Brain Cells Responsible for Keeping Us Awake

Brain Cells Responsible for Keeping Us Awake

  11:46:00 PM    Science Lover

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Bright light arouses us. Bright light makes it easier to stay awake. Very bright light not only arouses us but is known to have antidepressant effects. Conversely, dark rooms can make us sleepy. It's the reason some people use masks to make sure light doesn't wake them while they sleep.

Researchers have identified the group of neurons
that mediates whether light arouses us and keeps
us awake, or not. (Credit: iStockphoto/Osman Safi)

Now researchers at UCLA have identified the group of neurons that mediates whether light arouses us -- or not. Jerome Siegel, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA, and colleagues report in the current online edition of the Journal of Neuroscience that the cells necessary for a light-induced arousal response are located in the hypothalamus, an area at the base of the brain responsible for, among other things, control of the autonomic nervous system, body temperature, hunger, thirst, fatigue -- and sleep.

These cells release a neurotransmitter called hypocretin, Siegel said. The researchers compared mice with and without hypocretin and found that those who didn't have it were unable to stay awake in the light, while those who had it showed intense activation of these cells in the light but not while they were awake in the dark.

This same UCLA research group earlier determined that the loss of hypocretin was responsible for narcolepsy and the sleepiness associated with Parkinson's disease. But the neurotransmitter's role in normal behavior was, until now, unclear.

"This current finding explains prior work in humans that found that narcoleptics lack the arousing response to light, unlike other equally sleepy individuals, and that both narcoleptics and Parkinson's patients have an increased tendency to be depressed compared to others with chronic illnesses," said Siegel, who is also a member of the UCLA Brain Research Institute and chief of neurobiology research at the Sepulveda Veterans Affairs Medical Center in Mission Hills, Calif.



Prior studies of the behavioral role of hypocretin in rodents had examined the neurotransmitter's function during only light phases (normal sleep time for mice) or dark phases (their normal wake time), but not both. And the studies only examined the rodents when they were performing a single task.

In the current study, researchers examined the behavioral capabilities of mice that had their hypocretin genetically "knocked-out" (KO mice) and compared them with the activities of normal, wild-type mice (WT) that still had their hypocretin neurons. The researchers tested the two groups while they performed a variety of tasks during both light and dark phases.

Surprisingly, they found that the KO mice were only deficient at working for positive rewards during the light phase. During the dark phase, however, these mice learned at the same rate as their WT littermates and were completely unimpaired in working for the same rewards.

Consistent with the data in the KO mice, the activity of hypocretin neurons in their WT littermates was maximized when working for positive rewards during the light phase, but the cells were not activated when performing the same tasks in the dark phase.

"The findings suggest that administering hypocretin and boosting the function of hypocretin cells will increase the light-induced arousal response," Siegel said. "Conversely, blocking their function by administering hypocretin receptor blockers will reduce this response and thereby induce sleep."

Further, Siegel noted, "The administration of hypocretin may also have antidepressant properties, and blocking it may increase tendencies toward depression. So we feel this work has implications for treating sleep disorders as well as depression."

Other authors on the study included Ronald McGregor (first author), Ming-Fung Wu, Grace Barber and Lalini Ramanathan, all of UCLA, the Veterans Affairs Greater Los Angeles Healthcare System and the UCLA Brain Research Institute.

The research was supported by the National Institutes of Health and the Medical Research Service of the Department of Veterans Affairs. The authors report no conflict of interest.

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Deep Brain Stimulation Studies Show How Brain Buys Time for Tough Choices

Deep Brain Stimulation Studies Show How Brain Buys Time for Tough Choices

  8:22:00 PM    Science Lover

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Take your time. Hold your horses. Sleep on it. When people must decide between arguably equal choices, they need time to deliberate. In the case of people undergoing deep brain stimulation (DBS) for Parkinson's disease, that process sometimes doesn't kick in, leading to impulsive behavior. Some people who receive deep brain stimulation for Parkinson's disease behave impulsively, making quick, often bad, decisions.

Red is for reflection. The hotter the color, especially in the circled area, the more likely the brain was to take its time making difficult decisions. Parkinson's patients whose deep brain stimulators were on (right), were more impulsive -- a cooler blue. (Credit: Frank Lab/Brown University)

New research into why that happens has led scientists to a detailed explanation of how the brain devotes time to reflect on tough choices.

Michael Frank, professor of cognitive, linguistic, and psychological sciences at Brown University, studied the impulsive behavior of Parkinson's patients when he was at the University of Arizona several years ago. His goal was to model the brain's decision-making mechanics. He had begun working with Parkinson's patients because DBS, a treatment that suppresses their tremor symptoms, delivers pulses of electrical current to the subthalamic nucleus (STN), a part of the brain that Frank hypothesized had an important role in decisions. Could the STN be what slams the brakes on impulses, giving the medial prefrontal cortex (mPFC) time to think?

When the medial prefrontal cortex needs time to deliberate, it recruits help in warding off impulsive urges from elsewhere in the brain."We didn't have any direct evidence of that," said Frank, who is affiliated with the Brown Institute for Brain Science. "To test that theory for how areas of the brain interact to prevent you from making impulsive decisions and how that could be changed by DBS, you have to do experiments where you record brain activity in both parts of the network that we think are involved. Then you also have to manipulate the system to see how the relationship between recorded activity in one area and decision making changes as a function of stimulating the other area."

Frank and his team at Brown and Arizona did exactly that. They describe their findings in a study published online in the journal Nature Neuroscience.

The researchers' measurements from two experiments and analysis with a computer model support the theory that when the mPFC is faced with a tough decision, it recruits the STN to ward off more impulsive urges coming from the striatum, a third part of the brain. That allows it time to make its decision.

For their first experiment, the researchers designed a computerized decision-making experiment. They asked 65 healthy subjects and 14 subjects with Parkinson's disease to choose between pairs of generic line art images while their mPFC brain activity was recorded. Each image was each associated with a level of reward. Over time the subjects learned which ones carried a greater reward.

Sometimes, however, the subjects would be confronted with images of almost equal reward -- a relatively tough choice. That's when scalp electrodes detected elevated activity in the mPFC in certain low frequency bands. Lead author and postdoctoral scholar James Cavanagh found that when mPFC activity was larger, healthy participants and Parkinson's participants whose stimulators were off would take proportionally longer to decide. But when deep brain stimulators were turned on to alter STN function, the relationship between mPFC activity and decision making was reversed, leading to decision making that was quicker and less accurate.



The Parkinson's patients whose stimulators were on still showed the same elevated level of activity in the mPFC. The cortex wanted to deliberate, Cavanagh said, but the link to the brakes had been cut.

"Parkinson's patients on DBS had the same signals," he said. "It just didn't relate to behavior. We had knocked out the network."

In the second experiment, the researchers presented eight patients with the same decision-making game while they were on the operating table in Arizona receiving their DBS implant. The researchers used the electrode to record activity directly in the STN and found a pattern of brain activity closely associated with the patterns they observed in the mPFC.

"The STN has greater activity with greater [decision] conflict," he said. "It is responsive to the circumstances that the signals on top of the scalp are responsive to, and in highly similar frequency bands and time ranges."

A mathematical model for analyzing the measurements of accuracy and response time confirmed that the elevated neural activity and the extra time people took to decide was indeed evidence of effortful deliberation.

"It was not that they were waiting without doing anything," said graduate student Thomas Wiecki, the paper's second author. "They were slower because they were taking the time to make a more informed decision. They were processing it more thoroughly."

The results have led the researchers to think that perhaps the different brain regions communicate by virtue of these low-frequency signals. Maybe the impulsivity side effect of DBS could be mitigated if those bands could remain unhindered by the stimulator's signal. Alternatively, Wiecki said, a more sophisticated DBS system could sense that decision conflict is underway in the mPFC and either temporarily suspend its operation until the decision is made, or stimulate the STN in a more dynamic way to better mimic intact STN function.

These are not trivial ideas to foist upon DBS engineers, but by understanding the mechanics underlying the side effect -- and in healthy unhindered decision making -- the researchers say they now have a target to consider.

In addition to Frank, Cavanagh, and Wiecki, another Brown author is Christina Figueroa. Arizona authors include Michael Cohen, Johan Samanta, and Scott Sherman.

The Michael J. Fox Foundation funded the research.

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Holograms Reveal Brain's Inner Workings: Microscopy Technique Used to Observe Activity of Neurons Like Never Before

Holograms Reveal Brain's Inner Workings: Microscopy Technique Used to Observe Activity of Neurons Like Never Before

  9:36:00 AM    Science Lover

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Like far away galaxies, powerful tools are required to bring the minute inner workings of neurons into focus. Borrowing a technique from materials science, a team of neurobiologists, psychiatrists, and advanced imaging specialists from Switzerland's EPLF and CHUV report in The Journal of Neuroscience how Digital Holographic Microscopy (DHM) can now be used to observe neuronal activity in real-time and in three dimensions -- with up to 50 times greater resolution than ever before. The application has immense potential for testing out new drugs to fight neurodegenerative diseases such as Alzheimer's and Parkinson's.

This is a 3-D image of living neuron taken by DHM 
technology. (Credit: Courtesy of Lyncée Tec)

Neurons come in various shapes and are transparent. To observe them in a Petri dish, scientists use florescent dyes that change the chemical composition and can skew results. Additionally, this technique is time consuming, often damages the cells, and only allows researchers to examine a few neurons at a time. But these newly published results show how DHM can bypass the limitations of existing techniques.

"DHM is a fundamentally novel application for studying neurons with a slew of advantages over traditional microscopes," explains Pierre Magistretti of EPFL's Brain Mind Institute and a lead author of the paper. "It is non-invasive, allowing for extended observation of neural processes without the need for electrodes or dyes that damage cells."

Senior team member Pierre Marquet adds, "DHM gives precious information not only about the shape of neurons, but also about their dynamics and activity, and the technique creates 3D navigable images and increases the precision from 500 nanometers in traditional microscopes to a scale of 10 nanometers."

A good way to understand how DHM works is to imagine a large rock in an ocean of perfectly regular waves. As the waves deform around the rock and come out the other side, they carry information about the rock's shape. This information can be extracted by comparing it to waves that did not smash up against the rock, and an image of the rock can be reconstructed. DHM does this with a laser beam by pointing a single wavelength at an object, collecting the distorted wave on the other side, and comparing it to a reference beam. A computer then numerically reconstructs a 3D image of the object -- in this case neurons -- using an algorithm developed by the authors. In addition, the laser beam travels through the transparent cells and important information about their internal composition is obtained.



Normally applied to detect minute defects in materials, Magistretti, along with DHM pioneer and EPFL professor in the Advanced Photonics Laboratory, Christian Depeursinge, decided to use DHM for neurobiological applications. In the study, their group induced an electric charge in a culture of neurons using glutamate, the main neurotransmitter in the brain. This charge transfer carries water inside the neurons and changes their optical properties in a way that can be detected only by DHM. Thus, the technique accurately visualizes the electrical activities of hundreds of neurons simultaneously, in real-time, without damaging them with electrodes, which can only record activity from a few neurons at a time.

A major advance for pharmaceutical research

Without the need to introduce dyes or electrodes, DHM can be applied to High Content Screening -- the screening of thousands of new pharmacological molecules. This advance has important ramifications for the discovery of new drugs that combat or prevent neurodegenerative diseases such as Parkinson's and Alzheimer's, since new molecules can be tested more quickly and in greater numbers.

"Due to the technique's precision, speed, and lack of invasiveness, it is possible to track minute changes in neuron properties in relation to an applied test drug and allow for a better understanding of what is happening, especially in predicting neuronal death," Magistretti says. "What normally would take 12 hours in the lab can now be done in 15 to 30 minutes, greatly decreasing the time it takes for researchers to know if a drug is effective or not."

The promise of this technique for High Content Screening has already resulted in a start-up company at EPFL called LynceeTec (www.lynceetec.com).

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Mystery Ingredient in Coffee Boosts Protection Against Alzheimer's Disease, Study Finds

Mystery Ingredient in Coffee Boosts Protection Against Alzheimer's Disease, Study Finds

  9:59:00 AM    Science Lover

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A yet unidentified component of coffee interacts with the beverage's caffeine, which could be a surprising reason why daily coffee intake protects against Alzheimer's disease. A new Alzheimer's mouse study by researchers at the University of South Florida found that this interaction boosts blood levels of a critical growth factor that seems to fight off the Alzheimer's disease process.

The findings appear in the early online version of an article to be published June 28 in the Journal of Alzheimer's Disease. Using mice bred to develop symptoms mimicking Alzheimer's disease, the USF team presents the first evidence that caffeinated coffee offers protection against the memory-robbing disease that is not possible with other caffeine-containing drinks or decaffeinated coffee.

Previous observational studies in humans reported that daily coffee/caffeine intake during mid-life and in older age decreases the risk of Alzheimer's disease. The USF researchers' earlier studies in Alzheimer's mice indicated that caffeine was likely the ingredient in coffee that provides this protection because it decreases brain production of the abnormal protein beta-amyloid, which is thought to cause the disease.

The new study does not diminish the importance of caffeine to protect against Alzheimer's. Rather it shows that caffeinated coffee induces an increase in blood levels of a growth factor called GCSF (granulocyte colony stimulating factor). GCSF is a substance greatly decreased in patients with Alzheimer's disease and demonstrated to improve memory in Alzheimer's mice. A just-completed clinical trial at the USF Health Byrd Alzheimer's Institute is investigating GCSF treatment to prevent full-blown Alzheimer's in patients with mild cognitive impairment, a condition preceding the disease. The results of that trial are currently being evaluated and should be known soon.

"Caffeinated coffee provides a natural increase in blood GCSF levels," said USF neuroscientist Dr. Chuanhai Cao, lead author of the study. "The exact way that this occurs is not understood. There is a synergistic interaction between caffeine and some mystery component of coffee that provides this beneficial increase in blood GCSF levels."

The researchers would like to identify this yet unknown component so that coffee and other beverages could be enriched with it to provide long-term protection against Alzheimer's.

In their study, the researchers compared the effects of caffeinated and decaffeinated coffee to those of caffeine alone. In both Alzheimer's mice and normal mice, treatment with caffeinated coffee greatly increased blood levels of GCSF; neither caffeine alone or decaffeinated coffee provided this effect. The researchers caution that, since they used only "drip" coffee in their studies, they do not know whether "instant" caffeinated coffee would provide the same GCSF response.

The boost in GCSF levels is important, because the researchers also reported that long-term treatment with coffee (but not decaffeinated coffee) enhances memory in Alzheimer's mice. Higher blood GCSF levels due to coffee intake were associated with better memory. The researchers identified three ways that GCSF seems to improve memory performance in the Alzheimer's mice. First, GCSF recruits stem cells from bone marrow to enter the brain and remove the harmful beta-amyloid protein that initiates the disease. GCSF also creates new connections between brain cells and increases the birth of new neurons in the brain.



"All three mechanisms could complement caffeine's ability to suppress beta amyloid production in the brain" Dr. Cao said, "Together these actions appear to give coffee an amazing potential to protect against Alzheimer's -- but only if you drink moderate amounts of caffeinated coffee."

Although the present study was performed in Alzheimer's mice, the researchers indicated that they've gathered clinical evidence of caffeine/coffee's ability to protect humans against Alzheimer's and will soon publish those findings.

Coffee is safe for most Americans to consume in the moderate amounts (4 to 5 cups a day) that appear necessary to protect against Alzheimer's disease. The USF researchers previously reported this level of coffee/caffeine intake was needed to counteract the brain pathology and memory impairment in Alzheimer's mice. The average American drinks 1½ to 2 cups of coffee a day, considerably less than the amount the researchers believe protects against Alzheimer's.

"No synthetic drugs have yet been developed to treat the underlying Alzheimer's disease process" said Dr. Gary Arendash, the study's other lead author. "We see no reason why an inherently natural product such as coffee cannot be more beneficial and safer than medications, especially to protect against a disease that takes decades to become apparent after it starts in the brain."

The researchers believe that moderate daily coffee intake starting at least by middle age (30s -- 50s) is optimal for providing protection against Alzheimer's disease, although starting even in older age appears protective from their studies. "We are not saying that daily moderate coffee consumption will completely protect people from getting Alzheimer's disease," Dr. Cao said. "However, we do believe that moderate coffee consumption can appreciably reduce your risk of this dreaded disease or delay its onset."

The researchers conclude that coffee is the best source of caffeine to counteract the cognitive decline of Alzheimer's because its yet unidentified component synergizes with caffeine to increase blood GCSF levels. Other sources of caffeine, such as carbonated drinks, energy drinks, and tea, would not provide the same level of protection against Alzheimer's as coffee, they said.

Coffee also contains many ingredients other than caffeine that potentially offer cognitive benefits against Alzheimer's disease. "The average American gets most of their daily antioxidants intake through coffee," Dr. Cao said. "Coffee is high in anti-inflammatory compounds that also may provide protective benefits against Alzheimer's disease."

An increasing body of scientific literature indicates that moderate consumption of coffee decreases the risk of several diseases of aging, including Parkinson's disease, Type II diabetes and stroke. Just within the last few months, new studies have reported that drinking coffee in moderation may also significantly reduce the risk of breast and prostate cancers.

"Now is the time to aggressively pursue the protective benefits of coffee against Alzheimer's disease," Dr. Arendash said. "Hopefully, the coffee industry will soon become an active partner with Alzheimer's researchers to find the protective ingredient in coffee and concentrate it in dietary sources."

New Alzheimer's diagnostic guidelines, now encompassing the full continuum of the disease from no overt symptoms to mild impairment to clear cognitive decline, could double the number of Americans with some form of the disease to more than 10 million. With the baby-boomer generation entering older age, these numbers will climb even more unless an effective preventive measure is identified.

"Because Alzheimer's starts in the brain several decades before it is diagnosed, any protective therapy would obviously need to be taken for decades," Dr. Cao said. "We believe moderate daily consumption of caffeinated coffee is the best current option for long-term protection against Alzheimer's memory loss. Coffee is inexpensive, readily available, easily gets into the brain, appears to directly attack the disease process, and has few side-effects for most of us."

According to the researchers, no other Alzheimer's therapy being developed comes close to meeting all these criteria.

"Aside from coffee, two other lifestyle choices -- physical and cognitive activity -- appear to reduce the risk of dementia. Combining regular physical and mental exercise with moderate coffee consumption would seem to be an excellent multi-faceted approach to reducing risk or delaying Alzheimer's," Dr. Arendash said. "With pharmaceutical companies spending millions of dollars trying to develop drugs against Alzheimer's disease, there may very well be an effective preventive right under our noses every morning -- caffeinated coffee."

This USF study was funded by the NIH-designated Florida Alzheimer's Disease Research Center and the State of Florida.

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New Genetic Technique Converts Skin Cells Into Brain Cells

New Genetic Technique Converts Skin Cells Into Brain Cells

  6:16:00 PM    Science Lover

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A research breakthrough has proven that it is possible to reprogram mature cells from human skin directly into brain cells, without passing through the stem cell stage. The unexpectedly simple technique involves activating three genes in the skin cells; genes which are already known to be active in the formation of brain cells at the fetal stage.

Photomicrograph of fibroblast cells in tissue culture. 
(Credit: iStockphoto/Torsten Wittmann)

The new technique avoids many of the ethical dilemmas that stem cell research has faced.

For the first time, a research group at Lund University in Sweden has succeeded in creating specific types of nerve cells from human skin. By reprogramming connective tissue cells, called fibroblasts, directly into nerve cells, a new field has been opened up with the potential to take research on cell transplants to the next level. The discovery represents a fundamental change in the view of the function and capacity of mature cells. By taking mature cells as their starting point instead of stem cells, the Lund researchers also avoid the ethical issues linked to research on embryonic stem cells.

Head of the research group Malin Parmar was surprised at how receptive the fibroblasts were to new instructions.

"We didn't really believe this would work, to begin with it was mostly just an interesting experiment to try. However, we soon saw that the cells were surprisingly receptive to instructions." The study, which was published in the latest issue of the Proceedings of the National Academy of Sciences, also shows that the skin cells can be directed to become certain types of nerve cells.

In experiments where a further two genes were activated, the researchers have been able to produce dopamine brain cells, the type of cell which dies in Parkinson's disease. The research findings are therefore an important step towards the goal of producing nerve cells for transplant which originate from the patients themselves. The cells could also be used as disease models in research on various neurodegenerative diseases.



Unlike older reprogramming methods, where skin cells are turned into pluripotent stem cells, known as IPS cells, direct reprogramming means that the skin cells do not pass through the stem cell stage when they are converted into nerve cells. Skipping the stem cell stage probably eliminates the risk of tumours forming when the cells are transplanted. Stem cell research has long been hampered by the propensity of certain stem cells to continue to divide and form tumours after being transplanted.

Before the direct conversion technique can be used in clinical practice, more research is needed on how the new nerve cells survive and function in the brain. The vision for the future is that doctors will be able to produce the brain cells that a patient needs from a simple skin or hair sample. In addition, it is presumed that specifically designed cells originating from the patient would be accepted better by the body's immune system than transplanted cells from donor tissue.

"This is the big idea in the long run. We hope to be able to do a biopsy on a patient, make dopamine cells, for example, and then transplant them as a treatment for Parkinson's disease," says Malin Parmar, who is now continuing the research to develop more types of brain cells using the new technique.

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New genetic technique converts skin cells into brain cells

New genetic technique converts skin cells into brain cells

  12:34:00 AM    Science Lover

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A research breakthrough has proven that it is possible to reprogram mature cells from human skin directly into brain cells, without passing through the stem cell stage. The unexpectedly simple technique involves activating three genes in the skin cells; genes which are already known to be active in the formation of brain cells at the foetal stage.

converts skin cells into brain cells

The new technique avoids many of the ethical dilemmas that stem cell research has faced.

For the first time, a research group at Lund University in Sweden has succeeded in creating specific types of nerve cells from human skin. By reprogramming connective tissue cells, called fibroblasts, directly into nerve cells, a new field has been opened up with the potential to take research on cell transplants to the next level. The discovery represents a fundamental change in the view of the function and capacity of mature cells. By taking mature cells as their starting point instead of stem cells, the Lund researchers also avoid the ethical issues linked to research on embryonic stem cells.

Head of the research group Malin Parmar was surprised at how receptive the fibroblasts were to new instructions.

"We didn't really believe this would work, to begin with it was mostly just an interesting experiment to try. However, we soon saw that the cells were surprisingly receptive to instructions."

The study, which was published in the latest issue of the scientific journal PNAS, also shows that the skin cells can be directed to become certain types of nerve cells.

In experiments where a further two genes were activated, the researchers have been able to produce dopamine brain cells, the type of cell which dies in Parkinson's disease. The research findings are therefore an important step towards the goal of producing nerve cells for transplant which originate from the patients themselves. The cells could also be used as disease models in research on various neurodegenerative diseases.

Unlike older reprogramming methods, where skin cells are turned into pluripotent stem cells, known as IPS cells, direct reprogramming means that the skin cells do not pass through the stem cell stage when they are converted into nerve cells. Skipping the stem cell stage probably eliminates the risk of tumours forming when the cells are transplanted. Stem cell research has long been hampered by the propensity of certain stem cells to continue to divide and form tumours after being transplanted.

Before the direct conversion technique can be used in clinical practice, more research is needed on how the new nerve cells survive and function in the brain. The vision for the future is that doctors will be able to produce the brain cells that a patient needs from a simple skin or hair sample. In addition, it is presumed that specifically designed cells originating from the patient would be accepted better by the body's immune system than transplanted cells from donor tissue.

"This is the big idea in the long run. We hope to be able to do a biopsy on a patient, make dopamine cells, for example, and then transplant them as a treatment for Parkinson's disease", says Malin Parmar, who is now continuing the research to develop more types of brain cells using the new technique.

More information: 'Direct conversion of human fibroblasts to dopaminergic neurons', publ. PNAS 2011; 6 June 2011: http://www.pnas.or … 108.abstract

Provided by Lund University

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Brain Cell Communication: Why It's So Fast

Brain Cell Communication: Why It's So Fast

  11:55:00 PM    Science Lover

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Billions of brain cells are communicating at any given moment. Like an organic supercomputer they keep everything going, from breathing to solving riddles, and "programming errors" can lead to serious conditions such as schizophrenia, Parkinson's Disease and attention-deficit hyperactivity disorder.

Vesicle with three "linking bridges". (Credit: Image courtesy of University of Copenhagen)

The brain uses biochemical signal molecules

Today, the biochemical language of the nerve cells is the subject of intensive research right down at the molecular level, and for the first time researchers, some from the University of Copenhagen, have described just how nerve cells are capable of transmitting signals practically simultaneously.

The cells of the nervous system communicate using small molecule neurotransmitters such as dopamine, serotonin and noradrenalin. Dopamine is associated with cognitive functions such as memory, serotonin with mood control, and noradrenaline with attention and arousal.

The brain cell communication network, the synapses, transmit messages via chemical neurotransmitters packaged in small containers (vesicles) waiting at the nerve ends of the synapses. An electrical signal causes the containers and membrane to fuse and the neurotransmitters flow from the nerve ending to be captured by other nerve cells. This occurs with immense rapidity in a faction of a millisecond.

The vesicle uses three copies of the "linking bridge"

Researchers from the Universities of Copenhagen, Göttingen and Amsterdam have been studying the complex organic protein complexes that link vesicles and membrane prior to fusion, in order to find an explanation for the rapidity of these transmissions. They have discovered that the vesicle contains no fewer than three copies of the linking bridge or "SNARE complex."

With only one SNARE complex the vesicle takes longer to fuse with the membrane and the neurotransmitter is therefore secreted more slowly.

"The precursors for the SNARE complexes are present in the vesicles before they reach the target membrane," said Professor Jakob Balsev Sørensen from the Department of Neuroscience and Pharmacology at the University of Copenhagen. "Fast (synchronous) fusion is enabled when at least three of them work in tandem. If the vesicle only has one SNARE complex it can still fuse with the target membrane, but it takes much longer."

The discovery has just been published in Science.

"Our next step will be to investigate the factors that influence and regulate the number of SNARE complexes in the vesicles. Is this a way for the nerve cells to choose to communicate more or less rapidly, and is this regulation altered when the brain is diseased?", professor Sørensen says.

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Brain Coprocessors The need for operating systems to help brains and machines work together.

Brain Coprocessors The need for operating systems to help brains and machines work together.

  9:50:00 AM    Science Lover

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The last few decades have seen a surge of invention of technologies that enable the observation or perturbation of information in the brain. Functional MRI, which measures blood flow changes associated with brain activity, is being explored for purposes as diverse as lie detection, prediction of human decision making, and assessment of language recovery after stroke.

Implanted electrical stimulators, which enable control of neural circuit activity, are borne by hundreds of thousands of people to treat conditions such as deafness, Parkinson's disease, and obsessive-compulsive disorder. And new methods, such as the use of light to activate or silence specific neurons in the brain, are being widely utilized by researchers to reveal insights into how to control neural circuits to achieve therapeutically useful changes in brain dynamics. We are entering a neurotechnology renaissance, in which the toolbox for understanding the brain and engineering its functions is expanding in both scope and power at an unprecedented rate.

This toolbox has grown to the point where the strategic utilization of multiple neurotechnologies in conjunction with one another, as a system, may yield fundamental new capabilities, both scientific and clinical, beyond what they can offer alone. For example, consider a system that reads out activity from a brain circuit, computes a strategy for controlling the circuit so it enters a desired state or performs a specific computation, and then delivers information into the brain to achieve this control strategy. Such a system would enable brain computations to be guided by predefined goals set by the patient or clinician, or adaptively steered in response to the circumstances of the patient's environment or the instantaneous state of the patient's brain.

Some examples of this kind of "brain coprocessor" technology are under active development, such as systems that perturb the epileptic brain when a seizure is electrically observed, and prosthetics for amputees that record nerves to control artificial limbs and stimulate nerves to provide sensory feedback. Looking down the line, such system architectures might be capable of very advanced functions--providing just-in-time information to the brain of a patient with dementia to augment cognition, or sculpting the risk-taking profile of an addiction patient in the presence of stimuli that prompt cravings.

Given the ever-increasing number of brain readout and control technologies available, a generalized brain coprocessor architecture could be enabled by defining common interfaces governing how component technologies talk to one another, as well as an "operating system" that defines how the overall system works as a unified whole--analogous to the way personal computers govern the interaction of their component hard drives, memories, processors, and displays. Such a brain coprocessor platform could facilitate innovation by enabling neuroengineers to focus on neural prosthetics at an algorithmic level, much as a computer programmer can work on a computer at a conceptual level without having to plan the fate of every individual bit. In addition, if new technologies come along, e.g., a new kind of neural recording technology, they could be incorporated into a system, and in principle rapidly coupled to existing computation and perturbation methods, without requiring the heavy readaptation of those other components.

Developing such brain coprocessor architectures would take some work--in particular, it would require technologies standardized enough, or perhaps open enough, to be interoperable in a variety of combinations. Nevertheless, much could be learned from developing relatively simple prototype systems. For example, recording technologies by themselves can report brain activity, but cannot fully attest to the causal contribution that the observed brain activity makes to a specific behavioral or clinical outcome; control technologies can input information into neural targets, but by themselves their outcomes might be difficult to interpret due to endogenous neural information and unobserved neural processing. These scientific issues can be disambiguated by rudimentary brain coprocessors, built with readily available off-the-shelf components, that use recording technologies to assess how a given neural circuit perturbation alters brain dynamics. Such explorations may begin to reveal principles governing how best to control a circuit--revealing the neural targets and control strategies that most efficaciously lead to a goal brain state or behavioral effect, and thus pointing the way to new therapeutic strategies. Miniature, implantable brain coprocessors might be able to support new kinds of personalized medicine, for example continuously adapting a neural control strategy to the goals, state, environment, and history of an individual patient--important powers, given the dynamic nature of many brain disorders.

In the future, the computational module of a brain coprocessor may be powerful enough to assist in high-level human cognition or complex decision making. Of course, the augmentation of human intelligence has been one of the key goals of computer engineers for well over half a century. Indeed, if we relax the definition of brain coprocessor just a bit, so as not to require direct physical access to the brain, many consumer technologies being developed today are converging upon brain coprocessor-like architectures. A large number of new technologies are attempting to discover information useful to a user and to deliver this information to the user in real time. Also, these discovery and delivery processes are increasingly shaped by the environment (e.g., location) and history (e.g., social interactions, searches) of the user. Thus we are seeing a departure from the classical view (as initially anticipated by early thinkers about human-machine symbiosis such as J. C. R. Licklider) in which computers receive goals from humans, perform defined computations, and then provide the results back to humans.

Of course, giving machines the authority to serve as proactive human coprocessors, and allowing them to capture our attention with their computed priorities, has to be considered carefully, as anyone who has lost hours due to interruption by a slew of social-network updates or search-engine alerts can attest. How can we give the human brain access to increasingly proactive coprocessing technologies without losing sight of our overarching goals? One idea is to develop and deploy metrics that allow us to evaluate the IQ of a human plus a coprocessor, working together--evaluating the performance of collaborating natural and artificial intelligences in a broad battery of problem-solving contexts. After all, humans with Internet-based brain coprocessors (e.g., laptops running Web browsers) may be more distractible if the goals include long, focused writing tasks, but they may be better at synthesizing data broadly from disparate sources; a given brain coprocessor configuration may be good for some problems but bad for others. Thinking of emerging computational technologies as brain coprocessors forces us to think about them in terms of the impacts they have on the brain, positive and negative, and importantly provides a framework for thoughtfully engineering their direct, as well as their emergent, effects.

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Carbon Nanostructures: Elixir or Poison?

Carbon Nanostructures: Elixir or Poison?

  1:15:00 AM    Science Lover

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A Los Alamos National Laboratory toxicologist and a multidisciplinary team of researchers have documented potential cellular damage from "fullerenes" -- soccer-ball-shaped, cage-like molecules composed of 60 carbon atoms. The team also noted that this particular type of damage might hold hope for treatment of Parkinson's disease, Alzheimer's disease, or even cancer.

Los Alamos National Laboratory toxicologist Jun Gao works in his laboratory using a protective fume hood. (Credit: Photo by James R. Rickman)

The research recently appeared in Toxicology and Applied Pharmacology and represents the first-ever observation of this kind for spherical fullerenes, also known as buckyballs, which take their names from the late Buckminster Fuller because they resemble the geodesic dome concept that he popularized.

Engineered carbon nanoparticles, which include fullerenes, are increasing in use worldwide. Each buckyball is a skeletal cage of carbon about the size of a virus. They show potential for creating stronger, lighter structures or acting as tiny delivery mechanisms for designer drugs or antibiotics, among other uses. About four to five tons of carbon nanoparticles are manufactured annually.

"Nanomaterials are the 21st century revolution," said Los Alamos toxicologist Rashi Iyer, the principal research lead and coauthor of the paper. "We are going to have to live with them and deal with them, and the question becomes, 'How are we going to maximize our use of these materials and minimize their impact on us and the environment?'"

Iyer and lead author Jun Gao, also a Los Alamos toxicologist, exposed cultured human skin cells to several distinct types of buckyballs. The differences in the buckyballs lay in the spatial arrangement of short branches of molecules coming off of the main buckyball structure. One buckyball variation, called the "tris" configuration, had three molecular branches off the main structure on one hemisphere; another variation, called the "hexa" configuration, had six branches off the main structure in a roughly symmetrical arrangement; the last type was a plain buckyball.

The researchers found that cells exposed to the tris configuration underwent premature senescence -- what might be described as a state of suspended animation. In other words, the cells did not die as cells normally should, nor did they divide or grow. This arrest of the natural cellular life cycle after exposure to the tris-configured buckyballs may compromise normal organ development, leading to disease within a living organism. In short, the tris buckyballs were toxic to human skin cells.

Moreover, the cells exposed to the tris arrangement caused unique molecular level responses suggesting that tris-fullerenes may potentially interfere with normal immune responses induced by viruses. The team is now pursuing research to determine if cells exposed to this form of fullerenes may be more susceptible to viral infections.

Ironically, the discovery could also lead to a novel treatment strategy for combating several debilitating diseases. In diseases like Parkinson's or Alzheimer's, nerve cells die or degenerate to a nonfunctional state. A mechanism to induce senescence in specific nerve cells could delay or eliminate onset of the diseases. Similarly, a disease like cancer, which spreads and thrives through unregulated replication of cancer cells, might be fought through induced senescence. This strategy could stop the cells from dividing and provide doctors with more time to kill the abnormal cells.

Because of the minute size of nanomaterials, the primary hazard associated with them has been potential inhalation -- similar to the concern over asbestos exposure.

"Already, from a toxicological point of view, this research is useful because it shows that if you have the choice to use a tris- or a hexa-arrangement for an application involving buckyballs, the hexa-arrangement is probably the better choice," said Iyer. "These studies may provide guidance for new nanomaterial design and development."

These results were offshoots from a study (Shreve, Wang, and Iyer) funded to understand the interactions between buckyballs and biological membranes. Los Alamos National Laboratory has taken a proactive role by initiating a nanomaterial bioassessmnet program with the intention of keeping its nanomaterial workers safe while facilitating the discovery of high-function, low-bioimpact nanomaterials with the potential to benefit national security missions. In addition to Gao and Iyer, the LANL program includes Jennifer Hollingsworth, Yi Jiang, Jian Song, Paul Welch, Hsing Lin Wang, Srinivas Iyer, and Gabriel Montaño.

Los Alamos National Laboratory researchers will continue to attempt to understand the potential effects of exposure to nanomaterials in much the same way that Los Alamos was a worldwide leader in understanding the effects of radiation during the Lab's early history. Los Alamos workers using nanomaterials will continue to follow protocols that provide the highest degree of protection from potential exposure.

Meantime, Los Alamos research into nanomaterials provides a cautionary tale for nanomaterial use, as well as early foundations for worker protection. Right now, there are no federal regulations for the use of nanomaterials. Disclosure of use by companies or individuals is voluntary. As nanomaterial use increases, understanding of their potential hazards should also increase.

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Spinal cord stimulator could treat Parkinson’s

Spinal cord stimulator could treat Parkinson’s

  1:22:00 AM    Science Lover

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In studies on mice, led by neurologist Miguel Nicolelis, boffins have found that electrical stimulation of the spinal cord, rather than the brain, could provide an easier and cheaper way to treat Parkinson’s disease

A spinal cord stimulator has helped rodents with Parkinson’s disease move more easily, thus offering the hope of a less invasive way of treating the disease in humans, US-based researchers said on Thursday.

“We see an almost immediate and dramatic change in the animal’s ability to function when the device stimulates the spinal cord,” said Dr Miguel Nicolelis of Duke University, whose study appears in the journal Science.

If it works in humans, Nicolelis said, the device could be used to treat the disease early on, reaching far more patients than current stimulators, which are implanted deep in the brain and can benefit only about one third of Parkinson’s patients.

“It would be easier and safer to install a stimulator in the spinal cord than in the brain,” said Nicolelis. “Both devices use pulses of electricity to control the tremors and stiffness caused by Parkinson’s.”

Parkinson’s progressively kills brain cells that produce dopamine, a message-carrying chemical associated with movement. Dopamine replacement drugs can delay symptoms for a while but there is no good treatment and no cure.

“This technique is much easier, cheaper and can be done in conjunction with a much smaller dose of medication,” said Nicolelis. “It addresses Parkinson’s disease in a very different way.”

In healthy people, neurons fire at different rates as information is sent between the brain and the body to initiate motion. Nicolelis said the problem in Parkinson’s disease is that neurons become scrambled and begin firing all at once.

IMPROVING DRUG EFFECTS

“You create this beating pattern that prevents the neurons from actually producing the motor commands that animals and patients need to behave normally,” he said. “What we did was find a way to disrupt that.”

The new technique involves implanting two paper-thin metal probes into a small slit in the spine so they touch the outside of the spinal cord. Current is then passed over the area to deliver an electrical pulse, stimulating peripheral nerves that pass information between the brain and the body.

The researchers tested the device on mice with a form of Parkinson’s, in combination with different doses of a dopamine replacement drug known as L-dopa.

When they tried the device without the drug, the animals were 26 times more active. When used with the drug, only two doses were needed to produce movement, compared to five when used with only medication.

L-dopa tends to lose its effect over time, but Nicolelis said the treatment may help patients stay on the medication longer.

His team plans to begin testing the device in primates this year, and in humans by 2010.

Manufacturers such as St Jude Medical and Medtronic Inc in the US have devices for deep brain stimulation to treat movement disorders including Parkinson’s, essential tremor and dystonia, and are studying their use in obsessive-compulsive disorders and depression.

Miguel Nicolelis

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