Posts tagged neuroscience

A new study in Biological Psychiatry explores the influence of oxytocin

Difficulty in registering and responding to the facial expressions of other people is a hallmark of autism spectrum disorder (ASD). Relatedly, functional imaging studies have shown that individuals with ASD display altered brain activations when processing facial images.

The hormone oxytocin plays a vital role in the social interactions of both animals and humans. In fact, multiple studies conducted with healthy volunteers have provided evidence for beneficial effects of oxytocin in terms of increased trust, improved emotion recognition, and preference for social stimuli.

This combination of scientific work led German researchers to hypothesize about the influence of oxytocin in ASD. Dr. Gregor Domes, from the University of Freiburg and first author of the new study, explained: “In the present study, we were interested in the question of whether a single dose of oxytocin would change brain responses to social compared to non-social stimuli in individuals with autism spectrum disorder.”

They found that oxytocin did show an effect on social processing in the individuals with ASD, “suggesting that oxytocin may help to treat a basic brain function that goes awry in autism spectrum disorders,” commented Dr. John Krystal, Editor of Biological Psychiatry.

To conduct this study, they recruited fourteen individuals with ASD and fourteen control volunteers, all of whom completed a face- and house-matching task while undergoing imaging scans. Each participant completed this task and scanning procedure twice, once after receiving a nasal spray containing oxytocin and once after receiving a nasal spray containing placebo. The order of the sprays was randomized, and the tests were administered one week apart.

Using two sets of stimuli in the matching task, one of faces and one of houses, allowed the researchers to not only compare the effects of the oxytocin and placebo administrations, but also allowed them to discriminate findings between specific effects to only social stimuli and non-specific effects to more general brain processing.

What they found was intriguing. The data indicate that oxytocin specifically increases responses of the amygdala to social stimuli in individuals with ASD. The amygdala, the authors explain, “has been associated with processing of emotional stimuli, threat-related stimuli, face processing, and vigilance for salient stimuli”.

This finding suggests oxytocin might promote the salience of social stimuli in ASD. Increased salience of social stimuli might support behavioral training of social skills in ASD.

These data support the idea that oxytocin may be a promising approach in the treatment of ASD and could stimulate further research, even clinical trials, on the exploration of oxytocin as an add-on treatment for individuals with autism spectrum disorder.

(Source: alphagalileo.org)

The cells in our bodies can divide as often as once every 24 hours, creating a new, identical copy. DNA binding proteins called transcription factors are required for maintaining cell identity. They ensure that daughter cells have the same function as their mother cell, so that for example muscle cells can contract or pancreatic cells can produce insulin. However, each time a cell divides the specific binding pattern of the transcription factors is erased and has to be restored in both mother and daughter cells. Previously it was unknown how this process works, but now scientists at Karolinska Institutet have discovered the importance of particular protein rings encircling the DNA and how these function as the cell’s memory.

The DNA in human cells is translated into a multitude of proteins required for a cell to function. When, where and how proteins are expressed is determined by regulatory DNA sequences and a group of proteins, known as transcription factors, that bind to these DNA sequences. Each cell type can be distinguished based on its transcription factors, and a cell can in certain cases be directly converted from one type to another, simply by changing the expression of one or more transcription factors. It is critical that the pattern of transcription factor binding in the genome be maintained. During each cell division, the transcription factors are removed from DNA and must find their way back to the right spot after the cell has divided. Despite many years of intense research, no general mechanism has been discovered which would explain how this is achieved.

"The problem is that there is so much DNA in a cell that it would be impossible for the transcription factors to find their way back within a reasonable time frame. But now we have found a possible mechanism for how this cellular memory works, and how it helps the cell remember the order that existed before the cell divided, helping the transcription factors find their correct places", explains Jussi Taipale, professor at Karolinska Institutet and the University of Helsinki, and head of the research team behind the discovery.

The results are now being published in the scientific journal Cell. The research group has produced the most complete map yet of transcription factors in a cell. They found that a large protein complex called cohesin is positioned as a ring around the two DNA strands that are formed when a cell divides, marking virtually all the places on the DNA where transcription factors were bound. Cohesin encircles the DNA strand as a ring does around a piece of string, and the protein complexes that replicate DNA can pass through the ring without displacing it. Since the two new DNA strands are caught in the ring, only one cohesin is needed to mark the two, thereby helping the transcription factors to find their original binding region on both DNA strands.

"More research is needed before we can be sure, but so far all experiments support our model," says Martin Enge, assistant professor at Karolinska Institutet.

Transcription factors play a pivotal role in many illnesses, including cancer as well as many hereditary diseases. The discovery that virtually all regulatory DNA sequences bind to cohesin may also end up having more direct consequences for patients with cancer or hereditary diseases. Cohesin would function as an indicator of which DNA sequences might contain disease-causing mutations.

"Currently we analyse DNA sequences that are directly located in genes, which constitute about three per cent of the genome. However, most mutations that have been shown to cause cancer are located outside of genes. We cannot analyse these in a reliable manner - the genome is simply too large. By only analysing DNA sequences that bind to cohesin, roughly one per cent of the genome, it would allow us to analyse an individual’s mutations and make it much easier to conduct studies to identify novel harmful mutations," Martin Enge concludes.

(Source: ki.se)

The human body is a complicated system of blood vessels, nerves, organs, tissue and cells each with a specific job to do. When all are working together, it’s a symphony of form and function as each instrument plays its intended roles.

Biologist Rejji Kuruvilla and her fellow researchers uncovered what happens when one instrument is not playing its part.

Kuruvilla along with graduate students Philip Borden and Jessica Houtz, both from the Biology Department at Johns Hopkins University’s Krieger School of Arts and Sciences, and Dr. Steven Leach from the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins School of Medicine, recently published a paper in the journal Cell Reports exploring whether “cross-talk” or reciprocal signaling, takes place between the neurons in the sympathetic nervous system and the tissues that the nerves connect to. In this case the targeted tissue called islets, were in the pancreas.

“We knew that sympathetic neurons need molecular signals from the tissues that they connect with, to grow and survive,” said Kuruvilla. “What we did not know was whether the neurons would reciprocally signal to the target tissues to instruct them to grow and mature. It made sense to focus on the pancreas because of previous studies done in diabetic animal models where sympathetic nerves within the pancreas were found to retract early on in the disease, suggesting that dysfunction of the nerves could be an early trigger for pancreatic defects.”

The researchers spent approximately three years working with lab mice to test the various scenarios in which signaling between sympathetic neurons and islet cells might take place. The experiments focused on what effects removing the sympathetic nerves would have on pancreas development in newborn mice.

Previous studies had shown that pancreatic cells release a signal of their own, a nerve growth protein, that directs the sympathetic nerves toward the pancreas and provides necessary nutrition to sustain the nerves.

In turn, Kuruvilla’s team found that in mutant mice, the removal of the sympathetic neurons resulted in deformities in the architecture of the pancreatic islet cells and defects in insulin secretion and glucose metabolism.

Pancreatic islets are highly organized functional micro-organs with a defined size, shape and distinctive arrangement of endocrine cells. It’s this marriage of form and function that result in cells clustered close together, that creates greater, more efficient islet cell function.

However, the mutant mice, with their sympathetic neurons removed, had islet formations that were misshapen, sported lesions and developed in a patchy, uneven manner. Because of their dysfunctional islet cell development, postnatal mice did not secrete enough insulin when confronted with high glucose, and had high blood glucose levels as a result. Increased levels of blood glucose in humans is a hallmark of diabetes.

It’s known in neuroscience that the neurons in question from the sympathetic nervous system control the body’s “flight or fight” response and communicate with connected tissues by releasing a chemical messenger called norepinephrine. The release of norepinephrine also plays an important role in the development and maturation of islets, said Kuruvilla.

Using sympathetic neurons and islet cells grown together in a culture dish, the researchers observed that islet cells move toward the nerves and identified norepinephrine as the nerve signal that causes the movement of the islet cells.

“Seeing how these islet cells were responding to sympathetic neurons both in a dish and the effects of removing the nerves in a whole animal on islet shape and functions were pretty remarkable,” said Borden, lead author of the paper. “It was clear to us that sympathetic neurons were key to how islets were developing, something no one else had shown.”

Kuruvilla said these studies, identifying sympathetic nerves as a critical player in organizing pancreatic cells during development and influencing their later function, could add to a better understanding of treating diabetes in the future. The research also lends support to the value in considering the importance of external factors such as nerves and blood vessels when transplanting islet cells for the treatment of diabetes in patients.

“This study reveals interactions between two co-developing systems, sympathetic neurons and pancreatic islet cells, that has important implications for peripheral organ development, and for regeneration of these tissues following injury or disease,” said Kuruvilla.

(Source: releases.jhu.edu)

New research at Rutgers University may help shed light on how and why nervous system changes occur and what causes some people to suffer from life-threatening anxiety disorders while others are better able to cope.

Maureen Barr, a professor in the Department of Genetics, and a team of researchers, found that the architectural structure of the six sensory brain cells in the roundworm, responsible for receiving information, undergo major changes and become much more elaborate when the worm is put into a high stress environment.

Scientists have known for some time that changes in the tree-like dendrite structures that connect neurons in the human brain and enable our thought processes to work properly can occur under extreme stress, alter brain cell development and result in anxiety disorders like depression and Post Traumatic Stress Disorder affecting millions of Americans each year.

What scientists don’t understand for sure, Barr says, is the cause behind these molecular changes in the brain.

“This type of research provides us necessary clues that ultimately could lead to the development of drugs to help those suffering with severe anxiety disorders,” Barr says.

In the study published today in Current Biology, scientists at Rutgers have identified six sensory nerve cells in the tiny, transparent roundworm, known as the C. elegans and an enzyme called KPC-1/furin which triggers a chemical reaction in humans that is needed for essential life functions like blood-clotting. 

While the enzyme also appears to play a role in the growth of tumors and the activation of several types of virus and diseases in humans, in the roundworm the enzyme enables its simple neurons to morph into new elaborately branched shapes when placed under adverse conditions.

Normally, this one-millimeter long worm develops from an embryo through four larval stages before molting into a reproductive adult. Put it under stressful conditions of overcrowding, starvation and high temperature and the worm transforms into an alternative larval stage known as the dauer that becomes so stress-resistant it can survive almost anything – including the Space Shuttle Columbia disaster in 2003 of which they were the only living things to survive.  

“These worms that normally have a short life cycle turn into super worms when they go into the dauer stage and can live for months, although they are no longer able to reproduce,” Barr says.

What is so interesting to Barr is that when a perceived threat is over, these tiny creatures and their IL2 neurons transform back to a normal lifespan and reproductive state like nothing had ever happened. Under a microscope, the complicated looking tree-like connectors that receive information are pruned back and the worm appears as it did before the trauma occurred.

This type of neural reaction differs in humans who can suffer from extreme anxiety months or even years after the traumatic event even though they are no longer in a threatening situation.   

The ultimate goal, Barr says, is to determine how and why the nervous system responds to stress. By identifying molecular pathways that regulate neuronal remodeling, scientists may apply this knowledge to develop future therapeutics.

(Source: news.rutgers.edu)

When something gets in the way of our ability to see, we quickly pick up a new way to look, in much the same way that we would learn to ride a bike, according to a new study published in the Cell Press journal Current Biology on August 15.

Our eyes are constantly on the move, darting this way and that four to five times per second. Now researchers have found that the precise manner of those eye movements can change within a matter of hours. This discovery by researchers from the University of Southern California might suggest a way to help those with macular degeneration better cope with vision loss.

"The system that controls how the eyes move is far more malleable than the literature has suggested," says Bosco Tjan of the University of Southern California. "We showed that people with normal vision can quickly adjust to a temporary occlusion of their foveal vision by adapting a consistent point in their peripheral vision as their new point of gaze."

The fovea refers to the small, center-most portion of the retina, which is responsible for our high-resolution vision. We move our eyes to direct the fovea to different parts of a scene, constructing a picture of the world around us. In those with age-related macular degeneration, progressive loss of foveal vision leads to visual impairment and blindness.

In the new study, MiYoung Kwon, Anirvan Nandy, and Tjan simulated a loss of foveal vision in six normally sighted young adults by blocking part of a visual scene with a gray disc that followed the individuals’ eye gaze. Those individuals were then asked to complete demanding object-following and visual-search tasks. Within three hours of working on those tasks, people showed a remarkably fast and spontaneous adjustment of eye movements. Once developed, that change in their “point of gaze” was retained over a period of weeks and was reengaged whenever their foveal vision was blocked.

Tjan and his team say they were surprised by the rate of this adjustment. They note that patients with macular degeneration frequently do adapt their point of gaze, but in a process that takes months, not days or hours. They suggest that practice with a visible gray disc like the one used in the study might help speed that process of visual rehabilitation along. The discovery also reveals that the oculomotor (eye movement) system prefers control simplicity over optimality.

"Gaze control by the oculomotor system, although highly automatic, is malleable in the same sense that motor control of the limbs is malleable," Tjan says. "This finding is potentially very good news for people who lose their foveal vision due to macular diseases. It may be possible to create the right conditions for the oculomotor system to quickly adjust," Kwon adds.

(Source: eurekalert.org)

The active ingredient in an over-the-counter skin cream might do more than prevent wrinkles. Scientists have discovered that the drug, called kinetin, also slows or stops the effects of Parkinson’s disease on brain cells.

Scientists identified the link through biochemical and cellular studies, but the research team is now testing the drug in animal models of Parkinson’s. The research is published in the August 15, 2013 issue of the journal Cell.

“Kinetin is a great molecule to pursue because it’s already sold in drugstores as a topical anti-wrinkle cream,” says HHMI investigator Kevan Shokat of the University of California, San Francisco. “So it’s a drug we know has been in people and is safe.”

Parkinson’s disease is a degenerative disease that causes the death of neurons in the brain. Initially, the disease affects one’s movement and causes tremors, difficulty walking, and slurred speech. Later stages of the disease can cause dementia and broader health problems. In 2004, researchers studying an Italian family with a high prevalence of early-onset Parkinson’s disease discovered mutations in a protein called PINK1 associated with the inherited form of the disease.

Since then, studies have shown that PINK1 normally wedges into the membrane of damaged mitochondria inside cells that causes another protein, Parkin, to be recruited to the mitochondria, which are organelles responsible for energy generation. Neurons require high levels of energy production, therefore when mitochondrial damage occurs, it can lead to neuronal death. However, when Parkin is present on damaged mitochondria, studding the mitochondrial surface, the cell is able to survive the damage. In people who inherit mutations in PINK1, however, Parkin is never recruited to the organelles, leading to more frequent neuronal death than usual.

Shokat and his colleagues wanted to develop a way to turn on or crank up PINK1 activity, therefore preventing an excess of cell death, in those with inherited Parkinson’s disease. But turning on activity of a mutant enzyme is typically more difficult than blocking activity of an overactive version.

“When we started this project, we really thought that there would be no conceivable way to make something that directly turns on the enzyme,” says Shokat. “For any enzyme we know that causes a disease, we have ways to make inhibitors but no real ways to turn up activity.”

His team expected it would have to find a less direct way to mimic the activity of PINK1 and recruit Parkin. In the hopes of more fully understanding how PINK1 works, they began investigating how PINK1 binds to ATP, the energy molecule that normally turns it on. In one test, instead of adding ATP to the enzymes, they added different ATP analogues, versions of ATP with altered chemical groups that slightly change its shape. Scientists typically must engineer new versions of proteins to be able to accept these analogs, since they don’t fit into the typical ATP binding site. But to Shokat’s surprise, one of the analogs—kinetin triphosphate, or KTP—turned on the activity of not only normal PINK1, but also the mutated version, which doesn’t bind ATP.

“This drug does something that chemically we just never thought was possible,” says Shokat. “But it goes to show that if you find the right key for the right lock, you’ll be able to open the door.”

To test whether the binding of KTP to PINK1 led to the same consequences as the usual ATP binding, Shokat’s group measured the activity of PINK1 directly, as well as the downstream consequences of this activity, including the amount of Parkin recruited to the mitochondrial surface, and the levels of cell death. Adding the precursor of KTP, kinetin, to cells—both those with PINK1 mutations and those with normal physiology—amplified the activity of PINK1, increased the level of Parkin on damaged mitochondria, and decreased levels of neuron death, they found.

“What we have here is a case where the molecular target has been shown to be important to Parkinson’s in human genetic studies,” says Shokat. “And now we have a drug that specifically acts on this target and reverses the cellular causes of the disease.”

The similar results in cells with and without PINK1 mutations suggest that kinetin, which is a precursor to KTP, could be used to treat not only Parkinson’s patients with a known PINK1 mutation, but to slow progression of the disease in those without a family history by decreasing cell death.

Shokat is now performing experiments on the effects of kinetin in mice with various forms of Parkinson’s disease. However, the usefulness of animal models in Parkinson’s research has been debated, and therefore the positive results from the cellular data, he says, is as good an indicator as results in animals that this drug has potential to treat Parkinson’s in humans. Initial human studies will likely focus on the small population of patients with PINK1 mutations, and if successful in that group the drug could later be tested in a wider array of Parkinson’s patients.

(Source: hhmi.org)

There is no evidence that impaired blood flow or blockage in the veins of the neck or head is involved in multiple sclerosis, says a McMaster University study.

The research, published online by PLOS ONE Wednesday, found no evidence of abnormalities in the internal jugular or vertebral veins or in the deep cerebral veins of any of 100 patients with multiple sclerosis (MS) compared with 100 people who had no history of any neurological condition.

The study contradicts a controversial theory that says that MS, a chronic, neurodegenerative and inflammatory disease of the central nervous system, is associated with abnormalities in the drainage of venous blood from the brain. In 2008 Italian researcher Paolo Zamboni said that angioplasty, a blockage clearing procedure, would help MS patients with a condition he called chronic cerebrospinal venous insufficiency (CCSVI). This caused a flood of public response in Canada and elsewhere, with many concerned individuals lobbying for support of the ‘Liberation Treatment’ to clear the veins, as advocated by Zamboni.

“This is the first Canadian study to provide compelling evidence against the involvement of CCSVI in MS,” said principal investigator Ian Rodger, a professor emeritus of medicine in the Michael G. DeGroote School of Medicine. “Our findings bring a much needed perspective to the debate surrounding venous angioplasty for MS patients”.

In the study all participants received an ultrasound of deep cerebral veins and neck veins as well as a magnetic resonance imaging (MRI) of the neck veins and brain. Each participant had both examinations performed on the same day. The McMaster research team included a radiologist and two ultrasound technicians who had trained in the Zamboni technique at the Department of Vascular Surgery of the University of Ferrara.

(Source: dailynews.mcmaster.ca)