Posts tagged neuroscience

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:

• Long-term heroin abusers show differences in small chemical modifications of their DNA and the histone proteins attached to it, compared to non-abusers. These differences could account for some of the changes in DNA/histone structures that develop during addiction, suggesting a potential biological difference driving long-term abuse versus overdose (Yasmin Hurd, abstract 257.2, see attached summary).
• Male rats exposed to cocaine may pass epigenetic changes on to their male offspring, thereby altering the next generation’s response to the drug. Researchers found that male offspring in particular responded much less to the drug’s influence (Matheiu Wimmer, PhD, abstract 449.19, see attached summary).
• Drug addiction can remodel mouse DNA and chromosomal material in predictable ways, leaving “signatures,” or signs of the remodeling, over time. A better understanding of these signatures could be used to diagnose drug addiction in humans (Eric Nestler, PhD, abstract 59.02, see attached summary).

Other recent findings discussed show that:

• Researchers have identified a potentially new genetic mechanism, called piRNA, underlying long-term memory. Molecules of piRNA were previously thought to be restricted to egg and sperm cells (Eric Kandel, MD, see attached summary).
• Epigenetic DNA remodeling is important for forming memories. Blocking this process causes memory deficits and stunts brain cell structure, suggesting a mechanism for some types of intellectual disability (Marcelo Wood, PhD, see attached summary).

"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."

(Source: eurekalert.org)

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 21^st 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.”

(Source: releases.jhu.edu)

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.”

(Source: news.rutgers.edu)

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.”

(Source: health.ucsd.edu)

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.”

(Source: asunews.asu.edu)

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.

(Source: explore.georgetown.edu)

Research from Oregon Health & Science University’s Vollum Institute, published in the current issue of Nature (1, 2), is giving scientists a never-before-seen view of how nerve cells communicate with each other. That new view can give scientists a better understanding of how antidepressants work in the human brain — and could lead to the development of better antidepressants with few or no side effects.

The article in today’s edition of Nature came from the lab of Eric Gouaux, Ph.D., a senior scientist at OHSU’s Vollum Institute and a Howard Hughes Medical Institute Investigator. The article describes research that gives a better view of the structural biology of a protein that controls communication between nerve cells. The view is obtained through special structural and biochemical methods Gouaux uses to investigate these neural proteins.

The Nature article focuses on the structure of the dopamine transporter, which helps regulate dopamine levels in the brain. Dopamine is an essential neurotransmitter for the human body’s central nervous system; abnormal levels of dopamine are present in a range of neurological disorders, including Parkinson’s disease, drug addiction, depression and schizophrenia. Along with dopamine, the neurotransmitters noradrenaline and serotonin are transported by related transporters, which can be studied with greater accuracy based on the dopamine transporter structure.

The Gouaux lab’s more detailed view of the dopamine transporter structure better reveals how antidepressants act on the transporters and thus do their work.

The more detailed view could help scientists and pharmaceutical companies develop drugs that do a much better job of targeting what they’re trying to target — and not create side effects caused by a broader blast at the brain proteins.

"By learning as much as possible about the structure of the transporter and its complexes with antidepressants, we have laid the foundation for the design of new molecules with better therapeutic profiles and, hopefully, with fewer deleterious side effects," said Gouaux.

Gouaux’s latest dopamine transporter research is also important because it was done using the molecule from fruit flies, a dopamine transporter that is much more similar to those in humans than the bacteria models that previous studies had used.

The dopamine transporter article was one of two articles Gouaux had published in today’s edition of Nature. The other article also dealt with a modified amino acid transporter that mimics the mammalian neurotransmitter transporter proteins targeted by antidepressants. It gives new insights into the pharmacology of four different classes of widely used antidepressants that act on certain transporter proteins, including transporters for dopamine, serotonin and noradrenaline. The second paper in part was validated by findings of the first paper — in how an antidepressant bound itself to a specific transporter.

"What we ended up finding with this research was complementary and mutually reinforcing with the other work — so that was really important," Gouaux said. "And it told us a great deal about how these transporters work and how they interact with the antidepressant molecules."

(Source: ohsu.edu)