Tag: Neurology

A new breed of permanently ‘cheerful’ mouse is providing hope of a new treatment for clinical depression. TREK-1 is a gene that can affect transmission of serotonin in the brain. Serotonin is known to play an important role in mood, sleep and sexuality. By breeding mice with an absence of TREK-1, researchers were able create a depression-resistant strain. The details of this research, which involved an international collaboration with scientists from the University of Nice, France, are published in Nature Neuroscience this week.

“Depression is a devastating illness, which affects around 10% of people at some point in their life,” says Dr. Guy Debonnel an MUHC psychiatrist, professor in the Department of Psychiatry at McGill University, and principal author of the new research. “Current medications for clinical depression are ineffective for a third of patients, which is why the development of alternate treatments is so important.” Mice without the TREK-1 gene (‘knock-out’ mice) were created and bred in collaboration with Dr. Michel Lazdunski, co-author of the research, in his laboratory at the University of Nice, France. “These ‘knock-out’ mice were then tested using separate behavioral, electrophysiological and biochemical measures known to gauge ‘depression’ in animals,” says Dr. Debonnel. “The results really surprised us; our ‘knock-out’ mice acted as if they had been treated with antidepressants for at least three weeks.”

This research represents the first time depression has been eliminated through genetic alteration of an organism. “The discovery of a link between TREK-1 and depression could ultimately lead to the development of a new generation of antidepressant drugs,” noted Dr. Debonnel. According to Health Canada and Statistics Canada, approximately 8% of Canadians will suffer from depression at some point in their lifetime. Around 5% of Canadians seek medical advice for depression each year; a figure that has almost doubled in the past decade. Figures in the U.S. are comparable, with approximately 18.8 million American adults (about 9.5% of the population) suffering depression during their life.

Science Daily
September 12, 2006

Original web page at Science Daily

Scientists from Melbourne’s Howard Florey Institute have found special proteins that protect the brain after it has been damaged by a lack of oxygen, which occurs in conditions such as stroke, perinatal asphyxia, near-drowning and traumatic brain injury. Dr Nicole Jones and her team discovered that during oxygen deprivation, or ‘hypoxia’, these proteins (HIF1 and PHD2) increase. These proteins regulate processes like the production of red blood cells and new blood vessels, and the flow of glucose to the brain. Therefore they are involved in preventing further brain damage and repairing damage caused by the initial injury. This discovery takes the Howard Florey Institute’s scientists closer to developing preventative and regenerative treatments for brain damage caused by hypoxia.

Dr Jones said her discovery resulted from looking at how the body tries to protect itself and how the brain reacts when it experiences mild, non-damaging hypoxia. “I found that mild, non-damaging hypoxia actually protected the brain against a subsequent injury by activating certain proteins,” Dr Jones said. “Mild hypoxia appears to pre-condition neural tissues against a mass ‘suicide’ of healthy neurons after a stroke or other brain trauma. “In an experiment in rats, mild hypoxia followed by a major stroke resulted in less brain damage than if the rat experienced just a major stroke — all because these protective proteins were increased by the first non-damaging exposure to hypoxia. “I am now looking at developing both preventative and regenerative treatments that mimic these proteins’ protective and repairing effects,” she said. Dr Jones is now testing drug candidates, and would like to develop new drugs that activate these protective proteins in the brain.

While further research is required, Dr Jones and her team are hopeful that their investigations will lead to effective treatments that will help people experiencing hypoxia, and also to improve recovery from hypoxic induced brain damage. Dr Jones’ research has been recently published in the Journal of Cerebral Blood Flow and Metabolism and Neuroscience Letters. The Howard Florey Institute is Australia’s leading brain research centre. Its scientists undertake clinical and applied research that can be developed into treatments to combat brain disorders, and new medical practices. Their discoveries will improve the lives of those directly, and indirectly, affected by brain and mind disorders in Australia, and around the world. The Florey’s research areas cover a variety of brain and mind disorders including Parkinson’s disease, stroke, motor neuron disease, addiction, epilepsy, multiple sclerosis, autism and dementia.

Science Daily
September 12, 2006

Original web page at Science Daily

The compelling urge to satisfy one’s hunger enlists structures throughout the brain, as might be expected in a process so necessary for survival. But until now, studies of those structures and of the feeding cycle have been only fragmentary–measuring brain regions only at specific times in the feeding cycle. Now, however, Ivan de Araujo, Duke University Medical Center, and colleagues report they have mapped the activity of whole ensembles of neurons in multiple feeding-related brain areas across a full cycle of hunger-satiety-hunger. Their findings, reported in the August 17, 2006, issue of the journal Neuron, published by Cell Press, open the way to understanding how these ensembles of neurons integrate to form a sort of distributed “code” that governs the motivation that drives organisms to satisfy their hunger.

In their paper, Ivan de Araujo and colleagues implanted bundles of infinitesimal recording electrodes in areas of rat brain known to be involved in feeding, motivation, and behavior. Those areas include the lateral hypothalamus, orbitofrontal cortex, insular cortex, and amygdala. The researchers then recorded neuronal activity in those regions through a feeding cycle, in which the rats became hungry, fed on sugar water to satisfy that hunger, and then grew hungry again. “This allowed us to measure both the ability of single neurons to encode for specific phases of a feeding cycle and how neuronal populations integrate information conveyed by these phase-specific neurons in order to reflect the animal’s motivational state,” wrote the researchers.

By isolating and comparing signals from particular neurons in the various regions at various times in the cycle, the researchers gained insight into the roles neurons in those regions played in feeding motivation and satisfaction, they wrote. The researchers found that they could, indeed, distinguish neurons that were sensitive to changes in satiety states as the animals satisfied their hunger. They could also measure how populations of neurons changed their activity over the different phases of a feeding cycle, reflecting the physiological state of the animals. Importantly, they found that measuring the activity of populations of neurons was a much more effective way of measuring the satiety state of an animal than measuring activity of only individual neurons in an area. And the more neurons they included in such populations, the more accurate the measure of that satiety state, they found.

Araujo and colleagues concluded that their analysis showed that while single neurons were preferentially responsive to particular phases in the metabolic status of the animal as it went through a hunger-satiety-hunger cycle, “when combined as ensembles, however, these neurons gained the ability to provide a population code that allows for predictions on the current behavioral state (hunger/satiety) of the animal by integrating information conveyed by its constituent units.” “Our results support the hypothesis that while single neurons are preferentially responsive to variations in metabolic status, neural ensembles appear to integrate the information provided by these neural sensors to maintain similar levels of activity across comparable behavioral states,” they concluded. “This distributed code acting across separate hunger phases might constitute a neural mechanism underlying meal initiation under different peripheral and metabolic environments,” they wrote.

Science Daily
August 29, 2006

Original web page at Science Daily

Giving up your regular late-night snack may be hard, and not just because it’s a routine. The habit may genetically change an area of the brain to expect the food at that time, researchers at UT Southwestern Medical Center have discovered. By training mice to eat at a time when they normally wouldn’t, the researchers found that food turns on body-clock genes in a particular area of the brain. Even when the food stopped coming, the genes continued to activate at the expected mealtime. “This might be an entrance to the whole mysterious arena of how metabolic conditions in an animal can synchronize themselves with a body clock,” said Dr. Masashi Yanagisawa, professor of molecular genetics and senior author of the study. The UT Southwestern researchers report their findings in the Aug. 8 issue of the Proceedings of the National Academy of Sciences.

The daily ups-and-downs of waking, eating and other bodily processes are known as circadian rhythms, which are regulated by many internal and external forces. One class of genes involved in these cycles is known as Period or Per genes. When food is freely available, the strongest controlling force is light, which sets a body’s sleep/wake cycle, among other functions. Light acts on an area in the brain called the suprachiasmatic nucleus, or SCN. But because destroying the SCN doesn’t affect the body clock that paces feeding behavior, the circadian pacemaker for feeding must be somewhere else, Dr. Yanagisawa said. To find the answer, his group did a simple but labor-intensive experiment. The scientists set the mice on a regular feeding schedule, then examined their brain tissue to find where Per genes were turned on in sync with feeding times.

The researchers put the mice on a 12-hour light/dark cycle, and provided food for four hours in the middle of the light portion. Because mice normally feed at night, this pattern is similar to humans eating at inappropriate times. Dysfunctional eating patterns play a role in human obesity, particularly in the nocturnal eating often seen in obese people, the researchers noted. The mice soon fell into a pattern of searching for food two hours before each feeding time. They also flipped their normal day/night behavior, ignoring the natural cue that day is their usual time to sleep. After several days, the researchers found that the daily activation cycle of Per genes in the SCN was not affected by the abnormal feeding pattern. However, in a few different areas of the brain, particularly a center called the dorsomedial hypothamalic nucleus or DMH, the Per genes turned on strongly in sync with feeding time after seven days.

When the mice subsequently went two days without food, the genes continued to turn on in sync with the expected feeding time. “They started to show the same pattern of anticipatory behaviors several hours before the previously scheduled time of feeding,” said Dr. Yanagisawa, a Howard Hughes Medical Institute investigator. “So somewhere in the body, they clearly remembered this time of day.” Upcoming research will focus on how the centers that control various body clocks communicate with each other, Dr. Yanagisawa said.

Science Daily
August 14, 2006

Original web page at Science Daily

In a continuing effort to find out if the tiniest airborne particles pose a health risk, University of Rochester Medical Center scientists showed that when rats breathe in nano-sized materials they follow a rapid and efficient pathway from the nasal cavity to several regions of the brain, according to a study in the August issue of Environmental Health Perspectives. Researchers also saw changes in gene expression that could signal inflammation and a cellular stress response, but they do not know yet if a buildup of ultrafine particles causes brain damage, said lead author Alison Elder, Ph.D., research assistant professor of Environmental Medicine.

The study tested manganese oxide ultrafine particles at a concentration typically inhaled by factory welders. The manganese oxide particles were the same size as manufactured nanoparticles, which are controversial and being diligently investigated because they are the key ingredient in a growing industry — despite concerns about their safety. Nanotechnology is a new wave of science that deals with particles engineered from many materials such as carbon, zinc and gold, which are less than 100 nanometers in diameter. The manipulation of these materials into bundles or rods helps in the manufacturing of smaller-than-ever electronics, optical and medical equipment. The sub-microscopic particles are also used in consumer products such as toothpaste, lotions and some sunscreens.

Some doctors and scientists are concerned about what happens at the cellular level after exposure to the ultrafine or nano-sized particles, and the University of Rochester is at the forefront of this type of environmental health research. In 2004 the Defense Department selected the University Medical Center to lead a five-year, $5.5 million investigation into whether the chemical characteristics of nanoparticles determine how they will interact with or cause harm to animal and human cells.

In the current study, the particles passed quickly through the rats’ nostrils to the olfactory bulb, a region of the brain near the nasal cavity. They settled in the striatum, frontal cortex, cerebellum, and lungs. After 12 days, the concentration of ultrafine particles in the olfactory bulb rose 3.5-fold and doubled in the lungs, the study found. Although the ultra-tiny particles did not cause obvious lung inflammation, several biomarkers of inflammation and stress response, such as tumor necrosis factor and macrophage inflammatory protein, increased significantly in the brain, according to gene and protein analyses. “We suggest that despite differences between human and rodent olfactory systems, this pathway is likely to be operative in humans,” the authors conclude.

Science Daily
August 14, 2006

Original web page at Science Daily

Unlike mice and many other animals, humans seem to lack the biological hardware for detecting pheromones, airborne molecules that carry information about sex and status. Now, researchers have discovered receptors in mice that may enable them to detect pheromones even without this specialized hardware. If people use a similar system, we may not be completely shut out of the pheromone game. Pheromones are detected by the vomeronasal organ, a small opening at the back of the nasal cavity of many mammals. Most scientists doubt that humans have a working vomeronasal organ. Still, recent research indicates that people can respond to pheromones (ScienceNOW, 9 May), and animal studies have suggested that some creatures can detect pheromones with their olfactory epithelium, a sheet of neurons that picks up ordinary odors.

Searching for an explanation to this alternate pheromone-detection system, neuroscientists Stephen Liberles and Linda Buck of the Fred Hutchinson Cancer Research Center in Seattle scanned the mouse olfactory epithelium for potential pheromone receptors. Focusing their search on receptors not known to respond to any odor, the researchers identified one family of genes that appeared to be expressed in olfactory neurons but not in other tissues. The pattern of gene expression is strikingly similar to that for individual olfactory receptor genes, Liberles says. Each of these genes, which encode trace amine-associated receptors (TAARs), was expressed by only a smattering of olfactory neurons, and each of these neurons appeared to make only one type of TAAR, the researchers report online 30 July in Nature.

Although little is known about TAARs, previous studies have found that some of them are activated by compounds in mouse urine–a major source of pheromones. Two of these compounds, isoamylamine and trimethlyamine, appear in different concentrations in male and female mouse urine, and some evidence suggests that isoamylamine acts as a pheromone by accelerating the onset puberty in female mice. Together with the new findings, this suggests (but doesn’t prove) that TAARs are pheromone receptors, Liberles says. Humans have TAAR genes too, raising the possibility that we use them to detect pheromones.

The work contributes to a growing appreciation of the molecular diversity of olfactory and pheromone receptors, says Catherine Dulac, a neuroscientist at Harvard University. The next step, she says, will be to determine whether TAARs actually work like pheromone receptors in live animals.

ScienceNow
August 14, 2006

Original web page at ScienceNow

A drug that triggers the birth of neurons in rat brains has opened up the possibility of a new treatment for Parkinson’s disease. Animals given the drug generated dopamine-producing neurons in the substantia nigra, the area of the brain where cells are lost in people with Parkinson’s.

Christopher Eckman and Jackalina Van Kampen at the Mayo Clinic College of Medicine in Jacksonville, Florida, found that after infusing the drug 7-OH-DPAT into damaged rats’ brains for eight weeks, the numbers of neurons in the damaged region and the connections they made had both returned to near normal (The Journal of Neuroscience, vol 26, p 7272). “The recovery in the animals was nothing short of profound,” says Eckman.

New Scientist
August 1, 2006

Original web page at New Scientist

University of Florida scientists have used gene therapy to eliminate disabling muscle contractions in a mouse model of the most common form of adult-onset muscular dystrophy. The inherited disorder, known as myotonic dystrophy, is found in one of every 8,000 people and causes skeletal muscles to lose the ability to relax once they contract. “One of the principal manifestations of the disease is myotonia, or muscle hyperexcitability,” said Maurice Swanson, Ph.D., the paper’s senior author and a professor of molecular genetics and microbiology at UF’s College of Medicine and the UF Genetics Institute. “So when patients with myotonic dystrophy contract one of the muscles in their arm, it’s very difficult for them to release that contraction.” The muscles progressively weaken and eventually waste away. The disease also affects the heart muscle and is associated with irregular heart rhythms that can lead to sudden death. It also can result in cataracts, premature hair loss and mild to moderate mental retardation.

The work, to be published this week in the Proceedings of the National Academy of Sciences, builds on previous research at UF and the University of Rochester School of Medicine and Dentistry that revealed myotonic dystrophy is caused by malfunctioning genes that block the action of key proteins in cells, including one known as the muscleblind protein. These proteins, which help muscle and eye cells mature, stick to warped copies of RNA molecules that build up in a cell’s nucleus and prevent the proteins from working properly. In the current study, UF researchers used mice that carry the mutated genes and develop the muscle problems characteristic of myotonic dystrophy.

The scientists equipped the adeno-associated virus, or AAV-a safe and widely used vector in gene therapy-to express extra copies of the muscleblind protein. They then injected it into a muscle in the shin in the mutant mice. “We simply tried to correct some of problems that arise by flooding the muscle with extra copies of the muscleblind protein,” Swanson said. “We were able to correct the myotonia as early as four weeks after injection, and at 23 weeks it was completely eliminated in the muscle that was injected with AAV carrying this muscleblind protein.” Another six mice were in the control group and received injections of green fluorescent protein. Their muscle function did not improve. In effect, patients with myotonic dystrophy retain many of the newborn versions of all the proteins the body makes, Swanson said.

“We all know newborn muscle is very different than adult muscle,” he said. “It’s not just that adults have more muscle, but in adults, proteins are being expressed that have changed between the time we were newborns to the time we became adults. That transition to adult proteins is prevented in myotonic dystrophy. “Basically, these fetal forms of proteins that are expressed during embryonic and neonatal life are present in adult myotonic dystrophy patients and are incompatible with adult function of muscle,” he added. “The reason that’s true is muscleblind proteins are factors that regulate this transition from newborn to adult proteins. The muscleblind proteins’ responsibility in cells is to make that transition, to force the production of the adult proteins.”

In the next phase of the research, the scientists plan to inject the gene therapy solution directly into the bloodstream. “Myotonic dystrophy patients want all their muscles corrected, not just one,” Swanson said. “One way to get around this problem is to try systemic injections in this mouse model. We’d like to correct all abnormal muscle contractions, not just in a specific muscle group. “About 30 percent of myotonic dystrophy patients succumb to heart problems, so theoretically systemic injections might also prevent that,” he added.

Scientists eventually hope to find out whether correcting myotonia early by restoring normal levels of functioning muscleblind protein might prevent at least some of the muscle loss that characterizes the adult-onset disease. But researchers are years away from testing the gene therapy approach in people.

“Basically we have to make sure everything works correctly in mice before we can proceed to human trials,” Swanson said. “That’s a long way off.” Stephen Tapscott, M.D., Ph.D., a professor of neurology at the University of Washington and a researcher at the Center on Human Development and Disability at the Fred Hutchinson Cancer Research Center in Seattle, called the findings “an important advance for developing therapies for myotonic dystrophy.” “The demonstration that muscleblind can be delivered to diseased muscle and reverse the disease process in this mouse model achieves an important landmark step that will inform future preclinical and, ultimately, clinical studies in myotonic dystrophy,” he said.

Until now it was difficult to even contemplate a way of treating the disease because it is extraordinarily complex, said John Day, M.D., Ph.D., a professor of neurology at the University of Minnesota School of Medicine, but the research has identified a common element that underlies many of the disease’s different features. “A means of delivering the treatment to humans still needs to be developed, but this now provides proof of principle that the approach is effective in this important mouse model,” Day said. “For the first time this really raises the hope of people suffering from this common form of muscular dystrophy that a treatment could someday be forthcoming that will address the many serious components of this disease.”

Science Daily
August 1, 2006

Original web page at Science Daily

A DNA vaccine has successfully reduced the symptoms of Alzheimer’s disease in mice. The result could signal the first preventative and restorative treatment vaccine for Alzheimer’s without serious side effects. Alzheimer’s disease progresses as small proteins called amyloid beta (Ab) peptides are overproduced, forming plaques in the brain that interfere with its function. Memory loss and mental deterioration follow. A vaccination approach – getting the immune system to clean up the plaques – has been considered the most promising way to tackle the disease, but its success has been limited, until now. In 2002, for example, the US pharmaceutical company Elan halted trials of a vaccine that raised antibodies against Ab peptides, after some patients suffered brain inflammation.

The new vaccine is different because instead of using the Ab peptide itself to stimulate antibody production, it uses a stretch of DNA that codes for the Ab peptide, says Yoh Matsumoto, at the Tokyo Metropolitan Institute for Neuroscience, Japan, who led the research. Since DNA vaccination stimulates the immune system more gently than peptide vaccination, it should also avoid the brain swelling seen in the Elan trial. The researchers use mice engineered to develop Alzheimer’s-like symptoms by producing Ab peptides in the brain, which in turn form the plaques that lead to cognitive impairment.

Matsumoto’s team injected the mice with the DNA vaccine before Ab peptides had started to build up. The DNA is read by the muscle cells into which it is injected, and Ab peptide is produced. Antibodies to it are then raised by the immune system and cross into the brain. Mice treated preventatively, at 7 or 18 months of age, developed 15.5% or 38.5% fewer Ab peptides, respectively, than did untreated mice. This suggests that the vaccine was having a protective effect on the mice. When the DNA vaccine was used as a treatment in mice that had already started producing the Ab peptides, their Ab peptide burden was reduced by about 50%. “Ab peptide reduction to 50% that of unvaccinated mice is sufficient [for the return of normal cognitive function],” says Matsumoto. If these results are replicated in monkeys, he hopes that clinical trials in humans could start within 3 years. Nick Fox, of the Institute of Neurology at University College, London, UK, says that DNA vaccination is an extremely promising way of slowing the progression of Alzheimer’s. “The key will be what happens in humans,” he says.

New Scientist
July 3, 2006

Original web page at New Scientist

Duke University Medical Center researchers have discovered how the brain creates a scent symphony from signals sent by the nose. In studies in mice, the researchers found that nerve cells in the brain’s olfactory bulb — the first stop for information from the nose — do not perceive complex scent mixtures as single objects, such as the fragrance of a blooming rose. Instead, these nerve cells, or neurons, detect the host of chemical compounds that comprise a rose’s perfume. Smarter sections of the brain’s olfactory system then categorize and combine these compounds into a recognizable scent. According to the researchers, it’s as if the brain has to listen to each musician’s melody to hear a symphony.

Humans may rely on the same smell decoding system, because mice and men have similar brain structures for scent, including an olfactory bulb, the researchers said. “We wanted to understand how the brain puts together scent signals to make an odor picture. We discovered the whole is the sum of its parts,” said Da Yu Lin, Ph.D., who conducted the research as a graduate student studying with neurobiologist Lawrence Katz, Ph.D., a Howard Hughes Medical Institute investigator at Duke. The research appears June 16, 2006, in the journal Neuron. The study was supported by the National Institutes of Health, the Howard Hughes Medical Institute and the Ruth K. Broad Biomedical Research Foundation.

Scientists have long debated how the brain makes order out of the hundreds of volatile chemical compounds that assault the nose. Is the brain’s odor code redundant, with single cells responding to multiple components in the smell of a freshly baked cookie? Or does the brain process each scent component like a jigsaw puzzle piece, assembling the signals until it recognizes the picture is a cookie? To find answers, the Duke researchers exposed mice to different odors and measured response of neurons across the olfactory bulb with intrinsic signal imaging. The imaging technique maps brain activity by detecting changes in reflected light from the brain with a sensitive camera.

To start, the researchers separated and identified the volatile compounds in each odor with gas chromatography. “A complex mixture like urine has at least a hundred separate compounds in it,” Lin said. They analyzed scents as diverse as peanut butter, coffee and fresh bobcat urine shipped to the laboratory on dry ice. The researchers then exposed the mice to the original odor and its individual compounds. “We found that glomeruli, the functional units of the olfactory bulb, act as detectors for individual compounds,” Lin said. “There are no single detectors for complete smells.” Thus, to distinguish different scents, the brain must integrate the signals of multiple chemical components into an odor “picture.” The researchers suspect that this integration doesn’t happen in the olfactory bulb. Instead, the bulb likely passes the data to more advanced brain structures where it is assembled and recognized as a specific scent.

Understanding how the olfactory system works in mice may also provide broader insights into human perception, said Stephen Shea, Ph.D., a Duke University Medical Center research associate who participated in the study. Perception relies on combining multiple components, whether the input is smell, sight or sound. Shea suggested that probing the olfactory system could help scientists better understand, for example, how the various biological and neurological components underlying perception formed and evolved.

Science Daily
July 3, 2006

Original web page at Science Daily

The brain, that exquisite network of billions of communicating cells, starts to take form with the genesis of nerve cells. Most newborn nerve cells, also called neurons, must travel from their birthplace to the position they will occupy in the adult brain. Researchers at the Salk Institute for Biological Studies have identified a molecule expressed on the surface of certain migrating neurons that helps them find their correct position along on the way. Decreasing levels of that protein, an adhesion molecule called MDGA1, prevents neurons that normally make this protein from assuming their proper position, resulting in brain malformation, researchers report in the April 26th issue of the Journal of Neuroscience.

As Dennis D. M. O’Leary, Ph.D., senior author of the study and a Professor in the Molecular Neurobiology Laboratory put it, “proper neuronal positioning is essential for development of appropriate wiring, which is in turn critical for establishing a normal, functioning nervous system.” Neurons migrate throughout the brain, but migration is particularly important for development of part of the brain known as the cerebral cortex. The cortex sits like a skullcap over the rest of the brain and is responsible for sensory perception, higher-level reasoning, and, in humans, language. In mammals, the largest and evolutionarily newest part of the cortex, the neocortex, is recognized anatomically by its six horizontal layers.

The neocortex develops outward from an underlying zone of cells. From that zone, crawling neurons migrate radially out toward the surface or “superficial” part of the developing cortex, giving rise to a laminar structure. Neurons forming layers 2 and 3, the focus of the current study, are born last and so must elbow their way through cells lying in earlier formed layers to reach what will become the outermost layers. Without MDGA1, these neurons begin to migrate but get stuck before they reach their normal destination.

The MDGA1 gene was cloned and characterized first in rat by O’Leary and two former postdoctoral fellows, E. David Litwack, Ph.D. and Matthias Gesemann, Ph.D. They showed that MDGA1 is a cell adhesion molecule — a protein enabling cells to attach to other surfaces, something that they must do either to move or sit still and elaborate connections. They also showed that MDGA1 is expressed on subpopulations of migrating neurons throughout the developing nervous system, including layer 2/3 neurons in the neocortex, suggesting that MDGA1 may actually be required for migration.

In the current study, O’Leary and Akihide Takeuchi, M.D., Ph.D., a postdoctoral fellow and the study’s first author, tested this hypothesis. They first showed that layer 2/3 neurons make MDGA1 protein as they migrate to their destination. Then, utilizing a cutting-edge molecular technique called RNA interference, the Salk researchers silenced the MDGA1 gene. To do this, they painstakingly performed in utero surgery on embryonic mice — injecting an interfering RNA molecule into the lateral ventricle, a fluid-filled space next to the neocortex. Application of an electrical current forced the RNA into neural progenitor cells, and it was subsequently inherited by their neuronal progeny that form layer 2/3 and blocked their ability to make MDGA1 protein.

When Takeuchi and O’Leary examined the neocortex a few days later when the mice were born, they discovered that nearly all neurons containing the interfering RNA were stalled in aberrant deeper locations, indicating that loss of MDGA1 protein had stymied their attempt to travel the full distance to layer 2/3 and supporting the original hypothesis. The goal now is to determine how MDGA1 controls neuronal migration and what the long-term consequences are of its loss. Impaired function of neuronal adhesion molecules has been previously linked to neurological defects in humans. A cell adhesion molecule known as L1 has been shown to affect cell migration and positioning in other parts of the nervous system. Numerous mutations in the human L1 gene have been uncovered; individuals with these mutations often show severe defects in neuronal positioning and connectivity, which are clinically manifested in conditions such as hydrocephalus, mental retardation and spastic paraplegia.

Whether mutations in MDGA1 lead to brain disorders remains to be seen. “Much work needs to be done, and the appropriate tools need to be developed to do this work,” said O’Leary, “but we feel that these studies will eventually provide insight into neurological disorders that have their basis in malpositioning of neurons.”

Science Daily
June 6, 2006

Original web page at Science Daily

Scientists have long known that brains need neural activity to mature and that sensory input is most important during a specific window of time called the “critical period” when the brain is primed for aggressive learning. Vision, hearing and touch all develop during such critical periods, while other senses, such as the olfactory system, maintain lifelong plasticity. The visual system provides an exemplary model for studying developmental plasticity, however, because of the pioneering work of Nobel prize-winning HMS researchers David Hubel and Torsten Wiesel describing the visual system’s structure, prerequisite knowledge for investigating its flexibility. Although visual plasticity has been studied for over 40 years, exactly how sensory experience interacts with the built-in machinery that permits the brain to change its circuits is only beginning to be understood.

A new study focusing on the molecular roots of plasticity has found that visual stimulus turns up the expression of some genes and turns down the expression of others, somewhat like a conductor cueing the members of an orchestra. The study also found that during different stages of life in rodents, distinct sets of genes spring into action in response to visual input. These gene sets may work in concert to allow synapses and neural circuits to respond to visual activity and shape the brain, reports the May issue of Nature Neuroscience.

The investigators’ identification of many distinct sets of activity-dependent genes follows a shift in neuroscience research toward a more holistic view of the role of genes in neural development and plasticity. “What we found opens science up to a more global look at genes, from studying one gene at a time to looking at families of genes acting together,” said first author Marta Majdan, Harvard Medical School research fellow in neurobiology. These findings suggest that genetic therapies for neurodegenerative diseases, some of which are largely limited to treatment focused on a single gene, will require more extensive knowledge of molecular pathways and gene interactions to be successful.

Majdan and co-author Carla Shatz, department chair and HMS Nathan Marsh Pusey Professor of Neurobiology, studied rodents during the critical period in which visual input stimulates aggressive plasticity, shaping the mesh of neural connections in the cortex and tuning the strengths of messages relayed by synapses. In mice, this period begins shortly after they open their eyes and begin to see. Previous research had determined that visual activity changes the level of expression of, or regulates, individual genes such as Brain-derived neurotrophic factor (Bdnf).

To determine whether vision regulates other genes in these rodents, Majdan and Shatz imposed abnormal visual experiences on the rodents at a variety of ages including the critical period by removing one eye and leaving the other intact. They then compared gene expression profiles of the cortex supporting the open eye to that of the missing eye. They found that Bdnf is not alone-visual input changes the levels of expression of ten additional genes, dubbed the “common set,” at all ages investigated. By chemically inhibiting a MAP kinase already known to be linked to several common set genes, they found that this kinase acts as a relay, regulating these genes in response to visual activity.

The researchers found other sets of genes superimposed on this core pathway, but these sets are turned on and off by vision at specific ages before, during and after the critical period and into adulthood. “This suggests that sensory experience regulates different genes in your brain depending on your age and past experience,” said Shatz. “Thus, nurture, our experience of the world via our senses, acts through nature, sets of genes, to alter brain circuits.” These discoveries may lead to new ways of thinking about genetic therapies to correct early vision disorders. Because the brain is so altered by abnormal vision, restoring vision to a child afflicted with cataracts or strabismus, an eye misalignment which can impair vision, may not be enough to correct the damage. Nor will treatment involving single gene replacement.

“We need to try to find the major switches that turn on genes in the downstream network as opposed to looking at each element of the network and designing therapy based on each gene,” said Shatz. This study helps explain why it is that children learn so quickly and easily, and it lends credence to the idea that, in adults, mental activity leads to mental agility. “It is amazing that, even in our oldest mice we saw genes regulated by vision. Genes in the brain change with experience at every age, forming a basis for our ability to learn and remember even in adulthood,” said Shatz.

Science Daily
May 23, 2006

Original web page at Science Daily

MIT brain researchers have developed a “cocktail” of dietary supplements, now in human clinical trials, that holds promise for the treatment of Alzheimer’s disease. For years, doctors have encouraged people to consume foods such as fish that are rich in omega-3 fatty acids because they appear to improve memory and other brain functions. The MIT research suggests that a cocktail treatment of omega-3 fatty acids and two other compounds normally present in the blood, could delay the cognitive decline seen in Alzheimer’s disease, which afflicts an estimated 4 million to 5 million Americans. “It’s been enormously frustrating to have so little to offer people that have (Alzheimer’s) disease,” said Richard Wurtman, the Cecil H. Green Distinguished Professor of Neuropharmacology at MIT, who led the research team. The study appears in the May 9 issue of Brain Research.

Wurtman will present the research at the International Academy of Nutrition and Aging 2006 Symposium on Nutrition and Alzheimer’s Disease/Cognitive Decline in Chicago on Tuesday, May 2. The three compounds in the treatment cocktail – omega-3 fatty acids, uridine and choline – are all needed by brain neurons to make phospholipids, the primary component of cell membranes. After adding those supplements to the diets of gerbils, the researchers observed a dramatic increase in the amount of membranes that form brain cell synapses, where messages between cells are relayed. Damage in brain synapses is believed to cause the dementia that characterizes Alzheimer’s disease.

If the successful results obtained in gerbils can be duplicated in the ongoing human trials, the new treatment could offer perhaps not a cure but a long-term Alzheimer’s treatment similar to what L-dopa, a dopamine precursor, does for Parkinson’s patients, said Wurtman, a professor in the Department of Brain and Cognitive Sciences. “It doesn’t cure Parkinson’s, but what it does do is to help replace something that’s missing. It’s not permanent, but it has had an enormous impact on people who have Parkinson’s,” he said.

The new potential treatment offers a different approach from the traditional tactic of targeting the amyloid plaques and tangles that develop in the brains of Alzheimer’s patients. Until recently, most researchers believed these plaques and tangles caused the cognitive decline. But the failure of this hypothesis to lead to an effective treatment for Alzheimer’s disease has caused some scientists to theorize that, though the plaques and tangles are always associated with the disease, they may not be the main cause of the dementia, nor the best target for treating it.

Instead, the new research focuses on brain synapses, where neurotransmitters such as dopamine, acetylcholine, serotonin and glutamate carry messages from presynaptic neurons to receptors in the membranes of postsynaptic neurons. In Alzheimer’s patients, synapses in the cortex and hippocampus, which are involved in learning and memory, are damaged. After the dietary supplements were given, the researchers detected a large increase in the levels of specific brain proteins known to be concentrated within synapses, indicating that more synaptic membranes had formed, Wurtman said. Synaptic membrane protein levels rose if the gerbils were given either omega-3 fatty acids or uridine plus choline. However, the most dramatic upsurge was observed in gerbils fed all three compounds.

“To my knowledge, this is the first concrete explanation for the behavioral effects of taking omega-3 fatty acids,” said Wurtman. Choline can be found in meats, nuts and eggs, and omega-3 fatty acids are found in a variety of sources, including fish, eggs, flaxseed and meat from grass-fed animals. Uridine, which is found in RNA and produced by the liver and kidney, is not obtained from the diet. However, uridine is found in human breast milk, which is a good indication that supplementary uridine is safe for humans to consume, Wurtman said. Recent studies by the researchers at MIT, and by scientists at Cambridge University in England, showed that either uridine or omega-3 fatty acids can promote the growth of neurites, which are small outgrowths of neuronal cell membranes. That further supports the hypothesis that omega-3 fatty acids increase synaptic membrane formation, said Wurtman.

Alzheimer’s patients in the clinical trials, which will involve multiple medical centers, are being given a drink that contains the compounds under study, or a taste-matched placebo. “If it works as well on the brains of people with Alzheimer’s disease as it does in laboratory animals, I think there will be a lot of interest,” Wurtman said.

Science Daily
May 9, 2006

Original web page at Science Daily

Massachusetts General Hospital (MGH) researchers have made important progress in their ongoing effort to regenerate the inner ear’s hair cells, which convert sound vibrations to nerve impulses. In an upcoming issue of Proceeding of the National Academy of Sciences they report successfully creating a mouse model that allows them to build on earlier findings about the effect of deactivating a protein that controls the growth and division of hair cells. The paper, which is receiving early online publication, also finds that suppressing the retinoblastoma (Rb) protein has different effects in specific parts of the inner ear.

“In these first studies of the role of the Rb protein in the ears of postnatal mice, we have confirmed that — under the right conditions — mature hair cells can go through the cell cycle and produce new, functioning hair cells. But we’ve also confirmed that you need to block Rb reversibly and at an early stage of development, otherwise the hair cells will die,” says Zheng-Yi Chen, DPhil, of the MGH Neurology Service, the study’s senior author. In 2005 Chen was named to the Scientific American 50, the magazine’s annual list of outstanding leaders, for this continuing research project. Named for the hair-like projections on their surfaces, hair cells form a ribbon of vibration sensors along the length of the cochlea — the organ of the inner ear that senses sound — where they convert sonic vibrations to electrical signals that are carried to the brain. The cells are very sensitive to damage from excessive noise, infections and toxins. Once damaged, hair cells do not naturally regenerate in mammals, and their death accounts for most types of acquired hearing loss.

All cells grow and divide through a process called the cell cycle, and many proteins have been identified that control different cell cycle phases. In 2005 Chen’s group published a paper in the journal Science reporting that the Rb protein, known to suppress the cell cycle, could be important for halting the cell cycle in hair cells. They used a genetically modified mouse strain in which Rb was no longer made in the inner ear. By examining the inner ears of mouse embryos — that strain did not survive past birth — the researchers found more hair cells in the knockout mice than in the ears of normal mice at the same stage of development. The additional cells looked and functioned like normal hair cells and appeared to be actively regenerating.

For this followup study, the researchers developed a new strain of inner-ear Rb-knockout mice that survive for up to six months past birth. Their investigation of the effects of Rb deletion on the hair cells of the inner ear finds differences between the auditory portion of the organ, which controls hearing, and the vestibular area, which is involved with balance. While the Rb-negative auditory hair cells in early postnatal mice are dividing and growing, the cells do not mature properly and eventually die, resulting in the mice becoming deaf by the age of 3 months.
Vestibular hair cells, however, appear to grow and mature relatively normally and continue cell division even in mature mice. Adult Rb-knockout mice maintain some vestibular function, indicating that those hair cells are contributing to their sense of balance at the system level.

“We’ve shown that vestibular hair cell regeneration may be achieved and may be less of an obstacle than auditory cell regeneration,” Chen says. “Now we need to find ways to create a similar system in the auditory cells, and this new model will help us better understand the mechanisms behind functional hair cell regeneration. Our next step will be developing a transient, reversible block of Rb function to assess its role in both types of hair cell.” Chen is an assistant professor of Neurology of Harvard Medical School (HMS).

Science Daily
May 9, 2006

Original web page at Science Daily

Dr. Roger Rosenberg director of the Alzheimer’s Disease Center, led a research team including Dr. Bao-Xi Qu, assistant professor of neurology, that investigated in mice whether a specific antibody is therapeutically effective as a means to inhibit the formation of amyloid-beta storage in the brain. Accumulation of amyloid-beta 42 in humans is a hallmark of Alzheimer’s disease. By pressure-injecting the gene responsible for producing the specific protein — called amyloid-beta 42 — the researchers caused the mice to make antibodies and greatly reduce the protein’s build-up in the brain. Accumulation of amyloid-beta 42 in humans is a hallmark of Alzheimer’s disease.

“The whole point of the study is to determine whether the antibody is therapeutically effective as a means to inhibit the formation of amyloid-beta storage in the brain, and it is,” said Dr. Roger Rosenberg, the study’s senior author and director of the Alzheimer’s Disease Center at UT Southwestern. The gene injection avoids a serious side-effect that caused the cancellation of a previous multi-center human trial with amyloid-beta 42, researchers said. UT Southwestern did not participate in that trial. In that earlier study, people received injections of the protein itself and some developed dangerous brain inflammation. The new study is available online and appears in an upcoming issue of the Journal of the Neurological Sciences.

The researchers used mutant mice with two defective human genes associated with Alzheimer’s, genes that produce amyloid-beta 42. “By seven months, the mice are storing abundant amounts of amyloid-beta 42,” said Dr. Rosenberg, who holds the Abe (Brunky), Morris and William Zale Distinguished Chair in Neurology. While the mice were young, the scientists coated microscopically small gold particles with human amyloid-beta 42 genes attached to other genes that program cells to make the protein. The particles were then injected with a gene gun into the skin cells of the mice’s ears using a blast of helium.

After receiving 11 injections over several months, the mice showed a high level of antibodies to amyloid-beta 42, and a 60 percent to 77.5 percent reduction of plaques in their brains. As controls, the researchers also either injected mutant mice with the gene for a related but harmless protein, amyloid-beta 16, or with a gene vaccine that lacked any amyloid genes. These treatments did not cause antibody production, and the mice showed the large amounts of amyloid-beta 42 brain plaques normally seen in animals with these mutations.

The gene injection showed superior results compared to a previous human study in which amyloid-beta 42 protein itself was injected into muscle, Dr. Rosenberg said. That study was halted when a small percentage of participants developed inflammation of the brain and spinal cord. Injecting the gene, in contrast, caused no brain inflammation in the mice. Dr. Rosenberg said the difference was partly because in the human trial, the protein was injected along with a substance called an adjuvant, which increased the immune response to abnormal excessive levels, causing the dangerous brain inflammation. In addition, the immune response in humans may have involved antibodies called Th1, which were probably partly responsible for the inflammation. The gene injection in the mouse study produced Th2 antibodies, which have a low probability of causing brain inflammation. Furthermore, no adjuvant was needed for antibody production.

The gene immunization is now undergoing further animal studies, with the ultimate goal being a clinical trial in humans. The researchers also plan to see if it can reverse the size of established plaques in the brains of mice.

Science Daily
April 11, 2006

Original web page at Science Daily

A US team has identified what could be the earliest indication of Alzheimer’s, a discovery that may help to diagnose the disease and perhaps stop it progressing. Researchers believe that some people show signs of memory loss years before they develop Alzheimer’s. But they are not sure what causes these problems, or how they turn into full-blown dementia. To find out, Karen Ashe at the University of Minnesota, Minneapolis, and her team studied a strain of mice that, like people, develop mild memory problems in middle age before getting more severe Alzheimer’s symptoms. The mice were genetically engineered to make a version of a human protein called amyloid-β. Researchers know that this protein clogs the brains of Alzheimer’s patients late in the disease.

By extracting amyloid- from the animals’ brains, the team discovered a knot of 12 proteins that appears outside brain cells just as memory loss occurs. These clusters, which it calls Aβ *56, are different from the large plaques of amyloid- that form later in Alzheimer’s patients. The more of these clusters mice have, the worse their memories are, the team reports in Nature. And injecting clusters into the brains of rats causes temporary amnesia. The tactic of seeking the molecular changes that occur at the very first signs of memory loss is “somewhere between ingenious and lateral thinking”, says neuroscientist Richard Morris, who studies memory formation at the University of Edinburgh, UK. Before this, a lot of research focused on the later stages of the disease, when neurons are dying and it is hard to work back to the initial problem.

Ashe proposes that the clusters of amyloid-β could interrupt memory by jamming communication between neurons. She suggests that they could be one cause of the mild memory loss widely associated with old age. They could also prefigure the death of neurons and severe cognitive problems. “This may be the seed that defines who gets Alzheimer’s,” she says. The study adds to evidence that Alzheimer’s starts out when molecules of amyloid-β start to clump together. “These are the bad guys,” says Alzheimer’s specialist Dennis Selkoe of Brigham and Women’s Hospital in Boston, Massachusetts. The idea needs testing with additional experiments, Ashe says. She is scrutinizing the preserved brains of people who displayed early signs of Alzheimer’s and then died from other causes, to see whether they contain Aβ *56. Another key test is whether drugs that stop the protein clusters forming can halt memory loss in mice. “That’s the gold-standard proof of this hypothesis,” Ashe says.

Alzheimer’s is difficult to diagnose and incurable; there are an estimated 18 million sufferers worldwide. Spotting clusters of amyloid-β in the blood might help doctors to identify who is at risk of disease, helping them to target possible treatments. Drugs or vaccines that stop the clusters forming might block the brain’s decline. Researchers are already testing several methods to block the production or accumulation of amyloid-β in humans. “We’re in good shape in what needs to be done therapeutically,” Selkoe says.

Nature
March 28, 2006

Original web page at Nature