Shredded extracellular matrix (ECM) is toxic to neurons. Chen et al. Reveal a new mechanism for how ECM demolition causes brain damage. The study will appear in the December 29, 2008 issue of The Journal of Cell Biology (www.jcb.org).

A stroke or head injury kills large numbers of neurons through a process called excitotoxicity. A surge of the neurotransmitter glutamate jolts receptors such as the kainate receptor and stimulates cell death. Enzymes add to the death toll by chopping up ECM near the injury site. How ECM breakdown takes out neurons was mysterious. The standard view was that neurons perished because they got separated from the ECM as it dissolved.

Chen et al. Found otherwise when they engineered mice to lack the ECM component laminin in the hippocampus, a brain region often damaged by stroke or injury. If cells languished after parting from the ECM, the researchers reasoned that mice missing laminin would suffer more damage from excitotoxicity. But when excitotoxicity was spurred with an injection of kainate—a molecule that, like glutamate, activates the kainate receptor—the laminin-lacking mice showed less brain damage. After a dose of diced laminin, however, the mutant mice were vulnerable to kainate, indicating that the fragments are the culprit in cell death.

The researchers discovered that chopped-up ECM kills cells by ramping up production of one subunit of the kainate receptor, known as KA1. They speculate that hiking the amount of KA1 subunits might make the receptor more sensitive and thus more likely to trigger an overreaction by the cell.

Although drugs that obstruct the glutamate receptor slow brain cell death, they can lead to serious cognitive impairment and even coma. The study suggests that drugs that block KA1 might provide an alternative way to save brain cells after stroke or head trauma.

Many animals live longer when raised on low calorie diets.  But now researchers at Washington University School of Medicine in St. Louis have shown that they can extend the life spans of roundworms even when the worms are well fed — it just takes a chemical that blocks their sense of smell.

Three years ago, the researchers, led by Kerry Kornfeld, M.D., Ph.D., reported they found that a class of anticonvulsant medications made the roundworm Caenorhabditis elegans live longer.  But until now, they didn’t quite know what the drugs did to give the worms their longevity.  They report their latest findings in the Oct. 24 issue of the Public Library of Science Genetics.

“We’ve learned that the drugs inhibit neurons in the worm’s head that sense chemicals in their surroundings — the neurons are like the worm’s nose,” says Kornfeld, professor of developmental biology.  “Like roundworms that are grown in a food-scarce environment, the worms exposed to the anticonvulsant ethosuximide lived longer.  But these worms ate plenty of food.  That suggests that the worms’ sensation of food is critical to controlling their metabolism and life span.”

If roundworms sense that food is abundant, their metabolism adjusts accordingly.  Their bodies respond to promote rapid ingestion, rapid growth and rapid aging, Kornfeld explains.  In contrast, when the worms sense a shortage of food, they make “metabolic decisions” to delay growth, delay energy use and extend lifespan.

In the long term, Kornfeld’s goal is to identify compounds that could potentially delay human aging.  The research group for this project also included James Collins, Ph.D., Kim Evason, M.D., Ph.D., Chris Pickett, Ph.D., and Daniel Schneider.

Kornfeld’s lab studies C. elegans because they live only about two to three weeks, so experimental results can be obtained quickly.  In addition, the worms’ genome has been sequenced and extensively studied.

The scientists’ strategy has been to expose the roundworms to libraries of chemicals to identify compounds that delay aging and extend their lives.  That approach led to the unexpected result that some human anticonvulsants slow aging in C. elegans.

Now, further investigating the effect of one of those compounds, ethosuximide, the researchers found that it had the same life-extending effect as some well-studied genetic mutations in C. elegans.  These mutations inhibit the activity of some sensory neurons in the worm, and that helped the researchers conclude that ethosuximide also directly affected these neurons.  Roundworms treated with ethosuximide lived up to 29 percent longer than normal.

“Now we know what cells ethosuximide targets in C. elegans,” Kornfeld says.  “It’s likely that the drug prevents the nerve cells from being electrically active, but precisely how it does that is something we need to study further.  We also want to find out how the effect on the neurons is translated into an effect on the worms’ bodies to delay aging.”

Ethosuximide is used to treat seizure disorders in people.  Interestingly, a common side effect of the drug is the loss of the sense of taste.  Does that mean the ability to taste or smell food affects aging in people?  It’s probably not that simple, but it does hint at some sort of connection, Kornfeld says.  He says it’s possible that sensory perception cues have important metabolic consequences independent of what we actually eat.

“Emerging evidence suggests that core metabolic pathways that modulate lifespan in worms also modulate lifespan in vertebrates such as mice and perhaps humans,” Kornfeld says.  “Sensory pathways might also be fairly universal.  In an ancient common ancestor, these pathways might have caused metabolic adjustments that affect lifespan.  That could be reflected in our own biology.”

A brain isn’t born fully organized. It builds its abilities through experience, making physical connections between neurons and organizing circuits to store and retrieve information in milliseconds for years afterwards.Now that process has been caught in the act for the first time by a Duke University research team that watched a naïve brain organize itself to interpret images of motion.

“This is the first time that anyone has been able to watch as visual experience selectively shapes the functional properties of individual neurons,” said David Fitzpatrick, professor of neurobiology and director of the Duke Institute for Brain Sciences. “These results emphasize just how important experience is for the early development of brain circuits.” The group’s findings appear online Oct. 22 in the journal Nature.

Using an advanced imaging system that can see changes in calcium levels within individual neurons as an indication of electrical activity, the team has been able to see inside the brain of a one-month old ferret as it opened its eyes for the first time and learned how to interpret moving images.

They watched the brain learning how to see. As a ferret learned to discriminate one pattern of motion from another over the course of a few hours, the researchers could see large numbers of individual neurons in the visual cortex develop specific responses and become organized into functional assemblies called cortical columns. Additional experiments confirmed that the changes were dependent on the neurons being activated by the animal’s experience with moving visual images.

The measurements were made using something called “in vivo two-photon laser scanning microscopy,” which allows researchers to focus on a virtual slice of living tissue a few microns thick, and up to 300 microns below the surface of the brain. By scanning at multiple depths, the researchers were able to examine the properties of hundreds of neurons in a single animal. A fluorescent dye sensitive to calcium allowed the scientists to detect changes in the activity of individual neurons as the learning occurred.

Ferrets are born with their eyes closed and remain so for the first 30 days or so, Fitzpatrick explained. What the Duke team saw happening as the animals opened their eyes and watched moving images for the first time was the emergence of columns of neurons sensitive to a particular feature of the visual stimulus: its direction of motion.

In visual areas of the mature brain, individual neurons are programmed to be most responsive to a particular direction of motion. Some are most responsive to left-to-right motion, for example, and others will be most responsive to down-to-up or right-to-left and so on. As signals from a visual stimulus enter these brain centers for interpretation, the entire collection of neurons that has been programmed to detect motion will fire signals to cast their votes, in effect, on which direction the stimulus is moving. Those neurons which are programmed to be most responsive to the direction the stimulus is actually moving cast the loudest votes.

“Before experience with a moving stimulus, individual neurons respond almost equally to opposite directions of motion and there is little order in the way they are arranged,” Fitzpatrick said. “But as a result of experience with moving images, their response to a particular direction of motion strengthens and they begin to act like their neighbors, forming columns of neurons with similar preferences. We have been able to visualize the self-organizing process by which the brain uses experience to guide the construction of circuits that are critical for interpreting moving stimuli.”

The scientists next have to figure out how neurons end up preferring one motion direction over another, and what aspects of the circuit are altered to create the direction-selective responses.

Fitzpatrick is confident that the findings from these experiments can be generalized to other brain regions and will be of value in understanding neurological and psychiatric disorders.

“Many people don’t realize that the vast majority of cortical connections are being formed at a time when experience can influence neural activity,” he said. “Understanding how experience shapes the architecture of developing neural circuits, and identifying the underlying cellular and molecular mechanisms could provide the key to a number of developmental brain disorders.”

A UC Riverside-led team of biomedical scientists has found that a readily available drug called minocycline, used widely to treat acne and skin infections, can be used to treat Fragile X syndrome, the most common inherited cause of mental impairment and the most common cause of autism.

The study’s findings have already impacted future therapies, with the approval of a new clinical trial in Toronto, Canada, that will test minocycline in patients with Fragile X.

Neurons in the brain communicate with each other at specialized contact sites called synapses, with many of these synapses occurring on small mushroom-shaped structures called dendritic spines.

During early development dendritic spines have immature finger-like shapes.  But learning stabilizes the synapses and dendritic spines take on a mature mushroom shape, which make them more efficient.

The brains of patients with Fragile X syndrome have an overabundance of immature dendritic spines.

In their report, the researchers, led by Iryna Ethell and Douglas Ethell, faculty members in UCR’s Division of Biomedical Sciences, describe how dendritic spine development in mice with Fragile X is delayed by enzymes called matrix metalloproteinases (MMPs), which are involved in normal brain development and physiological processes.  They report that high levels of certain MMPs keep the synapses immature and inefficient.

But minocycline, they found, reduces these MMP levels in the mice, allowing the synapses to mature and make more efficient contacts between neurons in the brain.  The outcome: corrected brain abnormalities in dendritic spines, reduced anxiety and improved cognitive function.

Study results appear online, ahead of print, in the Journal of Medical Genetics.

In their experiments, the Ethells found that young Fragile X mice treated with minocycline showed an increase of dendritic spine maturation in the hippocampus, a brain area that is critical for learning and memory.  Besides less anxiety, minocycline-treated mice showed better exploration skills as compared to untreated mice.

The Ethells are enthusiastic about how their discovery already is leading to a clinical trial.

“Clinical studies often quickly follow such basic science because once there is a solid understanding of how problems arise, it is much easier to come up with solutions,” said Iryna Ethell, an associate professor of biomedical sciences.

The study was funded by a grant from the FRAXA Research Foundation.  FRAXA was founded in 1994 by three parents of children with Fragile X to support scientific research aimed at finding a treatment and a cure for Fragile X.

Dr. Michael Tranfaglia, FRAXA’s chief scientific officer, said of the UCR researchers, “This group has done something unique and incredibly valuable: They have identified an off-the-shelf treatment for Fragile X through their basic research.  By bringing their unique perspective to Fragile X research, they have helped us to understand why neurons are malformed in this disorder, and more importantly, how we can treat it.

“We were so impressed with their work that we just awarded Dr. Iryna Ethell the FRAXA Breakthrough Award for 2008.  This is easily the most important scientific breakthrough in the Fragile X field in many years.”

According to Dr. Carl Paribello, president of Fragile X Research Foundation of Canada and the director of the clinical trial (scheduled for early 2009) at Surrey Place Centre Fragile X Clinic in Toronto, Canada, the UCR-led study “will go a long way towards dispelling the idea that mental impairment cannot be treated.”

“The work could lead to the first treatment that actually targets the underlying defect in Fragile X syndrome and not just the symptoms,” Dr. Paribello said.

UCR’s Douglas Ethell, an assistant professor of biomedical sciences, noted that effective therapies for Fragile X syndrome are few and far between.  “This is a good time for identifying highly effective therapeutic strategies that might work in Fragile X patients,” he said.  “We are excited that our research has the potential to affect many lives.”

Fragile X affects 1 in 4000 males and 1 in 6000 females of all races and ethnic groups.  About 1 in 259 women carry Fragile X and could pass it to their children.  About 1 in 800 men carry Fragile X; their daughters will also be carriers.

Minocycline belongs to a group of antibiotics that has been used in people for more than fifty years to treat Lyme disease, acne, and other skin infections.

Minocycline may have beneficial effects in other disorders where higher-than-normal brain levels of MMP-9 are found.  It is currently under study for treating rheumatoid arthritis, multiple sclerosis (MS), Parkinson’s disease, and several other neurodegenerative conditions.

“In the future, new compounds that more specifically target MMP-9 can be developed and tested,” Douglas Ethell said.

Next in their research, the Ethells and their colleagues plan to refine the therapeutic strategy in Fragile X mice to determine the optimal age, if any, to administer minocycline.  They will also explore other MMP inhibitors that may be more effective than minocycline.

“We will investigate whether a combination of MMP inhibitors with other drugs, such as fenobam, can help mature the synapses in Fragile X mice,” Iryna Ethell said.

New research identifies a few critical neurons that initiate sex-specific behaviors in fruit flies and, when masculinized, can elicit male-typical courtship behaviors from females.  The study, published by Cell Press in the September 11th issue of the journal Neuron, demonstrates a direct link between sexual dimorphism in the brain and gender differences in behavior.

In the fruit fly, Drosophila melanogaster, males display a series of complex and stereotypic behaviors when they are courting a female.  Males chase the female while vibrating their wings, producing a love song that has an aphrodisiac influence on the female, who would otherwise take action to escape the male’s advances.  Later steps in the male courtship behavior involve the initiation and completion of copulation.

“Although previous studies have identified a few key brain areas, such as the dorsal posterior brain, that appear to play a pivotal role in initiating male sexual behavior, nothing is known about the identity of neurons and their circuits in the brain sites which are central to the generation of male courtship behavior,” says lead study author Professor Ken-ichi Kimura of the Hokkaido University of Education in Japan.

Professor Kimura and colleagues made use of a sophisticated technique that allowed them to identify, manipulate, and study small groups of cells in the fruit fly brain.  The researchers focused on neurons that expressed a gene called fruitless (fru), a known sex-determination gene.  The male-specific Fru protein is expressed in the brains of male flies, but not females.  Studies have indicated that fru functions in parallel with another sex-determination gene called doublesex (dsx) and that fru may function as a kind of master control gene to direct organization of brain centers for sexual behavior.

A fru/dsx-expressing cell cluster, known as P1, was identified as an important site for initiating male courtship behavior.  P1 cells are fated to die in females through the action of a feminizing protein called DsxF.  Interestingly, genetic manipulation of females so that they possessed male P1 neurons effectively provoked male-typical courtship behavior in the females, even when other parts of the brain were not masculinized.

“P1 is located in the dorsal posterior brain and is composed of 20 neurons that have projections which communicate with the bilateral protocerebrum,” explains Professor Kimura.  “We found that the masculinizing protein Fru is required in the male brain for correct positioning of the projections from the P1 neurons.”

Taken together, these findings demonstrate that the coordinated action of sex-determination genes dsx and fru confer the unique ability to initiate male-typical sexual behavior on P1 neurons.  This research represents one of only a few examples presenting direct evidence for sexually dimorphic mechanisms that underlie gender-specific behavior and is the first to identify a specific cluster of cells that initiate courtship.

Nodari et al. have discovered a major new class of molecules that activate the accessory olfactory (vomeronasal) system: sulfated steroids. Vomeronasal sensory neurons (VSNs) detect cues that are important for social communication. Mouse urine strongly activates VSNs, but few of its active compounds had been identified. Using fractionation, mass spectrometry, and multielectrode physiological recordings, Nodari et al. found that sulfated steroids account for 80% of the vomeronasal-stimulating activity in female urine. Testing synthetic steroids revealed that individual neurons responded selectively and with different sensitivity to one to four closely related compounds, but, as a population, VSNs detected all classes of steroid hormones known to control mammalian physiology. Sulfation is thought to help clear steroids from the body, and the levels of sulfated corticosterone increased following restraint stress, suggesting that urine levels of sulfated hormones reflect the recent physiological state. Interestingly, sulfated steroids were not detected in males, suggesting another major class ofVSNstimuli remains undiscovered.