Same musicians: brand new tune

A small ensemble of musicians can produce an infinite number of melodies, harmonies and rhythms. So too, do a handful of workhorse signaling pathways that interact to construct multiple structures that comprise the vertebrate body. In fact, crosstalk between two of those pathways—those governed by proteins known as Notch and BMP (for Bone Morphogenetic Protein) receptors—occurs over and over in processes as diverse as forming a tooth, sculpting a heart valve and building a brain.

A new study by Stowers Institute for Medical Research Investigator Ting Xie, Ph.D., reveals yet another duet played by Notch and BMP signals, this time with Notch calling the tune. That work, published in this week’s online issue of PNAS, uses mouse genetics to demonstrate how one Notch family protein, Notch2, shapes an eye structure known as the ciliary body (CB), most likely by ensuring that BMP signals remain loud and clear.

In vertebrates, the CB encircles the lens and performs two tasks essential for normal vision. First, it contains a tiny muscle that reshapes the lens when you change focus, or “accommodate”. And it also secretes liquid aqueous humor into the front compartment of the eye where it likely maintains correct eye pressure. Understanding CB construction is critical, as excessive pressure is one risk factor for glaucoma.

Eye development is a relatively new field for Xie, a recognized leader in the study of adult stem cells in the fruit fly: only recently did he branch out into mouse studies. “A few years ago I was asked to participate in a think tank-type meeting to discuss the potential application of cell therapy to treat glaucoma,” he says.
“I became interested in using retinal progenitor cells to treat diseases like glaucoma or macular degeneration. But I realized that first we needed to understand eye disease at the molecular level.” The new study is an important step in that direction.

Previously, investigators knew that once cells that form the CB are established in an embryo, the BMP pathway drives their “morphogenesis”, the term used by developmental biologists to describe the process of expanding and then sculpting a committed population of cells into a unique structure. “The Notch2 receptor was previously shown to be expressed in the developing mouse eye,” explains Chris Tanzie, M.D., Ph.D., a former graduate student in the Xie lab and the study’s co-first author. “But its function was unknown, and no one connected how various signaling pathways direct CB morphogenesis.”

To determine what Notch2 was doing in the developing eye, the Stowers team constructed a conditional knockout mouse, meaning that the Notch2 gene is deleted from the genome only in eye cells that give rise to the CB. In normal newborn mice a series of cellular “folds” that characterize the CB emerges over the first 7 days of life. But the mutant knockout mice showed a complete absence of folds, dramatic evidence that Notch2 is required to elaborate a CB.

Furthermore, in normal mice a protein called Jagged-1, which activates Notch2, was expressed in cells adjacent to Notch2-expressing CB cells during the same developmental period. Strikingly, the team’s collaborators in Richard Libby’s laboratory at the University of Rochester Medical Center, were able to demonstrate that just like the Notch2 mutants, Jagged-1 conditional knockout mice showed almost total loss of CB fold structures, a major hint that Notch2 was switched on by Jagged1 to drive CB formation.

Biochemical and microarray analysis provided further explanation for defects observed after Notch2 loss. Comparison of normal and Notch2-mutant eye cells revealed that not only did cells of mutant mice lose BMP signaling but that expression of two proteins known to interfere with BMP increased in those cells.

“Up-regulation of BMP antagonists following Notch2 loss is an important observation,” says Xie. “In other systems people often observe that Notch and BMP cooperatively regulate common targets by transcription factor collaboration at the transcriptional level, but this is a unique mechanism. We find that Notch2 keeps BMP signaling active by inhibiting its inhibitors.”

The study’s second co-first author is Yi Zhou, a University of Kansas Medical Center graduate student earning his Ph.D. in Xie’s lab. “Our work reveals a novel link between Notch and BMP pathways potentially involved in the pathogenesis of glaucoma,” says Zhou, noting one more tantalizing implication of the paper. “In addition, mutations in Jagged-1 and Notch2 are thought to underlie the human genetic disease known as Alagille Syndrome. Our work may lead to a better understanding of both.”

Alagille Syndrome is an inherited childhood disorder causing defects in organ systems including liver, heart and the skeleton. Xie is equally intrigued by potential connections between his group’s observations in the mouse eye and Alagille outcomes in humans. Nonetheless, he remains focused on nailing down how perturbation of the Jagged1-Notch2-BMP axis might cause eye disease.

“We now know how to build better mouse mutants to study CB development. In this work we show that Notch regulates BMP signaling but have not yet determined whether alterations in CB structure actually change interocular pressure,” he says. “Answering that question is our future goal.”

New drug enhances radiation treatment for brain cancer in preclinical studies

A novel drug may help increase the effectiveness of radiation therapy for the most deadly form of brain cancer, report scientists at Virginia Commonwealth University Massey Cancer Center. In mouse models of human glioblastoma multiforme (GBM), the new drug helped significantly extend survival when used in combination with radiation therapy.

Recently published in the journal Clinical Cancer Research, the study provides the first preclinical evidence demonstrating that an ATM kinase inhibitor radiosensitizes gliomas. Gliomas are brain tumors that originate from glial cells, which provide support for nerve cells and help regulate the internal environment of the brain. ATM, or ataxia telangiectasia mutated, is an enzyme that helps repair DNA damage. The scientists used an experimental drug, KU-60019, to block the activation of ATM, which led to the enhanced destruction of the gliomas due to their reduced ability to repair the DNA damage caused by the radiation treatment. The new approach was particularly effective against gliomas that have a mutation in the p53 tumor suppressor gene, which accounts for approximately 30 percent of all glioma cases.

"Sadly, the average life expectancy of patients diagnosed with glioblastoma is just 12 to 15 months," says the study’s lead researcher Kristoffer Valerie, Ph.D., co-leader of the Radiation Biology and Oncology research program and a professor in the Department of Radiation Oncology at VCU Massey Cancer Center. "By limiting the tumor’s ability to combat DNA damage caused by treatments such as radiation, we are hopeful that we can enhance our ability to specifically target the glioma, prolong survival and reduce damage to surrounding brain tissue."

Currently, GBM is treated with surgery, followed by chemotherapy and radiation therapy. Potentially, ATM kinase inhibitors like the one used in this study could enhance the effectiveness of some other cancer treatments that kill tumor cells by damaging DNA. The scientists chose radiation therapy in this study since it is already standard care and can be delivered to brain tumors with extreme accuracy, minimizing damage to surrounding healthy tissue.

"If these findings hold up in early phase clinical trials, we expect patients with p53 mutant gliomas to respond well to this treatment while showing few side effects. Also, we anticipate that this same treatment strategy could be effective for other cancers that are treated with DNA-damaging chemotherapies," says Valerie. "We are encouraged by these early findings and will continue to move forward with our research. However, more studies are needed before we can proceed with testing this new therapy in humans."

This first, ‘proof-of-principle’ study is an important follow-up of a study published several years ago on KU-60019 by Valerie and his research team that demonstrated KU-60019’s superior efficacy, specificity and potency on glioma cells as compared to a predecessor ATM inhibitor.

Valerie and his team are conducting additional studies examining the effects of KU-60019 and other ATM kinase inhibitors on gliomas, including studies that combine ATM kinase inhibitors with a type of drug known as a PARP inhibitor to increase the effectiveness of the treatment. PARP inhibitors block the action of poly ADP ribose polymerase (PARP), an enzyme that also aids in the repair of DNA damage. The researchers believe that combining an ATM kinase inhibitor with a PARP inhibitor may cause a condition referred to as “synthetic lethality,” which arises when the functions of at least two interacting genes are simultaneously inhibited, which, in turn, leads to tumor cell death.

Trying to be Happier Works When Listening to Upbeat Music

The song, “Get Happy,” famously performed by Judy Garland, has encouraged people to improve their mood for decades. Recent research at the University of Missouri discovered that an individual can indeed successfully try to be happier, especially when cheery music aids the process. This research points to ways that people can actively improve their moods and corroborates earlier MU research.

“Our work provides support for what many people already do – listen to music to improve their moods,” said lead author Yuna Ferguson, who performed the study while she was an MU doctoral student in psychological science. “Although pursuing personal happiness may be thought of as a self-centered venture, research suggests that happiness relates to a higher probability of socially beneficial behavior, better physical health, higher income and greater relationship satisfaction.”

In two studies by Ferguson, participants successfully improved their moods in the short term and boosted their overall happiness over a two week period. During the first study, participants improved their mood after being instructed to attempt to do so, but only if they listened to the upbeat music of Copland, as opposed to the more somber Stravinsky. Other participants, who simply listened to the music without attempting to change their mood, also didn’t report a change in happiness. In the second study, participants reported higher levels of happiness after two weeks of lab sessions in which they listened to positive music while trying to feel happier, compared to control participants who only listened to music.

However, Ferguson noted that for people to put her research into practice, they must be wary of too much introspection into their mood or constantly asking, “Am I happy yet?”

“Rather than focusing on how much happiness they’ve gained and engaging in that kind of mental calculation, people could focus more on enjoying their experience of the journey towards happiness and not get hung up on the destination,” said Ferguson.

Ferguson’s work corroborated earlier findings by Ferguson’s doctoral advisor and co-author of the current study, Kennon Sheldon, professor of psychological science in MU’s College of Arts and Science.

“The Hedonic Adaptation Prevention model, developed in my earlier research, says that we can stay in the upper half of our ‘set range’ of potential happiness as long as we keep having positive experiences, and avoid wanting too much more than we have,” said Sheldon. “Yuna’s research suggests that we can intentionally seek to make mental changes leading to new positive experiences of life. The fact that we’re aware we’re doing this, has no detrimental effect.”

Ferguson is now assistant professor of psychology at Pennsylvania State University Shenango. The study, “Trying to Be Happier Really Can Work: Two Experimental Studies,” was published in The Journal of Positive Psychology.

Getting a grip on sleep

All mammals sleep, as do birds and some insects. However, how this basic function is regulated by the brain remains unclear. According to a new study by researchers from the RIKEN Brain Science Institute, a brain region called the lateral habenula plays a central role in the regulation of REM sleep. In an article published today in the Journal of Neuroscience, the team shows that the lateral habenula maintains and regulates REM sleep in rats through regulation of the serotonin system. This study is the first to show a role of the lateral habenula in linking serotonin metabolism and sleep.

The lateral habenula is a region of the brain known to regulate the metabolism of the neurotransmitter serotonin in the brain and to play a key role in cognitive functions.

“Serotonin plays a central role in the pathophysiology of depression, however, it is not clear how abnormalities in regulation of serotonin metabolism in the brain lead to symptoms such as insomnia in depression,” explain Dr. Hidenori Aizawa and Dr. Hitoshi Okamoto who led the study.

Since animals with increased serotonergic activity at the synapse experienced less REM sleep, the researchers hypothesized that the lateral habenula, which regulates serotonergic activity in the brain, must modulate the duration of REM sleep.

They show that removing the lateral habenula in rats results in a reduction of theta rhythm, an oscillatory activity that appears during REM sleep, in the hippocampus, and shortens the rats’ REM sleep periods. However, this inhibitory effect of the lateral habenular lesion on REM sleep disappears when the serotonergic neurons in the midbrain are lesioned.

The team recorded neural activity simultaneously in the lateral habenula and hippocampus in a sleeping rat. They find that the lateral habenular neurons, which fire persistently during non-REM sleep, begin to fire rhythmically in accordance with the theta rhythm in the hippocampus when the animal is in REM sleep.

“Our results indicate that the lateral habenula is essential for maintaining theta rhythms in the hippocampus, which characterize REM sleep in the rat, and that this is done via serotonergic modulation,” concludes Dr Aizawa.

“This study reveals a novel role of the lateral habenula, linking serotonin and REM sleep, which suggests that an hyperactive habenula in patients with depression may cause altered REM sleep,” add the authors.

Wireless signals could transform brain trauma diagnostics

New technology developed at the University of California, Berkeley, is using wireless signals to provide real-time, non-invasive diagnoses of brain swelling or bleeding.

The device analyzes data from low energy electromagnetic waves that are similar to those used to transmit radio and mobile signals. The technology, described in the May 14 issue of the journal PLOS ONE, could potentially become a cost-effective tool for medical diagnostics and to triage injuries in areas where access to medical care, especially medical imaging, is limited.

The researchers tested a prototype in a small-scale pilot study of healthy adults and brain trauma patients admitted to a military hospital for the Mexican Army. The results from the healthy participants were clearly distinguishable from the patients with brain damage, and data for bleeding was distinct from data for swelling.

Boris Rubinsky, Professor of the Graduate School at UC Berkeley’s Department of Mechanical Engineering, led the research team along with César A. González, a professor in Mexico at the Instituto Politécnico Nacional, Escuela Superior de Medicina (National Polytechnic Institute’s Superior School of Medicine).

“There are large populations in Mexico and the world that do not have adequate access to advanced medical imaging, either because it is too costly or the facilities are far away,” said González. “This technology is inexpensive, it can be used in economically disadvantaged parts of the world and in rural areas that lack industrial infrastructure, and it may substantially reduce the cost and change the paradigm of medical diagnostics. We have also shown that the technology could be combined with cell phones for remote diagnostics.”

Rubinsky noted that symptoms of serious head injuries and brain damage are not always immediately obvious, and for treatment, time is of the essence. For example, the administration of clot-busting medication for certain types of strokes must be given within three hours of the onset of symptoms.

“Some people might delay traveling to a hospital to get examined because it is an hour or more away, or because it is exceedingly expensive,” said Rubinsky. “If people had access to an affordable device that could indicate whether there is brain damage or not, they could then make an informed decision about making that trip to a facility to get prompt treatment, which is especially important for head injuries.” 

The researchers took advantage of the characteristic changes in tissue composition and structure in brain injuries. For brain edemas, swelling results from an increase in fluid in the tissue. For brain hematomas, internal bleeding causes the buildup of blood in certain regions of the brain. Because fluid conducts electricity differently than brain tissue, it is possible to measure changes in electromagnetic properties. Computer algorithms interpret the changes to determine the likelihood of injury.

The study involved 46 healthy adults, ages 18 to 48, and eight patients with brain damage, ages 27 to 70.

The engineers fashioned two coils into a helmet-like device that was fitted over the heads of the study participants. One coil acted as a radio emitter and the other served as the receiver. Electromagnetic signals were broadcast through the brain from the emitter to the receiver.

“We have adjusted the coils so that if the brain works perfectly, we have a clean signal,” said Rubinsky. “Whenever there are interferences in the functioning of the brain, we detect them as changes in the received signal. We can tell from the changes, or ‘noises,’ what the brain injury is.”

Rubinsky noted that the waves are extremely weak, and are comparable to standing in a room with the radio or television turned on.

The device’s diagnoses for the brain trauma patients in the study matched the results obtained from conventional computerized tomography (CT) scans.

The tests also revealed some insights into the aging brain.

“With an increase in age, the average electromagnetic transmission signature of a normal human brain changes and approaches that of younger patients with a severe medical condition of hematoma in the brain,” said González. “This suggests the potential for the device to be used as an indication for the health of the brain in older patients in a similar way in which measurements of blood pressure, ECG, cholesterol or other health markers are used for diagnostic of human health conditions.”

Brain-Imaging Study Links Cannabinoid Receptors to Post-Traumatic Stress Disorder—Findings Bring First Pharmaceutical Treatment for Ptsd Within Reach—

In a first-of-its-kind effort to illuminate the biochemical impact of trauma, researchers at NYU Langone Medical Center have discovered a connection between the quantity of cannabinoid receptors in the human brain, known as CB1 receptors, and post-traumatic stress disorder, the chronic, disabling condition that can plague trauma victims with flashbacks, nightmares and emotional instability. Their findings, which appear online today in the journal Molecular Psychiatry, will also be presented this week at the annual meeting of the Society of Biological Psychiatry in San Francisco.

CB1 receptors are part of the endocannabinoid system, a diffuse network of chemicals and signaling pathways in the body that plays a role in memory formation, appetite, pain tolerance and mood. Animal studies have shown that psychoactive chemicals such as cannabis, along with certain neurotransmitters produced naturally in the body, can impair memory and reduce anxiety when they activate CB1 receptors in the brain. Lead author Alexander Neumeister, MD, director of the molecular imaging program in the Departments of Psychiatry and Radiology at NYU School of Medicine, and colleagues are the first to demonstrate through brain imaging that people with PTSD have markedly lower concentrations of at least one of these neurotransmitters —an endocannabinoid known as anandamide—than people without PTSD. Their study, which was supported by three grants from the National Institutes of Health, illuminates an important biological fingerprint of PTSD that could help improve the accuracy of PTSD diagnoses, and points the way to medications designed specifically to treat trauma.

“There’s not a single pharmacological treatment out there that has been developed specifically for PTSD,” says Dr. Neumeister. “That’s a problem. There’s a consensus among clinicians that existing pharmaceutical treatments such as antidepressant simple do not work. In fact, we know very well that people with PTSD who use marijuana—a potent cannabinoid—often experience more relief from their symptoms than they do from antidepressants and other psychiatric medications. Clearly, there’s a very urgent need to develop novel evidence-based treatments for PTSD.”

The study divided 60 participants into three groups: participants with PTSD; participants with a history of trauma but no PTSD; and participants with no history of trauma or PTSD. Participants in all three groups received a harmless radioactive tracer that illuminates CB1 receptors when exposed to positron emissions tomography (PET scans). Results showed that participants with PTSD, especially women, had more CB1 receptors in brain regions associated with fear and anxiety than volunteers without PTSD. The PTSD group also had lower levels of the neurotransmitter anandamide, an endocannabinoid that binds to CB1. If anandamide levels are too low, Dr. Neumeister explains, the brain compensates by increasing the number of CB1 receptors. “This helps the brain utilize the remaining endocannabinoids,” he says.

Much is still unknown about the effects of anandamide in humans but in rats the chemical has been shown to impair memory. “What is PTSD? It’s an illness where people cannot forget what they have experienced,” Dr. Neumeister says. “Our findings offer a possible biological explanation for this phenomenon.”

Current diagnostics for PTSD rely on subjective measures and patient recall, making it difficult to accurately diagnose the condition or discern its symptoms from those of depression and anxiety. Biological markers of PTSD, such as tests for CB1 receptors and anandamide levels, could dramatically improve diagnosis and treatment for trauma victims.

Among the 1.7 million men and women who have served in the wars in Iraq and Afghanistan, an estimated 20% have PTSD. But PTSD is not limited to soldiers. Trauma from sexual abuse, domestic violence, car accidents, natural disaster, violent assault or even a life-threatening medical diagnosis can lead to PTSD. The condition affects nearly 8 million Americans annually.

These findings were made possible through the collaborative efforts of researchers at NYU School of Medicine, Yale School of Medicine, Harvard Medical School, the Department of Veterans Affairs National Center for PTSD and the University of California at Irvine.

(Image caption: Hypothetical cannabinoid receptor CB1 binding to anandamide)

Fish oil may stall effects of junk food on brain

Data from more than 180 research papers suggests fish oils could minimise the effects that junk food can have on the brain, a review by researchers at the University of Liverpool has shown.

The team at the University’s Institute of Ageing and Chronic Disease reviewed research from around the world to see whether there was sufficient data available to suggest that omega-3s had a role to play in aiding weight loss.

Stimulating the brain

Research over the past 10 years has indicated that high-fat diets could disrupt neurogenesis, a process that generates new nerve cells, but diets rich in omega-3s could prevent these negative effects by stimulating the area of the brain that control feeding, learning and memory.

Data from 185 research papers revealed, however, that fish oils do not have a direct impact on this process in these areas of the brain, but are likely to play a significant role in stalling refined sugars and saturated fats’ ability to inhibit the brain’s control on the body’s intake of food.

Dr Lucy Pickavance, from the University’s Institute of Ageing and Chronic Disease, explains: “Body weight is influenced by many factors, and some of the most important of these are the nutrients we consume.  Excessive intake of certain macronutrients, the refined sugars and saturated fats found in junk food, can lead to weight gain, disrupt metabolism and even affect mental processing.

“These changes can be seen in the brain’s structure, including its ability to generate new nerve cells, potentially linking obesity to neurodegenerative diseases. Research, however, has suggested that omega-3 fish oils can reverse or even prevent these effects.  We wanted to investigate the literature on this topic to determine whether there is evidence to suggest that omega-3s might aid weight loss by stimulating particular brain processes.”

Research papers showed that on high-fat diets hormones that are secreted from body tissues into the circulation after eating, and which normally protect neurons and stimulate their growth, are prevented from passing into the brain by increased circulation of inflammatory molecules and a type of fat called triglycerides.

Molecules that stimulate nerve growth are also reduced, but it appears, in studies with animal models, that omega-3s restore normal function by interfering with the production of these inflammatory molecules, suppressing triglycerides, and returning these nerve growth factors to normal.

Positive step

Dr Pickavance added: “Fish oils don’t appear to have a direct impact on weight loss, but they may take the brakes off the detrimental effects of some of the processes triggered in the brain by high-fat diets.  They seem to mimic the effects of calorie restrictive diets and including more oily fish or fish oil supplements in our diets could certainly be a positive step forward for those wanting to improve their general health.”

The research is published in the British Journal of Nutrition. Dr Pickavance will also be discussing the effects of high-fat diets on meal patterns and the impacts of high-saturated fats on muscle composition at the 20^th European Congress on Obesity at the Liverpool Arena and Convention Centre later this month.