Neuroscience

Huntington’s disease is a devastating, incurable disorder that results from the death of certain neurons in the brain. Its symptoms show as progressive changes in behavior and movements.

The neurodegenerative disease is caused by a defect in the huntingtin gene (Htt) that causes an abnormal expansion in a part of DNA, called a CAG codon or triplet that codes for the amino acid glutamine. A healthy version of the Htt gene has between 20 and 23 CAG triplets. The mutational expansion in Htt can lead to long repeats of the CAG triplet, resulting in the mutant protein having a long sequence of several glutamine residues called a polyglutamine tract. This CAG triplet expansion in unrelated genes is the root of at least nine neurodegenerative disorders, including Huntington’s disease.

Rohit Pappu, PhD, professor of biomedical engineering at Washington University in St. Louis, and his colleagues in the School of Engineering & Applied Science and in the School of Medicine, are working to understand how expanded polyglutamine tracts form the types of supramolecular structures that are presumed to be toxic to neurons – a feature that polyglutamine expansions share with proteins associated with Alzheimer’s disease and Parkinson’s disease.

In recent work, Pappu and his research team showed that the amino acid sequences on either side of the polyglutamine tract within Htt can act as natural gatekeepers because they control the fundamental ability of polyglutamine tracts to form structures that are implicated in cellular toxicity. The results were published in PNAS Early Edition Nov.25.

“These are progressive onset disorders,” Pappu says. “The longer the polyglutamine tract gets, the more severe the disease, and the symptoms worsen with age. Our results are exciting because it means that any success we have in mimicking the effects of naturally occurring gatekeepers would be a significant step forward. And mechanistic studies are important in this regard because they enable us to learn from nature’s own strategies.

“Previous studies from other labs showed that the toxic effects of polyglutamine expansions are tempered by the sequence contexts of polyglutamine tracts in Htt, not just the lengths of the polyglutamine tracts”, Pappu says.

He and his research team focused on understanding the effects of sequence stretches that lie on either side of the polyglutamine tract in Htt.  The results show that the N-terminal stretch accelerates the formation of ordered structures that are presumed to be benign to cells, whereas the C-terminal stretch slows the overall transition into structures that are expected to create trouble for cells, suggesting that these naturally occurring sequences behave as gatekeepers. 

“It appears that where polyglutamine stretches are of functional importance, nature has ensured that they are flanked by gatekeeping sequences,” Pappu says.

Pappu and his team are now working to find way s to mimic the effects of the N- and C-terminal flanking sequences from Htt. His team is working closely with Marc Diamond, MD, the David Clayson Professor of Neurology at the School of Medicine, to understand how naturally occurring proteins interact with flanking sequences and see if they can coopt them to ameliorate the toxic functions in the polyglutamine expansions.

Scientists from Case Western Reserve University and University of Kansas Medical Center have restored behavior—in this case, the ability to reach through a narrow opening and grasp food—using a neural prosthesis in a rat model of brain injury.

Ultimately, the team hopes to develop a device that rapidly and substantially improves function after brain injury in humans. There is no such commercial treatment for the 1.5 million Americans, including soldiers in Afghanistan and Iraq, who suffer traumatic brain injuries (TBI), or the nearly 800,000 stroke victims who suffer weakness or paralysis in the United States, annually.

The prosthesis, called a brain-machine-brain interface, is a closed-loop microelectronic system. It records signals from one part of the brain, processes them in real time, and then bridges the injury by stimulating a second part of the brain that had lost connectivity.
Their work is published online this week in the science journal Proceedings of the National Academy of Sciences.

“If you use the device to couple activity from one part of the brain to another, is it possible to induce recovery from TBI? That’s the core of this investigation,” said Pedram Mohseni, professor of electrical engineering and computer science at Case Western Reserve, who built the brain prosthesis.

“We found that, yes, it is possible to use a closed-loop neural prosthesis to facilitate repair of a brain injury,” he said.

The researchers tested the prosthesis in a rat model of brain injury in the laboratory of Randolph J. Nudo, professor of molecular and integrative physiology at the University of Kansas. Nudo mapped the rat’s brain and developed the model in which anterior and posterior parts of the brain that control the rat’s forelimbs are disconnected.

Atop each animal’s head, the brain-machine-brain interface is a microchip on a circuit board smaller than a quarter connected to microelectrodes implanted in the two brain regions.

The device amplifies signals, which are called neural action potentials and produced by the neurons in the anterior of the brain. An algorithm separates these signals, recorded as brain spike activity, from noise and other artifacts. With each spike detected, the microchip sends a pulse of electric current to stimulate neurons in the posterior part of the brain, artificially connecting the two brain regions.

Two weeks after the prosthesis had been implanted and run continuously, the rat models using the full closed-loop system had recovered nearly all function lost due to injury, successfully retrieving a food pellet close to 70 percent of the time, or as well as normal, uninjured rats. Rat models that received random stimuli from the device retrieved less than half the pellets and those that received no stimuli retrieved about a quarter of them.

“A question still to be answered is must the implant be left in place for life?” Mohseni said. “Or can it be removed after two months or six months, if and when new connections have been formed in the brain?”

Brain studies have shown that, during periods of growth, neurons that regularly communicate with each other develop and solidify connections.

Mohseni and Nudo said they need more systematic studies to determine what happens in the brain that leads to restoration of function. They also want to determine if there is an optimal time window after injury in which they must implant the device in order to restore function.

For patients recovering from a traumatic brain injury (TBI), the rehabilitation process – compensating for changes in functioning, adaptation and even community reintegration – can be challenging. Unfortunately, not all rehab programs are created equal, and with the differences comes a difference in outcomes, according to a first-of-its-kind study published in The Journal of Head Trauma Rehabilitation.

Collectively authored by Baylor researchers, the outcomes study (titled “Comparative Effectiveness of Traumatic Brain Injury Rehabilitation: Differential Outcomes Across TBI Model Systems Centers”), set out to identify if outcomes at the post-discharge and one-year points varied across 21 Traumatic Brain Injury Model System (TBIMS) centers. The Baylor Institute of Rehabilitation (BIR) was one of the centers studied.

At the study’s onset, researchers had an idea of what they might find, but their findings revealed the opposite.

“We expected that, after accounting for differences in patient characteristics and severity of injury, patient outcomes would be similar across centers,” said Marie Dahdah, PhD, investigator at the Baylor Institute for Rehabilitation. “They were not. There were significant variations, with a 25 percent to 45 percent difference between the best performing site and the site with the lowest outcomes at discharge.”

While differences in outcomes have long been reported in designated trauma centers (and for other specialties, including general and cardiac surgery, transplant and oncology), the study was the first piece of research to demonstrate that those differences exist in the rehabilitation context.

The team acknowledged that those variances could be attributed to institutional structures, resources and clinical practices, but that more research is needed to determine which of these factors is associated with optimum outcomes.

“In order to identify factors that contribute to variation in patient outcomes across centers, we are undertaking research that identifies different patient, injury and process-level factors associated with functional outcomes of patients,” Dr. Dahdah said. “Those factors can then be targeted to improve patient outcomes.”

In other phases of this study, these Baylor investigators (along with teams from three other TBIMS sites) are reviewing the quantity and frequency of various types of rehabilitation therapies used in inpatient TBI settings. The team will also study evidenced-based best practices for speech, occupational, physical and recreational therapy interventions, as well as neurocognitive and psychosocial interventions.

The results from those subsequent studies could help identify gaps between current practices and evidence-based best practices, with the aim of helping inform rehabilitation programs across the country and ensuring that all centers have the same opportunities for quality outcomes.

“I think I speak for my entire research team when I say that our involvement in this type of research comes out of our collective desire to improve quality of rehabilitation care, thereby enhancing outcomes following TBI,” Dr. Dahdah said. “My hope is that by synthesizing and disseminating what is known about effective evidence-based rehabilitation interventions, BIR as part of the North Texas TBIMS will be able to encourage changes necessary to help institutions, clinicians and therapists to provide the best quality TBI rehabilitation care to their patients.”

Of course, with the Baylor Institute of Rehabilitation being among the 21-center pool, one very obvious question remains. How did BIR’s outcomes compare with the other 20 centers?

“I cannot count for you the number of times I have been asked that question,” Dr. Dahdah said. “To ensure the integrity of our study, even our research team is blind to the identity of the centers.”

But despite how well even the strongest inpatient rehab centers perform in a comparative context, there is always room for improvement, especially with best-practice regimens.

“Our research has already started discussions within the TBI Model Systems research community,” Dr. Dahdah said. “We believe more research needs to be done to identify the key determinants of patient outcomes so that benchmarks for quality rehabilitation care can be derived for patients and their families.”

TAU researchers discover gene that may predict human responses to specific antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants, but they don’t work for everyone. What’s more, patients must often try several different SSRI medications, each with a different set of side effects, before finding one that is effective. It takes three to four weeks to see if a particular antidepressant drug works. Meanwhile, patients and their families continue to suffer.

Now researchers at Tel Aviv University have discovered a gene that may reveal whether people are likely to respond well to SSRI antidepressants, both generally and in specific formulations. The new biomarker, once it is validated in clinical trials, could be used to create a genetic test, allowing doctors to provide personalized treatment for depression.

Doctoral students Keren Oved and Ayelet Morag led the research under the guidance of Dr. David Gurwitz of the Department of Molecular Genetics and Biochemistry at TAU’s Sackler Faculty of Medicine and Dr. Noam Shomron of the Department of Cell and Developmental Biology at TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience. Sackler faculty members Prof. Moshe Rehavi of the Department of Physiology and Pharmacology and Dr. Metsada Pasmnik-Chor of the Bioinformatics Unit were coauthors of the study, published in Translational Psychiatry.

"SSRIs only work for about 60 percent of people with depression," said Dr. Gurwitz. "A drug from other families of antidepressants could be effective for some of the others. We are working to move the treatment of depression from a trial-and-error approach to a best-fit, personalized regimen."

Good news for the depressed

More than 20 million Americans each year suffer from disabling depression that requires clinical intervention. SSRIs such as Prozac, Zoloft, and Celexa are the newest and the most popular medications for treatment. They are thought to work by blocking the reabsorption of the neurotransmitter serotonin in the brain, leaving more of it available to help brain cells send and receive chemical signals, thereby boosting mood. It is not currently known why some people respond to SSRIs better than others.

To find genes that may be behind the brain’s responsiveness to SSRIs, the TAU researchers first applied the SSRI Paroxetine — brand name Paxil — to 80 sets of cells, or “cell lines,” from the National Laboratory for the Genetics of Israeli Populations, a biobank of genetic information about Israeli citizens located at TAU’s Sackler Faculty of Medicine and directed by Dr. Gurwitz. The TAU researchers then analyzed and compared the RNA profiles of the most and least responsive cell lines. A gene called CHL1 was produced at lower levels in the most responsive cell lines and at higher levels in the least responsive cell lines. Using a simple genetic test, doctors could one day use CHL1 as a biomarker to determine whether or not to prescribe SSRIs.

"We want to end up with a blood test that will allow us to tell a patient which drug is best for him," said Oved. "We are at the early stages, working on the cellular level. Next comes testing on animals and people."

Rethinking how antidepressants work

The TAU researchers also wanted to understand why CHL1 levels might predict responsiveness to SSRIs. To this end, they applied Paroxetine to human cell lines for three weeks — the time it takes for a clinical response to SSRIs. They found that Paroxetine caused increased production of the gene ITGB3 — whose protein product is thought to interact with CHL1 to promote the development of new neurons and synapses. The result is the repair of dysfunctional signaling in brain regions controlling mood, which may explain the action of SSRI antidepressants.

This explanation differs from the conventional theory that SSRIs directly relieve depression by inhibiting the reabsorption of the neurotransmitter serotonin in the brain. Dr. Shomron adds that the new explanation resolves the longstanding mystery as to why it takes at least three weeks for SSRIs to ease the symptoms of depression when they begin inhibiting reabsorption after a couple days — the development of neurons and synapses takes weeks, not days.

The TAU researchers are working to confirm their findings on the molecular level and with animal models. Adva Hadar, a master’s student in Dr. Gurwitz’s lab, is using the same approach to find biomarkers for the personalized treatment of Alzheimer’s disease.

According to Gertrude Stein, “A rose is a rose is a rose,” but new research indicates that might not be the case when it comes to the rose’s scent. Researchers from the Monell Center and collaborating institutions have found that as much as 30 percent of the large array of human olfactory receptor differs between any two individuals. This substantial variation is in turn reflected by variability in how each person perceives odors.

Humans have about 400 different types of specialized sensors, known as olfactory receptor proteins, that somehow work together to detect a large variety of odors.

"Understanding how this huge array of receptors encodes odors is a challenging task," says study lead author Joel Mainland, PhD, a molecular biologist at Monell. "The activation pattern of these 400 receptors encodes both the intensity of an odor and the quality – for example, whether it smells like vanilla or smoke – for the tens of thousands of different odors that represent everything we smell.

Right now, nobody knows how the activity patterns are translated into a signal that our brain registers as the odor.”

Adding to the complexity of the problem, the underlying amino acid sequence can vary slightly for each of the 400 receptor proteins, resulting in one or more variants for each of the receptors. Each receptor variant responds to odors in a slightly different way and the variants are distributed across individuals such that nearly everyone has a unique combination of olfactory receptors.

To gain a better understanding of the extent of olfactory receptor variation and how this impacts human odor perception, Mainland and his collaborators used a combination of high-throughput assays to measure how single receptors and individual humans respond to odors. The results, published in Nature Neuroscience, provide a critical step towards understanding how olfactory receptors encode the intensity, pleasantness and quality of odor molecules.

The researchers first cloned 511 known variants of human olfactory receptors and embedded them in host cells that are easy to grow in the laboratory. The next step was to measure whether each receptor variant responded to a panel of 73 different odor molecules. This process identified 28 receptor variants that responded to at least one of the odor molecules.

Drilling down, the researchers next examined the DNA of 16 olfactory receptor genes, discovering considerable variation within the genes for discrete receptors.

Using sophisticated mathematical modeling to extrapolate from these results, Mainland predicts that the olfactory receptors of any two individuals differ by about 30 percent. This means that for any two randomly chosen individuals, approximately 140 of their 400 olfactory receptors will differ in how they respond to odor molecules.

To understand how variation in a single olfactory receptor affects odor perception, the researchers studied responses to odors in individuals having different variants of a receptor known as OR10G4. They found that variations in the OR10G4 receptor were related to how people perceive the intensity and pleasantness of guaiacol, a molecule that often is described as having a ‘smoky’ characteristic.

Moving forward, a current study is relating the olfactory receptor repertoire of hundreds of people with how those people respond to odors. The data will enable the researchers to identify additional examples of how changes in individual receptors affect olfactory perception.

"The long-term goal is to figure out how the receptors encode odor molecules well enough that we can actually create any odor we want by manipulating the receptors directly," said Mainland. "In essence, this would allow us to ‘digitize’ olfaction."

Researchers at University of Colorado School of Medicine may have figured out what causes Meniere’s disease and how to attack it. According to Carol Foster, MD, from the department of otolaryngology and Robert Breeze, MD, a neurosurgeon, there is a strong association between Meniere’s disease and conditions involving temporary low blood flow in the brain such as migraine headaches.

Meniere’s affects approximately 3 to 5 million people in the United States. It is a disabling disorder resulting in repeated violent attacks of dizziness, ringing in the ear and hearing loss that can last for hours and can ultimately cause permanent deafness in the affected ear. Up until now, the cause of the attacks has been unknown, with no theory fully explaining the many symptoms and signs of the disorder.

"If our hypothesis is confirmed, treatment of vascular risk factors may allow control of symptoms and result in a decreased need for surgeries that destroy the balance function in order to control the spell" said Foster. "If attacks are controlled, the previously inevitable progression to severe hearing loss may be preventable in some cases."

Foster explains that these attacks can be caused by a combination of two factors: 1) a malformation of the inner ear, endolymphatic hydrops (the inner ear dilated with fluid) and 2) risk factors for vascular disease in the brain, such as migraine, sleep apnea, smoking and atherosclerosis.

The researchers propose that a fluid buildup in part of the inner ear, which is strongly associated with Meniere attacks, indicates the presence of a pressure-regulation problem that acts to cause mild, intermittent decreases of blood flow within the ear. When this is combined with vascular diseases that also lower blood flow to the brain and ear, sudden loss of blood flow similar to transient ischemic attacks (or mini strokes) in the brain can be generated in the inner ear sensory tissues. In young people who have hydrops without vascular disorders, no attacks occur because blood flow continues in spite of these fluctuations. However, in people with vascular diseases, these fluctuations are sufficient to rob the ear of blood flow and the nutrients the blood provides. When the tissues that sense hearing and motion are starved of blood, they stop sending signals to the brain, which sets off the vertigo, tinnitus and hearing loss in the disorder.

Restoration of blood flow does not resolve the problem. Scientists believe it triggers a damaging after-effect called the ischemia-reperfusion pathway in the excitable tissues of the ear that silences the ear for several hours, resulting in the prolonged severe vertigo and hearing loss that is characteristic of the disorder. Although most of the tissues recover, each spell results in small areas of damage that over time results in permanent loss of both hearing and balance function in the ear.

Since the first linkage of endolymphatic hydrops and Meniere’s disease in 1938, a variety of mechanisms have been proposed to explain the attacks and the progressive deafness, but no answer has explained all aspects of the disorder, and no treatment based on these theories has proven capable of controlling the progression of the disease. This new theory, if proven, would provide many new avenues of treatment for this previously poorly-controlled disorder.

Life presents us with choices all the time: salad or pizza for lunch? Tea or coffee afterward? How we make these everyday decisions has been a topic of great interest to economists, who have devised theories about how we assign values to our options and use those values to make decisions.

An emerging field of study known as neuroeconomics is combining the economists’ insights with scientific study of the brain to learn more about decision-making processes and how they can go awry. In the Dec. 8 issue of Neuron, one of the field’s founders reports new links between brain cell activity and choices where two options have equal appeal.

“Neuroeconomics is not only helpful for the development of better economic theory, it is also relevant from a clinical point of view,” said author Camillo Padoa-Schioppa, PhD, assistant professor of neurobiology, economics and of biomedical engineering at Washington University School of Medicine in St. Louis. “There are a number of conditions that involve impaired economic decision-making, including drug addiction, brain injury, some forms of dementia, schizophrenia and obsessive-compulsive disorder.”

Scientists know that the orbitofrontal cortex, a region of the brain behind and above the eyes, plays a key role in making decisions. Patients with injuries to this part of the brain are often spectacularly bad at making decisions. They may do things like abandon longstanding relationships, gamble away money or lose it to swindlers, or become addicted to drugs.

To study the roles brain cells play in decision-making, Padoa-Schioppa developed a system for presenting primates a choice between two drinks, such as grape juice or apple juice. The type and amount of the drink varies, and researchers record the activity of individual brain neurons as the primates choose.

Based on the decisions of a single animal over multiple trials, scientists infer the subjective value the animal assigns to each drink and then look for ways this value is encoded in brain cells.

“For example, if we offer a larger amount of apple juice versus a smaller amount of grape juice, and the primate chooses each option equally often, we infer that this primate likes the grape juice better than the apple juice,” he explained. “The primate could be getting more juice by choosing the cup with apple juice, but it doesn’t always do so. That implies that the primate values grape juice more than apple juice.”

In 2006, Padoa-Schioppa and Harvard colleague John Assad, PhD, won international attention for using this system to identify brain cells whose firing rates encoded the subjective value of drink choices.

In a new analysis of data from the original experiment, Padoa-Schioppa showed that different groups of cells in the orbitofrontal cortex reflect different stages of the decision-making process.

“Some neurons encode the value of individual drinks; other neurons encode the choice outcome in a binary way ‒ these cells are either firing or silent depending on the chosen drink,” he explained. “Yet other neurons encode the value of the chosen option.”

Padoa-Schioppa then examined how different groups of cells determine decisions between options of equal value. He showed that toss-up decisions seemed to depend on changes in the initial state of the network of neurons in the orbitofrontal cortex.

“The fluctuations in the network took place before the primates were even offered a choice of juices, but they seem to somehow bias the decision,” Padoa-Schioppa said. “Neuronal signals are always noisy. In essence, close-call decisions are partly determined by random noise.”

He also found that decisions on choices of equal value were linked to the ease or difficulty with which nerve cells in parts of the orbitofrontal cortex communicate with each other. This property, known as synaptic efficacy, can be adjusted by the brain as part of the process of encoding information.

According to Padoa-Schioppa, these results provide new insights into the neuronal circuits that underlie economic decisions. He and his colleagues are using them to create a computational model of decision-making.

“The next step is to test that model,” Padoa-Schioppa said. “For example, we would like to bias decisions by artificially manipulating the activity of specific groups of cells.”

Researchers from the University of Bonn use reprogrammed patient neurons for drug testing

Why do certain Alzheimer medications work in animal models but not in clinical trials in humans? A research team from the University of Bonn and the biomedical enterprise LIFE & BRAIN GmbH has been able to show that results of established test methods with animal models and cell lines used up until now can hardly be translated to the processes in the human brain. Drug testing should therefore be conducted with human nerve cells, conclude the scientists. The results are published by Cell Press in the journal “Stem Cell Reports”.

In the brains of Alzheimer patients, deposits form that consist essentially of beta-amyloid and are harmful to nerve cells. Scientists are therefore searching for pharmaceutical compounds that prevent the formation of these dangerous aggregates. In animal models, certain non-steroidal anti-inflammatory drugs (NSAIDs) were found to a reduced formation of harmful beta-amyloid variants. Yet, in subsequent clinical studies, these NSAIDs failed to elicit any beneficial effects.

"The reasons for these negative results have remained unclear for a long time", says Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology of the University of Bonn and CEO of LIFE & BRAIN GmbH. "Remarkably, these compounds were never tested directly on the actual target cells – the human neuron", adds lead author Dr. Jerome Mertens of Prof. Brüstle’s team, who now works at the Laboratory of Genetics in La Jolla (USA). This is because, so far, living human neurons have been extremely difficult to obtain. However, with the recent advances in stem cell research it has become possible to derive limitless numbers of brain cells from a small skin biopsy or other adult cell types.

Scientists transform skin cells into nerve cells

Now a research team from the Institute for Reconstructive Neurobiology and the Department of Neurology of the Bonn University Medical Center together with colleagues from the LIFE & BRAIN GmbH and the University of Leuven (Belgium) has obtained such nerve cells from humans. The researchers used skin cells from two patients with a familial form of Alzheimer’s Disease to produce so-called induced pluripotent stem cells (iPS cells), by reprogramming the body’s cells into a quasi-embryonic stage. They then transformed the resulting so-called “jack-of-all-trades cells” into nerve cells.

Using these human neurons, the scientists tested several compounds in the group of non-steroidal anti-inflammatory drugs. As control, the researchers used nerve cells they had obtained from iPS cells of donors who did not have the disease. Both in the nerve cells obtained from the Alzheimer patients and in the control cells, the NSAIDs that had previously tested positive in the animal models and cell lines typically used for drug screening had practically no effect: The values for the harmful beta-amyloid variants that form the feared aggregates in the brain remained unaffected when the cells were treated with clinically relevant dosages of these compounds.

Metabolic processes in animal models differ from humans

"In order to predict the efficacy of Alzheimer drugs, such tests have to be performed directly on the affected human nerve cells", concludes Prof. Brüstle’s colleague Dr. Philipp Koch, who led the study. Why do NSAIDs decrease the risk of aggregate formation in animal experiments and cell lines but not in human neurons? The scientists explain this with differences in metabolic processes between these different cell types. "The results are simply not transferable", says Dr. Koch.

The scientists now hope that in the future, testing of potential drugs for the treatment of Alzheimer’s disease will be increasingly conducted using neurons obtained from iPS cells of patients. “The development of a single drug takes an average of ten years”, says Prof. Brüstle. “By using patient-specific nerve cells as a test system, investments by pharmaceutical companies and the tedious search for urgently needed Alzheimer medications could be greatly streamlined”.

The body is structured to ensure that any invading organisms have a tough time reaching the brain, an organ obviously critical to survival. Known as the blood-brain barrier, cells that line the brain and spinal cord are tightly packed, making it difficult for anything besides very small molecules to cross from the bloodstream into the central nervous system. While beneficial, this blockade also stands in the way of delivering drugs intended to treat neurological disorders, such as Alzheimer’s.

In a new study published in the journal Molecular Therapy, University of Pennsylvania researchers have found a way of traversing the blood-brain barrier, as well as a similar physiological obstacle in the eye, the retinal-blood barrier. By pairing a receptor that targets neurons with a molecule that degrades the main component of Alzheimer’s plaques, the biologists were able to substantially dissolve these plaques in mice brains and human brain tissue, offering a potential mechanism for treating the debilitating disease, as well as other conditions that involve either the brain or the eyes.

The work was led by Henry Daniell, a professor in Penn’s School of Dental Medicine’s departments of biochemistry and pathology and director of translational research. The research team included Penn Dental Medicine’s Neha Kohli, Donevan R. Westerveld, Alexandra C. Ayache and Sich L. Chan. Co-authors at the University of Florida College of Medicine, including Amrisha Verma, Pollob Shil, Tuhina Prasad, Ping Zhu and Quihong Li, analyzed retinal tissues. 

The researchers began their work by considering how they might breach the blood-brain barrier. Daniell hypothesized that a molecule might be permitted to cross if it was attached to a carrier that is able to pass over, as a sort of molecular crossing guard. The protein cholera toxin B, or CTB, a non-toxic carrier currently approved for use in humans by the Food and Drug Administration, is used in this study to traverse the blood-brain barrier.

They next identified a protein that could clear the plaques that are found in the brains of Alzheimer’s patients. These plaques, which are believed to cause the dementia associated with the disease, are made up of tangles of amyloid beta (Aβ), a protein that is found in soluble form in healthy individuals. Noting that myelin basic protein (MBP) has been shown to degrade Aβ chains, the team decided to couple it with CTB to see if MBP would be permitted to cross.

“These tangles of beta amyloid are known to be the problem in Alzheimer’s,” says Daniell. “So our idea was to chop the protein back to their normal size so they wouldn’t form these tangles.”

To test this idea, the Penn-led team first exposed healthy mice to the CTB-MBP compound by feeding them capsules of freeze-dried leaves that had been genetically engineered to express the fused proteins, a method developed and perfected by Daniell over many years as a means of orally administering various drugs and vaccines. Adding a green-fluorescent protein to the CTB carrier, the researchers tracked the “glow” to see where the mice took up the protein. They found the glowing protein in both the brain and retina.

“When we found the glowing protein in the brain and the retina we were quite thrilled,” said Daniell. “If the protein could cross the barrier in healthy mice, we thought it was likely that it could cross in Alzheimer’s patients brains, because their barrier is somewhat impaired.”

When CTB was not part of the fused protein, they did not see this expression, suggesting that their carrier protein, the crossing guard, was an essential part of delivering their protein of interest.

To then see what MBP would do once it got to the brain, Daniell and colleagues exposed the CTB-MBP protein to the brains of mice bred to have an Alzheimer’s disease. They used a stain that binds to the brain plaques and found that exposure to the CTB-MBP compound resulted in reductions of staining up to 60 percent, indicating that the plaques were dissolving.

Gaining confidence that their compound was appropriately targeting the plaques, the researchers worked with the National Institutes of Health to obtain brain tissue from people who died of Alzheimer’s and performed the same type of staining. Their results showed a 47 percent decrease in staining in the inferior parietal cortex, a portion of the brain found to play an important role in the development of Alzheimer’s-associated dementia.

As a final step, the researchers fed the CTB-MBP-containing capsules to 15-month-old mice, the equivalent of 80 or more human years, bred to develop Alzheimer’s disease. After three months of feeding, the mice had reductions in Aβ plaques of up to 70 percent in the hippocampus and up to 40 percent in the cortex, whereas mice fed capsules that contained lettuce leaves without CTB-MBP added and mice that were not fed any capsules did not have any reduction in evidence of brain plaques.

Because Alzheimer’s patients have also been found to have plaques in their eyes, the researchers examined the eyes of the mice fed the protein. They found that, indeed, the Alzheimer’s-mice did have retinal plaques, but those fed the CBP-MBP compound had undetectable Aβ plaques in their retinae.

“Really no one knows whether the memory problems that people who have Alzheimer’s disease are due to the dementia or problems with their eyes,” Daniell said. “Here we show it may be both, and that we can dissolve the plaques through an oral route.”

Daniell hopes that this technique of delivering proteins across the blood-brain and blood-retina barriers could serve to treat a variety of diseases beyond Alzheimer’s. Several current clinical trials have failed because of an inability to deliver drugs to the brain.  Currently, treatments of some eye conditions must physically penetrate the retina with an injection, an approach that requires anesthesia and risks retinal detachment. Treatment with an ingestible capsule would be safer, easier, and more cost-effective.

As a next step, Daniell hopes to collaborate with Alzheimer’s experts at Penn to advance these studies and add a behavioral component to determine whether the CBP-MBP compound not only removes plaques but also improves the memory and functioning of mice with the Alzheimer’s disease.

A discovery by Emory Alzheimer’s Disease Research Center and Scripps Research Institute scientists could lead to drugs that slow Alzheimer’s disease progression.

A straightforward drug strategy against Alzheimer’s is to turn down the brain’s production of beta-amyloid, the key component of the disease’s characteristic plaques. A toxic fragment of a protein found in healthy brains, beta-amyloid accumulates in the brains of people affected by the disease.

The enzyme that determines how much beta-amyloid brain cells generate is called BACE (beta-secretase or beta-site APP cleaving enzyme). Yet finding drugs that inhibit that elusive enzyme has been far from straightforward.

Now researchers have identified a way to shut down production of beta-amyloid by diverting BACE to a different part of the cell and inhibiting its activity. The results were published this week in Journal of Neuroscience.

"This is an indirect but highly effective way of blocking BACE, which controls the chokepoint step in beta-amyloid production," says lead author Jeremy Herskowitz, PhD, instructor in neurology at Emory’s Alzheimer’s Disease Research Center.

"Jeremy has found a promising approach toward reducing beta-amyloid production and potentially modifying Alzheimer’s disease progression, something for which there is immense need," says senior author James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. "Drugs that reduce beta-amyloid production would probably be mostly preventive. However, since amyloid-beta is toxic, such drugs could have some immediate effect on cognitive impairment."

In the paper, Herskowitz and his colleagues demonstrate that a specific inhibitor of the enzyme ROCK2 can cut beta-amyloid production in brain cells by more than 75 percent. Co-author Yangbo Feng, PhD, associate director of medicinal chemistry at Scripps Research Institute in Florida, previously discovered the ROCK2 inhibitor, called SR3677.

Alzheimer’s researchers were already interested in ROCK2 and a related enzyme, ROCK1, because of a connection with NSAIDs (non-steroid anti-inflammatory drugs) such as ibuprofen. Some NSAIDS can inhibit production of a particularly toxic form of beta-amyloid, and scientists believed NSAIDs were exerting their effects through the ROCKs.

Herskowitz first showed that in cultured cells, “knocking down” the ROCK2 gene reduced beta-amyloid production, but knocking down ROCK1 had the opposite effect.

"This says that anytime you’re hitting both ROCKs at once, the effects cancel each other out," he says.

The known drugs that affect the ROCKs seemed to affect both and thus have diminished effects. In contrast, SR3677 inhibits ROCK2 much more effectively than ROCK1, and it offered a way around the obstacle. Herskowitz found that by inhibiting ROCK2, SR3677 diverts BACE to a different part of the cell, where it is less likely to act on beta-amyloid’s parent protein.

He and ADRC colleagues found that ROCK2 levels are higher than usual in tissue samples from brains of patients with Alzheimer’s, including those with mild cognitive impairment, thought to be a precursor stage of the disease.

"There is plenty of ROCK2 in the brain, and its levels are elevated in Alzheimer’s patients, indicating that it’s an excellent drug target," Herskowitz says. "We are eager to pursue more extensive studies of this strategy in animal models of Alzheimer’s."

SR3677 can substantially inhibit beta-amyloid production in an animal model of Alzheimer’s, but so far, this effect has been observed when the drug is injected directly into the brain. More studies are required to learn if SR3677 or related drugs can pass the blood-brain barrier and thus be given by injection or orally, and what side effects could appear. ROCK inhibitors are also being investigated for treating other conditions such as glaucoma, hypertension and multiple sclerosis. 

Using a powerful gene-hunting technique for the first time in mammalian brain cells, researchers at Johns Hopkins report they have identified a gene involved in building the circuitry that relays signals through the brain. The gene is a likely player in the aging process in the brain, the researchers say. Additionally, in demonstrating the usefulness of the new method, the discovery paves the way for faster progress toward identifying genes involved in complex mental illnesses such as autism and schizophrenia — as well as potential drugs for such conditions. A summary of the study appears in the Dec. 12 issue of Cell Reports.

(Image: A mouse neuron with synapses shown: Red dots mark excitatory synapses, while green dots mark so-called inhibitory synapses. Credit: Kamal Sharma/Johns Hopkins University School of Medicine)

“We have been looking for a way to sift through large numbers of genes at the same time to see whether they affect processes we’re interested in,” says Richard Huganir, Ph.D., director of the Johns Hopkins University Solomon H. Snyder Department of Neuroscience and a Howard Hughes Medical Institute investigator, who led the study. “By adapting an automated process to neurons, we were able to go through 800 genes to find one needed for forming synapses — connections — among those cells.”

Although automated gene-sifting techniques have been used in other areas of biology, Huganir notes, many neuroscience studies instead build on existing knowledge to form a hypothesis about an individual gene’s role in the brain. Traditionally, researchers then disable or “knock out” the gene in lab-grown cells or animals to test their hypothesis, a time-consuming and laborious process.

In this study, Huganir’s group worked to test many genes all at once using plastic plates with dozens of small wells. A robot was used to add precise allotments of cells and nutrients to each well, along with molecules designed to knock out one of the cells’ genes — a different one for each well.

“The big challenge was getting the neurons, which are very sensitive, to function under these automated conditions,” says Kamal Sharma, Ph.D., a research associate in Huganir’s group. The team used a trial-and-error approach, adjusting how often the nutrient solution was changed and adding a washing step, and eventually coaxed the cells to thrive in the wells. In addition, Sharma says, they fine-tuned an automated microscope used to take pictures of the circuitry that had formed in the wells and calculated the numbers of synapses formed among the cells.

The team screened 800 genes in this way and found big differences in the well of cells with a gene called LRP6 knocked out. LRP6 had previously been identified as a player in a biochemical chain of events known as the Wnt pathway, which controls a range of processes in the brain. Interestingly, Sharma says, the team found that LRP6 was only found on a specific kind of synapse known as an excitatory synapse, suggesting that it enables the Wnt pathway to tailor its effects to just one synapse type.

“Changes in excitatory synapses are associated with aging, and changes in the Wnt pathway in later life may accelerate aging in general. However, we do not know what changes take place in the synaptic landscape of the aging brain. Our findings raise intriguing questions: Is the Wnt pathway changing that landscape, and if so, how?” says Sharma. “We’re interested in learning more about what other proteins LRP6 interacts with, as well as how it acts in different types of brain cells at different developmental stages of circuit development and refinement.”

Another likely outcome of the study is wider use of the gene-sifting technique, he says, to explore the genetics of complex mental illnesses. The automated method could also be used to easily test the effects on brain cells of a range of molecules and see which might be drug candidates.

While the human brain is in a resting state, patterns of neuronal activity which are associated to specific memories may spontaneously reappear. Such recurrences contribute to memory consolidation – i.e. to the stabilization of memory contents. Scientists of the DZNE and the University of Bonn are reporting these findings in the current issue of The Journal of Neuroscience. The researchers headed by Nikolai Axmacher performed a memory test on a series of persons while monitoring their brain activity by functional magnetic resonance imaging (fMRI). The experimental setup comprised several resting states including a nap inside a neuroimaging scanner. The study indicates that resting periods can generally promote memory performance.

Depending on one’s mood and activity different regions are active in the human brain. Perceptions and thoughts also influence this condition and this results in a pattern of neuronal activity which is linked to the experienced situation. When it is recalled, similar patterns, which are slumbering in the brain, are reactivated. How this happens, is still largely unknown.

The prevalent theory of memory formation assumes that memories are stored in a gradual manner. At first, the brain stores new information only temporarily. For memories to remain in the long term, a further step is required. „We call it consolidation“, Dr. Nikolai Axmacher explains, who is a researcher at the Department of Epileptology of the University of Bonn and at the Bonn site of the DZNE. “We do not know exactly how this happens. However, studies suggest that a process we call reactivation is of importance. When this occurs, the brain replays activity patterns associated with a particular memory. In principle, this is a familiar concept. It is a fact that things that are actively repeated and practiced are better memorized. However, we assume that a reactivation of memory contents may also happen spontaneously without there being an external trigger.”

A memory test inside the scanner
Axmacher and his team tested this hypothesis in an experiment that involved ten healthy participants with an average age of 24 years. They were shown a series of pictures, which displayed – among other things – frogs, trees, airplanes and people. Each of these pictures was associated with a white square as a label at a different location. The subjects were asked to memorize the position of the square. At the end of the experiment all images were shown again, but this time without the label. The study participants were then asked to indicate with a mouse cursor where the missing mark was originally located. Memory performance was measured as the distance between the correct and the indicated position.

“This is an associative task. Visual and spatial perceptions have to be linked together”, the researcher explains. “Such tasks involve several brain regions. These include the visual cortex and the hippocampus, which takes part in many memory processes.”

Brain activity was recorded by fMRI during the entire experiment, which lasted several hours and included resting periods and a nap inside the neuroimaging scanner.

Recurrent brain patterns increased the accuracy
For data processing a pattern recognition algorithm was trained to look for similarities between neuronal patterns observed during initial encoding and patterns appearing at later occasions. “This method is complex, but quite effective”, Axmacher says. “Analysis showed that neuronal activity associated with images that were shown initially did reappear during subsequent resting periods and in the sleeping phase.”

Memory performance correlated with the replay of neuronal activity patterns. “The more frequently a pattern had reappeared, the more accurate test participants could label the corresponding image”, Axmacher summarizes the findings. “These results support our assumption that neural patterns can spontaneously reappear and that they promote the formation of long-lasting memory contents. There was already evidence for this from animal studies. Our experiment shows that this phenomenon also happens in humans.”

Memory performance benefits from resting periods
The study indicates that resting periods can generally foster memory performance. “Though, our data did not show whether sleeping had a particular effect. This may be due to the experimental setup, which only allowed for a comparatively short nap”, Axmacher reckons. “By contrast, night sleep is considered to be beneficial for the consolidation of memory contents. But it usually takes many hours and includes multiple transitions between different stages of sleep. However, other studies suggest that even short naps may positively affect memory consolidation.”

An objective look at memory contents
It is up to speculation whether the recurring brain patterns triggered conscious memories or whether they remained below the threshold of perception. “I think it is reasonable to assume that during resting periods the test participants let their mind wander and that they recalled images they had just seen before. But this is a matter of subjective perception of the test participants. That’s something we did not look at because it is not essential for our investigation“, Axmacher says. “The strength of our approach lies rather in the fact that we look at memory contents from the outside, in an objective manner. And that we can evaluate them by pattern recognition. This opens ways to many questions of research. For example, brain patterns that reoccur spontaneously are also of interest in the context of experimental dream research.”

Even with today’s technology, it still takes both a male and a female to make a baby. But is it important for both parents to raise that child? Many studies have outlined the value of a mother, but few have clearly defined the importance of a father, until now. New findings from the Research Institute of the McGill University Health Centre (RI-MUHC) show that the absence of a father during critical growth periods, leads to impaired social and behavioural abilities in adults. This research, which was conducted using mice, was published today in the journal Cerebral Cortex. It is the first study to link father absenteeism with social attributes and to correlate these with physical changes in the brain.

“Although we used mice, the findings are extremely relevant to humans,” says senior author Dr. Gabriella Gobbi, a researcher of the Mental Illness and Addiction Axis at the RI-MUHC and an associate professor at the Faculty of Medicine at McGill University. “We used California mice which, like in some human populations, are monogamous and raise their offspring together.” 

“Because we can control their environment, we can equalize factors that differ between them,” adds first author, Francis Bambico, a former student of Dr. Gobbi at McGill and now a post-doc at the Centre for Addiction and Mental Health (CAMH) in Toronto. “Mice studies in the laboratory may therefore be clearer to interpret than human ones, where it is impossible to control all the influences during development.”

Dr. Gobbi and her colleagues compared the social behaviour and brain anatomy of mice that had been raised with both parents to those that had been raised only by their mothers. Mice raised without a father had abnormal social interactions and were more aggressive than counterparts raised with both parents. These effects were stronger for female offspring than for their brothers. Females raised without fathers also had a greater sensitivity to the stimulant drug, amphetamine. 

“The behavioural deficits we observed are consistent with human studies of children raised without a father,” says Dr. Gobbi, who is also a psychiatrist at the MUHC. “These children have been shown to have an increased risk for deviant behaviour and in particular, girls have been shown to be at risk for substance abuse. This suggests that these mice are a good model for understanding how these effects arise in humans.” 

In pups deprived of fathers, Dr. Gobbi’s team also identified defects in the mouse prefrontal cortex, a part of the brain that helps control social and cognitive activity, which is linked to the behaviourial deficits.

“This is the first time research findings have shown that paternal deprivation during development affects the neurobiology of the offspring,” says Dr. Gobbi. These results should incite researchers to look more deeply into the role of fathers during critical stages of growth and suggest that both parents are important in children’s mental health development.

A UW-Madison research team reports today that the brain can produce and release estrogen — a discovery that may lead to a better understanding of hormonal changes observed from before birth throughout the entire aging process.

The new research shows that the hypothalamus can directly control reproductive function in rhesus monkeys and very likely performs the same action in women.

Scientists have known for about 80 years that the hypothalamus, a region in the brain, is involved in regulating the menstrual cycle and reproduction. Within the past 40 years, they predicted the presence of neural estrogens, but they did not know whether the brain could actually make and release estrogen.

Most estrogens, such as estradiol, a primary hormone that controls the menstrual cycle, are produced in the ovaries. Estradiol circulates throughout the body, including the brain and pituitary gland, and influences reproduction, body weight, and learning and memory. As a result, many normal functions are compromised when the ovaries are removed or lose their function after menopause.

"Discovering that the hypothalamus can rapidly produce large amounts of estradiol and participate in control of gonadotropin-releasing hormone neurons surprised us," says Ei Terasawa, professor of pediatrics at the UW School of Medicine and Public Health and senior scientist at the Wisconsin National Primate Research Center. "These findings not only shift the concept of how reproductive function and behavior is regulated but have real implications for understanding and treating a number of diseases and disorders."

For diseases that may be linked to estrogen imbalances, such as Alzheimer’s disease, stroke, depression, experimental autoimmune encephalomyelitis and other autoimmune disorders, the hypothalamus may become a novel area for drug targeting, Terasawa says. “Results such as these can point us in new research directions and find new diagnostic tools and treatments for neuroendocrine diseases.”

The study, published today in the Journal of Neuroscience, “opens up entirely new avenues of research into human reproduction and development, as well as the role of estrogen action as our bodies age,” reports the first author of the paper, Brian Kenealy, who earned his Ph.D. this summer in the Endocrinology and Reproductive Physiology Program at UW-Madison. Kenealy performed three studies. In the first experiment, a brief infusion of estradiol benzoate administered into the hypothalamus of rhesus monkeys that had surgery to remove their ovaries rapidly stimulated GnRH release. The brain took over and began rapidly releasing this estrogen in large pulsing surges.

In the second experiment, mild electrical stimulation of the hypothalamus caused the release of both estrogen and GnRH (thus mimicking how estrogen could induce a neurotransmitter-like action). Third, the research team infused letrazole, an aromatase inhibitor that blocks the synthesis of estrogen, resulting in a lack of estrogen as well as GnRH release from the brain. Together, these methods demonstrated how local synthesis of estrogen in the brain is important in regulating reproductive function.

The reproductive, neurological and immune systems of rhesus macaques have proven to be excellent biomedical models for humans over several decades, says Terasawa, who focuses on the neural and endocrine mechanisms that control the initiation of puberty. “This work is further proof that these animals can teach us about so many basic functions we don’t fully understand in humans.”

Leading up to this discovery, Terasawa said, recent evidence had shown that estrogen acting as a neurotransmitter in the brain rapidly induced sexual behavior in quails and rats. Kenealy’s work is the first evidence of this local hypothalamic action in primates, and in those that don’t even have ovaries.

"The discovery that the primate brain can make estrogen is key to a better understanding of hormonal changes observed during every phase of development, from prenatal to puberty, and throughout adulthood, including aging," Kenealy says.

In a new paper published in the current issue of Neuron, McLean Hospital and Harvard Medical School researchers report that increased activity in the medial prefrontal cortex (mPFC) of the brain is linked to decreased activity in the amygdala, the portion of the brain used in the creation of memories of events that scared those exposed.

According to author Vadim Bolshakov, PhD, director of the Cellular Neurobiology Laboratory at McLean and professor at Harvard Medical School, this finding is significant in that it could lead to better methods to prevent PTSD.

"A single exposure to something traumatic or scary can be enough to create a fear memory—causing someone to expect and be afraid in similar situations in the future," said Bolshakov. "What we’re seeing is that we may one day be able to prevent those fear memories."

Bolshakov and his colleagues tested their theory using animal models. Dividing the mice into two groups, some were taught to fear an auditory stimulus while in others fear memory was extinguished Increased activation of mPFC in extinguished animals led to inhibition of the amygdala and significant decreases in fear responses.

"For example, if a sound ended with an extremely loud shriek, a subject would come to expect that scary noise at the end of the sound," explained Bolshakov. "What we found was when we suppressed the fear memory by decreasing activity in the amygdala, the subjects were not afraid of the end of the auditory stimulus any longer."

Bolshakov notes that this work could have serious implications for the treatment of a number of conditions including PTSD.

"While there is still a great deal of research that needs to be done before our work can be translated to clinical trials, what we are showing has the potential to ensure that individuals exposed to trauma were not haunted by the conditions surrounding their initial stressor."

Fear, at the right level, can increase alertness and protect against dangers. Disproportionate fear, on the other hand, can disrupt the sensory perception, be disabling, reduce happiness and therefore become a danger in itself.  Anxiety disorders are therefore a psychiatric condition that should not be underestimated. In these disorders, the fear is so strong that there is tremendous psychological strain and living a normal life appears to be impossible. Researchers at the MedUni Vienna have now found a possible explanation as to how social phobias and fear can be triggered in the brain: a missing inhibitory connection or missing “brake” in the brain.

Inside the brain, the amygdala and the orbitofrontal cortex in the frontal lobe form an important control circuit for regulating the emotions. This control circuit is termed the brain’s emotional control centre. Whereas in healthy subjects, this circuit has “negative feedback” and “calmness” was identified, scientists used functional magnetic resonance imaging (MRI) on people with social phobias and found the opposite to be true: an important inhibitory connection is different in these patients, which may explain why they are unable to control their fears.

In collaboration with the Centre for Medical Physics and Biomedical Technology and the University Department of Psychiatry and Psychotherapy at the MedUni Vienna, the research team lead by Christian Windischberger was also able to discover through its recent study at the MedUni Vienna’s High Field MR Centre of Excellence how the areas of the brain that are involved with processing emotions are able to influence each other.

The study participants were shown a series of “emotional faces” while undergoing functional magnetic resonance imaging. fMRI is a non-invasive method which uses radio waves and magnetic fields to measure changes in the levels of oxygen in the blood and therefore neuronal activity in individual regions of the brain. An analysis method developed at University College London was used to provide new perspectives on the data obtained.

Breaking the circle of fear
When emotional facial expressions were shown - from laughing to crying, from happiness to anger - neuronal activity was triggered in the brain. The result: on a purely external basis, the test subjects looked no different, but the healthy subjects were kept calm thanks to their automatic “brake”, despite the emotional nature of the images. For the social phobics, on the other hand, the photographs put their brains into “overdrive”, triggering very strong neuronal activity. This was demonstrated very clearly using the new analysis method: “We have the opportunity not only to localise brain activity and compare it between groups, but we can now also make statements regarding functional connections within the brain. In psychiatric conditions especially, we can assume that there are not complete failures of these connections going on, but rather imbalances in complex regulatory processes,” says Ronald Sladky, the study’s primary author.

This better understanding of the neuronal mechanisms involved will now be used to develop new approaches to treatment. The aim is to understand what effect medications and psycho-therapeutic support have on the networks involved in order to help patients break out of their circles of fear.

The ability to localize the source of sound is important for navigating the world and for listening in noisy environments like restaurants, an action that is particularly difficult for elderly or hearing impaired people. Having two ears allows animals to localize the source of a sound. For example, barn owls can snatch their prey in complete darkness by relying on sound alone. It has been known for a long time that this ability depends on tiny differences in the sounds that arrive at each ear, including differences in the time of arrival: in humans, for example, sound will arrive at the ear closer to the source up to half a millisecond earlier than it arrives at the other ear. These differences are called interaural time differences. However, the way that the brain processes this information to figure out where the sound came from has been the source of much debate.

A recent paper by Mass. Eye and Ear/Harvard Medical School researchers in collaboration with researchers at the Ecole Normale Superieure, France, challenge the two dominant theories of how people localize sounds, explain why neuronal responses to sounds are so diverse and show how sound can be localized, even with the absence of one half of the brain. Their research is described on line in the journal eLife.

“Progress has been made in laboratory settings to understand how sound localization works, but in the real world people hear a wide range of sounds with background noise and reflections,” said Dan F. M. Goodman, lead author and post-doctoral fellow in the Eaton-Peabody Laboratories at Mass. Eye and Ear, Harvard Medical School. “Theories based on more realistic environments are important. The theme of the paper is that previous theories about this have been too idealized, and if you use more realistic data, you come to an entirely different conclusion.”

“Two theories have come to dominate our understanding of how the brain localizes sounds: the peak coding theory (which says that only the most strongly responding brain cells are needed), and the hemispheric coding theory (which says that only the average response of the cells in the two hemispheres of the brain are needed),” Goodman said. “What we’ve shown in this study is that neither of these theories can be right, and that the evidence they presented only works because their experiments used unnatural/idealized sounds. If you use more realistic, natural sounds, then they both do very badly at explaining the data.”

Researchers showed that to do well with realistic sounds, one needs to use the whole pattern of neural responses, not just the most strongly responding or average response. They showed two other key things: first, it has long been known that the responses of different auditory neurons are very diverse, but this diversity was not used in the hemispheric coding theory.

“We showed that the diversity is essential to the brain’s ability to localize sounds; if you make all the responses similar then there isn’t enough information, something that was not appreciated before because if one has unnatural/idealized sounds you don’t see the difference” Goodman said.

Second, previous theories are inconsistent with the well-known fact that people are still able to localize sounds if they lose one half of our brain, but only sounds on the other side (i.e. if one loses the left half of the brain, he or she can still localize sounds coming from the right), he added.

“We can explain why this is the case with our new theory,” Goodman said.

People who carry a high-risk gene for Alzheimer’s disease show changes in their brains beginning in childhood, decades before the illness appears, new research from the Centre for Addiction and Mental Health (CAMH) suggests.

The gene, called SORL1, is one of a number of genes linked to an increased risk of late-onset Alzheimer’s disease, the most common form of the illness. SORL1 carries the gene code for the sortilin-like receptor, which is involved in recycling some molecules in the brain before they develop into beta-amyloid a toxic Alzheimer protein. SORL1 is also involved in lipid metabolism, putting it at the heart of the vascular risk pathway for Alzheimer’s disease as well.

“We need to understand where, when and how these Alzheimer’s risk genes affect the brain, by studying the biological pathways through which they work,” says Dr. Aristotle Voineskos, head of the Kimel Family Translational Imaging-Genetics Laboratory at CAMH, who led the study. “Through this knowledge, we can begin to design interventions at the right time, for the right people.” The study was recently published online in Molecular Psychiatry with Dr. Voineskos’s graduate student, Daniel Felsky as first author, and was a collaborative effort with the Zucker Hillside Hospital/Feinstein Institute in New York and the Rush Alzheimer’s Disease Center in Chicago.

To understand SORL1’s effects across the lifespan, the researchers studied individuals both with and without Alzheimer’s disease. Their approach was to identify genetic differences in SORL1, and see if there was a link to Alzheimer’s-related changes in the brain, using imaging as well as post-mortem tissue analysis.

In each approach, a link was confirmed.

In the first group of healthy individuals, aged eight to 86, researchers used a brain imaging technique called diffusion tensor imaging (DTI). Even among the youngest participants in the study, those with a specific copy of SORL1 showed a reduction in white matter connections in the brain important for memory performance and executive function. 

The second sample included post-mortem brain tissue from 189 individuals less than a year old to 92 years, without Alzheimer’s disease. Among those with that same copy of the SORL1 gene, the brain tissue showed a disruption in the process by which the gene translated its code to become the sortilin-like receptor.

Finally, the third set of post-mortem brains came from 710 individuals, aged 66 to 108, of whom the majority had mild cognitive impairment or Alzheimer’s. In this case, the SORL1 risk gene was linked with the presence of amyloid-beta, a protein found in Alzheimer’s disease. 

Dr. Voineskos notes that risk for Alzheimer’s disease results from a combination of factors – unhealthy diet, lack of exercise, smoking, high blood pressure combined with a person’s genetic profile – which all contribute to the development of the illness. “The gene has a relatively small effect, but the changes are reliable, and may represent one ‘hit’, among a pathway of hits required to develop Alzheimer’s disease later in life”.

While it’s too early to provide interventions that may target these changes, “individuals can take measures in their own lifestyle to reduce the risk of late-onset Alzheimer’s disease.” Determining whether there is an interaction with this risk gene and lifestyle factors will be one important next step.

In order to develop genetically-based interventions to prevent Alzheimer’s disease, the biological pathways of other risk genes also need to be systematically analyzed, the researchers note.

This research does, however, build on a previous CAMH imaging-genetics study on another gene related to Alzheimer’s disease. That study showed that a genetic variation of brain-derived neurotrophic factor (BDNF) affected brain structures in Alzheimer’s.

“The interesting connection is that BDNF may have important therapeutic value. But there is data to suggest that the effects of BDNF won’t work unless SORL1 is present, so there is the possibility that if you boost the activity of one gene, the other will increase,” says Dr. Voineskos, adding that BDNF therapeutics are in development. A next stage in the research, he says, is to look at the interaction of BDNF and SORL1.

A new study led by University of Kentucky researchers suggests that a diet low in vitamin D causes damage to the brain.

In addition to being essential for maintaining bone health, newer evidence shows that vitamin D serves important roles in other organs and tissue, including the brain. Published in Free Radical Biology and Medicine, the UK study showed that middle-aged rats that were fed a diet low in vitamin D for several months developed free radical damage to the brain, and many different brain proteins were damaged as identified by redox proteomics. These rats also showed a significant decrease in cognitive performance on tests of learning and memory.

"Given that vitamin D deficiency is especially widespread among the elderly, we investigated how during aging from middle-age to old-age how low vitamin D affected the oxidative status of the brain," said lead author on the paper Allan Butterfield, professor in the UK Department of Chemistry, director of the Center of Membrane Sciences, faculty of Sanders-Brown Center on Aging, and director of the Free Radical Biology in Cancer Core of the Markey Cancer Center. “Adequate vitamin D serum levels are necessary to prevent free radical damage in brain and subsequent deleterious consequences."

Previously, low levels of vitamin D have been associated with Alzheimer’s disease, and it’s also been linked to the development of certain cancers and heart disease. In both the developed world and in areas of economic hardship where food intake is not always the most nutritious, vitamin D levels in humans are often low, particularly in the elderly population. Butterfield recommends persons consult their physicians to have their vitamin D levels determined, and if low that they eat foods rich in vitamin D, take vitamin D supplements, and/or get at least 10-15 minutes of sun exposure each day to ensure that vitamin D levels are normalized and remain so to help protect the brain.

Exposure to air pollution appears to increase the risk for autism among people who carry a genetic disposition for the neurodevelopmental disorder, according to newly published research led by scientists at the Keck School of Medicine of the University of Southern California (USC).

"Our research shows that children with both the risk genotype and exposure to high air pollutant levels were at increased risk of autism spectrum disorder compared to those without the risk genotype and lower air pollution exposure," said the study’s first author, Heather E. Volk, Ph.D., M.P.H., assistant professor of research in preventive medicine and pediatrics at the Keck School of Medicine of USC and principal investigator at The Saban Research Institute of Children’s Hospital Los Angeles.

The study, “Autism spectrum disorder: Interaction of air pollution with the MET receptor tyrosine kinase gene,” is scheduled to appear in the January 2014 edition of Epidemiology.

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disability characterized by problems with social interaction, communication and repetitive behaviors. The Centers for Disease Control and Prevention estimates that one in 88 children in the United States has an ASD.

ASD is highly heritable, suggesting that genetics are an important contributing factor, but many questions about its causes remain. There currently is no cure for the disorder.

"Although gene-environment interactions are widely believed to contribute to autism risk, this is the first demonstration of a specific interaction between a well-established genetic risk factor and an environmental factor that independently contribute to autism risk," said Daniel B. Campbell, Ph.D., assistant professor of psychiatry and the behavioral sciences at the Keck School of Medicine of USC and the study’s senior author. "The MET gene variant has been associated with autism in multiple studies, controls expression of MET protein in both the brain and the immune system, and predicts altered brain structure and function. It will be important to replicate this finding and to determine the mechanisms by which these genetic and environmental factors interact to increase the risk for autism."

Independent studies by Volk and Campbell have previously reported associations between autism and air pollution exposure and between autism and a variant in the MET gene. The current study suggests that air pollution exposure and the genetic variant interact to augment the risk of ASD.

Campbell and Volk’s team studied 408 children between 2 and 5 years of age from the Childhood Autism Risks From Genetics and the Environment Study, a population-based, case-control study of preschool children from California. Of those, 252 met the criteria for autism or autism spectrum disorder. Air pollution exposure was determined based on the past residences of the children and their mothers, local traffic-related sources, and regional air quality measures. MET genotype was determined through blood sampling.

Campbell and Volk continue to study the interaction of air pollution exposure and the MET genotype in mothers during pregnancy.

Premature birth appears to trigger developmental processes in the white matter of the brain that could put children at higher risk of problems later in life, according to a study being presented next week at the annual meeting of the Radiological Society of North America (RSNA).

Preterm infants—generally those born 23 to 36 weeks after conception, as opposed to the normal 37- to 42-week gestation—face an increased risk of behavioral problems, ranging from impulsiveness and distractibility to more serious conditions like autism and attention deficit hyperactivity disorder (ADHD).

"In the United States, we have approximately 500,000 preterm births a year," said Stefan Blüml, Ph.D., director of the New Imaging Technology Lab at Children’s Hospital Los Angeles and associate professor of research radiology at the University of Southern California in Los Angeles. "About 60,000 of these babies are at high risk for significant long-term problems, which means that this is a significant problem with enormous costs."

Dr. Blüml and colleagues have been studying preterm infants to learn more about how premature birth might cause changes in brain structure that may be associated with clinical problems observed later in life. Much of the focus has been on the brain’s white matter, which transmits signals and enables communication between different parts of the brain. While some white matter damage is readily apparent on structural magnetic resonance imaging (MRI), Dr. Blüml’s group has been using magnetic resonance spectroscopy (MRS) to look at differences on a microscopic level.

In this study, the researchers compared the concentrations of certain chemicals associated with mature white matter and gray matter in 51 full-term and 30 preterm infants. The study group had normal structural MRI findings, but MRS results showed significant differences in the biochemical maturation of white matter between the term and preterm infants, suggesting a disruption in the timing and synchronization of white and gray matter maturation. Gray matter is the part of the brain that processes and sends out signals.

"The road map of brain development is disturbed in these premature kids," Dr. Blüml said. "White matter development had an early start and was ‘out of sync’ with gray matter development."

This false start in white matter development is triggered by events after birth, according to Dr. Blüml.

"This timeline of events might be disturbed in premature kids because there are significant physiological switches at birth, as well as stimulatory events, that happen irrespective of gestational maturity of the newborn," he said. "The most apparent change is the amount of oxygen that is carried by the blood."

Dr. Blüml said that the amount of oxygen delivered to the fetus’s developing brain in utero is quite low, and our brains have evolved to optimize development in that low oxygen environment. However, when infants are born, they are quickly exposed to a much more oxygen-rich environment.

"This change may be something premature brains are not ready for," he said.

While this change may cause irregularities in white matter development, Dr. Blüml noted that the newborn brain has a remarkable capacity to adapt or even “re-wire” itself—a concept known as plasticity. Plasticity not only allows the brain to govern new skills over the course of development, like learning to walk and read, but could also make the brains of preterm infants and young children more responsive to therapeutic interventions, particularly if any abnormalities are identified early.

"Our research points to the need to better understand the impact of prematurity on the timing of critical maturational processes and to develop therapies aimed at regulating brain development," Dr. Blüml said.

Asparagine, found in foods such as meat, eggs, and dairy products, was until now considered non-essential because it is produced naturally by the body. Researchers at the University of Montreal and its affiliated CHU Sainte-Justine Hospital found that the amino acid is essential for normal brain development. This is not the case for other organs. “The cells of the body can do without it because they use asparagine provided through diet. Asparagine, however, is not well transported to the brain via the blood-brain barrier,” said senior co-author of the study Dr. Jacques Michaud, who found that brain cells depend on the local synthesis of asparagine to function properly. First co-author José-Mario Capo-Chichi and colleague Grant Mitchell also made major contributions to the study.

In April 2009, a Quebec family experienced the worst tragedy for parents: before the age of one, one of their sons died of a rare genetic disease causing congenital microcephaly, intellectual disability, cerebral atrophy, and refractory seizures. The event was even more tragic because it was the third infant to die in this family from the same disease.

This tragedy led Dr. Michaud to discover the genetic abnormality responsible for this developmental disorder. “We are not at the verge of a miracle drug,” Michaud said, “but we at least know where to look.”

The team identified the gene affected by the mutation code for asparagine synthetase, the enzyme responsible for synthesizing the amino acid asparagine. The study is the first to associate a specific genetic variant with a deficiency of this enzyme. “In healthy subjects, it seems that the level of asparagine synthetase in the brain is sufficient to supply neurons,” Michaud said. “In individuals with the disability, the enzyme is not produced in sufficient quantity, and the resulting asparagine depletion affects the proliferation and survival of cells during brain development.”

Potential treatment

Children who are carriers of this mutation suffer, to varying degrees, from a variety of symptoms, including intellectual disability and cerebral atrophy, which can lead to death. The Quebec family lost three infant sons to this disorder. Two of their other children are alive and healthy.

Knowledge about gene mutations can be used to develop treatments. “Our results not only open the door to a better understanding of the disease,” Michaud said, “but they also give us valuable information about the molecular mechanisms involved in brain development, which is important for the development of new treatments.”

For example, asparagine supplement could be given to infants to ensure an adequate level of asparagine in the brain and the latter’s normal development. “The amount of supplementation remains to be determined, as well as its effectiveness,” said the geneticist. “Since these children are already born with neurological abnormalities, it is uncertain whether this supplementation would correct the neurological deficits.”

Creating a pediatric clinical genomics centre

To date, nine children from four different families have been identified as carriers of the mutation: three infants from Quebec, three from a Bengali family living in Toronto, and three Israelis, whose symptoms are less severe.

Dr. Michaud’s team discovered the genetic mutation by comparing the complete DNA of the Quebec family’s children with symptoms of the disease. The researchers then identified children, among other families, who carried the single candidate gene. The gene was revealed only in the affected children, but not in the unaffected children of the families studied.

The discovery comes at a time when CHU Sainte-Justine Mother and Child University Hospital has reached an agreement with Génome Québec to create the first pediatric clinical genomic centre in Canada. “This initiative will transform the quality of care for younger patients to ensure better prevention from childhood,” says Dr. Michaud. “More than 80% of genetic diseases occur in childhood or adolescence. “This new technology will allow us to sequence all the genes in the genome and obtain a genetic portrait of the children more quickly to know which disease they suffer from and to provide treatment, if available, or when it becomes available.”

A new discovery may help explain the surprisingly strong connections between sleep problems and neurodegenerative conditions such as Alzheimer’s disease. Sleep loss increases the risk of Alzheimer’s disease, and disrupted sleeping patterns are among the first signs of this devastating disorder.

Scientists at Washington University School of Medicine in St. Louis and the University of Pennsylvania have shown that brain cell damage similar to that seen in Alzheimer’s disease and other disorders results when a gene that controls the sleep-wake cycle and other bodily rhythms is disabled.

The researchers found evidence that disabling a circadian clock gene that controls the daily rhythms of many bodily processes blocks a part of the brain’s housekeeping cycle that neutralizes dangerous chemicals known as free radicals.

“Normally in the hours leading up to midday, the brain increases its production of certain antioxidant enzymes, which help clean up free radicals,” said first author Erik Musiek, MD, PhD, assistant professor of neurology at the School of Medicine. “When clock genes are disabled, though, this surge no longer occurs, and the free radicals may linger in the brain and cause more damage.”

Musiek conducted the research in the labs of Garret FitzGerald, MD, chairman of pharmacology at the University of Pennsylvania, and of David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology at Washington University School of Medicine, who are co-senior authors.

The study appears Nov. 25 in The Journal of Clinical Investigation.

Musiek studied mice lacking a master clock gene called Bmal1. Without this gene, activities that normally occur at particular times of day are disrupted.

“For example, mice normally are active at night and asleep during the day, but when Bmal1 is missing, they sleep equally in the day and in the night, with no circadian rhythm,” Musiek said. “They get the same amount of sleep, but it’s spread over the whole day. Rhythms in the way genes are expressed are lost.”

FitzGerald uses mice lacking Bmal1 to study whether clock cells have links to diabetes and heart disease. He has shown that clock genes influence blood pressure, blood sugar and lipid levels.

Several years ago, Musiek, who at the time was a neurology resident at the University of Pennsylvania, and FitzGerald decided to investigate how knocking out Bmal1 affects the brain. Holtzman, who has published pioneering work on sleep and Alzheimer’s disease, encouraged Musiek to continue and expand these studies when he came to Washington University as a postdoctoral fellow.

In the new study, Musiek found that as the mice aged, many of their brain cells became damaged and did not function normally. The patterns of damage were similar to those seen in Alzheimer’s disease and other neurodegenerative disorders.

“Brain cell injury in these mice far exceeded that normally seen in aging mice,” Musiek said. “Many of the injuries appear to be caused by free radicals, which are byproducts of metabolism. If free radicals come into contact with brain cells or other tissue, they can cause damaging chemical reactions.”

This led Musiek to examine the production of key antioxidant enzymes, which usually neutralize and help clear free radicals from the brain, thereby limiting damage. He found levels of several antioxidant proteins peak in the middle of the day in healthy mice. However, this surge is absent in mice lacking Bmal1. Without the surge, free radicals may remain in the brain longer, contributing to the damage Musiek observed.

“We’re trying to identify more specifics about how problems in clock genes contribute to neurodegeneration, both with and without influencing sleep,” Musiek said. “That’s a challenging distinction to make, but it needs to be made because clock genes appear to control many other functions in the brain in addition to sleeping and waking.”