PTSD may be preventable by a drug

Researchers have found a drug that may be able to prevent PTSD.

Scientists at Yerkes National Primate Research Center, Emory University have identified a drug that appears to make memories of fearsome events less durable in mice.

The finding may accelerate the development of treatments for preventing PTSD (post-traumatic stress disorder). The drug, called osanetant, targets a distinct group of brain cells in a region of the brain that controls the formation and consolidation of fear memories.

The results were published in the journal Neuron.

"Potentially, drugs that act on this group of cells could be used to block fear memory consolidation shortly after exposure to a trauma, which would aid in preventing PTSD," says Kerry Ressler, MD, PhD, professor of psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center. "PTSD is unique among psychiatric disorders in that we know when it starts -- at the time of the trauma. Finding ways to prevent its development in the first place -- in the emergency department or the battlefield -- is an important and exciting avenue of research in this area."

The first author of the paper is postdoctoral fellow Raül Andero Galí, PhD. Ressler and Andero were sifting through a list of many genes that are activated in the brains of mice after they learn to become afraid of a sound, because the sound is paired with a mild electric shock. The researchers were probing for changes in the central amygdala, a region of the brain known to regulate fear learning.

Out of thousands of genes they examined, their "top gene" was Tachykinin 2 or Tac2. The Tac2 gene was turned on more strongly during fear learning in mice that were previously exposed to a model of traumatic stress.

"The Tac2 gene is robustly activated after fear learning and belongs to a pathway that can be specifically blocked with a drug," Ressler says. "It was interesting that Tac2 is highly expressed in one particular part of the amygdala, but with low or no expression in other brain areas related to the formation of fear memories. Also, we found that the cells that express Tac2 are distinct from those other investigators had previously identified as being involved in fear expression."

Tac2 is part of a family of messengers in the nervous system known as tachykinins. Drugs that block a product encoded by Tac2's relative, Tac1, are antiemetics, often prescribed when someone is receiving chemotherapy for cancer.

Osanetant, which blocks the action of Tac2, has been tested in previous clinical studies for schizophrenia and was safe but not effective in addressing that disorder. It has not been tested in humans for PTSD prevention.

"Osanetant is a safe and well-tolerated drug in humans and could be potentially used to prevent PTSD when given shortly after trauma, although more research is needed," Andero says.

Under the influence of osanetant, mice could still learn to become afraid of a sound paired with a shock, but the mice did not freeze as much in response to the sound a day later, even if the drug was given an hour after training.

"Our goal is to specifically impair emotional memories related to a traumatic event instead of all memories associated with it. Thus, the trauma and its circumstances are remembered but the consolidation of fear memories is impaired, which could decrease the likelihood of developing fear-related disorders," Andero says.

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Study claims toxins are eliminated by brain during sleep

A new study using mice showed that the brain clears out toxins from itself during sleep.

A good night's rest may literally clear the mind. Using mice, researchers showed for the first time that the space between brain cells may increase during sleep, allowing the brain to flush out toxins that build up during waking hours. These results suggest a new role for sleep in health and disease. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH.

"Sleep changes the cellular structure of the brain. It appears to be a completely different state," said Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center in New York, and a leader of the study.

For centuries, scientists and philosophers have wondered why people sleep and how it affects the brain. Only recently have scientists shown that sleep is important for storing memories. In this study, Dr. Nedergaard and her colleagues unexpectedly found that sleep may be also be the period when the brain cleanses itself of toxic molecules.

Their results, published in Science, show that during sleep a plumbing system called the glymphatic system may open, letting fluid flow rapidly through the brain. Dr. Nedergaard's lab recently discovered the glymphatic system helps control the flow of cerebrospinal fluid (CSF), a clear liquid surrounding the brain and spinal cord.

"It's as if Dr. Nedergaard and her colleagues have uncovered a network of hidden caves and these exciting results highlight the potential importance of the network in normal brain function," said Roderick Corriveau, Ph.D., a program director at NINDS.

Initially the researchers studied the system by injecting dye into the CSF of mice and watching it flow through their brains while simultaneously monitoring electrical brain activity. The dye flowed rapidly when the mice were unconscious, either asleep or anesthetized. In contrast, the dye barely flowed when the same mice were awake.

"We were surprised by how little flow there was into the brain when the mice were awake," said Dr. Nedergaard. "It suggested that the space between brain cells changed greatly between conscious and unconscious states."

To test this idea, the researchers used electrodes inserted into the brain to directly measure the space between brain cells. They found that the space inside the brains increased by 60 percent when the mice were asleep or anesthetized.

"These are some dramatic changes in extracellular space," said Charles Nicholson, Ph.D., a professor at New York University's Langone Medical Center and an expert in measuring the dynamics of brain fluid flow and how it influences nerve cell communication.

Certain brain cells, called glia, control flow through the glymphatic system by shrinking or swelling. Noradrenaline is an arousing hormone that is also known to control cell volume. Similar to using anesthesia, treating awake mice with drugs that block noradrenaline induced unconsciousness and increased brain fluid flow and the space between cells, further supporting the link between the glymphatic system and consciousness.

Previous studies suggest that toxic molecules involved in neurodegenerative disorders accumulate in the space between brain cells. In this study, the researchers tested whether the glymphatic system controls this by injecting mice with labeled beta-amyloid, a protein associated with Alzheimer's disease, and measuring how long it lasted in their brains when they were asleep or awake. Beta-amyloid disappeared faster in mice brains when the mice were asleep, suggesting sleep normally clears toxic molecules from the brain.

"These results may have broad implications for multiple neurological disorders," said Jim Koenig, Ph.D., a program director at NINDS. "This means the cells regulating the glymphatic system may be new targets for treating a range of disorders."

The results may also highlight the importance of sleep.

"We need sleep. It cleans up the brain," said Dr. Nedergaard.

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Brain cell production increases during sleep

A study shows that brain cell production is boosted during sleep which may help research on how brain repair occurs during sleep.

Sleep increases the reproduction of the cells that go on to form the insulating material on nerve cell projections in the brain and spinal cord known as myelin, according to an animal study published in the September 4 issue of The Journal of Neuroscience. The findings could one day lead scientists to new insights about sleep's role in brain repair and growth.

Scientists have known for years that many genes are turned on during sleep and off during periods of wakefulness. However, it was unclear how sleep affects specific cells types, such as oligodendrocytes, which make myelin in the healthy brain and in response to injury. Much like the insulation around an electrical wire, myelin allows electrical impulses to move rapidly from one cell to the next.

In the current study, Chiara Cirelli, MD, PhD, and colleagues at the University of Wisconsin, Madison, measured gene activity in oligodendrocytes from mice that slept or were forced to stay awake. The group found that genes promoting myelin formation were turned on during sleep. In contrast, the genes implicated in cell death and the cellular stress response were turned on when the animals stayed awake.

"These findings hint at how sleep or lack of sleep might repair or damage the brain," said Mehdi Tafti, PhD, who studies sleep at the University of Lausanne in Switzerland and was not involved with this study.

Additional analysis revealed that the reproduction of oligodendrocyte precursor cells (OPCs) -- cells that become oligodendrocytes -- doubles during sleep, particularly during rapid eye movement (REM), which is associated with dreaming.

"For a long time, sleep researchers focused on how the activity of nerve cells differs when animals are awake versus when they are asleep," Cirelli said. "Now it is clear that the way other supporting cells in the nervous system operate also changes significantly depending on whether the animal is asleep or awake."

Additionally, Cirelli speculated the findings suggest that extreme and/or chronic sleep loss could possibly aggravate some symptoms of multiple sclerosis (MS), a disease that damages myelin. Cirelli noted that future experiments may examine whether or not an association between sleep patterns and severity of MS symptoms exists.

This research was funded by the University of Wisconsin-Madison Department of Psychiatry.

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Study: Cause of Narcolepsy may have been discovered

Scientists believe that brain cells that produce histamine may be the key behind determining the cause of narcolepsy.

Scientists have found that an excess number of brain cells that produce the chemical histamine may play a key role in human narcolepsy - a disorder of the central nervous system characterised by uncontrollable periods of deep sleep.

Researchers at the University of California, Los Angeles Center for Sleep Research, in 2000, published findings showing that people suffering from narcolepsy had 90 per cent fewer neurons containing the neuropeptide hypocretin in their brains than healthy people.

Subsequent work by this group and others demonstrated that hypocretin is an arousing chemical that keeps us awake and elevates both mood and alertness; the death of hypocretin cells, the researchers said, helps explain the sleepiness of narcolepsy. But it has remained unclear what kills these cells.

Now, the same UCLA team has found that an excess of another brain cell type containing histamine may be the cause of the loss of hypocretin cells in human narcoleptics.

UCLA professor of psychiatry Jerome Siegel and colleagues reported in the journal Annals of Neurology that people with the disorder have nearly 65 per cent more brain cells containing the chemical histamine.

Their research suggests that this excess of histamine cells causes the loss of hypocretin cells in human narcoleptics.

Narcolepsy is a chronic neurological disorder caused by the brain`s inability to control sleep?wake cycles. It causes sudden bouts of sleep and is often accompanied by cataplexy, an abrupt loss of voluntary muscle tone that can cause a person to collapse.

For the study, researchers examined five narcoleptic brains and seven control brains from human cadavers. Prior to death, all the narcoleptics had been diagnosed by a sleep disorder center as having narcolepsy with cataplexy.

These brains were also compared with the brains of three narcoleptic mouse models and to the brains of narcoleptic dogs.

The researchers found that the humans with narcolepsy had an average of 64 per cent more histamine neurons. The team did not see an increased number of these cells in any of the animal models of narcolepsy.

"Humans and animals with narcolepsy share the same symptoms, but we did not see the histamine cell changes we saw in humans in the animal models we examined," said Siegel, senior author of the research.

"We know that narcolepsy in the animal models is caused by engineered genetic changes that block hypocretin function. However, in humans, we did not know why the hypocretin cells die. "Our current findings indicate that the increase of histamine cells that we see in human narcolepsy may cause the loss of hypocretin cells," he said. 

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Epilepsy in mouse cured by cell transplant

Researchers were able to control epilepsy and seizures in mice by transporting brain cells.

In an effort to put an end to the debilitating consequences of recurrent seizures and ineffective treatments for epilepsy patients, a cell transplant may be the key.

Researchers from the University of California San Francisco (UCSF) published a study on May 5 in Nature Neuroscience detailing a one-time medial ganglionic eminence (MGE) cell transplant that was able to control the seizures of mice with epilepsy.  MGE cells are a type of progenitor cells that could differentiate into interneurons, or nerve cells that inhibit signaling.

The transplant prevented overactive signaling of nerve cells and was performed in the hippocampus region of the brain that is responsible for learning and memory functions and linked with seizures.  

"These cells migrate widely and integrate into the adult brain as new inhibitory neurons," said Scott Baraban, professor in residence of neurological surgery at UCSF. "This is the first report in a mouse model of adult epilepsy in which mice that already were having seizures stopped having seizures after treatment."

Epilepsies are known to induce violent muscle contractions and, in other cases, loss of consciousness and control which can lead to serious injuries. The condition is a result of excessive and abnormal firing of nerve signals in the brain.

Researchers transplanted these inhibitory cells, which were able to reduce the uncontrollable signals, eliminating seizures in half of the mice and drastically reducing impulsive seizures in the other half.  Specifically, the MGE cells were taken from mouse embryos and, when implanted, they migrated and spawned into interneurons to repair the broken neural system in epileptic mice.

Other positive outcomes from the most recent study included reduced agitation and hyperactivity in mice. The mice also performed better in exercises that tested their learning and memory skills.

In another study, more progress has been done to help predict seizures in epileptic patients who are limited by current treatment options. In this case, electrodes are surgically implanted between the skull and brain and communicate to another electrode in the chest. The data accumulated from this device monitors when a seizure is likely to occur.

According to the Centers for Disease Control and Prevention (CDC), two-thirds of people with epilepsy receive the best outcomes by using drugs to control seizures, while the remaining population only benefit partially and experience a recurrence of seizures. However, researchers say some of these therapeutic options have no significance at all.

"Our results are an encouraging step toward using inhibitory neurons for cell transplantation in adults with severe forms of epilepsy," said Barbaran. "This procedure offers the possibility of controlling seizures and rescuing cognitive deficits in these patients."

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New Stem Cell Found that May Heal Brain Injury and Disease

Researchers at Lund University in Sweden have discovered a new stem cell in the adult brain. These cells can proliferate and form several different cell types -- most importantly, they can form new brain cells. Scientists hope to take advantage of the finding to develop methods to heal and repair disease and injury in the brain.

Analyzing brain tissue from biopsies, the researchers for the first time found stem cells located around small blood vessels in the brain. The cell's specific function is still unclear, but its plastic properties suggest great potential.

"A similar cell type has been identified in several other organs where it can promote regeneration of muscle, bone, cartilage and adipose tissue," said Patrik Brundin, M.D., Ph.D., Jay Van Andel Endowed Chair in Parkinson's Research at Van Andel Research Institute (VARI), Head of the Neuronal Survival Unit at Lund University and senior author of the study.

In other organs, researchers have shown clear evidence that these types of cells contribute to repair and wound healing. Scientists suggest that the curative properties may also apply to the brain. The next step is to try to control and enhance stem cell self-healing properties with the aim of carrying out targeted therapies to a specific area of the brain.

"Our findings show that the cell capacity is much larger than we originally thought, and that these cells are very versatile," said Gesine Paul-Visse, Ph.D., Associate Professor of Neuroscience at Lund University and the study's primary author. "Most interesting is their ability to form neuronal cells, but they can also be developed for other cell types. The results contribute to better understanding of how brain cell plasticity works and opens up new opportunities to exploit these very features."

The study, published in the journal PLoS ONE, is of interest to a broad spectrum of brain research. Future possible therapeutic targets range from neurodegenerative diseases to stroke.

"We hope that our findings may lead to a new and better understanding of the brain's own repair mechanisms," said Dr. Paul-Visse. "Ultimately the goal is to strengthen these mechanisms and develop new treatments that can repair the diseased brain."

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Scientists create brain cells from human skin in possible breakthrough for autism, Alzheimer's research

Brain and skin from common stem cells. JR

Scientists who have generated brain tissue from human skin are claiming a major breakthrough.

The researchers wrote on the University of Cambridge website that their findings could speed up the hunt for new treatments for diseases of the cerebral cortex, such as epilepsy and autism, to neurodegenerative conditions such as Alzheimer’s disease.

"Today’s findings will enable scientists to study how the human cerebral cortex develops, how it ‘wires up’ and how that can go wrong (a common problem leading to learning disabilities)," they wrote.

Their findings were published in the journal Nature Neuroscience.

Created cerebral cortex cells – those that make up the brain’s grey matter -- will allow them to "recreate brain diseases, such as Alzheimer’s, in the lab," they wrote, providing "previously impossible insight."

It may also allow them to develop and test new drugs to stop the diseases progressing.

Britain's Sunday Telegraph reported that until now, it has only been possible to generate tissue from the cerebral cortex by using controversial embryonic stem cells, obtained by the destruction of an embryo.

...

''We can study brain development and what goes wrong when it is affected by disease in a way we haven't been able to before. We see it as a major breakthrough in what will now be possible.''

Read more: http://www.globalpost.com/dispatch/news/regions/europe/united-kingdom/120213/brain-tissue-skin-alzheimers-epilepsy-stroke-cambridge-university

Brain Cell Malfunction in Schizophrenia Identified

Scientists at The Scripps Research Institute have discovered that DNA stays too tightly wound in certain brain cells of schizophrenic subjects. The findings suggest that drugs already in development for other diseases might eventually offer hope as a treatment for schizophrenia and related conditions in the elderly.

The research, now available online in the new Nature journal, Translational Psychiatry, shows the deficit is especially pronounced in younger people, meaning treatment might be most effective early on at minimizing or even reversing symptoms of schizophrenia, a potentially devastating mental disorder associated with hallucinations, delusions, and emotional difficulties, among other problems.

"We're excited by the findings," said Scripps Research Associate Professor Elizabeth Thomas, a neuroscientist who led the study, "and there's a tie to other drug development work, which could mean a faster track to clinical trials to exploit what we've found."

A Promising New Field

Over the past few years, researchers have increasingly recognized that cellular-level changes not tied to genetic defects play important roles in causing disease. There is a range of such so-called epigenetic effects that change the way DNA functions without changing a person's DNA code.

One critical area of epigenetic research is tied to histones. These are the structural proteins that DNA has to wrap around. "There's so much DNA in each cell of your body that it could never fit in your cells unless it was tightly and efficiently packed," said Thomas. Histone "tails" regularly undergo chemical modifications to either relax the DNA or repack it. When histones are acetylated, portions of DNA are exposed so that the genes can be used. The histone-DNA complexes, known as chromatin, are constantly relaxing and condensing to expose different genes, so there is no single right or wrong configuration. But the balance can shift in ways that can cause or exacerbate disease.

DNA is the guide that cellular machinery uses to construct the countless proteins essential to life. If portions of that guide remain closed when they shouldn't because histones are not acetylated properly, then genes can be effectively turned off when they shouldn't be with any number of detrimental effects. Numerous research groups have found that altered acetylation may be a key factor in other conditions, from neurodegenerative disorders such as Huntington's disease and Parkinson's disease to drug addiction.

A Good Idea

Thomas had been studying the roles of histone acetylation in Huntington's disease and began to wonder whether similar mechanisms of gene regulation might also be important in schizophrenia. In both diseases, past research in the Thomas lab had shown that certain genes in sufferers were much less active than in healthy people. "It occurred to me that we see the same gene alterations, so I thought, 'Hey, let's just try it,'" she said.

Working with lead author Bin Tang, a postdoctoral fellow in her lab, and Brian Dean, an Australian colleague at the University of Melbourne, Thomas obtained post-mortem brain samples from schizophrenic and healthy brains held at medical "Brain Banks" in the United States and Australia. The brains come from either patients who themselves agreed to donate some or all of their bodies for scientific research after death, or from patients whose families agreed to such donations.

A great deal of epigenetic research has focused on chemical alterations to DNA itself. Histone alterations have been much more difficult to study because such research requires that the histones and DNA remain chemically intact. Many researchers feared that these bonds were disrupted in the brain after death. However, Thomas's group was able to develop a technique for maintaining the histone-DNA interactions. "While many people thought this was lost, we were able to show that indeed these interactions are preserved in post-mortem brain, allowing us to carry out these studies," said Thomas.

Compared to healthy brains, the brain samples from subjects with schizophrenia showed lower levels of acetylation in certain histone portions that would block gene expression. Another critical finding was that in younger subjects with schizophrenia, the problem was much more pronounced.

Need for New Treatment Options

Just what causes the acetylation defects among schizophrenic subjects -- what keeps certain pages of the DNA guide closed -- isn't clear, but from a medical perspective it doesn't matter. If researchers can reliably show that acetylation is a cause of the problem, they can look for ways to open the closed guide pages and hopefully cure or improve the condition in patients.

Thomas sees great potential. Based on the more pronounced results in younger brains, she believes that treatment with histone deacetylase inhibitors might well prove helpful in reversing or preventing the progression of the condition, especially in younger patients. Current drugs for schizophrenia tend to treat only certain symptoms, such as hallucinations and delusions, and the drugs have major side effects including movement problems, weight gain, and diabetes. If deacetylase inhibitors effectively treat a root cause of the disease and prove sufficiently non-toxic, they might improve additional symptoms and provide a major expansion of treatment options.

Interestingly, some of the cognitive deficits that plague elderly people look quite similar biologically to schizophrenia, and the two conditions share at least some brain abnormalities. So deacetylase inhibitors might also work as a treatment for age-related problems, and might even prove an effective preventive measure for people at high risk of cognitive decline based on family history or other indicators.

Read more: http://www.sciencedaily.com/releases/2011/12/111228111731