scott Grafton, professor of psychology and director of the UCSB Brain Imaging Center. “What we are interested in is functional plasticity of the brain –– how the brain changes when we learn actions, or motor sequences as we refer to them in this paper,” Wymbs said.

The study was conducted using human subjects in the Magnetic Resonance Imaging (MRI) scanner in the Brain Imaging Center. The experiment involved three days of training with people performing and practicing three separate motor sequences for up to 200 trials each during the collection of functional MRI data. The subjects were all right-handed but they were asked to learn the sequences using the four fingers of their left hands. Participants practiced the sequences during the operation of the MRI scanner by tapping out responses with a button box that looked like a set of piano keys, with long, rectangular buttons.

"People would see a static image shown on a video screen that detailed the sequence to be typed out," Wymbs said. "They’re lying down inside the scanner and they see this image above their eyes. Interestingly, some people reported that the images looked like something out of (the video game) Guitar Hero, and, indeed, it does look a bit like guitar tablature. They would have to type out the ‘notes’ from left to right, as you normally would when reading music.

"After practicing a sequence for 200 trials, they would get pretty good at it," Wymbs added. "After awhile, the note patterns become familiar. At the start of the training, it would take someone about four and a half seconds to complete each sequence of 12 button presses. By the end of the experiment, the average participant could produce the same sequence in under three seconds."

The researchers’ goal was to look at which areas of the brain support the two-part process of chunking. “We feel that the motor process, or the concatenation process as we refer to it in the paper, tends to take over as you continue to practice and continue to learn the sequences,” Wymbs said. “That’s the one that’s tied to the motor output system –– the thing that’s actually accomplishing what we set out to do.”

With the experience of repeating a motor sequence, such as typing out a phone number, speaking, typing on a computer, or even texting, it becomes more automatic. “With automaticity comes the recruitment of core motor output regions,” Wymbs said.

The scientists discovered that the putamen –– a brain region that is critically important to movement –– supports the concatenation process of motor chunking, with robust connectivity to parts of the brain that are intimately tied to the output of skilled motor behavior. On the other hand, they found that cortical regions in the left hemisphere respond more during the parsing process of motor chunking. “These regions have been linked to the manipulation of motor information, which is something that we probably do more of when we just begin to learn the sequences as chunks,” Wymbs said.

"Initially, when you’re doing one of these 12-element sequences, you want to pause,” Wymbs added. “That would evoke more of the parsing mechanism. But then, over time, as you learn a sequence so that it becomes more automatic, and the concatenation process takes over and it wants to put all of these individual elements into a single fluid behavior.”

According to Wymbs, the findings could have implications for the study and diagnosis of Parkinson’s and other diseases of the motor system that involve action. “We show here that there are two potentially competing systems that lead to the isolation of different systems that both work to allow us to process things efficiently when we’re learning,” Wymbs said.

Provided by University of California - Santa Barbara

Source: medicalxpress.com

ScienceDaily (June 12, 2012) — Studying how nerve cells send and receive messages, Johns Hopkins scientists have discovered new ways that genetic mutations can disrupt functions in neurons and lead to neurodegenerative disease, including amyotrophic lateral sclerosis (ALS).

Neurons are shown in green. A normal neuron is on the left and p150glued mutant neuron is on the right. The red cargo accumulates in the mutant but not in the normal neuron. Areas with the highest cargo accumulation are yellow at the tip of the neuron. (Credit: Image courtesy of Johns Hopkins Medicine)

In a report published April 26 in Neuron, the research team says it has discovered that a mutation responsible for a rare, hereditary motor neuron disease called hereditary motor neuropathy 7B (HMN7B) disrupts the link between molecular motors and the nerve cell tip where they reside. This mutation results in the production of a faulty protein that prevents material from being transported from the cell’s edge, which is located at the muscle and extends back toward its “body” in the central nervous system. In pinpointing how and where this cargo transport is disrupted, the scientists are now closer to understanding mechanisms underlying this condition and ALS.

"An important question we need to answer is how defects in proteins that normally perform important cellular functions for neurons lead to disease," says Alex Kolodkin, Ph.D., a Howard Hughes Medical Institute Investigator and professor of neuroscience at the Johns Hopkins University School of Medicine. "A major issue in understanding neurodegenerative diseases is determining how certain proteins that are expressed in all types of neurons, or even in all cells in the body, can lead to devastating effects in one, or a few, subsets of neurons." Kolodkin notes that many neurodegenerative diseases involve proteins that serve general functions required in nearly every type of cell in the body, including the transport of material between different parts of a cell, yet certain alterations in these proteins can result in specific neurological disorders.

One particular protein, p150glued, is known to play a role in at least two of these disorders, HMN7B, which is similar to ALS, and Perry syndrome, which leads to symptoms similar to Parkinson’s disease. p150glued is part of a larger complex of proteins that forms a molecular “motor” capable of transporting various molecules and other “cargo” from the nerve end toward the cell body. To better understand how mutations in p150glued lead to HMN7B and Perry syndrome, the researchers turned to fruit flies, which are easy to genetically manipulate and where the same protein has been well studied.

They engineered the fruit fly p150glued protein to contain the same mutations as those implicated in the two diseases and used microscopy techniques that enable them to follow in live cells the movement of fluorescently tagged cargo along motor neurons.

They found, surprisingly, that the movement of cargo along the length of the cell was normal. However, at the far end of the cell, they found that the HMN7B-associated mutation caused an unusually large accumulation of cargo. “This was an unexpected finding,” says Thomas Lloyd, M.D., Ph.D., an assistant professor in neurology and neuroscience at the Johns Hopkins School of Medicine. “We need to better understand how this is causing disease.”

Using flies engineered to contain mutations in other motor proteins, and again watching cargo transport in live cells, the team found that p150glued works in concert with another motor to control cargo transport. Their results suggest that when p150glued is compromised, this control is lost and cargo accumulates at the nerve end, leading to disease.

"It’s still unclear how these two different mutations in different regions of the same protein cause very distinct neurodegenerative diseases," Lloyd says. Encouraged by their results, the team plans to continue using fruit flies to unravel the molecular mechanisms underlying these diseases.

Source: Science Daily

ScienceDaily (June 11, 2012) — The world needs new antibiotics to overcome the ever increasing resistance of disease-causing bacteria — but it doesn’t need the side effect that comes with some of the most powerful ones now available: hearing loss. Today, researchers report they have developed a new approach to designing antibiotics that kill even “superbugs” but spare the delicate sensory cells of the inner ear.

These delicate hair cells from the inner ear of mice were tested to see the effects of powerful antibiotics on structures that are crucial to hearing. At left, cells that were exposed to the antibiotic gentamycin showed signs of high levels of damaging free radicals (seen in green). But cells treated with the veterinary drug apramycin. shown at right, didn’t show these effects — adding to evidence that this drug could be used to treat humans without damaging hearing. (Credit: University of Michigan, Schacht laboratory)

Surprisingly, they have found that apramycin, an antibiotic already used in veterinary medicine, fits this bill — setting the stage for testing in humans.

In a paper published online in the Proceedings of the National Academy of Sciences, a team from Switzerland, England and the University of Michigan show apramycin’s high efficacy against bacteria, and low potential for causing hearing loss, through a broad range of tests in animals. That testing platform is now being used to evaluate other potential antibiotics that could tackle infections such as multidrug-resistant tuberculosis.

The research aims to overcome a serious limitation of aminoglycoside antibiotics, a class of drugs which includes the widely used kanamycin, gentamicin and amikacin.

While great at stopping bacterial infections, these drugs also cause permanent partial hearing loss in 20 percent of people who take them for a short course, and up to 100 percent of people who take them over months or years, for example to treat tuberculosis or lung infections in cystic fibrosis.

U-M researcher Jochen Schacht, Ph.D., a professor of biological chemistry and otolaryngology and director of the Kresge Hearing Research Institute at the U-M Medical School, has spent decades studying why these drugs cause this “ototoxicity” — a side effect that makes doctors hesitant to prescribe them. Hearing damage has also caused patients to discontinue treatment before their antibiotic prescription is over, potentially allowing drug-resistant strains of bacteria to flourish.

Schacht has found that the drugs produce damaging free radicals inside the hair cells of the inner ear. Hair cells, named for the tiny sound-sensing hairs on their surface, are the linchpin of hearing — and once destroyed, cannot be regrown.

In the new paper, Schacht and his research group joined teams led by University of Zurich microbiologist Erik Böttger, and structural biologist and Nobel Prize winner Venkatraman Ramakrishnan of England’s Medical Research Council Laboratory of Molecular Biology, as well as scientists from ETH Zurich. Each team brought its particular expertise to the issue, and after four years of work they developed and tested this new approach to designing antibiotics.

"Aminoglycosides are some of the most valuable broad-spectrum antibiotics and indispensable drugs today, but we need new options to combat drug-resistant bacteria. Importantly, we must find ways to overcome their ototoxicity," Schacht says. "Instead of the trial-and-error approach of the past, this new hypothesis-driven tactic allows us to design drugs with simultaneous attention toward both antibacterial action and impact on hair cells."

According to the World Health Organization, about 440,000 new cases of multidrug-resistant tuberculosis emerge annually, causing at least 150,000 deaths worldwide. Aminoglycoside antibiotics, while carefully controlled in the U.S., Europe, and other developed countries are available over the counter in many developing nations, leading to overuse that makes it even easier for drug-resistant strains of many kinds of bacteria to emerge and spread.

The new paper outlines a rational approach to designing drugs to combat this threat without ototoxicity, based on a theoretical framework that emerged from the work of the three laboratories and centers around the role of ribosomes, the structures inside the cell that “read” DNA and translate the genetic message into proteins. Böttger’s lab, at the Institut für Medizinische Mikrobiologie which he directs, studies aminoglycoside effects on mitochondrial ribosomes and antibacterial activity with an eye toward designing new ones. Ramakrishnan’s lab studies ribosomes, and partners from ETH Zurich also collaborated.

Aminoglycosides bind to the ribosomes inside bacterial cells, preventing the ability to produce proteins. But while the drugs spare most human ribosomes, they can attach to ribosomes in the mitochondria of cells, which are similar to bacterial ribosomes.

Consistent with U-M-generated theories about ototoxicity, the drugs then cause the production of free radicals in such quantities that they overwhelm the hair cells’ defense mechanisms — destroying the cells and causing hearing loss.

The team’s approach is to design drugs that more specifically target bacterial ribosomes over mitochondrial ribosomes, simultaneously testing the impact on hair cells as well as the ability to kill bacteria. In this way, the researchers try to avoid creating antibiotics that harm hearing.

They are already using the platform employed for this study — which involves cells from mouse ears, and tests of hearing and hair cell damage in guinea pigs — to test other promising novel drugs synthesized based on the theoretical framework that was driving the current research.

Meanwhile, the team hopes to launch a clinical trial of apramycin, an antibiotic that could prove immediately useful because multidrug-resistant TB and lung-infecting bacteria have not shown resistance to the drug yet.

The research also lends more evidence to support the use of antioxidants to protect the hearing of patients taking current aminoglycoside antibiotics. Schacht has already led a clinical trial in China that showed a major reduction in hearing loss if aspirin was given at the same time as aminoglycoside antibiotics. “This kind of protection is important, while we search for the long-term answer to drug resistance without ototoxicity,” he says.

Source: Science Daily

June 11, 2012

Researchers at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital have identified a portion of the brain responsible for determining how far away a sound originates, a process that does not rely solely on how loud the sound is. The investigators’ report, which will appear in the early edition of Proceeding of the National Academy of Sciences, is receiving early online release this week.

This is an image of human cerebral cortex, digitally “inflated” to smooth out normal folds and ridges, showing in red the portion of auditory cortex that responds to the distance from which sounds arrive. Credit: Jyrki Ahveninen, Ph.D., Martinos Center for Biomedical Imaging, Massachusetts General Hospital

"Although sounds get louder when the source approaches us, humans are able to discriminate between loud sounds that come from far away and softer sound from a closer source, suggesting that our brains use distance cues independent of loudness," says Jyrki Ahveninen, PhD, of the Martinos Center, senior author of the PNAS report. "Using functional MRI we found a group of neurons in the auditory cortex sensitive to the distance of sound sources and different from those that process changes in loudness. In addition to providing basic scientific information, our results could help future studies of hearing disorders.”

The human brain has distinct areas for processing sensory information – signals responsible for vision, hearing, taste etc. Studies of the visual cortex, located at the back of the brain, have produced detailed maps of areas handling particular portions of the visual field. But understanding of the auditory cortex, located on the side of the head above and behind the ear, is quite limited. While it is known that the portion of the auditory cortex extending toward the back of the head determines where a sound comes from, exactly how the brain translates complex auditory signals to determine both the location and distance from which a sound originates is not yet known.

In their search for auditory neurons that process sound distance, the research team faced some particular challenges. In research laboratories that study hearing, sounds must be delivered to study participants through headphones, which means the acoustical “space” in which a sound is generated must be simulated. This must be done with exquisite accuracy, since environmental aspects causing sound to reverberate probably contribute to distance perception. Since the MRI equipment itself generates a loud noise, the researchers scanned participants’ brains once every 12 seconds to measure responses to sounds presented during intervening quiet periods.

In the first experiment, study participants – 12 adults with normal hearing – listened to a series of paired sounds of varying degrees of loudness and at simulated distances ranging from 15 to 100 cm and were asked to indicate whether the second sound was closer or farther away than the first. Although the differences in loudness varied randomly, participants were quite accurate in distinguishing the simulated distances of the sounds. Acoustical analysis of the particular sound cues presented indicated that the reverberations produced by a sound, which are more pronounced in a closed environment and for sounds traveling farther, may be more important distance cues than are the differences between sounds perceived by a participant’s two ears.

After the first experiment confirmed the accuracy of the simulated acoustical environment, functional MR images taken while participants listened to another series of paired sounds recorded how activity in the auditory cortex changed in response to sounds of varying loudness and direction as well as during sound of constant levels and silence. The images produced identified a small area that appears to be sensitive to cues indicating distance but not loudness. As far as the investigators know, this is the first time neurons sensitive to sound-source distances have been discovered.

"The identified area is located near other auditory cortical areas that process spatial information," says corresponding author Norbert Kopco, PhD. "This is consistent with a general model of perceptual processing in the brain, suggesting that in hearing, as in vision and other senses, spatial information is processed separately from information about the object’s identity or characteristics such as the musical pitch of sound. Our study also illustrates how important it is to combine expertise from different fields – in our case imaging/physiology, psychology, and computational neuroscience – to advance our understanding of such a complex system as the human brain.”

Provided by Massachusetts General Hospital

Source: medicalxpress.com

ScienceDaily (June 11, 2012) — In a pair of related studies, scientists from the Florida campus of The Scripps Research Institute have identified several proteins that help regulate cells’ response to light — and the development of night blindness, a rare disease that abolishes the ability to see in dim light.

In the new studies, published recently in the journals Proceedings of the National Academy of Sciences (PNAS) and The Journal of Cell Biology, Scripps Florida scientists were able to show that a family of proteins known as Regulator of G protein Signaling (RGS) proteins plays an essential role in vision in a dim-light environment.

"We were looking at the fundamental mechanisms that shape our light sensation," said Kirill Martemyanov, a Scripps Research associate professor who led the studies. "In the process, we discovered a pair of molecules that are indispensible for our vision and possibly play critical roles in the brain."

In the PNAS study, Martemyanov and his colleagues identified a pair of regulator proteins known as RGS7 and RGS11 that are present specifically in the main relay neurons of the retina called the ON-bipolar cells. “The ON-bipolar cells provide an essential link between the retinal light detectors — photoreceptors and the neurons that send visual information to the brain,” explained Martemyanov. “Stimulation with light excites these neurons by opening the channel that is normally kept shut by the G proteins in the dark. RGS7 and RGS11 facilitate the G protein inactivation, thus promoting the opening of the channel and allowing the ON-bipolar cells to transmit the light signal. It really takes a combined effort of two RGS proteins to help the light overcome the barrier for propagating the excitation that makes our dim vision possible.”

In the Journal of Cell Biology study, Martemyanov and his colleagues unraveled another key aspect of the RGS7/RGS11 regulatory response — they identified a previously unknown pair of orphan G protein-coupled receptors (GPCRs) that interact with these RGS proteins and dictate their biological function.

GPCRs are a large family of more than 700 proteins, which sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters, and light. After binding these molecules, GPCRs trigger the appropriate response inside the cell. However, for many GPCRs the activating molecules have not yet been identified and these are called “orphan” receptors.

The Martemyanov group has found that two orphan GPCRs — GPR158 and GPR179 — recruit RGS proteins and thus help serve as brakes for the conventional GPCR signaling rather than play an active signaling role.

In the case of retinal ON-bipolar cells, GPR179 is required for the correct localization of RGS7 and RGS11. Their mistargeting in animal models lacking GPR179 or human patients with mutations in the GPR179 gene may account for their night blindness, according to the new study. Intriguingly, in the brain GPR158 appears to play a similar role in localizing RGS proteins, but instead of contributing to vision, it helps RGS proteins regulate the m-opioid receptor, a GPCRs that mediates pleasurable and pain-killing effects of opioids.

"We are really in the very beginning of unraveling this new biology and understanding the role of discovered orphan GPR158/179 in regulation of neurotransmitter signaling in the brain and retina," Martemyanov said. "The hope is that better understanding of these new molecules will lead to the design of better treatments for addictive disorders, pain, and blindness."

Source: Science Daily

ScienceDaily (June 11, 2012) — Researchers at the University of Missouri have demonstrated the effectiveness of a potential new therapy for stroke patients in an article published in the journal Molecular Neurodegeneration. Created to target a specific enzyme known to affect important brain functions, the new compound being studied at MU is designed to stop the spread of brain bleeds and protect brain cells from further damage in the crucial hours after a stroke.

In a model of induced stroke in mice, MU researchers have shown the success of a treatment in stopping further bleeding in the brain after a stroke (above). The outlined area shows the stroke damage. (Credit: Image courtesy of University of Missouri School of Medicine)

Stroke is a leading cause of death in the U.S. with more than 800,000 deaths occurring each year from stroke and other cardiac events. Other than surgery, existing emergency treatments for stroke victims such as the use of a tissue plasminogen activator (tPA) must be administered within hours of the stroke onset because of the risk for brain hemorrhaging. The injectable medication can only be used to treat the most common type of stroke that occurs when blood clots block blood flow to the brain, called ischemic stroke.

"For a stroke victim, time is a matter of life and death. While we are still in the research phase for this type of compound, we believe it could be combined with tPA in the future to buy ischemic stroke patients a longer window of time to receive emergency treatment," said Zezong Gu, MD, PhD, the article’s corresponding author and assistant professor of pathology and anatomical sciences at the MU School of Medicine. The new compound being studied also has potential for use in patients experiencing hemorrhagic stroke, which is a less common type of stroke caused by bleeding within the brain, Gu said.

MU researchers collaborated with a team at the University of Notre Dame to study the effects of the new compound, a thiirane class of gelatinase selective inhibitors, on the function of a type of matrix metalloproteinase (MMP) enzyme, particularly MMP-9. MMP-9 is part of a group of more than 20 enzymes or MMPs that are known to contribute to many key pathological events in the brain after stroke, traumatic brain injury and other neurodegenerative events.

In 2005, Gu served as a lead author on a research paper published in the Journal of Neuroscience that identified MMP-9 as a promising target for development of therapeutic drugs for stroke patients. Since then, his lab at MU medical school’s Center for Translational Neuroscience has been studying the function of MMP enzymes and how to inhibit the harmful effects of MMP-9.

"MMPs play a role in the structure of blood vessels in the brain and are also needed in the interactions between cells during development and tissue remodeling," Gu said. "Unregulated, the activity of these enzymes contributes to neurological disorders and stroke. With this compound, we’ve now confirmed a potential method to rescue the blood vessels from the damaging effects of MMP-9 and protect neurons at the same time."

MU researchers successfully used a model of ischemic stroke in mice and studied the effects of the MMP-9 inhibitor compound on brain activity after a stroke.

"Our lab at the Center for Translational Neuroscience is one of only a few in the United States that has successfully induced a blood clot in the brains of mice," said Jiankun Cui, MD, the article’s lead author and assistant professor of pathology and anatomical sciences at the MU School of Medicine. "To be able to study the effectiveness of this potential new treatment under these conditions provides us with a highly unique set of data showing this compound can disrupt key harmful pathological events that occur after a stroke."

Source: Science Daily

ScienceDaily (June 11, 2012) — Out of control competitive aggression could be a result of a lagging neurotransmitter called dopamine, say researchers presenting a study at the Society of Nuclear Medicine’s 2012 Annual Meeting. During a computer game against a putative cheating adversary, participants who had a lower capacity to synthesize this neurotransmitter in the brain were more distracted from their basic motivation to earn money and were more likely to act out with aggression.

Out of control competitive aggression could be a result of a lagging neurotransmitter called dopamine, say researchers. During a computer game against a putative cheating adversary, participants who had a lower capacity to synthesize this neurotransmitter in the brain were more distracted from their basic motivation to earn money and were more likely to act out with aggression. (Credit: © lassedesignen / Fotolia)

For many people, anger is an almost automatic response to life’s challenges. In clinical psychiatry, scientists look at not only the impact of aggressive behavior on the individual, their loved ones and the community but also the triggers in the brain that lead to aggressive response. The neurobiology of aggression is not well understood, but scientists are aware of a relationship between the neurotransmitter serotonin and certain aggressive behaviors. The objective of this study was to explore whether higher levels of another brain chemical called dopamine, involved in pleasure and reward, increased aggressive response in its subjects. To scientists’ surprise, it was not as they first theorized.

"The results of this study were astonishingly opposite of what was previously hypothesized," says Ingo Vernaleken, M.D., lead author of the study and research scientist for the department of psychiatry at RWTH Aachen University in Aachen, Germany. "Subjects with more functional dopaminergic reward-systems were not more aggressive in competitive situations and could concentrate even more on the game. Subjects with lower dopaminergic capacity were more likely to be distracted by the cheating behavior."

In this study, 18 healthy adults in their twenties were tested for aggression using the psychological behavioral task known as the point subtraction aggression paradigm (PSAP). Participants were asked to play a computer game that required them to press a bar multiple times with the incentive of winning money, but they were also told that an adversary in the next room who is able to cheat may steal some of their winnings. What the paranoid participants did not know was that there was no adversary. The computer program is designed to perform randomized deductions of the subjects’ monetary reward to simulate the cheating competitor.The participant had three choices to react: punish the cheater, shield against the adversary by repeatedly pressing a defense button, or continue playing the game in order to maximize their ability to win cash, which indicated resilience.

"The PSAP focuses on aggressive reaction within a competitive situation," says Vernaleken. "Aggression and its neurobiological mechanisms in humans have been only moderately investigated in the past. Furthermore, most of the previous studies mainly covered the more reactive part of aggression, which merely reflects impulsive behavior and appears to be associated merely with the serotonin system. This investigation focuses on the association with the dopaminergic reward-system, which reflects goal-directed aggression."

Subjects’ brains were imaged using positron emission tomography, which provides a range of information about physiological functions inside the body, depending on the imaging probe used. In this investigation, F-18 FDOPA, a biomarker that lights up enzymes’ ability to synthesize this transmitter, was used and the uptake of this drug in the brain was analyzed to gauge the correlation between the participants’ dopamine synthesis capacity and aggressive behavior.

Results of the study showed a significant impact on aggressive response in areas in the brain where dopamine synthesis was present, especially in the basal ganglia, which among other functions include the motivation center. Minimized aggression was associated with higher dopamine levels in both the midbrain and the striatum, which plays a role in planning and executive function. People with greater capacity for dopamine synthesis were more invested in the monetary reward aspect of the PSAP, instead of acting in defense or with aggression against their perceived adversary, whereas subjects with lower capacities had a higher vulnerability to act either aggressive, defensive or both.

"Thus, we think that a well-functioning reward system causes more resilience against provocation," says Vernaleken. "However, we cannot exclude that in a situation where the subject would directly profit from aggressive behavior, in absence of alternatives, the correlation might be the other way around."

Further research is required to explore the link between dopamine and a range of aggressive behavior. More insight into these relationships could potentially lead to new psychological therapies and drug treatments to moderate or prevent aggressive response.

Source: Science Daily