Neuroscience
Month
A study out today in the journal Nature Medicine suggests a potential new treatment for the seizures that often plague children with genetic metabolic disorders and individuals undergoing liver failure. The discovery hinges on a new understanding of the complex molecular chain reaction that occurs when the brain is exposed to too much ammonia.
The study shows that elevated levels of ammonia in the blood overwhelm the brain’s defenses, ultimately causing nerve cells to become overexcited. The researchers have also discovered that bumetanide – a diuretic drug used to treat high blood pressure – can restore normal electrical activity in the brains of mice with the condition and prevent seizures.
“Ammonia is a ubiquitous waste product of regular protein metabolism, but it can accumulate in toxic levels in individuals with metabolic disorders,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the University of Rochester Medical Center (URMC) Center for Translational Neuromedicine and lead author of the article. “It appears that the key to preventing the debilitating neurological effects of ammonia toxicity is to correct a molecular malfunction which causes nerve cells in the brain to become chemically unbalanced.”
In healthy people, ammonia is processed in the liver, converted to urea, and expelled from the body in urine. Because it is a gas, ammonia can slip through the blood-brain-barrier and make its way into brain tissue. Under normal circumstances, the brain’s housekeeping cells – called astrocytes – sweep up this unwanted ammonia and convert it into a compound called glutamine which can be more easily expelled from the brain.
However, individuals with certain genetic metabolic disorders and people with impaired liver function because of chronic hepatitis, alcoholism, acetaminophen overdose, and other toxic liver conditions cannot remove ammonia from their bodies quickly enough. The result is a larger than normal concentration of ammonia in the blood, a condition called hyperammonemia.
When too much ammonia makes its way into the central nervous system, it can lead to tremors, seizures and, in extreme cases, can cause comas and even lead to death. In children with metabolic disorders the frequent seizures can lead to long-term neurological impairment.
While ammonia has long been assumed to be the culprit behind the neurological problems associated with inherited metabolic disorders and liver failure, the precise mechanisms by which it triggers seizures and comas have not been fully understood. The new study reveals that ammonia causes a chain of events that alters the chemistry and electrical activity of the brain’s nerve cells, causing them to fire in uncontrolled bursts.
One of the keys to unraveling the effects of ammonia on the brain has been new imagining technologies such as two-photon microscopy which allow researchers to watch this phenomenon in real time in the living brains of mice. As suspected, they observed that when high levels of ammonia enter the brain, astrocytes become quickly overwhelmed and cannot remove it fast enough.
The abundant ammonia in the brain mimics the function of potassium, an important player in neurotransmission, and tricks neurons into becoming depolarized. This makes it more likely that electrical activity in the brain will exceed the threshold necessary to trigger seizures.
Furthermore, the researchers observed that one of the neuron’s key molecular gatekeepers – a transporter known as NKCC1 – was also fooled into thinking that the ammonia was potassium. As a result, it went into overdrive, loading neurons with too much chloride. This in turn prevents the cells from stabilizing itself after spikes in activity, keeping the cells in a heightened level of electrical “excitability.”
The team found that the drug bumetanide, a known NKCC1 inhibitor, blocked this process and prevented the cells from overloading with chloride. By knocking down this “secondary” cellular effect of ammonia, the researchers were able to control the seizures in the mice and prolong their survival.
“The neurologic impact of hyperammonemia is a tremendous clinical problem without an effective medical solution,” said Nedergaard. “The fact that bumetanide is already approved for use gives us a tremendous head start in terms of developing a potential treatment for this condition. This study provides a framework to further explore the therapeutic potential of this and other NKCC1 inhibitors.”
Pregnant women may pass on the effects of stress to their fetus by way of bacterial changes in their vagina, suggests a study in mice. It may affect how well their baby’s brain is equipped to deal with stress in adulthood.
The bacteria in our body outnumber our own cells by about 10 to 1, with most of them found in our gut. Over the last few years, it has become clear that the bacterial ecosystem in our body – our microbiome – is essential for developing and maintaining a healthy immune system.
Our gut bugs also help to prevent germs from invading our bodies, and help to absorb nutrients from food.
A baby gets its first major dose of bacteria in life as it passes through its mother’s birth canal. En route, the baby ingests the mother’s vaginal microbes, which begin to colonise the newborn’s gut.
Chris Howerton, then at the University of Pennsylvania in Philadelphia, and his colleagues wanted to know if this initial population of bacteria is important in shaping a baby’s neurological development, and whether that population is influenced by stress during pregnancy.
Stressful pregnancy
The first step was to figure out what features of the mother’s vaginal microbiome might be altered by stress, and then see if any of those changes were transmitted to the offspring’s gut.
To do this, the team exposed 10 pregnant mice to a different psychologically stressful experience, such as exposing them to fox odour, keeping their cages lit at night, or temporarily restraining them every day for what would be the equivalent of the first trimester of their pregnancy. Another 10 pregnant mice were housed normally during the same time.
The team took samples of their vaginal bacteria throughout the pregnancy and again just after the mice had given birth. These samples were genetically sequenced to see what types of bacteria were present.
The microbiomes of the stressed mice were remarkably different to those of the unstressed mice after they had each given birth. There were more types of bacteria present, and the proportion of one common gut bacteria, Lactobacillus, was significantly reduced.
Like mother, like pup
To see whether these changes had been passed on to the pups, a few days after birth the pups’ nascent gut bacteria was removed from their colon and sequenced. Sure enough, the same bacterial patterns were seen in the pups of stressed mothers.
By analysing tissue from the pups’ hypothalamus – a brain area involved in hormone control, behaviour and sleep, among other things – the team was able to infer which genes were affected by the stress-induced changes in each mother’s microbiome.
They found that the expression of 20 genes was affected by the decrease in Lactobacillus, including genes related to the production of new neurons and the growth of synaptic connections in the brain.
These genetic outcomes in the brain are probably a result of a different suite of nutrients and metabolites circulating in the “stressed” pup’s blood, thanks to the altered gut flora they inherited. Indeed, when the team analysed the blood of the pups of the stressed mothers, they found that there were fewer molecules present necessary for the formation of essential neurotransmitters – chemicals that transmit signals to the brain. Furthermore, there were lower levels of a molecule thought to protect the brain from harmful oxidative stress.
"These changes are significant and are likely to be important for determining how the brain initially develops and how it will respond in the future to things like stress or changes in the environment," says Tracy Bale, Howerton’s supervisor during the research and director of the University of Pennsylvania lab.
As well as changing the nutrients available, the microbiome could also affect the brain via the immune system or by innervating the nerves in the gut that connect to it. “These three mechanisms aren’t mutually exclusive. It’s likely that they all play a role,” says Howerton.
Human angle
If the same effects are seen in humans, there may be a straightforward solution. “We can easily manipulate the bacteria we have inside of us,” says Howerton. For example, if a certain cocktail of bacteria is found to be beneficial to the newborns of stressed mothers, we could give it to them right after birth, he suggests. This approach could also benefit babies born via C-section, who do not pass through their mother’s birth canal, or those born to mothers whose gut bacteria has been disrupted as a result of antibiotic use during pregnancy.
Bale is now investigating the link between bacteria and brain development in pregnant women who have been through several traumatic experiences to analyse the effects on their babies’ gut bacteria. She also intends to follow their children’s behaviour as they grow up.
Resource rationale
"This is a remarkable trans-disciplinary study in how it bridged multiple organ systems to illuminate a complex question," says Catherine Hagan from the University of Missouri in Columbia. She says that more work needs to be done to show a causal link. "Mice are not tiny people – people are not big mice – more data is needed to understand how stress in mothers affects brain development in children," she says. "That said, mice and people have enough in common that this study provides a rationale for allocating resources to address such a concern."
"At the end of the day, most of what makes you ‘you’, and what drives your quality of life, comes down to the brain," says Bale. "It’s this very important, vulnerable tissue that is susceptible to many perturbations. If the microbiome is proven to be one of these driving forces, then it’s essential we know just how factors in our environment can change it and can reprogram the brain."
A drug that mimics some effects of alcohol but lacks its harmful properties would have real benefit for public health, a leading scientist has argued.
Professor David Nutt, the Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, has identified candidate molecules that reproduce the pleasurable effects of alcohol but are much less toxic. He is looking for investors to help develop the product and bring it to the market.
Alcohol mimics a chemical called GABA which is produced in the brain, but it also acts on receptors for other brain chemicals. The alcohol substitute would be designed to target GABA receptors very selectively, avoiding undesirable side effects such as hangovers and loss of coordination. An antidote could also be made to block the receptor, allowing drinkers to sober up quickly.
Professor Nutt told the Today programme on BBC Radio 4 that he first tested such a compound many years ago, but even better substitutes could be developed.
“There’s no question that you can produce a whole range of effects like alcohol by manipulating this system in the brain,” he said. “In some experiments, the effect is indistinguishable from alcohol.
“What we want to do is get rid of any the unwanted effects of inebriation, like aggression and memory impairment, and we just want to keep the pleasure and the sense of relaxation.
“We think by clever molecular modelling we can get rid of the risk of addiction as well.”
Professor Nutt hopes to make a range of cocktails containing his synthetic alcohol substitute. He has spoken to investors about taking the product to market, but many are wary that the drug might be controlled by legislation.
“I would like the government to make a recommendation that we try to improve on the health of our people by allowing these kind of substitute alcohols to be legal.”
Alcohol is responsible for 2.5 million deaths worldwide each year. Making safer alternatives available could reduce the harms significantly, Professor Nutt argued.
“I think this would be a serious revolution in health benefits, just as the e-cigarette is going to revolutionise the smoking of tobacco. I find it weird that we haven’t been talking about this before because it’s such an obvious target for health improvement.”
Nicotine withdrawal might take over your body, but it doesn’t take over your brain. The symptoms of nicotine withdrawal are driven by a very specific group of neurons within a very specific brain region, according to a report in Current Biology, a Cell Press publication, on November 14. Although caution is warranted, the researchers say, the findings in mice suggest that therapies directed at this group of neurons might one day help people quit smoking.
(Image: Fotolia)
"We were surprised to find that one population of neurons within a single brain region could actually control physical nicotine withdrawal behaviors," says Andrew Tapper of the Brudnick Neuropsychiatric Research Institute at the University of Massachusetts Medical School.
Tapper and his colleagues first obtained mice addicted to nicotine by delivering the drug to mice in their water for a period of 6 weeks. Then they took the nicotine away. The mice started scratching and shaking in the way a dog does when it is wet. Close examination of the animals’ brains revealed abnormally increased activity in neurons within a single region known as the interpeduncular nucleus.
When the researchers artificially activated those neurons with light, animals showed behaviors that looked like nicotine withdrawal, whether they had been exposed to the drug or not. The reverse was also true: treatments that lowered activity in those neurons alleviated nicotine withdrawal symptoms.
That the interpeduncular nucleus might play such a role in withdrawal from nicotine makes sense because the region receives connections from other areas of the brain involved in nicotine use and response, as well as feelings of anxiety. The interpeduncular nucleus is also densely packed with nicotinic acetylcholine receptors that are the molecular targets of nicotine.
It is much less clear whether the findings related to nicotine will be relevant to other forms of addiction, but there are some hints that they may.
"Smoking is highly prevalent in people with other substance-use disorders, suggesting a potential interaction between nicotine and other drugs of abuse," Tapper says. "In addition, naturally occurring mutations in genes encoding the nicotinic receptor subunits that are found in the interpeduncular nucleus have been associated with drug and alcohol dependence."
A protein shed by HIV-infected brain cells alters synaptic connections between networks of nerve cells, according to new research out of the University of Minnesota. The findings could explain why nearly half of all patients infected with the AIDS virus experience some level of neurocognitive impairment.
The research was published in the current volume of the Journal of Neuroscience.
“The synaptic changes didn’t appear to be a symptom of nerve death,” said Nicholas Hargus, Ph.D., lead author on the paper and a post-doctoral fellow in the Department of Pharmacology in the University of Minnesota Medical School. “Instead, the changes appeared to be a protective response resulting from the over-excitation of the network by the HIV protein transactivator of transcription (Tat). Essentially, the neuroprotective mechanism has gone awry.”
HIV-associated neurocognitive disorders (HAND) are an indirect result of HIV, as the disease itself does not infect neurons. Tat has been shown to contribute heavily to the development of HAND in patients. Hargus and Stanley Thayer, Ph.D., professor in the Department of Pharmacology, wanted to learn more about the relationship between Tat and HAND to better understand how to treat the disorders.
Researchers replicated the impact of the Tat in a rat model and tracked the changes to the synaptic proteins. They found changes in both inhibitory and excitatory synapses were initiated by specific Tat binding activity. This discovery indicated a pharmacological change due to exposure to Tat.
“We found drugs altering synaptic transmission between nerve cells reversed the synaptic changes induced by Tat,” said Thayer. “In the future, this could provide a target for the development of drugs to act upon and improve cognitive function in patients.”
Ongoing experiments are investigating the relationship between drug-induced changes in synaptic connections and the changes in cognitive function. In the future, high throughput approaches to assess synaptic function will be developed for evaluating drug candidates.
A research team at Worcester Polytechnic Institute (WPI) and The Rockefeller University in New York has developed a novel system to image brain activity in multiple awake and unconstrained worms. The technology, which makes it possible to study the genetics and neural circuitry associated with animal behavior, can also be used as a high-throughput screening tool for drug development targeting autism, anxiety, depression, schizophrenia, and other brain disorders.
Image: Neurons in the worms (marked by arrows) glow as the animals sense attractive odors.
The team details their technology and early results in the paper “High-throughput imaging of neuronal activity in Caenorhabditis elegans,” published on-line in advance of print by the journal Proceedings of the National Academy of Sciences.
"One of our major objectives is to understand the neural signals that direct behavior—how sensory information is processed through a network of neurons leading to specific decisions and responses," said Dirk Albrecht, PhD, assistant professor of biomedical engineering at WPI and senior author of the paper. Albrecht led the research team both at WPI and at Rockefeller, where he served previously as a postdoctoral researcher in the lab of Cori Bargmann, PhD, a Howard Hughes Medical Institute Investigator and a co-author of the new paper.
To study neuronal activity, Albrecht’s lab uses the tiny worm Caenorhabditis elegans (C. elegans), a nematode found in many environments around the world. A typical adult C. elegans is just 1 millimeter long and has 969 cells, of which 302 are neurons. Despite its small size, the worm is a complex organism able to do all of the things animals must do to survive. It can move, eat, mate, and process environmental cues that help it forage for food or react to threats. As a bonus for researchers, C.elegans is transparent. By using various imaging technologies, including optical microscopes, one can literally see into the worm and watch physiological processes in real time.
Numerous studies have been done by “worm labs” around the world exploring various neurological processes in C. elegans. These have typically been done using one worm at a time, with the animal’s body fixed in place on a slide. In their new paper, Albrecht’s team details how they imaged, recorded, and analyzed specific neurons in multiple animals as they wormed their way around a custom-designed microfluidic array, called an arena, where they were exposed to favorable or hostile sensory cues.
Specifically, the team engineered a strain of worms with neurons near the head that would glow when they sensed food odors. In experiments involving up to 23 worms at a time, Albrecht’s team infused pulses of attractive or repulsive odors into the arena and watched how the worms reacted. In general, the worms moved towards the positive odors and away from the negative odors, but the behaviors did not always follow this pattern. “We were able to show that the sensory neurons responded to the odors similarly in all the animals, but their behavioral responses differed significantly,” Albrecht said. “These animals are genetically identical, and they were raised together in the same environment, so where do their different choices come from?”
In addition to watching the head neurons light up as they picked up odor cues, the new system can trace signaling through “interneurons.” These are pathways that connect external sensors to the rest of the network (the “worm brain”) and send signals to muscle cells that adjust the worm’s movement based on the cues. Numerous brain disorders in people are believed to arise when neural networks malfunction. In some cases the malfunction is dramatic overreaction to a routine stimulus, while in others it is a lack of appropriate reactions to important cues. Since C. elegans and humans share many of the same genes, discovering genetic causes for differing neuronal responses in worms could be applicable to human physiology. Experimental compounds designed to modulate the action of nerve cells and neuronal networks could be tested first on worms using Albrecht’s new system. The compounds would be infused in the worm arena, along with other stimuli, and the reaction of the worms’ nervous systems could be imaged and analyzed.
"The basis of our work is to combine biomedical engineering and neuroscience to answer some of these fundamental questions and hopefully gain insight that would be beneficial for understanding and eventually treating human disorders," Albrecht said.
The novel compound IRL-1620 may be useful in treating Alzheimer’s disease (AD) as it has been shown to prevent cognitive impairment and oxidative stress in animal models. This research is being presented at the 2013 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition, the world’s largest pharmaceutical sciences meeting, in San Antonio, Nov. 10–14.
AD is a form of dementia that worsens over time, leading to a slow decline in cognitive functions and affecting memory, thinking, and behavior. More than 5 million Americans are living with AD, according to the Alzheimer’s Association.
Anil Gulati, M.D., Ph.D., FCP, and Seema Briyal, Ph.D., along with their colleagues from Midwestern University, administered Amyloid beta (Aβ), a main component of certain deposits located in AD patients’ brains, to normal and diabetic rats on days 1, 7, and 14. Spatial learning and memory were tested in a Morris water maze. The pool was divided into four equal quadrants, and an escape platform was hidden below the surface at a fixed location in one of the quadrants.
The rats had to find the platform within 60 seconds. The average time it took on day 4 for Aβ-treated rats to locate the platform was 55.05 seconds, though a majority of this group was not able to find it in the designated time. Aβ rats treated with IRL-1620 were able to locate the platform in 26.53 seconds, nearly half the time. After five days, Aβ rats treated with IRL-1620 showed a 60 percent improvement in learning and memory.
“Our research is based on the idea of using the Endothelin (ET) system in the treatment of AD,” said Gulati. “The ET system is traditionally known to play a role in the regulation of blood flow. This is important in the potential treatment of AD since disturbances in blood flow could damage the brain’s ability to clear damaging particles, leading to a build-up of toxic substances and cognitive impairment.”
The next stage of Gulati’s research is to further investigate the endothelin receptor type B’s mechanisms of neuroprotection and to look into possible resulting tissue changes following AD.
The FDA has approved five medications to treat the symptoms of AD. Current drugs help mask the symptoms but do not treat the underlying disease. A breakthrough Alzheimer’s treatment would target the underlying disease and stop or delay the cell damage that eventually leads to the worsening of symptoms.
Why does it take longer to recognise a familiar face when seen in an unfamiliar setting, like seeing a work colleague when on holiday? A new study published today in Nature Communications has found that part of the reason comes down to the processes that our brain performs when learning and recognising faces.
During the experiment, participants were shown faces of people that they had never seen before, while lying inside an MRI scanner in the Department of Psychology at Royal Holloway. They were shown some of these faces numerous times from different angles and were asked to indicate whether they had seen that person before or not.
While participants were relatively good at recognising faces once they had seen them a few times, using a new mathematical approach, the scientists found that people’s decisions of whether they recognised someone were also dependent on the context in which they encountered the face. If participants had recently seen lots of unfamiliar faces, they were more likely to say that the face they were looking at was unfamiliar, even if they had seen the face several times before and had previously reported that they did recognise the face.
Activity in two areas of the brain matched the way in which the mathematical model predicted people’s performance.
“Our study has characterised some of the mathematical processes that are happening in our brain as we do this,” said lead author Dr Matthew Apps. “One brain area, called the fusiform face area, seems to be involved in learning new information about faces and increasing their familiarity.
“Another area, called the superior temporal sulcus, we found to have an important role in influencing our report of whether we recognise someone’s face, regardless of whether we are actually familiar with them or not. While this seems rather counter-intuitive, it may be an important mechanism for simplifying all the information that we need to process about faces.”
“Face recognition is a fundamental social skill, but we show how error prone this process can be. To recognise someone, we become familiar with their face, by learning a little more about what it looks like,” said co-author Professor Manos Tsakiris.
“At the same time, we often see people in different contexts. The recognition biases that we measured might give us an advantage in integrating information about identity and social context, two key elements of our social world.”
Massachusetts General Hospital (MGH) investigators have used a new sequencing method to identify a group of genes used by the brain’s immune cells – called microglia – to sense pathogenic organisms, toxins or damaged cells that require their response. Identifying these genes should lead to better understanding of the role of microglia both in normal brains and in neurodegenerative disorders and may lead to new ways to protect against the damage caused by conditions like Alzheimer’s and Parkinson’s diseases. The study, which has been published online in Nature Neuroscience, also finds that the activity of microglia appears to become more protective with aging, as opposed to increasingly toxic, which some previous studies had suggested.
"We’ve been able to define, for the first time, a set of genes microglia use to sense their environment, which we are calling the microglial sensome," says Joseph El Khoury, MD, of the MGH Center for Immunology and Inflammatory Diseases and Division of Infectious Diseases, senior author of the study. "Identifying these genes will allow us to specifically target them in diseases of the central nervous system by developing ways to upregulate or downregulate their expression."
A type of macrophage, microglia are known to constantly survey their environment in order to sense the presence of infection, inflammation, and injured or dying cells. Depending on the situation they encounter, microglia may react in a protective manner – engulfing pathogenic organisms, toxins or damaged cells – or release toxic substances that directly destroy microbes or infected brain cells. Since this neurotoxic response can also damage healthy cells, keeping it under control is essential, and excess neurotoxicity is known to contribute to the damage caused by several neurodegenerative disorders.
El Khoury’s team set out to define the transcriptome – the complete set of RNA molecules transcribed by a cell – of the microglia of healthy, adult mice and compared that expression profile to those of macrophages from peripheral tissues of the same animals and of whole brain tissue. Using a technique called direct RNA sequencing, which is more accurate than previous methods, they identified a set of genes uniquely expressed in the microglia and measured their expression levels, the first time such a gene expression ‘snapshot’ has been produced for any mammalian brain cell, the authors note.
Since aging is known to alter gene expression throughout the brain, the researchers then compared the sensome of young adult mice to that of aged mice. They found that – contrary to what previous studies had suggested – the expression of genes involved in potentially neurotoxic actions, such as destroying neurons, was downregulated as animals aged, while the expression of neuroprotective genes involved in sensing and removing pathogens was increased. El Khoury notes that the earlier studies suggesting increased neurotoxicity with aging did not look at the cells’ full expression profile and often were done in cultured cells, not in living animals.
"Establishing the sensome of microglia allows us to clearly understand how they interact with and respond to their environment under normal conditions," he explains. "The next step is to see what happens under pathologic conditions. We know that microglia become more neurotoxic as Alzheimer’s disease and other neurodegenerative disorders progress, and recent studies have identified two of the microglial sensome genes as contributing to Alzheimer’s risk. Our next steps should be defining the sensome of microglia and other brain cells in humans, identifying how the sensome changes in central nervous system disorders, and eventually finding ways to safely manipulate the sensome pharmacologically."
University of Adelaide researchers have taken a step forward in unravelling the causes of a commonly inherited intellectual disability, finding that a genetic mutation leads to a reduction in certain proteins in the brain.
ARX is among the top four types of intellectual disability linked to the X-chromosome in males. So far, 115 families, including many large Australian families, have been discovered to carry an ARX (Aristaless related homeobox) mutation that gives rise to intellectual disability.
"There is considerable variation in the disability across families, and within families with a single mutation. Symptoms among males always include intellectual disability, as well as a range of movement disorders of the hand, and in some cases severe seizures," says Associate Professor Cheryl Shoubridge, Head of Molecular Neurogenetics with the University of Adelaide’s Robinson Institute.
ARX mutations were first discovered by the University of Adelaide’s Professor Jozef Gecz in 2002. To date, researchers have detected 52 different ARX mutations and 10 distinct clinical syndromes.
Associate Professor Shoubridge is lead author of a new paper on ARX intellectual disability published in the journal Human Molecular Genetics.
In laboratory studies, Associate Professor Shoubridge’s team has shown that mutations lead to a significant reduction in ARX proteins in the brain, but the actual causes and mechanisms involved in this remain unknown. Her team tested six genes that the ARX protein interacts with, and found that one of them - a gene likely to be important to early brain development - appears to be adversely affected by the reduction of ARX proteins.
"This plays an important role in setting up architecture and networks in the brain, which become disrupted due to the mutation", Associate Professor Shoubridge says.
"The discovery of this genetic link is an important step forward but there is still much work to be done. We’re now looking further at the mechanism of the reduction in ARX protein and what that means for the brain at a functional level."
Associate Professor Shoubridge says up to 3% of the population is affected by some kind of intellectual disability, costing $14.7 billion each year in Australia alone.
"The personal cost to families is enormous, especially in the most severe cases. Being able to unravel why and how these disabilities occur is very important to us and to the many people whose lives are affected by these conditions," she says.
A growing body of evidence shows the impact of diet on brain function, and identifies patterns of brain activity associated with eating disorders such as binge eating and purging. The findings were presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.
Millions of people worldwide suffer from eating disorders such as anorexia, bulimia, and binge eating. With increased risk for psychiatric and chronic diseases, today’s studies are valuable in helping generate new strategies to treat disorders from obesity to anorexia.
Today’s new findings show that:
Other recent findings discussed show that:
“As scientists uncover the impacts of diet on brain function, the adage ‘You are what you eat,’ takes on new meaning,” said press conference moderator Fernando Gomez-Pinilla, PhD, of the University of California, Los Angeles, an expert in the impact of the environment on brain health. “We cannot separate the nutritional benefits of food for the body from that of the mind. What we put into the body also shapes the brain, for better or for worse.”
New findings show that extensive musical training affects the structure and function of different brain regions, how those regions communicate during the creation of music, and how the brain interprets and integrates sensory information. The findings were presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.
These insights suggest potential new roles for musical training including fostering plasticity in the brain, an alternative tool in education, and treating a range of learning disabilities.
Today’s new findings show that:
Some of the brain changes that occur with musical training reflect the automation of task (much as one would recite a multiplication table) and the acquisition of highly specific sensorimotor and cognitive skills required for various aspects of musical expertise.
“Playing a musical instrument is a multisensory and motor experience that creates emotions and motions — from finger tapping to dancing — and engages pleasure and reward systems in the brain. It has the potential to change brain function and structure when done over a long period of time,” said press conference moderator Gottfried Schlaug, MD, PhD, of Harvard Medical School/Beth Israel Deaconess Medical Center, an expert on music, neuroimaging and brain plasticity. “As today’s findings show, intense musical training generates new processes within the brain, at different stages of life, and with a range of impacts on creativity, cognition, and learning.”
New studies released today reveal links between social status and specific brain structures and activity, particularly in the context of social stress. The findings were presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.
Using human and animal models, these studies may help explain why position in social hierarchies strongly influences decision-making, motivation, and altruism, as well as physical and mental health. Understanding social decision-making and social ladders may also aid strategies to enhance cooperation and could be applied to everyday situations from the classroom to the boardroom.
Today’s new findings show that:
Other recent findings discussed show that:
“Social subordination and social instability have been associated with an increased incidence of mental illness in humans,” said press conference moderator Larry Young, PhD, of Emory University, an expert in brain functions involved with social behavior. “We now have a better picture of how these situations impact the brain. While this information could lead to new treatments, it also calls on us to evaluate how we construct social hierarchies — whether in the workplace or school — and their impacts on human well-being.”
Many of us have steeled ourselves for those ‘needle in a haystack’ tasks of finding our vehicle in an airport car park, or scouring the supermarket shelves for a favourite brand.
A new scientific study has revealed that our understanding of how the human brain prepares to perform visual search tasks of varying difficulty may now need to be revised.
When people search for a specific object, they tend to hold in mind a visual representation of it, based on key attributes like shape, size or colour. Scientists call this ‘advanced specification’. For example, we might search for a friend at a busy railway station by scanning the platform for someone who is very tall or who is wearing a green coat, or a combination of these characteristics.
Researchers from the School of Psychology at the University of Lincoln, UK, set out to better explain how these abstract visual representations are formed. They used fMRI scanners to record neural activity when volunteers prepared to search for a target object: a coloured letter amid a screen of other coloured letters.
Their findings, published in the journal ‘Brain Research’, are the first to fully isolate the different areas of the human brain involved in this ‘prepare to search’ function. Surprisingly, they show that the advanced frontal areas of the brain, usually key to advanced cognitive tasks, appear to take a backseat. Instead it is the basic back areas of the brain and the sub-cortical areas that do the work.
Dr Patrick Bourke from the University of Lincoln’s School of Psychology, who led the study, said: “Up until now, when researchers have studied visual search tasks they have also found that frontal areas of the brain were active. This has been assumed to indicate a control system: an ‘executive’ that largely resides in the advanced front of the brain which sends signals to the simpler back of the brain, activating visual memories. Here, when we isolated the ‘prepare’ part of the task from the actual search and response phase we found that this activation in the front was no longer present.”
This finding has important implications for understanding the fundamental brain processes involved. It was previously thought that the Intra-parietal region of the brain, which is linked to visual attention, was the central component of the supposed ‘front-back’ control network, relaying useful information (such as a shape or colour bias) from frontal areas of the brain to the back, where simple visual representations of the object are held. If the frontal areas are not activated in the preparation phase, this cannot be the case.
The study also showed that the pattern of brain activation varied depending on the anticipated difficulty of the search task, even when the target object was the same. This indicates that rather than holding in mind a single representation of an object, a new target is constructed each time, depending on the nature of the task.
Dr Bourke added: “While consistent with previous brain imaging work on visual search, these results change the interpretations and assumptions that have been applied previously. Notably, they highlight a difference between studies of animals’ brains and those of humans. Studies with monkeys convincingly show the front-back control system and we thought we understood how this worked. At the same time our findings are consistent with a growing body of brain imaging work in humans that also shows no frontal brain activation when short term memories are held.”
People in middle age who have a high blood pressure measure called pulse pressure are more likely to have biomarkers of Alzheimer’s disease in their spinal fluid than those with lower pulse pressure, according to research published in the November 13, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.
Pulse pressure is the systolic pressure, or the top number in a blood pressure reading, minus the diastolic, or the bottom number. Pulse pressure increases with age and is an index of the aging of the vascular system.
The study involved 177 people ages 55 to 100 with no symptoms of Alzheimer’s disease. Participants had their pulse pressure taken and lumbar punctures to obtain spinal fluid.
The study found that people who have higher pulse pressure are more likely to have the Alzheimer’s biomarkers amyloid beta, or plaques, and p-tau protein, or tangles, in their cerebral spinal fluid than those with lower pulse pressure. For every 10 point rise in pulse pressure, the average level of p-tau protein in the spinal fluid rose by 1.5 picograms per millileter. A picogram is one trillionth of a gram.
“These results suggest that the forces involved in blood circulation may be related to the development of the hallmark Alzheimer’s disease signs that cause loss of brain cells,” said study author Daniel A. Nation, PhD, of the VA San Diego Healthcare System.
The relationship was found in people age 55 to 70, but not in people age 70 to 100.
“This is consistent with findings indicating that high blood pressure in middle age is a better predictor of later problems with memory and thinking skills and loss of brain cells than high blood pressure in old age,” Nation said.
People who are in love are less able to focus and to perform tasks that require attention. Researcher Henk van Steenbergen concludes this, together with colleagues from Leiden University and the University of Maryland. The article has appeared in the journal Motivation and Emotion.
The more in love, the less focused you are
Forty-three participants who had been in a relationship for less than half a year performed a number of tasks during which they had to discriminate irrelevant from relevant information as soon as possible. It appeared that the more in love they were, the less able they were to ignore the irrelevant information. Love intensity thus was related to how well someone is able to focus. There was no difference between men and women.
Cognitive control
The participants listened to music that elicited romantic feelings and thought of a romantic event to intensify their love feelings. Participants also completed a questionnaire that was used to assess the intensity of their love feelings. The results of the study by Henk van Steenbergen differed from results from previous studies. Those previous studies showed that the ability to ignore distracting information is required to maintain a long-term romantic relationship. Being able to control oneself (also called “cognitive control”) and to resist temptations that could threaten the relationship is essential in long-term love.
Thinking of your beloved
In the study by Van Steenbergen, in contrast, the participants had become involved in a romantic relationship only a few months ago. “When you have just become involved in a romantic relationship you’ll probably find it harder to focus on other things because you spend a large part of your cognitive resources on thinking of your beloved”, Van Steenbergen says. “For long-lasting love in a long-term relationship, on the other hand, it seems crucial to have proper cognitive control.” Over time, a balance between less and more cognitive control may be critical for a successful relationship.
Why is romantic love associated with cognitive control?
Van Steenbergen emphasizes that the link between romantic love and cognitive control is a new area of research. “The reason why romantic love is associated with cognitive control is still unknown. It could be that lovers use all their cognitive resources to think about their beloved, which leaves them no resources to perform a boring task. It could also be that the association goes in the opposite direction: people who have reduced cognitive control may experience more intense love feelings than people who have higher levels of cognitive control.” Future research will have to clarify this.
Patients with traumatic brain injury (TBI) had increased deposits of β-Amyloid (Αβ) plaques, a hallmark of Alzheimer Disease (AD), in some areas of their brains in a study by Young T. Hong, Ph.D., of the University of Cambridge, England, and colleagues.
There may be epidemiological or pathophysiological (changes because of injury) links between TBI and AD, and Αβ plaques are found in as many as 30 percent of patients who die in the acute phase after a TBI. The plaques appear within hours of the injury and can occur in patients of all ages, according to the study background.
Researchers used imaging and brain tissue acquired during autopsies to examine Αβ deposition in patients with TBI. Researchers performed positron emission tomography (PET) imaging using carbon 11-labeled Pittsburgh Compound B ([11C]PIB), a marker of brain amyloid deposition, in 15 participants with a TBI and 11 healthy patients. Autopsy-acquired brain tissue was obtained from 16 people who had a TBI, as well as seven patients with a nonneurological cause of death.
The study’s findings indicate that patients with TBI showed increases in [11C]PIB binding, which may be a marker of Αβ plaque in some areas of the brain.
“The use of ([11C]PIB PET for amyloid imaging following TBI provides us with the potential for understanding the pathophysiology of TBI, for characterizing the mechanistic drivers of disease progression or suboptimal recovery in the subacute phase of TBI, for identifying patients at high risk of accelerated AD, and for evaluating the potential of antiamyloid therapies,” the authors conclude.
A polymer originally designed to help mend broken bones could be successful in delivering chemotherapy drugs directly to the brains of patients suffering from brain tumours, researchers at The University of Nottingham have discovered.
Their study, published in the journal PLOS ONE, shows that the biomaterial can be easily applied to the cavity created following brain cancer surgery and used to release chemotherapy drugs over several weeks.
The targeted nature of the therapy could also reduce the toxic effects of chemotherapy drugs on healthy parts of the body, potentially reducing the debilitating side-effects that many patients experience after cancer treatment.
Patient survival
Dr Ruman Rahman, of the University’s Children’s Brain Tumour Research Centre (CBTRC), who led the study, said: “Our system is an innovative method of drug delivery for the treatment of brain tumours and is intended to be administered immediately after surgery by the operating neurosurgeon.
“Ultimately, this method of drug delivery, in combination with existing therapies, may result in more effective treatment of brain tumours, prolonged patient survival and reduced morbidity.”
Brain tumours are the major cause of cancer-related death in children and adults up to the age of 40. Most relapses occur when surgeons are unable to remove all of the cancerous cells during surgery – something which can be particularly challenging in very young children and babies and by the very nature of a type of adult brain cancer called glioblastoma.
Although alternative systems for delivery of drugs directly to the brain have been developed, they are used infrequently because their success has been limited. This new drug delivery system is the first that can be moulded to the shape of the brain tumour cavity and the first to deliver several different drugs over a clinically meaningful period of time.
The Nottingham polymer formulation is made from two types of micro-particles called PLGA and PEG and has been developed and patented by leading tissue engineer Professor Kevin Shakesheff, based in the University’s School of Pharmacy. A powder at room temperature, it can be mixed to a toothpaste-like consistency with the addition of water.
Unique properties
The unique properties of the polymer lie in its ability to set into a rigid structure only when it reaches body temperature (37 degrees), a feature perfectly tailored for use in medical therapies. It was originally developed as a scaffold on to which new bone cells could be grown to speed up the knitting back together of broken bones.
Dr Ruman Rahman at the CBTRC and Dr Cheryl Rahman from the School of Pharmacy spotted the potential for the polymer to deliver chemotherapy drugs directly to patients’ brain tumours. The work was performed at the CBTRC with neurosurgeon Mr Stuart Smith and neuro-oncologist Professor Richard Grundy. The cavity left by the removal of a tumour would be lined with the polymer while in paste form, which would start to solidify and gradually release the chemotherapy drugs after the incision has been closed. This would directly target any residual cells not initially removed during surgery.
In the lab, the Nottingham scientists were able to successfully demonstrate the slow-release properties of the material by placing paste loaded with three commonly used chemotherapy drugs into a solution of saline and measuring the quantities of the drugs given out by the material over time.
To establish whether the material itself is safe to use on patients in this form of therapy, they used it to create a 3D model onto which they were able to grow brain tumour cells and healthy brain blood vessel cells without any toxicity. They then simulated surgery on a sheep’s brain from an abattoir by moulding the paste around a brain cavity and warming the brain to human body temperature to harden the polymer.
The brain was then scanned using CT and MRI technology to demonstrate that it is still possible to distinguish the polymer from normal brain tissue on a routine brain scan, an aspect crucial for doctors when dealing with follow-up care for brain tumour patients who have undergone surgery.
Robust material
The team also dealt with concerns that the material could disintegrate and release its chemotherapy contents too quickly during the subsequent radiotherapy which many cancer patients undergo following surgery. By placing the biomaterial loaded with chemotherapy drugs into a head cavity of a medical training dummy and subjecting it to the same duration and intensity of radiotherapy used for brain tumour patients they were able to successfully demonstrate the robust integrity of the structure.
Finally they showed that a chemotherapy drug called etoposide could be effective at killing brain cancer cells in a mouse when released from the polymer formulation. The next stage of the research will be to extend the study in mice with brain tumours to test whether animals with the drug-loaded polymers survive longer. The team are also investigating the release of other chemotherapeutic drugs that hold promise, supported by a recent grant award from Sparks.
As the research used a biomaterial and chemotherapy drugs already approved for medical use, many of the usual ethical approval hurdles to allow further investigation have already been cleared.
The first clinical test, anticipated in 3 years’ time, will be to devise a multi-centre phase 0 clinical trial which would involve testing the therapy on a small number of patients for whom other clinical treatments have not been successful and would otherwise only be offered palliative care.
“This is a very exciting development and holds considerable promise for the treatment of malignant brain tumours in the near future” commented Professor Grundy, Co-Director of the CBTRC.
Research released today reveals new mechanisms and areas of the brain associated with anxiety and depression, presenting possible targets to understand and treat these debilitating mental illnesses. The findings were presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.
More than 350 million people worldwide suffer from clinical depression and between 5 and 25 percent of adults suffer from generalized anxiety, according to the World Health Organization. The resulting emotional and financial costs to people, families, and society are significant. Further, antidepressants are not always effective and often cause severe side effects.
Today’s new findings show that:
Other recent findings discussed show that:
“Today’s findings represent our rapidly growing understanding of the individual molecules and brain circuits that may contribute to depression and anxiety,” said press conference moderator Lisa Monteggia, PhD, of the University of Texas Southwestern Medical Center, an expert on mechanisms of antidepressant action. “These exciting discoveries represent the potential for significant changes in how we diagnose and treat these illnesses that touch millions.”
Research released today reveals a new model for a genetic eye disease, and shows how animal models — from fruit flies to armadillos and monkeys — can yield valuable information about the human brain. The findings were presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.
Animal models have long been central in how we understand the human brain, behavior, and nervous system due to similarities in many brain areas and functions across species. Almost every major medical advance in the last century was made possible by carefully regulated, humane animal research. Today’s findings build on this rich history and demonstrate what animals can teach us about ourselves.
Today’s new findings show that:
Other recent findings discussed show that:
“Neuroscience has always relied on responsible animal research to better understand how our brains and bodies develop, function, and break down,” said press conference moderator Leslie Tolbert, of the University of Arizona, whose work in insects provides insights into brain development. “Today’s studies reveal new ways that research on unlikely-seeming animals, such as armadillos, fruit flies, and worms, could have real impact on our understanding of the human brain and what can go wrong in disease.”
Scientists are gaining a new level of understanding of multiple sclerosis (MS) that may lead to new treatments and approaches to controlling the chronic disease, according to new research released today at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.
MS is a severe, often crippling, autoimmune disease caused by the body’s immune system attacking the nervous system. Today, more than two million people worldwide suffer from MS and other neuroinflammatory diseases. MS usually strikes in early adulthood and manifests with symptoms including vision loss, paralysis, numbness, and fatigue. The disease can be intermittent or progressive and currently has no cure.
Today’s new findings show that:
Other recent findings discussed show that:
“The findings shown today represent real promise for the millions suffering from MS,” said press conference moderator Jeffrey Rothstein of Johns Hopkins University and an expert in neurodegenerative diseases. “These studies are breakthroughs in understanding and treating a disease that remains uncured, difficult to diagnose, and for which it is very difficult to prevent progression.”
As little as 20 minutes of moderate exercise three times per week during pregnancy enhances the newborn child’s brain development, according to researchers at the University of Montreal and its affiliated CHU Sainte-Justine children’s hospital. This head-start could have an impact on the child’s entire life. “Our research indicates that exercise during pregnancy enhances the newborn child’s brain development,” explained Professor Dave Ellemberg, who led the study. “While animal studies have shown similar results, this is the first randomized controlled trial in humans to objectively measure the impact of exercise during pregnancy directly on the newborn’s brain. We hope these results will guide public health interventions and research on brain plasticity. Most of all, we are optimistic that this will encourage women to change their health habits, given that the simple act of exercising during pregnancy could make a difference for their child’s future.” Ellemberg and his colleagues Professor Daniel Curnier and PhD candidate Élise Labonté-LeMoyne presented their findings today at the Neuroscience 2013 congress in San Diego.
Not so long ago, obstetricians would tell women to take it easy and rest during their pregnancy. Recently, the tides have turned and it is now commonly accepted that inactivity is actually a health concern. “While being sedentary increases the risks of suffering complications during pregnancy, being active can ease post-partum recovery, make pregnancy more comfortable and reduce the risk of obesity in the children,” Curier explained. “Given that exercise has been demonstrated to be beneficial for the adult’s brain, we hypothesized that it could also be beneficial for the unborn child through the mother’s actions.”
To verify this, starting at the beginning of their second trimester, women were randomly assigned to an exercise group or a sedentary group. Women in the exercise group had to perform at least 20 minutes of cardiovascular exercise three times per week at a moderate intensity, which should lead to at least a slight shortness of breath. Women in the sedentary group did not exercise. The brain activity of the newborns was assessed between the ages of 8 to 12 days, by means of electroencephalography, which enables the recording of the electrical activity of the brain. “We used 124 soft electrodes placed on the infant’s head and waited for the child to fall asleep on his or her mother’s lap. We then measured auditory memory by means of the brain’s unconscious response to repeated and novel sounds,” Labonté-LeMoyne said. “Our results show that the babies born from the mothers who were physically active have a more mature cerebral activation, suggesting that their brains developed more rapidly.”
The researchers are now in the process of evaluating the children’s cognitive, motor and language development at age 1 to verify if these differences are maintained.
New human and animal research released today demonstrates how experiences impact genes that influence behavior and health. Today’s studies, presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health, provide new insights into how experience might produce long-term brain changes in behaviors like drug addiction and memory formation.
The studies focus on an area of research called epigenetics, in which the environment and experiences can turn genes “on” or “off,” while keeping underlying DNA intact. These changes affect normal brain processes, such as development or memory, and abnormal brain processes, such as depression, drug dependence, and other psychiatric disease — and can pass down to subsequent generations.
Today’s new findings show that:
Other recent findings discussed show that:
"DNA may shape who we are, but we also shape our own DNA," said press conference moderator Schahram Akbarian, of the Icahn School of Medicine at Mount Sinai, an expert in epigenetics. "These findings show how experiences like learning or drug exposure change the way genes are expressed, and could be incredibly important in developing treatments for addiction and for understanding processes like memory."
Johns Hopkins engineers and cardiology experts have teamed up to develop a fingernail-sized biosensor that could alert doctors when serious brain injury occurs during heart surgery. By doing so, the device could help doctors devise new ways to minimize brain damage or begin treatment more quickly.
In the Nov. 11 issue of the journal Chemical Science, the team reported on lab tests demonstrating that the prototype sensor had successfully detected a protein associated with brain injuries.
“Ideally, the testing would happen while the surgery is going on, by placing just a drop of the patient’s blood on the sensor, which could activate a sound, light or numeric display if the protein is present,” said the study’s senior author, Howard E. Katz, a Whiting School of Engineering expert in organic thin film transistors, which form the basis of the biosensor.
The project originated about two years ago when Katz, who chairs the Department of Materials Science and Engineering, was contacted by Allen D. Everett, a Johns Hopkins Children’s Center pediatric cardiologist who studies biomarkers linked to pulmonary hypertension and brain injury. As brain injury can occur with heart surgery in both adults and children, the biosensor Everett proposed should work on patients of all ages. He is particularly concerned, however, about operating room injuries to children, whose brains are still developing.
“Many of our young patients need one or more heart surgeries to correct congenital heart defects, and the first of these procedures often occurs at birth,” Everett said. “We take care of these children through adulthood, and we have all have seen the neurodevelopment problems that occur as a consequence of their surgery and post-operative care. These are very sick children, and we have done a brilliant job of improving overall survival from congenital heart surgery, but we have far to go to improve the long-term outcomes of our patients. This is our biggest challenge for the 21st century.”
He said that recent studies found that after heart surgery, about 40 percent of infant patients will have brain abnormalities that show up in MRI scans. The damage is most often caused by strokes, which can be triggered and made worse by multiple events during surgery and recovery, when the brain is most susceptible to injury. These brain injuries can lead to deficiencies in the child’s mental development and motor skills, as well as hyperactivity and speech delay.
To address these problems, Everett sought an engineer to design a biosensor that responds to glial fibrillary acidic protein (GFAP), which is a biomarker linked to brain injuries. “If we can be alerted when the injury is occurring,” he said, “then we should be able to develop better therapies. We could improve our control of blood pressure or redesign our cardiopulmonary bypass machines. We could learn how to optimize cooling and rewarming procedures and have a benchmark for developing and testing new protective medications.”
At present, Everett said, doctors have to wait years for some brain injury-related symptoms to appear. That slows down the process of finding out whether new procedures or treatments to reduce brain injuries are effective. The new device may change that. “The sensor platform is very rapid,” Everett said. “It’s practically instantaneous.”
To create this sensor, materials scientist Katz turned to an organic thin film transistor design. In recent years sensors built on such platforms have shown that they can detect gases and chemicals associated with explosives. These transistors were an attractive choice for Everett’s request because of their potential low cost, low power consumption, biocompatibility and their ability to detect a variety of biomolecules in real time. Futhermore, the architecture of these transistors could accommodate a wide variety of other useful electronic materials.
The sensing area is a small square, 3/8ths-of-an-inch on each side. On the surface of the sensor is a layer of antibodies that attract GFAP, the target protein. When this occurs, it changes the physics of other material layers within the sensor, altering the amount of electrical current that is passing through the device. These electrical changes can be monitored, enabling the user to know when GFAP is present.
“This sensor proved to be extremely sensitive,” Katz said. “It recognized GFAP even when there were many other protein molecules nearby. As far as we’ve been able to determine, this is the most sensitive protein detector based on organic thin film transistors.”
Through the Johns Hopkins Technology Transfer Office, the team members have filed for full patent protection for the new biosensor. Katz said the team is looking for industry collaborators to conduct further research and development of the device, which has not yet been tested on human patients. But with the right level of effort and support, Katz believes the device could be put into clinical use within five years. “I’m getting tremendous personal satisfaction from working on a major medical project that could help patients,” he said.
Everett, the pediatric cardiologist, said the biosensor could eventually be used outside of the operating room to quickly detect brain injuries among athletes and accident victims. “It could evolve into a point-of-care or point-of-injury device,” he said. “It might also be very useful in hospital emergency departments to screen patients for brain injuries.”
Scientists at Rutgers and Emory universities have discovered that a compound often emitted by mold may be linked to symptoms of Parkinson’s disease.
Arati Inamdar and Joan Bennett, researchers in the School of Environmental and Biological Sciences at Rutgers, used fruit flies to establish the connection between the compound – popularly known as mushroom alcohol – and the malfunction of two genes involved in the packaging and transport of dopamine, the chemical released by nerve cells to send messages to other nerve cells in the brain.
The findings were published online today in the Proceedings of the National Academy of Sciences.
“Parkinson’s has been linked to exposure to environmental toxins, but the toxins were man-made chemicals,” Inamdar said. “In this paper, we show that biologic compounds have the potential to damage dopamine and cause Parkinson’s symptoms.”
For co-author Bennett, the research was more than academic. Bennett was working at Tulane University in New Orleans when Hurricane Katrina struck the Gulf Coast in 2005. Her flooded house became infested with molds, which she collected in samples, wearing a mask, gloves and protective gear.
“I felt horrible – headaches, dizziness, nausea,” said Bennett, now a professor of plant pathology and biology at Rutgers. “I knew something about ‘sick building syndrome’ but until then I didn’t believe in it. I didn’t think it would be possible to breathe in enough mold spores to get sick.” That is when she formed her hypothesis that volatiles might be involved.
Inamdar, who uses fruit flies in her research, and Bennett began their study shortly after Bennett arrived at Rutgers. Bennett wanted to understand the connection between molds and symptoms like those she had experienced following Katrina.
The scientists discovered that the volatile organic compound 1-octen-3-ol, otherwise known as mushroom alcohol, can cause movement disorders in flies, similar to those observed in the presence of pesticides, such as paraquat and rotenone. Further, they discovered that it attacked two genes that deal with dopamine, degenerating the neurons and causing the Parkinson’s-like symptoms.
Studies indicate that Parkinson’s disease – a progressive disease of the nervous system marked by tremor, muscular rigidity and slow, imprecise movement — is increasing in rural areas, where it’s usually attributed to pesticide exposure. But rural environments also have a lot of mold and mushroom exposure.
“Our work suggests that 1-octen-3-ol might also be connected to the disease, particularly for people with a genetic susceptibility to it,” Inamdar said. “We’ve given the epidemiologists some new avenues to explore.”
A team of scientists led by researchers from the University of California, San Diego School of Medicine and Ludwig Institute for Cancer Research have identified a novel therapeutic approach for the most frequent genetic cause of ALS, a disorder of the regions of the brain and spinal cord that control voluntary muscle movement, and frontotemporal degeneration, the second most frequent dementia.
Published ahead of print in last week’s online edition of the journal PNAS, the study establishes using segments of genetic material called antisense oligonucleotides – ASOs – to block the buildup and selectively degrade the toxic RNA that contributes to the most common form of ALS, without affecting the normal RNA produced from the same gene.
The new approach may also have the potential to treat frontotemporal degeneration or frontotemporal dementia (FTD), a brain disorder characterized by changes in behavior and personality, language and motor skills that also causes degeneration of regions of the brain.
In 2011, scientists found that a specific gene known as C9orf72 is the most common genetic cause of ALS. It is a very specific type of mutation which, instead of changing the protein, involves a large expansion, or repeated sequence of a set of nucleotides – the basic component of RNA.
A normal C9orf72 gene contains fewer than 30 of the nucleotide repeat unit, GGGGCC. The mutant gene may contain hundreds of repeats of this unit, which generate a repeat containing RNA that the researchers show aggregate into foci.
“Remarkably, we found two distinct sets of RNA foci, one containing RNAs transcribed in the sense direction and the other containing anti-sense RNAs,” said first author Clotilde Lagier-Tourenne, MD, PhD, UC San Diego Department of Neurosciences and Ludwig Institute for Cancer Research.
The researchers also discovered a signature of changes in expression of other genes that accompanies expression of the repeat-containing RNAs. Since they found that reducing the level of expression of the C9orf72 gene in a normal adult nervous system did not produce this signature of changes, the evidence demonstrated a toxicity of the repeat-containing RNAs that could be relieved by reducing the levels of those toxic RNAs.
“This led to our use of the ASOs to target the sense strand. We reduced the accumulation of expanded RNA foci and corrected the sense strand of the gene. Importantly, we showed that we could remove the toxic RNA without affecting the normal RNA that encodes the C9orf72 protein. This selective silencing of a toxic RNA is the holy grail of gene silencing approaches, and we showed we had accomplished it,” Lagier-Tourenne added.
Targeting the sense strand RNAs with a specific ASO did not, however, affect the antisense strand foci nor did it correct the signature of gene expression changes. “Doing that will require separate targeting of the antisense strand – or both - and has now become a critical question,“ Lagier-Tourenne said.
“This approach is exciting as it links two neurodegenerative diseases, ALS and FTD, to the field of expansion, which has gained broadened interest from investigators,” said co-principal investigator John Ravits, MD, UC San Diego Department of Neurosciences. “At the same time, our study also demonstrates the – to now – unrecognized role of anti-sense RNA and its potential as a therapeutic target.”
All animals have to make decisions every day. Where will they live and what will they eat? How will they protect themselves? They often have to make these decisions as a group, too, turning what may seem like a simple choice into a far more nuanced process. So, how do animals know what’s best for their survival?
For the first time, Arizona State University researchers have discovered that at least in ants, animals can change their decision-making strategies based on experience. They can also use that experience to weigh different options.
The findings are featured today in the early online edition of the scientific journal Biology Letters, as well as in its Dec. 23 edition.
Co-authors Taka Sasaki and Stephen Pratt, both with ASU’s School of Life Sciences, have studied insect collectives, such as ants, for years. Sasaki, a postdoctoral research associate, specializes in adapting psychological theories and experiments that are designed for humans to ants, hoping to understand how the collective decision-making process arises out of individually ignorant ants.
“The interesting thing is we can make decisions and ants can make decisions – but ants do it collectively,” said Sasaki. “So how different are we from ant colonies?”
To answer this question, Sasaki and Pratt gave a number of Temnothorax rugatulus ant colonies a series of choices between two nests with differing qualities. In one treatment, the entrances of the nests had varied sizes, and in the other, the exposure to light was manipulated. Since these ants prefer both a smaller entrance size and a lower level of light exposure, they had to prioritize.
“It’s kind of like a humans and buying a house,” said Pratt, an associate professor with the school. “There’s so many options to consider – the size, the number of rooms, the neighborhood, the price, if there’s a pool. The list goes on and on. And for the ants it’s similar, since they live in cavities that can be dark or light, big or small. With all of these things, just like with a human house, it’s very unlikely to find a home that has everything you want.”
Pratt continued to explain that because it is impossible to find the perfect habitat, ants make various tradeoffs for certain qualities, ordering them in a queue of most important aspects. But, when faced with a decision between two different homes, the ants displayed a previously unseen level of intelligence.
According to their data, the series of choices the ants faced caused them to reprioritize their preferences based on the type of decision they faced. Ants that had to choose a nest based on light level prioritized light level over entrance size in the final choice. On the other hand, ants that had to choose a nest based on entrance size ranked light level lower in the later experiment.
This means that, like people, ants take the past into account when weighing options while making a choice. The difference is that ants somehow manage to do this as a colony without any dissent. While this research builds on groundwork previously laid down by Sasaki and Pratt, the newest experiments have already raised more questions.
“You have hundreds of these ants, and somehow they have to reach a consensus,” Pratt said. “How do they do it without anyone in charge to tell them what to do?”
Pratt likened individual ants to individual neurons in the human brain. Both play a key role in the decision-making process, but no one understands how every neuron influences a decision.
Sasaki and Pratt hope to delve deeper into the realm of ant behavior so that one day, they can understand how individual ants influence the colony. Their greater goal is to apply what they discover to help society better understand how humanity can make collective decisions with the same ease ants display.
“This helps us learn how collective decision-making works and how it’s different from individual decision-making,” said Pratt. “And ants aren’t the only animals that make collective decisions – humans do, too. So maybe we can gain some general insight.”
A pilot study by a multi-disciplinary team of investigators at Georgetown University suggests that a simple dot test could help doctors gauge the extent of dopamine loss in individuals with Parkinson’s disease (PD). Their study is being presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience.
“It is very difficult now to assess the extent of dopamine loss — a hallmark of Parkinson’s disease — in people with the disease,” says lead author Katherine R. Gamble, a psychology PhD student working with two Georgetown psychologists, a psychiatrist and a neurologist. “Use of this test, called the Triplets Learning Task (TLT), may provide some help for physicians who treat people with Parkinson’s disease, but we still have much work to do to better understand its utility,” she adds.
Gamble works in the Cognitive Aging Laboratory, led by the study’s senior investigator, Darlene Howard, PhD, Davis Family Distinguished Professor in the department of psychology and member of the Georgetown Center for Brain Plasticity and Recovery.
The TLT tests implicit learning, a type of learning that occurs without awareness or intent, which relies on the caudate nucleus, an area of the brain affected by loss of dopamine.
The test is a sequential learning task that does not require complex motor skills, which tend to decline in people with PD. In the TLT, participants see four open circles, see two red dots appear, and are asked to respond when they see a green dot appear. Unbeknownst to them, the location of the first red dot predicts the location of the green target. Participants learn implicitly where the green target will appear, and they become faster and more accurate in their responses.
Previous studies have shown that the caudate region in the brain underlies implicit learning. In the study, PD participants implicitly learned the dot pattern with training, but a loss of dopamine appears to negatively impact that learning compared to healthy older adults.
“Their performance began to decline toward the end of training, suggesting that people with Parkinson’s disease lack the neural resources in the caudate, such as dopamine, to complete the learning task,” says Gamble.
In this study of 27 people with PD, the research team is now testing how implicit learning may differ by different PD stages and drug doses.
“This work is important in that it may be a non-invasive way to evaluate the level of dopamine deficiency in PD patients, and which may lead to future ways to improve clinical treatment of PD patients,” explains Steven E. Lo, MD, associate professor of neurology at Georgetown University Medical Center, and a co-author of the study.
They hope the TLT may one day be a tool to help determine levels of dopamine loss in PD.