Brain capable of making its own version of Valium

The oral drug Valium – also known by its generic name, diazepam – was once popular with doctors in the 1970s as a treatment for seizures brought on by epilepsy. However, the drug, also used to treat anxiety, has fallen out of favor in recent years as it is prone to abuse and often dangerous if taken in high doses.

Now, in light of a recent study, the need for Valium to treat epilepsy may be even further diminished. Researchers from Stanford University School of Medicine have discovered a naturally occurring protein in the brains of mammals that acts like Valium, stopping certain types of seizures from occurring. Researchers hope that if they are able to discover a way to boost this protein naturally, doctors would no longer have a need to prescribe Valium.

The protein, identified as diazepam binding inhibitor (DBI), essentially acts like the brain’s very own brake system, sensing when a seizure is about to occur and arresting the process before it can spiral out of control.

“Our thinking on brain circuits and epilepsy has been that our brains have their own ways to control seizures, and this is why most of us aren’t having seizures every day,” study author John Huguenard, professor of neurology and neurological sciences at Stanford, told FoxNews.com. “But what happens as a seizure starts, a few cells in the brain may get too active, and you get an avalanche of activity that eventually can take up most of the brain circuitry. The brain’s own ‘Valium’ is acting as an anti-avalanche method, checking things when they’re first starting.”

According to Huguenard, the brain has two main groups of nerve cells. The first type of cells – excitatory cells – are responsible for stimulating other cells and sending messages from one area of the brain to another. This messaging process, known as excitation, is responsible for communicating what we see, what we smell, what we do, etc.

The other key type of cells are known as inhibitory cells, which are responsible for keeping the brain circuitry under control. If one area of the brain gets too excited and starts to receive too many signals at once, the inhibitory cells kick into gear and slow the process in order to restore balance.

“In terms of this form of epilepsy we’ve been studying, if a certain group of brain cells can’t communicate well through this inhibitory process, then (the animals) have seizures,” Huguenard said.

The protein DBI is a crucial component of the inhibitory process, as it boosts the actions of an important neurotransmitter called gamma-aminobutyric acid (GABA). Roughly one-fifth of the inhibitory nerve cells in the brain operate by secreting GABA, which binds to receptors located on excitatory cells, rendering them temporarily unable to fire any more electrical signals.  

Without DBI, GABA cannot be enhanced, and the excitatory cells ultimately don’t get the message telling them to calm down. However, up until now, this function of DBI was not well understood by researchers.

To determine exactly how DBI operates in the brains of mammals, Huguenard and his team analyzed a group of bioengineered mice with the DBI gene mutation, meaning their brains were incapable of producing DBI.

“When we tested seizures in these animals and tested communication, we found that (the inhibitory process) was ineffective and that the animals had more seizures,” Huguenard said. “It told us that this gene is producing a product in the brain that is controlling the seizures.”

When they re-introduced the DBI-gene back into the brains of these mice, GABA-induced inhibition was restored and the mice suffered from fewer seizures.

Benzodiazepine drugs, like Valium, work in a very similar way to DBI by also enhancing GABA-induced inhibition. But they often come at a high cost. Many who take these medications long-term develop a physical dependence on the drug, experiencing serious withdrawal symptoms if they cease taking it. Some studies have also found Valium to have an adverse effect on both short-term and long-term cognition.

While the researchers only examined the brains of mice, they are optimistic DBI exists similarly in the brains of humans as well. If the results end up translating to the human mind, Huguenard hopes to find a way to naturally boost DBI in the brain, negating the need for Valium to help control seizures.

“The ultimate goal would be to develop new lines of therapy that would take this general approach – taking the brain’s mechanism for dealing with seizures and making them even more effective,” Huguenard said.

The research was published May 30 in the journal Neuron.

Sleep Promotes Consolidation of Emotional Memory in Healthy Children but Not in Children with Attention-Deficit Hyperactivity Disorder

Fronto-limbic brain activity during sleep is believed to support the consolidation of emotional memories in healthy adults. Attention deficit-hyperactivity disorder (ADHD) is accompanied by emotional deficits coincidently caused by dysfunctional interplay of fronto-limbic circuits. This study aimed to examine the role of sleep in the consolidation of emotional memory in ADHD in the context of healthy development. 16 children with ADHD, 16 healthy children, and 20 healthy adults participated in this study. Participants completed an emotional picture recognition paradigm in sleep and wake control conditions. Each condition had an immediate (baseline) and delayed (target) retrieval session. The emotional memory bias was baseline–corrected, and groups were compared in terms of sleep-dependent memory consolidation (sleep vs. wake). We observed an increased sleep-dependent emotional memory bias in healthy children compared to children with ADHD and healthy adults. Frontal oscillatory EEG activity (slow oscillations, theta) during sleep correlated negatively with emotional memory performance in children with ADHD. When combining data of healthy children and adults, correlation coefficients were positive and differed from those in children with ADHD. Since children displayed a higher frontal EEG activity than adults these data indicate a decline in sleep-related consolidation of emotional memory in healthy development. In addition, it is suggested that deficits in sleep-related selection between emotional and non-emotional memories in ADHD exacerbate emotional problems during daytime as they are often reported in ADHD.

Early brain responses to words predict developmental outcomes in children with autism

The pattern of brain responses to words in 2-year-old children with autism spectrum disorder predicted the youngsters’ linguistic, cognitive and adaptive skills at ages 4 and 6, according to a new study.

The findings, published May 29 in PLOS ONE, are among the first to demonstrate that a brain marker can predict future abilities in children with autism.

“We’ve shown that the brain’s indicator of word learning in 2-year-olds already diagnosed with autism predicts their eventual skills on a broad set of cognitive and linguistic abilities and adaptive behaviors,” said lead author Patricia Kuhl, co-director of the University of Washington’s Institute for Learning & Brain Sciences.

“This is true four years after the initial test, and regardless of the type of autism treatment the children received,” she said.

In the study, 2-year-olds – 24 with autism and 20 without – listened to a mix of familiar and unfamiliar words while wearing an elastic cap that held sensors in place. The sensors measured brain responses to hearing words, known as event-related potentials.

The research team then divided the children with autism into two groups based on the severity of their social impairments and took a closer look at the brain responses. Youngsters with less severe symptoms had brain responses that were similar to the typically developing children, in that both groups exhibited a strong response to known words in a language area located in the temporal parietal region on the left side of the brain.

This suggests that the brains of children with less severe symptoms can process words in ways that are similar to children without the disorder.

In contrast, children with more severe social impairments showed brain responses more broadly over the right hemisphere, which is not seen in typically developing children of any age.

“We think this measure signals that the 2-year-old’s brain has reorganized itself to process words. This reorganization depends on the child’s ability to learn from social experiences,” Kuhl said. She cautioned that identifying a neural marker that predicts future autism diagnoses with assurance is still a ways off.

The researchers also tested the children’s language skills, cognitive abilities, and social and emotional development, beginning at age 2, then again at ages 4 and 6.

The children with autism received intensive treatment and, as a group, they improved on the behavioral tests over time. But the outcome for individual children varied widely and the more their brain responses to words at age 2 were like those of typically developing children, the more improvement in skills they showed by age 6.

In other studies, Kuhl has found that social interactions accelerate language learning in babies. Infants use social cues, such as tracking adults’ eye movements to learn the names of things, and must be interested in people to learn in this way. Paying attention to people is a way for babies to sort through all that is happening around them and serves as a gate to know what is important.

But with autism, social impairments impede children’s interest in, and ability to pick up on, social cues. They find themselves paying attention to many other things, especially objects as opposed to people.

“Social learning is what most humans are about,” Kuhl said. “If your brain can learn from other people in a social context you have the capability to learn just about anything.”

She hopes that the new findings will lead to brain measures that can be used much earlier in development – at 12 months or younger – to help identify children at risk for autism.

“This line of work may lead to new interventions applied early in development, when the brain shows its highest level of neural plasticity,” Kuhl said.

Neuroscientists Discover New Phase of Synaptic Development

Breakthrough Could Lead to Better Understanding of Learning and Memory

Students preparing for final exams might want to wait before pulling an all-night cram session — at least as far as their neurons are concerned. Carnegie Mellon University neuroscientists have discovered a new intermediate phase in neuronal development during which repeated exposure to a stimulus shrinks synapses. The findings are published in the May 8 issue of the Journal of Neuroscience.

It’s well known that synapses in the brain, the connections between neurons and other cells that allow for the transmission of information, grow when they’re exposed to a stimulus. New research from the lab of Carnegie Mellon Associate Professor of Biological Sciences Alison L. Barth has shown that in the short term, synapses get even stronger than previously thought, but then quickly go through a transitional phase where they weaken.

"When you think of learning, you think that it’s cumulative. We thought that synapses started small and then got bigger and bigger. This isn’t the case," said Barth, who also is a member of the joint Carnegie Mellon/University of Pittsburgh Center for the Neural Basis of Cognition. "Based on our data, it seems like synapses that have recently been strengthened are peculiarly vulnerable — more stimulation can actually wipe out the effects of learning.

"Psychologists know that for long-lasting memory, spaced training - like studying for your classes after very lecture, all semester long — is superior to cramming all night before the exam," Barth said. "This study shows why. Right after plasticity, synapses are almost fragile — more training during this labile phases is actually counterproductive."

Previous research from Barth’s lab established the biochemical mechanisms responsible for the strengthening of synapses in the neocortex, the part of the brain responsible for thought and language, but only measured the synapses after 24 hours. In the current study, post-doctoral student Jing A. Wen investigated how the synapses developed throughout the first 24 hours of exposure to a stimulus using a specialized transgenic mouse model created by Barth. The model senses its surroundings using only one whisker, which alters its ability to sense its environment and creates a sensory imbalance that increases plasticity in the brain. Since each whisker is linked to a specific area of the cortex, researchers can easily track neuronal changes.

Wen found that during this first day of learning, synapses go through three distinct phases. In the initiation phase, synaptic plasticity is spurred on by NMDA receptors. Over the next 12 hours or so, the synapses get stronger and stronger. As the stimulus is repeated, the NDMA receptors change their function and start to weaken the synapses in what the researchers have called the labile phase. After a few hours of weakening, another receptor, mGluR5, initiates a stabilization phase during which the synapses maintain their residual strength.

Furthermore, the researchers found that they could maintain the super-activated state found at the beginning of the labile phase by stopping the stimulus altogether or by injecting a glutamate receptor antagonist drug at an optimal time point. The findings are analogous to those seen in many psychological studies that use space training to improve memory.

"While synaptic changes can be long lasting, we’ve found that in this initial period there are a number of different things we could play with," Barth said. "The discovery of this labile phase suggests there are ways to control learning through the manipulation of the biochemical pathways that maintain memory."

From trauma to tau - Researchers tie brain injury to toxic form of protein

University of Texas Medical Branch at Galveston researchers have uncovered what may be a key molecular mechanism behind the lasting damage done by traumatic brain injury.

The discovery centers on a particular form of a protein that neuroscientists call tau, which has also been associated with Alzheimer’s disease and other neurodegenerative conditions. Under ordinary conditions, tau is essential to neuron health, but in Alzheimer’s the protein aggregates into two abnormal forms: so-called “neurofibrillary tangles,” and collections of two, three, or four or more tau units known as “oligomers.”

Neurofibrillary tangles are not believed to be harmful, but tau oligomers are toxic to nerve cells. They are also are thought to have an additional damaging property — when they come into contact with healthy tau proteins, they cause them to also clump together into oligomers, and so spread toxic tau oligomers to other parts of the brain.

Now, in experiments with laboratory rats, using novel antibodies developed at UTMB, scientists have found that traumatic brain injuries also generate tau oligomers. The destructive protein assemblages formed within four hours after injury and persisted for at least two weeks — long enough to suggest that they might contribute to lasting brain damage.

Significantly, the rats used in the experiments were normal, unlike the genetically modified animals used in most tau research. The findings are thus likely to be more relevant to human traumatic brain injuries.

“Although people have given some attention to the formation of neurofibrillary tangles after traumatic brain injury, we were the first to look at tau oligomers, because we have an antibody that allows us to separate them out and see how much of the total tau is the toxic species,” said Bridget Hawkins, lead author of a paper on the research now online in the Journal of Biological Chemistry. “We saw that it’s a substantial amount — enough to play an important role in the effects of traumatic brain injury.”

Those effects can include memory deficits, which have been recently shown by UTMB researchers to be induced by tau oligomers. Other long-term ramifications of TBI include seizures, and disruptions in the sleep-wake cycle. The UTMB scientists hypothesize that these problems could be avoided if physicians had a way to stop the process of tau oligomerization.

One possibility is a treatment based on the antibodies used to label tau oligomers in this project, which were developed as part of an effort to develop a vaccine against different neurodegenerative disorders.

“We have antibodies that can specifically target these tau oligomers without interfering with the function of healthy tau,” said UTMB associate professor Rakez Kayed, the senior author on the paper. “This is a new approach — we’re starting by targeting them in animals — but we hope to eventually humanize these antibodies for clinical trials.”

New chemical approach to beat Alzheimer’s disease

Scientists at the University of Liverpool and Callaghan Innovation in New Zealand have developed a new chemical approach to help harness the natural ability of complex sugars to treat Alzheimer’s disease.

The team used a new chemical method to produce a library of sugars, called heparan sulphates, which are known to control the formation of the proteins in the brain that cause memory loss.

Chemically produced in the lab

Heparan sulphates are found in nearly every cell of the body, and are similar to the natural blood-thinning drug, heparin. Now scientists have discovered how to produce them chemically in the lab, and found that some of these sugars can inhibit an enzyme that creates small proteins in the brain.

These proteins, called amyloid, disrupt the normal function of cells leading to the progressive memory loss that is characteristic of Alzheimer’s disease.

Professor Jerry Turnbull, from the University’s Institute of Integrative Biology, said: “We are targeting an enzyme, called BACE, which is responsible for creating the amyloid protein. The amyloid builds up in the brain in Alzheimer’s disease and causes damage. BACE has proved to be a difficult enzyme to block despite lots of efforts by drug companies.”

“We are using a new approach, harnessing the natural ability of sugars, based on the blood-thinning drug heparin, to block the action of BACE.”

Dr Peter Tyler, from Callaghan Innovation, added: “We have developed new chemical methods that have allowed us to make the largest set of these sugars produced to date. These new compounds will now be tested to identify those with the best activity and fewest possible side effects, as these have potential for development into a drug treatment that targets the underlying cause of this disease.”

Current treatments only help symptoms

There are more than 800,000 people in the UK, and 50,000 in New Zealand living with dementia. Over half of these have Alzheimer’s disease, the most common cause of dementia. The cost of these diseases to the UK economy stands at £23 billion, more than the cost of cancer and heart disease combined. Current treatments for dementia can help with symptoms, but there are no drugs available that can slow or stop the underlying disease.