Posts tagged brain

May 24, 2012

Within the nervous system, a handful of signaling pathways modulate development of a cornucopia of different neuronal subtypes. “Even small alterations in neuron differentiation pathways can disrupt subsequent circuit organization and catalyze the genesis of neurological disorders,” explains Adrian Moore of the RIKEN Brain Science Institute in Wako.

Figure 1: Interplay between Notch signaling and Hamlet activity gives rise to diverse olfactory receptor neurons (ORNs), each with distinct structures and subsets of olfactory receptors (left). The precursor cell (right) divides to yield two daughter cells, one of which undergoes Notch (N)-mediated gene activation. Hamlet (Ham) subsequently resets Notch’s genetic effects, and the absence or subsequent restoration of Notch signaling determines which type of ORN (Naa or Nab) will result from differentiation. Credit: 2012 Adrian Moore, RIKEN Brain Science Institute

Recent work from Moore’s team, which includes Keita Endo of the University of Tokyo, has revealed mechanisms governing this complexity in the fruit fly olfactory system. Within the antennae—the fly equivalent of the nose—it was known that cells called neuronal precursors undergo multiple rounds of ‘asymmetric division’, wherein each resulting daughter cell follows a distinct developmental path, yielding different combinations of olfactory receptor neurons (ORNs). Moore’s team showed specifically that ORN precursors undergo two rounds of division, yielding four different cellular subtypes, three of which will typically mature into ORNs.

Earlier work from Endo showed that the activation or suppression of signaling by the Notch protein helps differentiate these cellular fates, but other factors were clearly involved. Their joint research demonstrated that a second protein, Hamlet, modulates the effects of Notch. 

“This [process] provides an important foundation for all future studies of odorant receptor expression and axon targeting control on the olfactory system,” says Moore. The researchers found that presence or absence of Notch and Hamlet activity plays a central role in establishing the identity of these subtypes, and this in turn determines both the connections formed by the resulting ORNs as well as the subset of olfactory receptor proteins that will be expressed (Fig. 1). 

Moore and Endo’s study also revealed a surprising mode of action for Hamlet. Chromosomal DNA is wrapped around clusters of protein, and chemical changes to those proteins profoundly alter local gene activity—a mechanism called ‘epigenetic regulation’. They found that Hamlet selectively deactivates genes activated by Notch by triggering such changes. This means that immature ORNs produced by division of a Notch-activated cell can essentially be ‘reset’ by Hamlet. The ultimate developmental fate of those cells is then determined, in part, by whether or not they subsequently undergo a new round of Notch activation. 

Moore and colleagues also observed that, beyond simply switching off active Notch genes, Hamlet may define subsets of target genes that can subsequently be reactivated by Notch signaling. “The modifications induced by Hamlet may help establish cell fate by marking gene promoters for use later during differentiation,” says Moore. “This could prove fundamental to understanding the process of neuronal diversification.”

Provided by RIKEN

Source: medicalxpress.com

May 24, 2012

(Medical Xpress) — Research from Karolinska Institutet shows that the human olfactory bulb - a structure in the brain that processes sensory input from the nose - differs from that of other mammals in that no new neurons are formed in this area after birth. The discovery, which is published in the scientific journal Neuron, is based on the age-determination of the cells using the carbon-14 method, and might explain why the human sense of smell is normally much worse than that of other animals.

"I’ve never been so astonished by a scientific discovery," says lead investigator Jonas Frisén, Tobias Foundation Professor of stem cell research at Karolinska Institutet. "What you would normally expect is for humans to be like other animals, particularly apes, in this respect."

It was long thought that all brain neurons were formed up to the time of birth, after which production stopped. A paradigm shift occurred when scientists found that nerve cells were being continually formed from stem cells in the mammalian brain, which changed scientific views on the plasticity of the brain and raised hopes of being able to replace neurons lost during some types of neurological disease.

In the adult mammal, new nerve cells are formed in two regions of the brain: the hippocampus and the olfactory bulb. While the former has an important part to play in memory, the latter is essential to the interpretation of smells. However, owing to the difficulty of studying the formation of new neurons in humans, the extent to which this phenomenon also occurs in the human brain has remained unclear. In this present study, researchers at Karolinska Institutet and their Austrian and French colleagues made use of the sharp rise in atmospheric carbon-14 caused by Cold War nuclear tests to find an answer to this question.

Carbon-14 is incorporated in DNA, making it possible to gauge the age of the cells by measuring how much of the isotope they contain. Doing this, the team found that the olfactory bulb neurons in their adult human subjects had carbon-14 levels that matched those at the atmosphere at the time of their birth. This is a strong indication that there is no significant generation of new neurons in this part of the brain, something that sets humans apart from all other mammals.

"Humans are less dependent on their sense of smell for their survival than many other animals, which may be related to the loss of new cell generation in the olfactory bulb, but this is just speculation,” says Professor Frisén.

Professor Frisén and his team now plan to study the extent of neuron generation in the hippocampus, a part of the brain that is important for higher cerebral functions in humans.

Provided by Karolinska Institutet

Source: medicalxpress.com

ScienceDaily (May 23, 2012) — Blame it on your genes? Researchers from The Miriam Hospital’s Weight Control and Diabetes Research Center say individuals with variations in certain “obesity genes” tend to eat more meals and snacks, consume more calories per day and often choose the same types of high fat, sugary foods.

Blame it on your genes? Researchers say individuals with variations in certain “obesity genes” tend to eat more meals and snacks and consume more calories per day. (Credit: © Gennadiy Poznyakov / Fotolia)

Their study, published online by the American Journal of Clinical Nutrition and appearing in the June issue, reveals certain variations within the FTO and BDNF genes — which have been previously linked to obesity — may play a role in eating habits that can cause obesity.

The findings suggest it may be possible to minimize genetic risk by changing one’s eating patterns and being vigilant about food choices, in addition to adopting other healthy lifestyle habits, like regular physical activity.

"Understanding how our genes influence obesity is critical in trying to understand the current obesity epidemic, yet it’s important to remember that genetic traits alone do not mean obesity is inevitable," said lead author Jeanne M. McCaffery, Ph.D., of The Miriam Hospital’s Weight Control and Diabetes Research Center.

"Our lifestyle choices are critical when it comes to determining how thin or heavy we are, regardless of your genetic traits," she added. "However, uncovering genetic markers can possibly pinpoint future interventions to control obesity in those who are genetically predisposed."

Previous research has shown individuals who carry a variant of the fast mass and obesity-associated gene FTO and BDNF (or brain-derived neurotrophic factor gene) are at increased risk for obesity. The genes have also been linked with overeating in children and this is one of the first studies to extend this finding to adults. Both FTO and BDNF are expressed in the part of the brain that controls eating and appetite, although the mechanisms by which these gene variations influence obesity is still unknown.

As part of the Look AHEAD (Action in Health and Diabetes) trial, more than 2,000 participants completed a questionnaire about their eating habits over the past six months and also underwent geneotyping. Researchers focused on nearly a dozen genes that have been previously associated with obesity. They then examined whether these genetic markers influenced the pattern or content of the participants’ diet.

Variations in the FTO gene specifically were significantly associated with a greater number of meals and snacks per day, greater percentage of energy from fat and more servings of fats, oils and sweets. The findings are largely consistent with previous research in children.

Researchers also discovered that individuals with BDNF variations consumed more servings from the dairy and the meat, eggs, nuts and beans food groups. They also consumed approximately 100 more calories per day, which McCaffery notes could have a substantial influence on one’s weight.

"We show that at least some of the genetic influence on obesity may occur through patterns of dietary intake," she said. "The good news is that eating habits can be modified, so we may be able to reduce one’s genetic risk for obesity by changing these eating patterns."

McCaffery says that while this research greatly expands their knowledge on how genetics may influence obesity, the data must be replicated before the findings can be translated into possible clinical measures.

Source: Science Daily

May 23rd, 2012

Study supports urate protection against Parkinson’s disease, hints at novel mechanism

In vitro study indicates urate protection extends beyond antioxidant effect

Use of the antioxidant urate to protect against the neurodegeneration caused by Parkinson’s disease appears to rely on more than urate’s ability to protect against oxidative damage. In the May issue of the open-access journal PLoS One, researchers from the MassGeneral Institute for Neurodegenerative Diseases (MGH-MIND) describe experiments suggesting the involvement of a novel mechanism in urate’s protection of cultured brain cells against Parkinson’s-like damage.

“Our experiments showed, unexpectedly, that urate’s ability to protect neurons requires the presence of neighboring cells called astrocytes,” says Michael Schwarzschild, MD, PhD, of MGH-MIND, the study’s senior author. “The results suggest there may be multiple ways that raising urate could help protect against neurodegeneration in diseases like Parkinson’s and further support the development of treatments designed to elevate urate in the brain.” Schwarzschild and colleagues in the Parkinson’s Study Group currently are conducting a clinical trial investigating one approach to that strategy.

Characterized by tremors, rigidity, difficulty walking and other symptoms, Parkinson’s disease is caused by destruction of brain cells that produce the neurotransmitter dopamine. Several epidemiological studies suggested that healthy people with elevated levels of urate, a normal component of the blood, may have a reduced risk of developing Parkinson’s disease, and investigations by Schwarzschild’s team found that Parkinson’s patients with higher naturally occuring urate levels had slower progression of their symptoms.

The current study was designed to investigate whether both added urate and urate already present within the cells protect cultured dopamine-producing neurons against Parkinson-like degeneration. In addition, since previous studies suggested that urate’s protective effects depended on the presence of astrocytes,  star-shaped cells of the central nervous system that provide both structural and metabolic support to neurons,  the MGH-MIND team explored how the presence of astrocytes affects the ability of urate to protect against damage induced by MPP+, a toxic molecule that produces the same kind of neurodegeneration seen in Parkinson’s and is widely used in research studies.

Raising urate levels could help to protect against neurodegenerative diseases like Parkinsons. Image adapted from Flickr user Niels_Olson.

The experiments showed that, while added urate reduced MPP+-induced cell death by about 50 percent in cultured dopamine-producing mouse neurons, urate treatment virtually eliminated neuronal death in cultures containing both neurons and astrocytes. They also showed that reducing intracellular urate levels by induced expression of the enzyme that breaks it down increased neuronal vulnerability to MPP+ toxicity significantly in cultures that included astrocytes but only slightly in neuron-rich cultures. The fact that the presence of astrocytes greatly increases the protection of both externally applied urate and urate produced within cells indicates that the effect depends on more than urate’s ability to directly protect neurons against oxidative stress.

“A valuable next step will be determining whether endogenous urate is protective in live animal models of Parkinson’s disease,” says Schwarzschild. “It also will be important to determine whether we can selectively increase urate levels in brain cells by targeting urate transporter molecules. The approach now in early clinical trials examines whether treatment with the urate precursor inosine, which increases urate levels throughout the body, can slow the progression of the disease. If we could raise urate levels in brain cells without changing them in the rest of the body, we could avoid the risks of of excessive urate, which when accumulated in joints can cause gout.”

Source: Neuroscience News

May 23, 2012

Researchers have shown in mice how immune cells in the brain target and remove unused connections between brain cells during normal development. This research, supported by the National Institutes of Health, sheds light on how brain activity influences brain development, and highlights the newly found importance of the immune system in how the brain is wired, as well as how the brain forms new connections throughout life in response to change.

Disease-fighting cells in the brain, known as microglia, can prune the billions of tiny connections (or synapses) between neurons, the brain cells that transmit information through electric and chemical signals. This new research demonstrates that microglia respond to neuronal activity to select synapses to prune, and shows how this pruning relies on an immune response pathway – the complement system – to eliminate synapses in the way that bacterial cells or other pathogenic debris are eliminated. The study was led by Beth Stevens, Ph.D., assistant professor of neurology at Boston Children’s Hospital and Harvard Medical School.

The brain is created with many more synapses than it retains into adulthood. As the brain develops, it goes through dynamic changes to refine its circuitry, trimming away the synaptic connections that do not have a lot of activity, and preserving the stronger, more active synapses. This period, known as synaptic pruning, is a key part of normal brain development.

Scientists do not have a clear understanding of how these synapses are selected, targeted and then pruned. However, precise elimination of unused synapses and strengthening those that are most needed is essential for normal brain function. Many childhood disorders, such as amblyopia (a loss of vision in one eye that can occur when the eyes are misaligned), various forms of mental retardation, epilepsy and autism are thought to be due to abnormal brain development.

Microglia originate in the bone marrow and transform into an activated state to defend the body against infections. Activated microglia are also found in other disease states, ranging from stroke to Alzheimer’s disease. It is not always clear, however, if these cells cause degeneration of brain cells, or if they are part of the brain’s recovery process. In more recent years, several research groups reported that activated microglia are also present in the normal brain. Additionally, during the most robust synaptic pruning periods there is an increased number of activated microglia present and clustered around synapses.

As reported in the May 24 issue of Neuron, scientists in Dr. Stevens’s lab used the visual system in mice to study synaptic pruning, a model that undergoes robust change and remodeling during development and which has circuitry that is well-defined and easy to manipulate. Researchers labeled neurons that project from the eye into an area of the brain called the lateral geniculate nucleus, or LGN, and found that reactive microglia contained portions of the synapses from the labeled neurons. They also saw that these labeled pieces of synaptic material were specifically found inside the microglia’s lysosomes – compartments responsible for digesting foreign particles.

The researchers then investigated if the amount of neuronal activity at a synapse determines whether microglia target it for removal. They used a drug to increase activity in the neurons projecting from one eye and saw less pruning of synapses in the corresponding brain region, as compared to the untreated eye. When they used a drug to reduce activity, this resulted in more pruning compared to the untreated eye. The researchers think microglia select a synapse for removal based on the synapse’s level of activity. This may be directly relevant to amblyopia, a loss of vision in one eye that can occur when the eyes are misaligned. Children with amblyopia will preferentially use one eye and vision in the less used eye deteriorates due loss of synapses and cells in the LGN.

Earlier research revealed that proteins involved in the complement system are found near synapses during development and are necessary for pruning. To see if these same proteins are used by microglia to shape neuronal connections, the researchers disrupted complement pathway proteins that are found only in the brain’s immune cells. Their results indicate that these complement proteins signal the microglia to trim away synapses, and suggest that immune system pathways are key to proper synaptic pruning.

"The concept that microglia prune synapses using immune system pathways has been difficult to prove,” said Edmund Talley, Ph.D., program director at the National Institute of Neurological Disorders and Stroke, “This exquisitely careful and meticulous research confirms the role of microglia in brain development, plasticity and learning.”

Dr. Stevens said the study sheds light on the role of microglia in the normal brain, and supports further investigations into the role of microglia in brain disease. “Almost every neurodegenerative brain disease involves several interesting common denominators,” she said. “It’s becoming increasingly recognized that early synapse loss is a hallmark of many neurodegenerative diseases.”

Provided by NIH/National Institute of Neurological Disorders and Stroke

Source: medicalxpress.com

May 23, 2012

When grabbing a coffee mug out of a cluttered cabinet or choosing a pen to quickly sign a document, what brain processes guide your choices?

New research from Carnegie Mellon University’s Center for the Neural Basis of Cognition (CNBC) shows that the brain’s visual perception system automatically and unconsciously guides decision-making through valence perception. Published in the journal Frontiers in Psychology, the review hypothesizes that valence, which can be defined as the positive or negative information automatically perceived in the majority of visual information, integrates visual features and associations from experience with similar objects or features. In other words, it is the process that allows our brains to rapidly make choices between similar objects.

The findings offer important insights into consumer behavior in ways that traditional consumer marketing focus groups cannot address. For example, asking individuals to react to package designs, ads or logos is simply ineffective. Instead, companies can use this type of brain science to more effectively assess how unconscious visual valence perception contributes to consumer behavior.

To transfer the research’s scientific application to the online video market, the CMU research team is in the process of founding the start-up company neonlabs through the support of the National Science Foundation (NSF) Innovation Corps (I-Corps).

"This basic research into how visual object recognition interacts with and is influenced by affect paints a much richer picture of how we see objects," said Michael J. Tarr, the George A. and Helen Dunham Cowan Professor of Cognitive Neuroscience and co-director of the CNBC. “What we now know is that common, household objects carry subtle positive or negative valences and that these valences have an impact on our day-to-day behavior.”

Tarr added that the NSF I-Corps program has been instrumental in helping the neonlabs’ team take this basic idea and teaching them how to turn it into a viable company. “The I-Corps program gave us unprecedented access to highly successful, experienced entrepreneurs and venture capitalists who provided incredibly valuable feedback throughout the development process,” he said.

NSF established I-Corps for the sole purpose of assessing the readiness of transitioning new scientific opportunities into valuable products through a public-private partnership. The CMU team of Tarr, Sophie Lebrecht, a CNBC and Tepper School of Business postdoctoral fellow, Babs Carryer, an embedded entrepreneur at CMU’s Project Olympus, and Thomas Kubilius, president of Pittsburgh-based Bright Innovation and adjunct professor of design at CMU, were awarded a $50,000, six-month grant to investigate how understanding valence perception could be used to make better consumer marketing decisions. They are launching neonlabs to apply their model of visual preference to increase click rates on online videos, by identifying the most visually appealing thumbnail from a stream of video. The web-based software product selects a thumbnail based on neuroimaging data on object perception and valence, crowd sourced behavioral data and proprietary computational analyses of large amounts of video streams.

"Everything you see, you automatically dislike or like, prefer or don’t prefer, in part, because of valence perception," said Lebrecht, lead author of the study and the entrepreneurial lead for the I-Corps grant. "Valence links what we see in the world to how we make decisions."

Lebrecht continued, “Talking with companies such as YouTube and Hulu, we realized that they are looking for ways to keep users on their sites longer by clicking to watch more videos. Thumbnails are a huge problem for any online video publisher, and our research fits perfectly with this problem. Our approach streamlines the process and chooses the screenshot that is the most visually appealing based on science, which will in the end result in more user clicks.”

Today (May 23), Lebrecht will join the other 23 I-Corps project teams in Palo Alto, Calif., for the final presentation of each team’s I-Corps journey from basic science idea to real-world business application. She will present neonlabs’ solution, outlining the customer landscape, competition and business model.

Carnegie Mellon is well known for its entrepreneurial culture. The university’s Greenlighting Startups initiative, a portfolio of five business incubators, is designed to speed company creation at CMU. In the past 15 years, Carnegie Mellon faculty and students have helped to create more than 300 companies and 9,000 jobs; the university averages 15 to 20 new startups each year.

"CMU has been an amazing place to build neonlabs," Lebrecht said. "There’s a great intellectual community and facilities here as well as people unbelievably experienced in tech transfer and startups who have been so incredibly generous with their time."

Provided by Carnegie Mellon University

Source: medicalxpress.com

May 23rd, 2012

Well-connected brains make you smarter in older age
Brains that maintain healthy nerve connections as we age help keep us sharp in later life, new research funded by the charity Age UK has found

Brains that maintain healthy nerve connections as we age help keep us sharp in later life, new research funded by the charity Age UK has found.

Older people with robust brain ‘wiring’, that is, the nerve fibres that connect different, distant brain areas, can process information quickly and that this makes them generally smarter, the study suggests.

According to the findings, joining distant parts of the brain together with better wiring improves mental performance, suggesting that intelligence is not found in a single part of the brain.

However a loss of condition of this wiring or ‘white matter’, the billions of nerve fibres that transmit signals around the brain, can negatively affect our intelligence by altering these networks and slowing down our processing speed.

The research by the University of Edinburgh shows for the first time that the deterioration of white matter with age is likely to be a significant cause of age-related cognitive decline.

The research team used three different brain imaging techniques in compiling the results, including two that have never been used before in the study of intelligence.

Healthy nerve connections in the brain help to reduce mental decline and dementia in older people. Image by Flickr user Brian Auer. See below for attribution.

These techniques measure the amount of water in brain tissue, indicate structural loss in the brain, and show how well the nerve fibres are insulated.

The researchers examined scans and results of thinking and reaction time tests from 420 people in the Lothian Birth Cohort of 1936, a group of nearly 1100 people whose intelligence & general health have been tracked since they were 11

The research was part of the Disconnected Mind Project, a large study of the causes of people’s differences in cognitive ageing, led by Professor Ian Deary.

Study author Doctor Lars Penke said “Our results suggest a first plausible way how brain structure differences lead to higher intelligence. The results are exciting for our understanding of human intelligence differences at all ages.”

“They also suggest a clear target for seeking treatment for mental difficulties, be they pathological or age-related. That the brain’s nerve connections tend to stay the same throughout the brain means we can now look at factors that affect the overall condition of the brain, like its bloody supply.”

Professor Deary said that uncovering the secrets of good thinking skills in old age is a high priority. “The research team is now looking at what keeps the brain’s connections healthy. We value our thinking skills, and research should address how we might retain them or slow their decline with age.”

Doctor Mark Bastin, who co-authored the study, said “These findings are exciting as they show how quantitative brain imaging can provide novel insights into the links between brain structure and cognitive ability. This is a key research area given the importance of identifying strategies for retaining good mental ability into older age.”

Professor James Goodwin, Head of Research at Age UK, said: “This research is very exciting as it could have a real impact on tackling mental decline in later life, including dementia. With new understanding on how the brain functions we can work out why mental faculties decline with age in some people and not others and look at what can be done to improve our minds’ chances of ageing better.”

Source: Neuroscience News

May 23, 2012

Researchers at New York University and Albert Einstein College of Medicine of Yeshiva University have discovered new ways neurons work together to ease the transition between sleep and wakefulness. Their findings, which appear in the journal Neuron, provide additional insights into sleep-wake patterns and offer methods to explore what may disrupt them.

Their study explored the biological, or circadian, clocks of Drosophila fruit flies, which are commonly used for research in this area. This is because it is relatively easy to find mutants with malfunctioning biological clocks and then to identify the genes underlying the altered behavior. Such studies in fruit flies have allowed the identification of similar “clock genes" in mammals, which function in largely the same manner as they do in a fly’s clock.

In the Neuron study, the researchers moved up a level to study how pacemaker clock neurons—which express clock genes—interact with each other. Specifically, they looked at the relationship between master pacemaker neurons, which control the overall pace of the circadian system, and non-master pacemaker neurons, whose role in circadian rhythms has been less clear.

To do so, they examined flies with normally functioning master and non-master clock neurons and compared them with mutant flies in which the signaling of these neurons was either increased or decreased. These comparisons allowed the researchers to isolate the individual roles of these neurons and, in particular, to understand how master and non-master pacemaker neurons work together to control circadian rhythms.

Their results revealed a previously unknown role for non-master pacemaker neurons. Specifically, these neurons employ a neurotransmitter, glutamate, which suppresses signaling of the master pacemaker neurons during the evening. Artificially increasing this suppression by the non-master clock neurons in the morning made it much harder for flies to wake up. So in normal flies, these non-master pacemaker neurons have to stand aside at dawn, allowing the master pacemaker neurons to fire to wake up the fly. The authors concluded that the balance between signaling of these two groups of clock neurons helps to set the precise time of the transition between sleep and wakefulness.

"Our work shifts the emphasis away from clock genes and starts to address how clock neurons function in a neural network to regulate behavior," explained Justin Blau, an associate professor in NYU’s Department of Biology and one of the study’s co-authors. "And it shows the importance of studying individual groups of clock neurons, since different subsets can have opposite effects on animal behavior.”

"This work helps to elucidate the neurotransmitters and receptors that facilitate communication between specific groups of nerve cells that regulate circadian rhythm," said co-author Myles Akabas, professor of Physiology & Biophysics and of Neuroscience at Albert Einstein College of Medicine. "It demonstrates the power of collaborative interdisciplinary research to address the molecular and cellular basis for behavior."

Provided by New York University

Source: medicalxpress.com

May 23, 2012 by R. Alan Leo

For decades, neurologists have known that a diet high in fat and extremely low in carbohydrates can reduce epileptic seizures that resist drug therapy. But how the diet worked, and why, was a mystery—so much so that in 2010, The New York Times Magazine called it “Epilepsy’s Big, Fat Miracle.”

Now, researchers at Dana-Farber Cancer Institute and Harvard Medical School have proposed an answer, linking resistance to seizures to a protein that modifies cellular metabolism in the brain. The research, to be published in the May 24th issue of the journal Neuron, may lead to the development of new treatments for epilepsy.

The research was led jointly by Nika Danial, HMS assistant professor of cell biology at Dana-Farber Cancer Institute, and Gary Yellen, professor of neurobiology at Harvard Medical School. The first author was Alfredo Giménez-Cassina, a research fellow in Danial’s lab.

Epilepsy is a neurological disorder characterized by repeated seizures, an electrical storm in the brain that can manifest as convulsions, loss of motor control, or loss of consciousness. Some cases of epilepsy can be improved by a diet that drastically reduces sugar intake, triggering neurons to switch from their customary fuel of glucose to fat byproducts called ketone bodies. The so-called ketogenic diet, which mimics effects of starvation, was described more than 80 years ago and received renewed interest in the 1990s. Recent studies corroborate that it works, but shed little light on how.

"The connection between metabolism and epilepsy has been such a puzzle," said Yellen, who was introduced to the ketogenic diet through his wife, Elizabeth Thiele, HMS professor of neurology, who directs the Pediatric Epilepsy Program at MassGeneral Hospital for Children, but was not directly involved in the study. "I’ve met a lot of kids whose lives are completely changed by this diet," Yellen said. "It’s amazingly effective, and it works for many kids for whom drugs don’t work."

"We knew we needed to come at this link between metabolism and epilepsy from a new angle," said Danial, who had previously discovered a surprising double duty for a protein known for its role in apoptosis: The protein, BCL-2-associated Agonist of Cell Death, or BAD, also regulated glucose metabolism.

Giménez-Cassina further discovered that certain modifications in BAD switched metabolism in brain cells from glucose to ketone bodies. “It was then that we realized we had come upon a metabolic switch to do what the ketogenic diet does to the brain without any actual dietary therapy,” said Gimenez-Cassina, who went on to show that these same BAD modifications protect against seizures in experimental models of epilepsy. Still, it wasn’t clear exactly how.

Yellen suspected the solution involved potassium ion channels. While sodium and calcium ion channels tend to excite cells, including neurons, potassium channels tend to suppress cell electrical activity. His lab had previously linked ketone bodies to the activation of ATP-sensitive potassium (KATP) channels in neurons. Yellen had hypothesized that the ketogenic diet worked because ketone bodies provide neurons enough fuel for normal function, but when the electrical and energy storm of an epileptic seizure threatens, the activated KATP channels can shut the storm down. But the effects of diets are broad and complex, so it was impossible to say for sure.

The effects that Danial’s lab had discovered—BAD’s ability to alter metabolism and seizures—offered a new avenue for studying the therapeutic effects of altered metabolism. Together, the researchers decided to investigate whether Danial’s switch governed Yellen’s pathway, and whether they could reverse engineer the seizure protection of a ketogenic diet.

They could. Working in genetically altered mice, the researchers modified the BAD protein to reduce glucose metabolism and increase ketone body metabolism in the brain. Seizures decreased, but the benefit was erased when they knocked out the KATP channel—strong evidence that a BAD-KATP pathway conferred resistance to epileptic seizures. Further experiments suggested that it was indeed BAD’s role in metabolism, not cell death that mattered. The findings make the BAD protein a promising target for new epilepsy drugs.

"Diet sounds like this wholesome way to treat seizures, but it’s very hard. I mean, diets in general are hard, and this diet is really hard," said Yellen, whose wife’s Center for Dietary Therapy in Epilepsy hosts a candy-free Halloween party for its many patients on the ketogenic diet. “So finding a pharmacological substitute for this would make lots of people really happy.”

Provided by Harvard Medical School

Source: medicalxpress.com

May 23, 2012

A new study finds that transplanting embryonic cells into adult mouse spinal cord can alleviate persistent pain. The research, published by Cell Press in the May 24th issue of the journal Neuron, suggests that reduced pain results from successful integration of the embryonic cells into the host spinal cord. The findings open avenues for clinical strategies aimed not just at treating the symptoms of chronic debilitating pain, but correcting the underlying disease pathology.

There are two major classes of chronic pain: inflammatory pain that results from injury to tissue, such as muscle and bone, and neuropathic pain from injury to nerves, for example, in the limbs or face. Damage to nerves can occur after physical trauma and from chemotherapy drugs. With neuropathic pain, the pain occurs in the absence of stimulation, and there is hypersensitivity and exacerbated pain to stimuli that would not normally cause pain. Neuropathic pain is thought to involve the loss of inhibitory neurons that release the chemical GABA, which is an inhibitory neurotransmitter that controls the excitability of neurons, including neurons that transmit pain information.

"Pharmacological approaches to managing neuropathic pain enhance GABA-mediated inhibition. However, some patients do not respond to these therapies and there are significant adverse side effects," explains senior study author, Dr. Allan Basbaum from the University of California, San Francisco. "Therefore, new therapeutic approaches for neuropathic pain are essential." Dr. Basbaum and colleagues explored whether replacement of the damaged inhibitory neurons might be useful for reducing neuropathic pain.

The researchers transplanted immature GABA neurons from mouse fetal brain into the spinal cord of mice with nerve injury-induced pain, a model for human neuropathic pain. The transplanted cells not only survived, but made connections with appropriate targets and integrated into the host spinal cord circuitry. This resulted in an almost complete reversal of the mechanical hypersensitivity generated in a nerve injury model of neuropathic pain. In contrast, the transplant procedure was not effective at reducing pain in a mouse model of inflammatory pain, which is induced by tissue injury.

Taken together, the findings have exciting implications for a cell-based treatment of neuropathic pain in humans. “Our strategy not only ameliorates the symptoms of neuropathic pain but, importantly, is also potentially disease modifying,” concludes Dr. Basbaum. “It is worth considering whether transplants such as these might have clinical utility in humans, a great advantage being that the adverse side effects associated with drug administration can be avoided.”

Provided by Cell Press

Source: medicalxpress.com