Posts tagged neuron

People with degenerative neurological conditions could benefit from research that shows why their brain cells stop communicating properly.

Scientists believe that the findings could help to develop treatments that slow the progress of a broad range of brain disorders such as Huntington’s, Alzheimer’s and Parkinson’s diseases.

The team at the University, led by Professor Tom Gillingwater, analysed how connection points between brain cells break down during disease and identified six proteins that control the process.

Sending Signals

When connection points in the brain, known as synapses, stop working - because of injury or disease - the chain of brain signalling breaks down and cannot be repaired.

The research from The Roslin Institute and Centre for Integrative Physiology at the University will help scientists identify drugs that target these proteins.

This could eventually enable clinicians to slow the progress of these disorders.

This study has identified key proteins that may control what goes wrong in a range of brain disorders. We now hope to identify drugs that prevent the breakdown of communication between brain cells and, as a result, halt the progress of these devastating neurodegenerative conditions. — Dr Thomas Wishart Career Track Fellow, The Roslin Institute at the University

(Source: ed.ac.uk)

Millions of Americans take antidepressants such as Prozac, Effexor, and Paxil, but the explanations for how they work never satisfied René Hen, a professor of psychiatry, neuroscience and pharmacology.

So the French-born researcher began a series of experiments a decade ago that are now helping to overturn conventional wisdom about the class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) and providing new insights into the biological mechanisms in the brain that affect mood and cognition.

Adult-born neurons in the hippocampus have been engineered to express channelrhodopsin (red), a protein that allows the activation of these neurons and the study of their impact on pattern separation and mood. (Image credit: Mazen Kheirbek and René Hen)

SSRIs, it has long been thought, work by inhibiting brain cells from reabsorbing serotonin, a signaling agent in the brain associated with positive mood. Yet unlike with psychoactive substances, the effects of the drugs take weeks to be felt—even though the increase in serotonin circulating in the brain begins almost immediately. Something more, Hen concluded, must be happening after that to create such a profound effect in depressed patients.

In 2003, Hen demonstrated an important finding in mice: The change in mood—measured by the amount of time it took the animals to overcome anxiety and feed in new environments—appeared to be due in part to the production of new brain cells in the hippocampus, an area of the brain associated with learning and memory. And those new brain cells, Hen thinks, are the result of growth-stimulating chemicals released in the brain, in response to the increased serotonin.

Last year, Hen published another groundbreaking study, suggesting how these new brain cells might affect mood. The new brain cells are located in the dentate gyrus, an area of the hippocampus involved in pattern separation, a cognitive process that helps us to recognize that something is new and different from similar experiences and stimuli. This information is then sent to other brain regions where the new stimulus is assigned a positive or negative emotional value.

Using genetic manipulations that block or enhance the production of brain cells in the dentate gyrus, Hen demonstrated that the new brain cells led to a marked improvement not just in the cognitive abilities of mice, but also in their mood. “What we think, even though it hasn’t been proven yet, is that some depressed human patients also have a problem with pattern separation,” Hen says. “What we are hoping is, if we can boost production of new neurons in their hippocampus, maybe we can improve pattern separation in patients and decrease general symptoms.”

Hen sees numerous ways that a disruption in pattern separation might lead to negative emotions such as anxiety and depression. The hippocampus is located next to, and is strongly linked with, another brain structure, the almond-shaped amygdala, thought to be the seat of our emotions.

If wrong judgments were assigned to novel stimuli in the amygdala, that could easily trigger the brain’s fight-or-flight instinct or, at the very least, produce fear. That might help explain features of anxiety disorders—why survivors of the 9/11 terrorist attacks suffering from post-traumatic stress disorder, for instance, might be hit with a panic attack whenever they see an airplane fly over a skyscraper, Hen says.

A deficit in pattern separation might also help explain why depressed patients often are unable to experience pleasure, exhibit a lack of interest in novel experiences, and feel profound malaise. Perhaps they are simply unable to register an experience as novel or pleasurable because they are unable to recognize it as sufficiently different from prior experiences.

Hen is quick to point out that new brain cell production in the hippocampus is just one effect of a cascade of neurochemical changes unleashed by SSRIs. Other researchers have demonstrated, among other things, that the drugs also have a strong impact on the prefrontal cortex, the area of the brain associated with executive functions such as decision-making and restraint.

Even so, Hen hopes his findings will have significant implications for some depressed patients—and perhaps even reveal why certain antidepressants work for some people and not others. Over the next several years, he plans to explore his hypotheses further by evaluating the pattern-separation abilities of depressed patients before and after they are treated with SSRIs.

“There is still a long way to go, but we are at least starting to provide a theoretical framework,” Hen says. “With complex disorders such as anxiety and depression, you are dealing with many parts of the brain. We think we have identified the biological basis for one of the symptoms present in a subgroup of patients, and maybe by targeting it, we will be able to help them.”

(Source: news.columbia.edu)

A new oral medication to treat patients in the early stages of multiple sclerosis has shown considerable promise in two clinical trials, researchers announced on Wednesday.

The medication is on track to become just the third oral drug available to M.S. patients, and potentially the safest and most effective, experts said. The second oral drug, called Aubagio, was approved just last week.

M.S. was virtually untreatable only two decades ago, but today nine “disease modifying” drugs are available for early-stage patients; a half-dozen more are in the late stages of development. Most patients in the early stage of the disease, a form called relapsing-remitting M.S., take drugs by injection.

The two new studies, published online in The New England Journal of Medicine, found that the drug BG-12, developed by Biogen Idec, reduced relapse rates in patients with relapsing M.S. by about 50 percent. The drug also significantly reduced the frequency of new brain lesions often associated with these attacks, and slowed the progression of disease compared with a placebo.

The studies were Phase 3 trials, a last step on the road to drug approval. The Food and Drug Administration is required to make a decision about the drug’s approval before the end of this year.

“This drug is clearly quite effective in managing disease and reducing disability, and the safety profile looks quite good,” said Timothy Coetzee, the chief research officer at the National Multiple Sclerosis Society, who was not involved in the studies.

Multiple sclerosis is often a progressive disease in which the immune system damages neurons in the brain and spinal cord. A majority of people with M.S. have relapsing-remitting M.S., characterized by flare-ups that cause lesions in the brain to develop and neurological symptoms to emerge or worsen. Eventually, more than half of patients develop a progressive form of M.S., leading to permanent disabilities.

Interferons, the drugs most commonly used in relapsing M.S., reduce relapses by about 30 percent, and have not been shown to slow the progression of the disease and disability. The newly approved Aubagio also reduces relapses by about 30 percent, and it has the advantage of being an oral drug.

Two drugs that are substantially more effective, Tysabri and Gilenya, come with serious risks including, in rare cases, death. They are used as second-line treatments when an initial approach fails, and patients require some monitoring.

In the new studies, called Define and Confirm, patients were randomized into two groups, taking 240 milligrams of BG-12 either twice or three times a day. Patients in a third group took a placebo. The combined results showed that the drug reduced the relapse rate by about 50 percent. There was minimal difference between the twice-daily and thrice-daily regimens.

Taking BG-12 twice a day reduced the number of new or newly enlarging brain lesions by 71 percent to 99 percent, depending on the type of lesion and the study. The Define study found a statistically significant 38 percent reduction in the progression to disability.

The most frequent side effects were a temporary flushing and warm feeling and gastrointestinal symptoms including nausea, diarrhea, cramping and vomiting. Though both types of side effects were common, they tended to diminish after the first few weeks of use and were tolerated by most patients.

BG-12 is an anti-inflammatory that works by protecting nerves against injury. It is a fumaric acid, very similar to one widely used in Germany for the treatment of psoriasis. “The safety track record is well known and appears to be very strong,” said Dr. Robert Fox, lead author of one of the two new studies and medical director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.

“It’s a bright day for M.S. patients, but there is a gray cloud in that we still don’t have anything for those with progressive M.S.,” he added.

Stress has long been pegged as the enemy of attention, disrupting focus and doing substantial damage to working memory — the short-term juggling of information that allows us to do all the little things that make us productive.

By watching individual neurons at work, a group of psychologists at the University of Wisconsin-Madison has revealed just how stress can addle the mind, as well as how neurons in the brain’s prefrontal cortex help “remember” information in the first place.

Working memory is short-term and flexible, allowing the brain to hold a large amount of information close at hand to perform complex tasks. Without it, you would have forgotten the first half of this sentence while reading the second half. The prefrontal cortex is vital to working memory.

"In many respects, you’d look pretty normal without a prefrontal cortex," said Craig Berridge, UW-Madison psychology professor. "You don’t need that part of the brain to hear or talk, to keep long-term memories, or to remember what you did as a child or what you read in the newspaper three days ago."

But without your prefrontal cortex you’d be unable to stay on task or modulate your emotions well.

"People without a prefrontal cortex are very distractible," Berridge said. "They’re very impulsive. They can be very argumentative."

The neurons of the prefrontal cortex help store information for short periods. Like a chalkboard, these neurons can be written with information, erased when that information is no longer needed, and rewritten with something new.

It’s how the neurons maintain access to that short-term information that leaves them vulnerable to stress. David Devilbiss, a scientist working with Berridge and lead author on a study published today in the journal PLOS Computational Biology, applied a new statistical modeling approach to show that rat prefrontal neurons were firing and re-firing to keep recently stored information fresh.

"Even though these neurons communicate on a scale of every thousandth of a second, they know what they did one second to one-and-a-half seconds ago," Devilbiss said. "But if the neuron doesn’t stimulate itself again within a little more than a second, it’s lost that information."

Apply some stress — in the researchers’ case, a loud blast of white noise in the presence of rats working on a maze designed to test working memory — and many neurons are distracted from reminding themselves of … what was it we were doing again?

"We’re simultaneously watching dozens of individual neurons firing in the rats’ brains, and under stress those neurons get even more active," said Devilbiss, whose work was supported by the National Science Foundation and National Institutes of Health. "But what they’re doing is not retaining information important to completing the maze. They’re reacting to other things, less useful things."

Without the roar of white noise, which has been shown to impair rats in the same way it does monkeys and humans, the maze-runners were reaching their goal about 90 percent of the time. Under stress, the animals completed the test at a 65 percent clip, with many struggling enough to fall to blind chance.

Recordings of the electrical activity of prefrontal cortex neurons in the maze-running rats showed these neurons were unable to hold information key to finding the next chocolate chip reward. Instead, the neurons were frenetic, reacting to distractions such as noises and smells in the room.

The effects of stress-related distraction are well-known and dangerous.

"The literature tells us that stress plays a role in more than half of all workplace accidents, and a lot of people have to work under what we would consider a great deal of stress," Devilbiss said. "Air traffic controllers need to concentrate and focus with a lot riding on their actions. People in the military have to carry out these thought processes in conditions that would be very distracting, and now we know that this distraction is happening at the level of individual cells in the brain."

The researchers’ work may suggest new directions for treatment of prefrontal cortex dysfunction.

"Based on drug studies, it had been believed stress simply suppressed prefrontal cortex activity," Berridge said. "These studies demonstrate that rather than suppressing activity, stress modifies the nature of that activity. Treatments that keep neurons on their self-stimulating task while shutting out distractions may help protect working memory."

(Source: news.wisc.edu)

Looking at a tangled mass of network cables plugged into a crowded router doesn’t yield much insight into the network traffic that runs through the hardware.

Similarly, Lynn H. Matthias Professor of Electrical and Computer Engineering Barry Van Veen says that looking at the three pounds of interwoven neurons that make up the hardware of the human brain doesn’t give the complete picture of the brain activity that supports human cognition and consciousness.

Working with multiple collaborators, Van Veen has applied signal analysis techniques to the electric or magnetic fields measured noninvasively at the scalp through electroencephalography (EEG) or magnetoencephalography (MEG) to develop methods for identifying network models of brain function — essentially, traffic patterns of neural activity present in the human brain.

"It’s analogous to coming up with a new microscope," says Van Veen.

Having a reliable traffic map of normal brain function provides a baseline for comparison for understanding how different disorders, substances and devices affect the brain. “Now that we’ve got the tool ready, the opportunities to try it out on scientifically interesting questions are really blossoming,” says Van Veen.

For instance, network models may provide a better blueprint for how medical devices can interface with the brain. Van Veen recently began working with biomedical engineering Associate Professor Justin Williams to apply his work toward making better brain-machine interfaces.

But the implications of network models go beyond engineering questions. The effect of alcohol on the brain just begs for network analysis, according to Van Veen. The network model could allow researchers to see precisely which parts of the brain are altered by alcohol consumption. It could provide insight into how short-term memory works, help explain the effects of schizophrenia and monitor treatment, help measure the depth and effectiveness of different types of anesthesia, and even help give insight into the brain activity that precedes — or prevents — a miraculous recovery from a coma.

"We’re developing this tool as a significant improvement over what people have had access to before," says Van Veen. "The possibilities for using it to study different aspects of brain function are nearly unlimited."

(Source: news.wisc.edu)