Posts tagged neuroscience
Articles and news from the latest research reports.
Study paves way to design drugs aimed at multiple protein targets at once
An international research collaboration led by scientists at the University of North Carolina School of Medicine and the University of Dundee, in the U.K., have developed a way to efficiently and effectively make designer drugs that hit multiple protein targets at once.
This accomplishment, described in the Dec. 13, 2012 issue of the journal Nature, may prove invaluable for developing drugs to treat many common human diseases such as diabetes, high blood pressure, obesity, cancer, schizophrenia, and bi-polar disorder.
These disorders are called complex diseases because each have a number of genetic and non-genetic influences that determine susceptibility, i.e., whether someone will get the disease or not.
“In terms of the genetics of schizophrenia we know there are likely hundreds of different genes that can influence the risk for disease and, because of that, there’s likely no single gene and no one drug target that will be useful for treating it, like other common complex diseases,” said study co-leader, Brian L. Roth, MD, PhD, Michael J. Hooker Distinguished Professor of Pharmacology in the UNC School of Medicine, professor in the Division of Chemical Biology and Medicinal Chemistry in the UNC Eshelman School of Pharmacy, and director of the National Institute of Mental Health Psychoactive Drug Screening Program.
In complex neuropsychiatric conditions, infectious diseases and cancer, Roth points out that for the past 20 years drug design has been selectively aimed at a single molecular target, but because these are complex diseases, the drugs are often ineffective and thus many never reach the market.
Moreover, a drug that acts on a single targeted protein may interact with many other proteins. These undesired interactions frequently cause toxicity and adverse effects. “And so the realization has been that perhaps one way forward is to make drugs that hit collections of drug targets simultaneously. This paper provides a way to do that,” Roth said.
The new way involves automated drug design by computer that takes advantage of large databases of drug-target interactions. The latter have been made public through Roth’s lab at UNC and through other resources.
Experimental Agent Briefly Eases Depression Rapidly in Test
A drug that works through the same brain mechanism as the fast-acting antidepressant ketamine briefly improved treatment-resistant patients’ depression symptoms in minutes, with minimal untoward side effects, in a clinical trial conducted by the National Institutes of Health. The experimental agent, called AZD6765, acts through the brain’s glutamate chemical messenger system.
Existing antidepressants available through prescription, which work through the brain’s serotonin system, take a few weeks to work, imperiling severely depressed patients, who can be at high risk for suicide. Ketamine also works in hours, but its usefulness is limited by its potential for dissociative side-effects, including hallucinations. It is being studied mostly for clues to how it works.
“Our findings serve as a proof of concept that we can tap into an important component of the glutamate pathway to develop a new generation of safe, rapid-acting practical treatments for depression,” said Carlos Zarate, M.D., of the NIH’s National Institute of Mental Health, which conducted the research.
Zarate, and colleagues, reported on their results online Dec. 1, 2012 in the journal Biological Psychiatry.
AZD6765, like ketamine, works by blocking glutamate binding to a protein on the surface of neurons, called the NMDA receptor. It is a less powerful blocker of the NMDA receptor, which may be a reason why it is better tolerated than ketamine.
About 32 percent of 22 treatment-resistant depressed patients infused with ASD6765 showed a clinically meaningful antidepressant response at 80 minutes after infusion that lasted for about half an hour – with residual antidepressant effects lasting two days for some. By contrast, 52 percent of patients receiving ketamine show a comparable response, with effects still detectable at seven days. So a single infusion of ketamine produces more robust and sustained improvement, but most patients continue to experience some symptoms with both drugs.
However, depression rating scores were significantly better among patients who received AZD6765 than in those who received placebos. The researchers deemed this noteworthy, since, on average, these patients had failed to improve in seven past antidepressant trials, and nearly half failed to respond to electroconvulsive therapy (ECT).
The patients reported only minor side effects, such as dizziness and nausea, which were not significantly different from those experienced with the placebo.
Zarate and colleagues say their results warrant further trials with AZD6765, testing whether repeated infusions a few times per week or higher doses might produce longer-lasting results.
(Source: nimh.nih.gov)
Japanese researchers build robot with most humanlike muscle-skeleton structure yet
Researchers at the University of Tokyo have taken another step towards creating a robot with a faithfully recreated human skeleton and muscle structure. Called Kenshiro, the robot has been demonstrated at the recent Humanoids 2012 conference in Osaka, Japan.
How Our Sense of Touch is a Lot Like the Way We Hear
Sliman Bensmaia, PhD, assistant professor of organismal biology and anatomy at the University of Chicago, studies the neural basis of tactile perception, or how our hands convey this information to the brain. In a new study published in the Journal of Neuroscience, he and his colleagues found that the timing and frequency of vibrations produced in the skin when you run your hands along a surface, like searching a wall for a light switch, play an important role in how we use our sense of touch to gather information about the objects and surfaces around us.
The sense of touch has traditionally been thought of in spatial terms, i.e. receptors in the skin are spread out across a grid of sorts, and when you touch something this grid of receptors transmits information about the surface to your brain. In their new study, Bensmaia, two former undergraduates, and a postdoctoral scholar in his lab—Matthew Best, Emily Mackevicius and Hannes Saal—found that the skin is also highly sensitive to vibrations, and that these vibrations produce corresponding oscillations in the afferents, or nerves, that carry information from the receptors to the brain. The precise timing and frequency of these neural responses convey specific messages about texture to the brain, much like the frequency of vibrations on the eardrum conveys information about sound.
Neurons communicate through electrical bits, similar to the digital ones and zeros used by computers. But, Bensmaia said, “One of the big questions in neuroscience is whether it’s just the number of bits that matters, or if the specific sequence of bits in time also plays a role. What we show in this paper is that the sequence of bits in time does matter, and in fact for some of the skin receptors, the timing matters with millisecond precision.”
Researchers have known for years that these afferents respond to skin vibrations, but they studied their responses using so-called sinusoidal waves, which are smooth, repetitive patterns. These perfectly uniform vibrations can be produced in a lab, but the kinds of vibrations produced in the skin by touching surfaces in the real world are messy and erratic.
AHRF Researcher Describes Cochlear Amplification Using Novel Optical Technique
It has long been known that the inner ear actively amplifies sounds it receives, and that this amplification can be attributed to forces generated by outer hair cells in the cochlea. How the ear actually accomplishes this, however, has remained somewhat of a mystery. Now, Jonathan A. N. Fisher, PhD, and colleagues at The Rockefeller University, in New York, describe how the cochlea actively self-amplifies sound it receives to help increase the range of sounds that can be heard.
Fisher and colleagues used a new optical technique that inactivates prestin, a motor protein involved in the movement of the outer hair cells. The outer hair cells are part of the hair cell bundles (which also include the inner hair cells)- the true sensory cells of the inner ear. The main body of the hair cells sits in the basilar membrane- the tissue that lines the interior of the bony cochlea. The “hair” part of these cells, called the stereocilia, sticks up into the fluid-filled space of the cochlea, where they are pushed by the fluid as sound waves travel through it.
The sound waves traveling down the cochlea produce actual waves that can be observed along the basilar membrane as visualized in the animation (from the Howard Hughes Medical Institute). The cochlea picks up different sound frequencies along its length, with higher frequency sounds picked up at center of the “snail” and the lower frequency sounds being picked up at the part of the cochlea closest to the eardrum.
The outer hair cells have been known to provide amplification of sound waves picked up by the inner hair cells by actively changing their shape to increase the amplitudes of the sound waves. These outer hair cells can do this because the membrane protein can contract and cause the stereocillia to be deflected by the overlying tectorial membrane.
Fisher and colleagues developed a light-sensitive drug that when illuminated by an ultraviolet laser can inactivate prestin in select locations within the cochlea. Using this novel technique, the researchers were able to affect prestin at very specific locations along the basilar membrane.
The researchers found that by inactivating prestin at very specific locations, the sound-evoked waves that carry mechanical signals to sensory hair cells were re-shaped and of smaller amplitude- indicating that without prestin, amplification is dampened compared to what the researchers saw when prestin was allowed to function normally.
Kentucky team inhibits Alzheimer’s biomarkers in animal model by targeting astrocytes
A research team composed of University of Kentucky researchers has published a paper which provides the first direct evidence that activated astrocytes could play a harmful role in Alzheimer’s disease. The UK Sanders-Brown Center on Aging has also received significant new National Institutes of Health (NIH) funding to further this line of study.
Chris Norris, an associate professor in the UK College of Medicine Department of Molecular and Biomedical Pharmacology, as well as a member of the faculty at the UK Sanders-Brown Center on Aging, is the senior author on a paper published recently in the Journal of Neuroscience, entitled “Targeting astrocytes to ameliorate neurologic changes in a mouse model of Alzheimer’s disease.” The first author on the article, Jennifer L. Furman, was a graduate student in the Norris laboratory during completion of the study.
The astrocyte is a very abundant non-neuronal cell type that performs absolutely critical functions for maintaining healthy nervous tissue. However, in neurodegenerative diseases, like Alzheimer’s disease, many astrocytes exhibit clear physical changes often referred to as “astrocyte activation.” The appearance of activated astrocytes at very early stages of Alzheimer’s has led to the idea that astrocytes contribute to the emergence and/or maintenance of other pathological markers of the disease, including synaptic dysfunction, neuroinflammation and accumulation of amyloid plaques.
Using an animal model, researchers directly modulated the activation state of hippocampal astrocytes using a form of gene therapy.
Mice received the gene therapy at a very young age, before the development of extensive amyloid plaque pathology, and were assessed 10 months later on a variety of Alzheimer’s biomarkers.
The research team found that inhibition of astrocyte activation blunted the activation of microglia (a cell that mediates neuroinflammation), reduced toxic amyloid levels, improved synaptic function and plasticity, and preserved cognitive function.
Norris and collaborators suggest that similar astrocyte-based approaches could be developed to treat humans suffering from Alzheimer’s disease, or possibly other neurodegenerative diseases. This study provides proof of principle that therapeutically targeting astrocytes can be beneficial.
(Source: eurekalert.org)
UAlberta medical researchers make key discovery in fight against Alzheimer’s disease
Medical researchers at the University of Alberta have discovered a drug intended for diabetes appears to restore memory in Alzheimer’s brain cells.
Jack Jhamandas, a researcher with the Faculty of Medicine & Dentistry at the U of A, is the principal investigator with the team whose research results were recently published in the peer-reviewed publication The Journal of Neuroscience. He works in the Division of Neurology.
The team took brain tissue from animal models with Alzheimer’s disease and tested the tissue in the lab, looking specifically at the cells’ memory capacity. When brain cells are shocked by a barrage of electrical impulses, the cells “remember” the experience and this is a typical way to test or measure memory in the lab setting.
Amyloid protein, which is found in abnormally large amounts in the memory and cognition parts of the brains of Alzheimer’s patients, diminishes memory. A sister protein, known as amylin, which comes from the pancreas of diabetic patients, has the same impact on memory cells.Jhamandas and his team demonstrated last year that a diabetes drug that never made it to market, known as AC253, could block the toxic effects of amyloid protein that lead to brain cell death.
In the lab, Jhamandas and his teammates, which included Ryoichi Kimura, a visiting scientist from Japan, tested the memory of normal brain cells and those with Alzheimer’s—both from animal models. When the drug AC253 was given to brain cells with Alzheimer’s and the shock memory tests were redone, memory was restored to levels similar to those in normal cells.
“This is very important because it tells us that drugs like this might be able to restore memory, even after Alzheimer’s disease may have set in,” says Jhamandas.
Does the Brain Become Unglued in Autism?
A new study published in Biological Psychiatry suggests that autism is associated with reductions in the level of cellular adhesion molecules in the blood, where they play a role in immune function.
Cell adhesion molecules are the glue that binds cells together in the body. Deficits in adhesion molecules would be expected to compromise processes at the interfaces between cells, influencing tissue integrity and cell-to-cell signaling. In the brain, deficits in adhesion molecules could compromise brain development and communication between nerve cells.
Over the years, deficits in neural cell adhesion molecules have been implicated in schizophrenia and other psychiatric disorders. One adhesion molecule, neurexin, is strongly implicated in the heritable risk for autism.
Cell adhesion molecules also play a crucial role in regulating immune cell access to the central nervous system. Prior research provided evidence of immune system dysfunction in individuals diagnosed with autism spectrum disorder (ASD). This led scientists from the University of California, Davis to examine whether adhesion molecules are altered in children with ASD.
"For the first time, we show that levels of soluble sPECAM-1 and sP-selectin, two molecules that mediate leukocyte migration, are significantly decreased in young children with ASD compared with typically developing controls of the same age," explained the authors. "This finding is consistent with previous reports of decreased levels of both sPECAM-1 and sP-selectin in adults with high-functioning autism."
They also found that repetitive behavior scores and sPECAM-1 levels were associated in children with ASD. Repetitive, stereotyped behaviors are a typical feature of ASD and these data suggest a potential relationship between molecule levels and the severity of repetitive behaviors.
Finally, they also discovered that head circumference was associated with increased sPECAM-1 levels in the typically developing children, but not in the children with ASD. This indicates that perhaps sPECAM-1 plays a role in normal brain growth, as larger head circumference is a known feature of individuals with autism.
(Image courtesy of Cord Blood Registry)
The image of mental fatigue
Functional magnetic resonance imaging offers insights into mental fatigue
We all perhaps know the feeling of mental exhaustion, but what does it mean physiologically to have mental fatigue? A new study carried out using brain scans could help scientists uncover the neurobiological mechanisms underlying mental fatigue.
According to Bui Ha Duc and Xiaoping Li of the National University of Singapore writing in a forthcoming issue of the International Journal Computer Applications in Technology, mental fatigue has become commonplace as many people face increasing mental demands from stressful jobs, longer working hours with less time to relax and increasingly suffer sleep problems. Mental fatigue has received attention from those involved generally in health and well being as well as from the military and transport industry. After all, mental fatigue not only affects the health of individuals but can also have implications for road safety and international security.
The researchers used functional magnetic resonance imaging (fMRI) to monitor activity in the brains of ten student volunteers (male and female aged 19 to 25 years) deprived of sleep for 25 hours and given a simple task repeatedly through that period. They carried out scans at 9am, 2pm, 3am, 9am the following day. All volunteers had to have avoided alcohol and caffeine for the 24 hours prior to the experiment, were all physically and mentally fit prior to participation and none had any sleep problems.
The activation of the left thalamus increases with sleep deprivation, going in an exactly opposite trend to the inferior parietal that (following the circadian rhythm) decreases in activation from 9 am to 3 am next day and then increases in activation. This finding fits with logic as the inferior parietal cortex integrates information from different sensory modalities. As all the information has to go through the thalamus and then is sent by the thalamus to the inferior parietal, when the inferior parietal decreases in activation, the thalamus must increase its activation to get the information sent through.
The team explains that a gradual increase in mental fatigue led to decreased activity in the volunteers’ brains in specific regions: the anterior cingulate gyrus, right inferior frontal, left middle frontal and right superior temporal cortex. The anterior cingulate cortex has been described as an interface between motivation, cognition and action, and has been implicated in using reinforcement information to control behavior. The fMRI scans suggest that decreased activity in this part of the brain is therefore linked to those familiar feelings of mental fatigue including lethargy and slowness of thinking.
"The research provides a neurophysiologic basis for measuring the level of mental fatigue by EEG, as well as for the intervention by non-invasive neural stimulation to maintain wakefulness," the team says. "We have developed devices for both, which will be commercialized by our spinoff company, Newrocare Pte Ltd."
(Source: eurekalert.org)
Researcher Finds Gender Differences In Seasonal Auditory Changes
Auditory systems differ between sexes in sparrows depending on the season, a Georgia State University neuroscientist has found. The work adds to our knowledge of how the parts of the nervous system, including that of humans, are able to change.
Megan Gall, a post-doctoral researcher with Georgia State’s Neuroscience Institute, tested the peripheral auditory systems of male and female house sparrows, comparing the hearing of each gender during non-breeding seasons and breeding seasons.
Gall measured frequency selectivity – the ability to tell sounds that are close in frequency apart, and temporal resolution, the ability to tell sounds apart that are very close together in time.
“We found that males have the same frequency selectivity and temporal resolution across breeding seasons,” Gall said. “In the fall, males and females aren’t different. But in the breeding season, females had better frequency selectivity, but this came at the expense of worse temporal resolution.”
The study was published in the Proceedings of The Royal Society B, a British scientific journal.
The difference shows “plasticity,” the ability to change, she said. Plasticity is an important concept in neuroscience, as scientists have increasingly been able to show that neurological systems have the ability to change.
Gall said the work shows, for the first time, that there’s seasonal plasticity in these properties in the periphery of the auditory system, the ear and the auditory nerve, not just inside the parts of the brain that control auditory function.
Similar changes happen in humans, she said. Women show different auditory sensitivities during the course of a menstrual cycle. “I always like to say that if your husband says he can’t hear you, it may be that he can’t. His auditory system is different than yours,” Gall said.
The changes might have evolved over time for different reasons, she said, with one reason being that it is harder for the body to maintain a certain kind of tissues involved in hearing.