Posts tagged science

In a landmark discovery, the final piece in the puzzle of understanding how the brain circuitry vital to normal fertility in humans and other mammals operates has been put together by researchers at New Zealand’s University of Otago.

Their new findings, which appear in the leading international journal Nature Communications, will be critical to enabling the design of novel therapies for infertile couples as well as new forms of contraception.

The research team, led by Otago neuroscientist Professor Allan Herbison, have discovered the key cellular location of signalling between a small protein known as kisspeptin* and its receptor, called Gpr54. Kisspeptin had earlier been found to be crucial for fertility in humans, and in a subsequent major breakthrough Professor Herbison showed that this molecule was also vital for ovulation to occur.

In the latest research, Professor Herbison and colleagues at Otago and Heidelberg University, Germany, provide conclusive evidence that the kisspeptin-Gpr54 signalling occurs in a small population of nerve cells in the brain called gonadotropin-releasing hormone (GnRH) neurons.

Using state-of-the-art techniques, the researchers studied mice that lacked Gpr54 receptors in only their GnRH neurons and found that these did not undergo puberty and were infertile. They then showed that infertile mice could be rescued back to completely normal fertility by inserting the Gpr54 gene into just the GnRH neurons.

Professor Herbison says the findings represent a substantial step forward in enabling new treatments for infertility and new classes of contraceptives to be developed.

"Infertility is a major issue affecting millions of people worldwide. It’s currently estimated that up to 20 per cent of New Zealand couples are infertile, and it is thought that up to one-third of all cases of infertility in women involve disorders in the area of brain circuitry we are studying.

"Our new understanding of the exact mechanism by which kisspeptin acts as a master controller of reproduction is an exciting breakthrough which opens up avenues for tackling what is often a very heart-breaking health issue. Through detailing this mechanism we now have a key chemical switch to which drugs can be precisely targeted," Professor Herbison says.

As well as the findings’ benefits for advancing new therapies for infertility and approaches to controlling fertility, they suggest that targeting kisspeptin may be valuable in treating diseases such as prostate cancer that are influenced by sex steroid hormone levels in the blood, he says.

Professor Herbison noted that the research findings represent a long-standing collaborative effort with the laboratory of Professor Gunther Schutz at Heidelberg University, Germany.

Professor Herbison is Director of the University’s Centre for Neuroendocrinology, which is the world-leading research centre investigating how the brain controls fertility.

"We are delighted to have published this work in one of the top scientific journals and also to be able to maintain the leading role of New Zealand researchers in understanding fertility control," he says.

(Source: eurekalert.org)

The toxoplasma parasite can be deadly, causing spontaneous abortion in pregnant women or killing immune-compromised patients, but it has even stranger effects in mice.

Infected mice lose their fear of cats, which is good for both cats and the parasite, because the cat gets an easy meal and the parasite gets into the cat’s intestinal tract, the only place it can sexually reproduce and continue its cycle of infection.

New research by graduate student Wendy Ingram at the University of California, Berkeley, reveals a scary twist to this scenario: the parasite’s effect seem to be permanent. The fearless behavior in mice persists long after the mouse recovers from the flu-like symptoms of toxoplasmosis, and for months after the parasitic infection is cleared from the body, according to research published today (Sept. 18) in the journal PLoS ONE.

“Even when the parasite is cleared and it’s no longer in the brains of the animals, some kind of permanent long-term behavior change has occurred, even though we don’t know what the actual mechanism is,” Ingram said. She speculated that the parasite could damage the smell center of the brain so that the odor of cat urine can’t be detected. The parasite could also directly alter neurons involved in memory and learning, or it could trigger a damaging host response, as in many human autoimmune diseases.

Ingram became interested in the protozoan parasite, Toxoplasma gondii, after reading about its behavior-altering effects in mice and rats and possible implications for its common host, the domesticated cat, and even humans. One-third of people around the world have been infected with toxoplasma and probably have dormant cysts in their brains. Kept in check by the body’s immune system, these cysts sometimes revive in immune-compromised people, leading to death, and some preliminary studies suggest that chronic infection may be linked to schizophrenia or suicidal behavior.

Pregnant women are already warned to steer clear of kitty litter, since the parasite is passed through cat feces and can cause blindness or death in the fetus. One main source of spread is undercooked pork, Ingram said.

With the help of Michael Eisen and Ellen Robey, UC Berkeley professors of molecular and cell biology, Ingram set out three years ago to discover how toxoplasma affects mice’s hard-wired fear of cats. She tested mice by seeing whether they avoided bobcat urine, which is normal behavior, versus rabbit urine, to which mice don’t react. While earlier studies showed that mice lose their fear of bobcat urine for a few weeks after infection, Ingram showed that the three most common strains of Toxoplasma gondii make mice less fearful of cats for at least four months.

Using a genetically altered strain of toxoplasma that is not able to form cysts and thus is unable to cause chronic infections in the brain, she demonstrated that the effect persisted for four months even after the mice completely cleared the microbe from their bodies. She is now looking at how the mouse immune system attacks the parasite to see whether the host’s response to the infection is the culprit.

“This would seem to refute – or at least make less likely – models in which the behavior effects are the result of direct physical action of parasites on specific parts of the brain,” Eisen wrote in a blog post about the research.

“The idea that this parasite knows more about our brains than we do, and has the ability to exert desired change in complicated rodent behavior, is absolutely fascinating,” Ingram said. “Toxoplasma has done a phenomenal job of figuring out mammalian brains in order to enhance its transmission through a complicated life cycle.”

(Source: newscenter.berkeley.edu)

Brain regions associated with memory shrink as adults age, and this size decrease is more pronounced in those who go on to develop neurodegenerative disease, reports a new study published Sept. 18 in the Journal of Neuroscience. The volume reduction is linked with an overall decline in cognitive ability and with increased genetic risk for Alzheimer’s disease, the authors say.

Image: Network of brain regions, highlighted in red and yellow, show atrophy in both healthy aging and neurodegenerative disease. The regions highlighted are susceptible to normal aging and dementia.

“Our results identify a specific pattern of structural brain changes that may provide a possible brain marker for the onset of Alzheimer’s disease,” said Nathan Spreng, assistant professor of human development and the Rebecca Q. and James C. Morgan Sesquicentennial Faculty Fellow in Cornell’s College of Human Ecology.

The study is one of the first to measure structural changes in a collection of brain regions – not just one single area – over the adult life course and from normal aging to neurodegenerative disease, said Spreng, who co-authored the study with Gary R. Turner of York University in Toronto.

Overall, they studied brain data from 848 individuals spanning the adult lifespan, using data from the Open Access Series of Imaging Studies and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). About half of the ADNI sample was assessed multiple times over several years, allowing the researchers to measure brain changes over time and determine who did and did not progress to dementia.

The researchers found that brain volume in the default network (a set of brain regions associated with internally generated thoughts such as memory) declined in both healthy and pathological aging. The researchers noted the greatest decline in Alzheimer’s patients and in those who progressed from mild cognitive impairment to Alzheimer’s disease. Reduced brain volumes in these regions were associated with declines in cognitive ability, the presence of known biological markers of Alzheimer’s disease and with carrying the APOE4 variant of APOE gene, a known risk factor for Alzheimer’s.

“While elements of the default network have previously been implicated in aging and neurodegenerative disease, few studies have examined broad network changes over the full adult life course with such large participant samples and including both behavioral and genetic data,” said Spreng. “Our findings provide evidence for a network-based model of neurodegenerative disease, in which progressive brain changes spread through networks of connected brain regions.”

(Source: news.cornell.edu)

Scientists at the University of Alabama at Birmingham have identified a molecular pathway that seems to contribute to the ability of malignant glioma cells in a brain tumor to spread and invade previously healthy brain tissue. Researchers said the findings, published Sept. 19, 2013, in the journal PLOS ONE, provide new drug-discovery targets to rein in the ability of these cells to move.

Gliomas account for about a third of brain tumors, and survival rates are poor; only about half of the 10,000 Americans diagnosed with malignant glioma survive the first year, and only about one quarter survive for two years.

“Malignant gliomas are notorious, not only because of their resistance to conventional chemotherapy and radiation therapy, but also for their ability to invade the surrounding brain, thus causing neurological impairment and death,” said Hassan Fathallah-Shaykh, M.D., Ph.D., associate professor in the UAB Department of Neurology. “Brain invasion, a hallmark of gliomas, also helps glioma cells evade therapeutic strategies.”

Fathallah-Shaykh said there is a great deal of interest among scientists in the idea that a low-oxygen environment induces glioma cells to react with aggressive movement, migration and brain invasion. A relatively new cancer strategy to shrink tumors is to cut off the tumor’s blood supply – and thus its oxygen source – through the use of anti-angiogenesis drugs. Angiogenesis is the process of making new blood vessels.

“Stop angiogenesis and you shut off a tumor’s blood and oxygen supply, denying it the components it needs to grow,” said Fathallah-Shaykh. “Drugs that stop angiogenesis are believed to create a kind of killing field. This study identified four glioma cell lines that dramatically increased their motility when subjected to a low-oxygen environment – in effect escaping the killing field to create a new colony elsewhere in the brain.”

Fathallah-Shaykh and his team then identified two proteins that form a pathway linking low oxygen, or hypoxia, to increased motility.

“We identified a signaling protein that is activated by hypoxia called Src,” said Fathallah-Shaykh. “We also identified a downstream protein called neural Wiskott-Aldrich syndrome protein (N-WASP), which is regulated by Src in the cell lines with increased motility.”

The researchers then used protein inhibitors to shut off Src and N-WASP. When either protein was inhibited, low oxygen lost its ability to augment cell movement.

“These findings indicate that Src, N-WASP and the linkage between them – which is something we don’t fully understand yet – are key targets for drugs that would interfere with the ability of a cell to move.” said Fathallah-Shaykh. “If we can stop them from moving, then techniques such as anti-angiogenesis should be much more effective. Anti-motility drugs could be a key component in treating gliomas in the years to come.”

(Source: uab.edu)

Researchers at UT Southwestern Medical Center have identified a cellular switch that potentially can be turned off and on to slow down, and eventually inhibit the growth of the most commonly diagnosed and aggressive malignant brain tumor.

Findings of their investigation show that the protein RIP1 acts as a mediator of brain tumor cell survival, either protecting or destroying cells. Researchers believe that the protein, found in most glioblastomas, can be targeted to develop a drug treatment for these highly malignant brain tumors. The study was published online Aug. 22 in Cell Reports.

"Our study identifies a new mechanism involving RIP1that regulates cell division and death in glioblastomas," said senior author Dr. Amyn Habib, associate professor of neurology and neurotherapeutics at UT Southwestern, and staff neurologist at VA North Texas Health Care System. "For individuals with glioblastomas, this finding identified a target for the development of a drug treatment option that currently does not exist."

In the study, researchers used animal models to examine the interactions of the cell receptor EGFRvIII and RIP1. Both are used to activate NFκB, a family of proteins that is important to the growth of cancerous tumor cells. When RIP1 is switched off in the experimental model, NFκB and the signaling that promotes tumor growth is also inhibited. Furthermore, the findings show that RIP1 can be activated to divert cancer cells into a death mode so that they self-destruct.

According to the American Cancer Society, about 30 percent of brain tumors are gliomas, a fast-growing, treatment-resistant type of tumor that includes glioblastomas, astrocytomas, oligodendrogliomas, and ependymomas. In many cases, survival is tied to novel clinical trial treatments and research that will lead to drug development.

(Source: eurekalert.org)

Research on synapse stabilization could aid understanding of autism, schizophrenia, intellectual disability

When we’re born, our brains aren’t very organized. Every brain cell talks to lots of other nearby cells, sending and receiving signals across connections called synapses.

But as we grow and learn, things get a bit more stable. The brain pathways that will serve us our whole lives start to organize, and less-active, inefficient synapses shut down.

But why and how does this happen? And what happens when it doesn’t go normally? New research from the University of Michigan Medical School may help explain.

In a new paper in Nature Neuroscience, a team of U-M neuroscientists reports important findings about how brain cells called neurons keep their most active connections with other cells, while letting other synapses lapse.

Specifically, they show that SIRP alpha, a protein found on the surface of various cells throughout the body, appears to play a key role in the process of cementing the most active synaptic connections between brain cells. The research, done in mouse brains, was funded by the National Institutes of Health and several foundations.

The findings boost understanding of basic brain development – and may aid research on conditions like autism, schizophrenia, epilepsy and intellectual disability, all of which have some basis in abnormal synapse function.

“For the brain to be really functional, we need to keep the most active and most efficient connections,” says senior author Hisashi Umemori, M.D., Ph.D., a research assistant professor at U-M’s Molecular and Behavioral Neuroscience Institute and assistant professor of biological chemistry in the Medical School. “So, during development it’s crucial to establish efficient connections, and to eliminate inactive ones. We have identified a key molecular mechanism that the brain uses to stabilize and maturate the most active connections.”

Umemori says the new findings on SIRP alpha grew directly out of previous work on competition between neurons, which enables the most active ones to become part of pathways and circuits. (Read more on this research)

The team suspected that there must be some sort of signal between the two cells on either side of each synapse — something that causes the most active synapses to stabilize. So they set out to find out what it was.

SIRP-rise findings

The group had previously shown that SIRP-alpha was involved in some way in a neuron’s ability to form a presynaptic nerve terminal – an extension of the cell that reaches out toward a neighboring cell, and can send the chemical signals that brain cells use to talk to one another.

SIRP-alpha is also already known to serve an important function in the rest of the body – essentially, helping normal cells tell the immune system not to attack them. It may also help cancer cells evade detection by the immune system’s watchdogs.

In the new study, the team studied SIRP alpha function in the brain – and started to understand its role in synapse stabilization. They focused on the hippocampus, a region of the brain very important to learning and memory.

Through a range of experiments, they showed that when a brain cell receives signals from a neighboring cell across a synapse, it actually releases SIRP-alpha into the space between the cells. It does this through the action of molecules inside the cell – called CaMK and MMP – that act like molecular scissors, cutting a SIRP-alpha protein in half so that it can float freely away from the cell.

The part of the SIRP-alpha protein that floats into the synapse “gap” latches on to a receptor on the other side, called a CD47 receptor. This binding, in turn, appears to tell the cell that the signal it sent earlier was indeed received – and that the synapse is a good one. So, the cell brings more chemical signaling molecules down that way, and releases them into the synapse.

As more and more nerve messages travel between the “sending” and “receiving” cells on either side of that synapse, more SIRP-alpha gets cleaved, released into the synapse, and bound to CD47.

The researchers believe this repeated process is what helps the cells determine which synapses to keep – and which to let wither.

Umemori says the team next wants to look at what happens when SIRP-alpha doesn’t get cleaved as it should – and at what’s happening in cells when a synapse gets eliminated.

“This step of shedding SIRP-alpha must be critical to developing a functional neural network,” he says. “And if it’s not done well, disease or disorders may result. Perhaps we can use this knowledge to treat diseases caused by defects in synapse formation.”

He notes that the gene for the CD47 receptor is found in the same general area of our DNA as several genes that are suspected to be involved in schizophrenia.

If the development of our nervous system is disturbed, we risk developing serious neurological diseases, impairing our sensory systems, movement control or cognitive functions. This is true for all organisms with a well-developed nervous system, from man to worm. New research from BRIC, University of Copenhagen reveals how a tiny molecule called mir-79 regulates neural development in roundworms. The molecule is required for correct migration of specific nerve cells during development and malfunction causes defects in the nervous system of the worm. The research has just been published in the journal Science.

Hundreds of worms lie in a small plastic plate under the laboratory microscope. Over the last three years, the group of Associate Professor Roger Pocock has used the roundworm C. elegans tostudy the development of the nervous system. They have just made an important discovery.

“Our new results show that a small molecule called mir-79 is indispensable for development of the worm’s nervous system. mir-79 acts by equipping special signal molecules with a transmitter, which tells the nerve cells how they should migrate during development of the worm. If we remove mir-79 with gene technology, development of the worm nervous system goes awry”, says postdoc Mikael Egebjerg Pedersen, who is responsible for the experimental studies.

mir-79 adds just the right combination of sugar

The research shows that mir-79 acts by controlling the addition of certain groups of sugars to selected signaling molecules. In the world of cells, sugar molecules act as transmitters.

When the nerve cells come into contact with the sugar-transmitters, they are informed where to locate themselves during neural development. If the researchers remove mir-79, the migration of the nerve cells is misguided causing neuronal defects in the worms.

“It has earlier been shown that signaling molecules guide nerve migration, but our research shows that mir-79 regulates nerve cell migration by controlling the correct balance of sugar-transmitters on signaling molecules. If mir-79 does not function, the worm nervous system is malformed. In the wild, such defects would be harmful for worm survival”, explains Roger Pocock who leads the research group behind the finding.

Worm studies reveal important clues for neuronal repair

A version of mir-79 called mir-9 is found in humans. Therefore, these results are important for understanding how our nervous system develops during fetal development. In addition, the results add to the understanding of how nerve cells may be stimulated to repair damage in our brain or spinal cord.

“Our nervous system is a tissue which is not easily repaired after damage. So, how certain molecular cues can stimulate nerve cells to migrate is an important brick in the puzzle. This will enable us to understand how nerve tissue can be regenerated after, for example, a stroke or an accident. If we can use such knowledge to mimic the signals, we may be able to stimulate nerve cells to migrate into a damaged area”, says Roger Pocock.

Worms are a fantastic model to study how the nervous system develops and how nerve cells form neuronal circuits. Most of the genes that control nervous system development in the worm are also found in humans. At the same time, the reduced complexity of the worm nervous system allows researchers to investigate central biological mechanisms. With new technologies they can mark single cells or molecules, and as worms are transparent, the researchers can track the marked molecules or cells live during worm development.

The next step for the researchers is to investigate how the regulatory pathway they have revealed is regulated in cultures of human cells.

(Source: news.ku.dk)

NIH-funded discovery began with asking how the brain learns to see

A class of proteins that controls visual system development in the young brain also appears to affect vulnerability to Alzheimer’s disease in the aging brain. The proteins, which are found in humans and mice, join a limited roster of molecules that scientists are studying in hopes of finding an effective drug to slow the disease process.

Image: PirB (red) is heavily concentrated on the surface of growing nerve cells. Courtesy of Dr. Carla Shatz, Stanford.

"People are just beginning to look at what these proteins do in the brain. While more research is needed, these proteins may be a brand new target for Alzheimer’s drugs," said Carla Shatz, Ph.D., the study’s lead investigator. Dr. Shatz is a professor of biology and neurobiology at Stanford University in California, and the director of Stanford’s interdisciplinary biosciences program, BioX.

She and her colleagues report that LilrB2 (pronounced “leer-bee-2”) in humans and PirB (“peer-bee”) in mice can physically partner with beta-amyloid, a protein fragment that accumulates in the brain during Alzheimer’s disease. This in turn triggers a harmful chain reaction in brain cells. In a mouse model of Alzheimer’s, depleting PirB in the brain prevented the chain reaction and reduced memory loss.

The research was funded in part by the National Eye Institute, the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS), all part of the National Institutes of Health. It is reported in the Sept. 20 issue of Science.

"These findings provide valuable insight into Alzheimer’s, a complex disorder involving the abnormal build-up of proteins, inflammation and a host of other cellular changes," said Neil Buckholtz, Ph.D., director of the neuroscience division at NIA. "Our understanding of the various proteins involved, and how these proteins interact with each other, may one day result in effective interventions that delay, treat or even prevent this dreaded disease."

Alzheimer’s disease is the most common cause of dementia in older adults, and affects as many as 5 million Americans. Large clumps—or plaques—of beta-amyloid and other proteins accumulate in the brain during Alzheimer’s, but many researchers believe the disease process starts long before the plaques appear. Even in the absence of plaques, beta-amyloid has been shown to cause damage to brain cells and the delicate connections between them.

Dr. Shatz’s discovery took a unique path. She is a renowned neuroscientist, but Alzheimer’s disease is not her focus area. For decades, she has studied plasticity—the brain’s capacity to learn and adapt—focusing mostly on the visual system.

"Dr. Shatz has always been a leader in the field of plasticity, and now she’s taken yet another innovative step—giving us new insights into the abnormal plasticity that occurs in Alzheimer’s disease," said Michael Steinmetz, Ph.D., a program director at NEI. "These findings rest squarely on basic research into the development of the visual system." NEI has funded Dr. Shatz for more than 35 years.

During development, the eyes compete to connect within a limited territory of the brain—a process known as ocular dominance plasticity. The competition takes place during a limited time in early life. If visual experience through one eye is impaired during that time—for example, by a congenital cataract (present from birth)—it can permanently lose territory to the other eye.

"Ocular dominance is a classic example of how a brain circuit can change with experience," Dr. Shatz said. "We’ve been trying to understand it at a molecular level for a long time."

Her search eventually led to PirB, a protein on the surface of nerve cells in the mouse brain. She discovered that mice without the gene for PirB have an increase in ocular dominance plasticity. In adulthood, when the visual parts of their brains should be mature, the connections there are still flexible. This established PirB as a “brake on plasticity” in the healthy brain, Dr. Shatz said.

It wasn’t long before she began to wonder if PirB might also put a brake on plasticity in Alzheimer’s disease. In the current study, she pursued that question with Taeho Kim, Ph.D., a postdoctoral fellow in her lab, and Christopher M. William, M.D., Ph.D., a neuropathology fellow at Massachusetts General Hospital in Boston. Bradley Hyman, M.D., Ph.D., a professor of neurology at Mass General, was a collaborator on the project.

First, the team repeated the genetic experiment that Dr. Shatz had done in normal mice—but this time, they deleted the PirB gene in the Alzheimer’s mice. By about nine months of age, these mice typically develop learning and memory problems. But that didn’t happen in the absence of PirB.

Next, the researchers began thinking about how PirB might fit into the Alzheimer’s disease process, and particularly how it might interact with beta-amyloid. Dr. Kim theorized that since PirB resides on the surface of nerve cells, it might act as a binding site—or receptor—for beta-amyloid. Indeed, he found that PirB binds tightly to beta-amyloid, especially to tiny clumps of it that are believed to ultimately grow into plaques.

Beta-amyloid is known to weaken synapses—the connections between nerve cells. The researchers found that PirB appears to be an accomplice in this process. Without PirB, synapses in the mouse brain were resistant to the effects of beta-amyloid. Other experiments showed that binding between PirB and beta-amyloid can trigger a cascade of harmful reactions that can lead to the breakdown of synapses.

Although PirB is a mouse protein, humans have a closely related protein called LilrB2. The researchers found that this protein also binds tightly to beta-amyloid. By examining brain tissue from people with Alzheimer’s disease, they also found evidence that LilrB2 may trigger the same harmful reactions that PirB can trigger in the mouse brain.

"These are novel results, and direct interaction between beta-amyloid and PirB-related proteins opens up welcome avenues for investigating new drug targets for Alzheimer’s disease," said Roderick Corriveau, Ph.D., a program director at NINDS.

Dr. Shatz said she hopes to interest other researchers to work on developing drugs to block PirB and LilrB2. Currently, no drugs treat the underlying causes of Alzheimer’s disease. Most of the interventions that have reached clinical testing are designed to clear away beta-amyloid. To date, only two other beta-amyloid receptors (PrP-C and EphB2) have been found and are being pursued as drug targets.

(Source: nei.nih.gov)