Posts tagged neuroscience

May 14, 2012 By Sandy Evangelista

(Medical Xpress) — Swiss scientists have proven that light intensity influences our cognitive performance and how alert we feel, and that these positive effects last until early evening.

Credit: 2012 EPFL

Tests conducted in EPFL’s Solar Energy and Building Physics Laboratory (LESO) have confirmed the hypothesis that light influences our subjective feeling of sleepiness. The research team, led by Mirjam Münch, also showed that the effects of light exposure last until the early evening, and that light intensity has an impact on cognitive mechanisms. The results of this research were recently published in the journal Behavioral Neuroscience.

Light synchronizes our biological clocks. It is collected in the eye by photoreceptors that use photopigments (pigments that change when exposed to light), known as melanopsin. These cells, which differ from rods and cones, are considered a third class of photoreceptors in the retina and were discovered just ten years ago. They’re not there to form an image, but to perceive and absorb photons in the visible light spectrum. In addition, they are stimulated by blue light.

Exploring office lighting

Münch and her team wanted to know how our circadian rhythm could be influenced by our perception of light during the daytime. They created realistic office lighting conditions and recruited 29 young participants. “For this study, we took into account the intensity of natural and artificial light without specifically evaluating their spectra.”

From daytime to dusk

To synchronize their internal biological clocks, the volunteers had to maintain a regular sleep schedule during the seven days leading up to the test. They wore bracelets equipped with light sensors and accelerometers, so that the scientists could monitor their movements.

The study itself took place over two eight-hour sessions. The participants spent the first six hours in an experiment room, first in well-lighted conditions (1000-2000 lux, more or less equivalent to natural light in a room). In the second session, the light intensity was about 170 lux, which is what the eye perceives in a room without a window, lit with artificial light. For this experiment, light intensity was measured at eye-level. Every 30 minutes, the subjects were asked to assess how alert or sleepy they felt.

Finally, at the end of each session, the participants underwent two hours of supplemental memory tests in a darkened room – less than 6 lux. During these last two hours, the researchers took saliva samples in order to measure cortisol and melatonin concentrations. These two hormones are produced in a in a 24-hour cycle by the human body.

Boosted by the light

The volunteers who were subjected to higher light intensity during the afternoon were more alert all the way into the early evening. When they were subjected to light intensity ten times weaker, however, they showed signs of sleepiness and obtained lower scores on the memory tests.

These results were observed even in the absence of changes in cortisol and melatonin concentrations in their saliva. “With this study, we have discovered that light intensity has a direct effect on the subjective feeling of sleepiness as well as on objective cognitive performance, and that the benefits of more intense light during the daytime last long past the time of exposure,” concludes Münch.

Provided by Ecole Polytechnique Federale de Lausanne

Source: medicalxpress.com

ScienceDaily (May 13, 2012) — Scientists at Weill Cornell Medical College have discovered that the single protein — alpha 2 delta — exerts a spigot-like function, controlling the volume of neurotransmitters and other chemicals that flow between the synapses of brain neurons. The study, published online in Nature, shows how brain cells talk to each other through these signals, relaying thoughts, feelings and action, and this powerful molecule plays a crucial role in regulating effective communication.

In the study, the investigators also suggest how the widely used pain drug Lyrica might work. The alpha 2 delta protein is the target of this drug and the new work suggests an approach to how other drugs could be developed that effectively twist particular neurotransmitter spigots on and off to treat neurological disorders. The research findings surprised the research team, which includes scientists from University College London.

"We are amazed that any single protein has such power," says the study’s lead investigator Dr. Timothy A. Ryan, professor of Biochemistry and associate professor of Biochemistry in Anesthesiology at Weill Cornell Medical College. "It is indeed rare to identify a biological molecule’s function that is so potent, that seems to be controlling the effectiveness of neurotransmission."

The researchers found that alpha 2 delta determines how many calcium channels will be present at the synaptic junction between neurons. The transmission of chemical signals is triggered at the synapse by the entry of calcium into these channels, so the volume and speed of neurotransmission depends on the availability of these channels.

Researchers discovered that taking away alpha 2 delta from brain cells prevented calcium channels from getting to the synapse. “But if you add more alpha 2 delta, you can triple the number of channels at synapses,” Dr. Ryan says. “This change in abundance was tightly linked to how well synapses carry out their function, which is to release neurotransmitters.”

Before this study, it was known that Lyrica, which is used for neuropathic pain, seizures and fibromyalgia, binds to alpha 2 delta, but little was understood about how this protein works to control synapses.

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ScienceDaily (May 11, 2012) — Neuroscientist Patrik Verstreken, associated with VIB and KU Leuven, succeeded in undoing the effect of one of the genetic defects that leads to Parkinson’s using vitamin K2. His discovery gives hope to Parkinson’s patients.

Male fruit fly (Drosophila Melanogaster). Scientists have succeeded in undoing the effect of one of the genetic defects that leads to Parkinson’s using vitamin K2. The research was done in fruit flies. (Credit: © Studiotouch / Fotolia)

This research was done in collaboration with colleagues from Northern Illinois University (US) and was recently published in the journal Science.

"It appears from our research that administering vitamin K2 could possibly help patients with Parkinson’s. However, more work needs to be done to understand this better," says Patrik Verstreken.

Malfunctioning power plants are at the basis of Parkinson’s.

If we looked at cells as small factories, then mitochondria would be the power plants responsible for supplying the energy for their operation. They generate this energy by transporting electrons. In Parkinson’s patients, the activity of mitochondria and the transport of electrons have been disrupted, resulting in the mitochondria no longer producing sufficient energy for the cell. This has major consequences as the cells in certain parts of the brain will start dying off, disrupting communication between neurons. The results are the typical symptoms of Parkinson’s: lack of movement (akinesia), tremors and muscle stiffness.

The exact cause of this neurodegenerative disease is not known. In recent years, however, scientists have been able to describe several genetic defects (mutations) found in Parkinson’s patients, including the so-called PINK1 and Parkin mutations, which both lead to reduced mitochondrial activity. By studying these mutations, scientists hope to unravel the mechanisms underlying the disease process.

Paralyzed fruit flies

Fruit flies (Drosophila) are frequently used in lab experiments because of their short life spans and breeding cycles, among other things. Within two weeks of her emergence, every female is able to produce hundreds of offspring. By genetically modifying fruitflies, scientists can study the function of certain genes and proteins. Patrik Verstreken and his team used fruitflies with a genetic defect in PINK1 or Parkin that is similar to the one associated with Parkinson’s. They found that the flies with a PINK1 or Parkin mutation lost their ability to fly.

Upon closer examination, they discovered that the mitochondria in these flies were defective, just as in Parkinson’s patients. Because of this they generated less intracellular energy — energy the insects needed to fly. When the flies were given vitamin K2, the energy production in their mitochondria was restored and the insects’ ability to fly improved. The researchers were also able to determine that the energy production was restored because the vitamin K2 had improved electron transport in the mitochondria. This in turn led to improved energy production.

Conclusion

Vitamin K2 plays a role in the energy production of defective mitochondria. Because defective mitochondria are also found in Parkinson’s patients with a PINK1 or Parkin mutation, vitamin K2 potentially offers hope for a new treatment for Parkinson’s.

Source: Science Daily

May 11, 2012

Regenerating sensory hair cells, which produce electrical signals in response to vibrations within the inner ear, could form the basis for treating age- or trauma-related hearing loss. One way to do this could be with gene therapy that drives new sensory hair cells to grow.

Researchers at Emory University School of Medicine have shown that introducing a gene called Atoh1 into the cochleae of young mice can induce the formation of extra sensory hair cells.

Their results show the potential of a gene therapy approach, but also demonstrate its current limitations. The extra hair cells produce electrical signals like normal hair cells and connect with neurons. However, after the mice are two weeks old, which is before puberty, inducing Atoh1 has little effect. This suggests that an analogous treatment in adult humans would also not be effective by itself.

The findings were published May 9 in the Journal of Neuroscience.

"We’ve shown that hair cell regeneration is possible in principle," says Ping Chen, PhD, associate professor of cell biology at Emory University School of Medicine. “In this paper, we have identified which cells are capable of becoming hair cells under the influence of Atoh1, and we show that there are strong age-dependent limitations on the effects of Atoh1 by itself.”

The first author of the paper, Michael Kelly, now a postdoctoral fellow at the National Institute on Deafness and Other Communication Disorders, was a graduate student in Emory’s Neuroscience program.

Kelly and his coworkers engineered mice to turn on the Atoh1 gene in the inner ear in response to the antibiotic doxycycline. Previous experimenters had used a virus to introduce Atoh1 into the cochleae of animals. This approach resembles gene therapy, but has the disadvantage of being slightly different each time, Chen says. In contrast, the mice have the Atoh1 gene turned on in specific cells along the lining of the inner ear, called the cochlear epithelium, but only when fed doxycycline.

Young mice given doxycycline for two days had extra sensory hair cells, in parts of the cochlea where developing hair cells usually appear, and also additional locations (see accompanying image).

The extra hair cells could generate electrical signals, although those signals weren’t as strong as mature hair cells. Also, the extra hair cells appeared to attract neuronal fibers, which suggests that those signals could connect to the rest of the nervous system.

"They can generate electrical signals, but we don’t know if they can really function in the context of hearing.” Chen says. “For that to happen, the hair cells’ signals need to be coordinated and integrated.”

Although doxycycline could turn on Atoh1 all over the surface of the cochlea, extra sensory hair cells did not appear everywhere. When they removed cochleae from the mice and grew them in culture dishes, her team was able to provoke even more hair cells to grow when they added a drug that inhibits the Notch pathway.

Manipulating the Notch pathway affects several aspects of embryonic development and in some contexts appears to cause cancer, so the approach needs to be refined further. Chen says that it may be possible to unlock the age-related limits on hair cell regeneration by supplying additional genes or drugs in combination with Atoh1, and the results with the Notch drug provide an example.

"Our future goals are to develop approaches to stimulate hair cell formation in older animals, and to examine functional recovery after Atoh1 induction," she says.

Provided by Emory University

Source: medicalxpress.com

May 11, 2012

A brain study in infant rats demonstrates that the anti-epilepsy drug phenobarbital stunts neuronal growth, which could prompt new questions about using the first-line drug to treat epilepsy in human newborns.

In Annals of Neurology EarlyView posted online May 11, researchers at Georgetown University Medical Center (GUMC) report that the anti-epilepsy drug phenobarbital given to rat pups about a week old changed the way the animals’ brains were wired, causing cognitive abnormalities later in life.

The researchers say it has been known that some of the drugs used to treat epilepsy increase the amount of neurons that die shortly after birth in the rat brain, but, until this study, no one had shown whether this action had any adverse impact on subsequent brain development.

"Our study is the first to show that the exposure to these drugs — and just a single exposure — can prevent brain circuits from developing their normal connectivity, meaning they may not be wired correctly, which can have long-lasting effects on brain function,” says the study’s senior investigator, Karen Gale, Ph.D., a professor of pharmacology at GUMC. “These findings suggest that in the growing brain, these drugs are not as benign as one would like to believe.”

For their study, the Georgetown researchers studied four agents including phenobarbital.

"The good news is not all anti-epilepsy drugs have this disruptive effect in the animal studies," Gale says.

The researchers found that the anti-epilepsy drug levetiracetam did not stunt synaptic growth. Animals treated with a third drug, lamotrigine, showed neural maturation, but it was delayed. An additional finding involved melatonin. When added to phenobarbital, it appeared to prevent the persistent adverse neural effects in the rat pups. Melatonin has been used clinically to protect cells from injury in humans.

"Many clinicians have been advocating for a reexamination of the use of these drugs in infants, and our findings provide experimental data to support that need," says the study’s co-lead investigator, Patrick A. Forcelli, Ph.D., a postdoctoral fellow in the department of pharmacology and physiology at GUMC. "Phenobarbital has been used to treat seizures for over 100 years — well before a Food and Drug Administration approval process was established— and for more than 50 years, it has been the first drug of choice in the treatment of seizures in neonates."

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May 11, 2012

Neurons are arranged in periodic patterns that repeat over large distances in two areas of the cerebral cortex, suggesting that the entire cerebral cortex has a stereotyped organization, reports a team of researchers led by Toshihiko Hosoya of the RIKEN Brain Science Institute. The entire cortex has a stereotypical layered structure with the same cell types arranged in the same way, but how neurons are organized in the other orientation—parallel to the brain’s surface—is poorly understood.

Figure 1: In the mouse visual cortex, neurons expressing id2 mRNA (magenta) are found in regularly repeating clusters. Reproduced from Ref. 1 © 2011 Hisato Maruoka et al., RIKEN Brain Science Institute

Hosoya and his colleagues therefore examined layer V (5) of the mouse cortex, which contains two classes of large pyramidal neurons that look identical but differ in the connections they form. One projects axons straight down to regions beneath the cortex; the other projects to the cortex on the opposite side of the brain.

First, the researchers examined expression of the id2 gene in cells of the visual cortex, because these cells form clusters in that part of the brain. They found that id2 is expressed in nearly all cells that project axons downward, but not in those that cross over. Hosoya and colleagues verified this by visualizing the connections of cells using fluorescent cholera toxin, which binds to cell membranes and travels along the axons.

Further examination of gene expression patterns in tissue slices revealed that the cells are arranged in clusters aligned perpendicular to the brain’s surface, and that the clusters are organized in a regular pattern, with the same basic unit repeating every thirty micrometers (Fig. 1). They also observed the same pattern in layer V of the somatosensory cortex, suggesting that this organization is common to all other areas.

By generating a strain of mutant mice expressing green fluorescent protein in the progenitor cells that produce the cells in layer V during brain development, Hosoya and his colleagues investigated the embryonic origin of these cells. This revealed that each cluster contains neurons that are produced by different progenitor cells.

Finally, the researchers showed that the regular pattern persists in the adult visual cortex, and that neurons in each cluster show the same activity patterns in response to visual stimulation. “Our preliminary data suggest that at least several other areas in the cortex have the same structure,” says Hosoya. “It’s likely that the entire cortex has the same organization, and I expect that the human cortex has the same structure.”

Provided by RIKEN

Source: medicalxpress.com

May 11, 2012

Global network activity in the brain modulates local neural circuitry via calcium signaling in non-neuronal cells called astrocytes (Fig. 1), according to research led by Hajime Hirase of the RIKEN Brain Science Institute. The finding clarifies the link between two important processes in the brain.

Figure 1: Astrocytes are star-shaped cells with numerous fine projections that ensheath synapses in the brain. © 2012 Hajime Hirase

Activity in large-scale brain networks is thought to modulate changes in neuronal connectivity, so-called ‘synaptic plasticity’, in the cerebral cortex. The neurotransmitter acetylcholine regulates global brain activity associated with attention and awareness, and is involved in plasticity.

To investigate how these processes are linked, Hirase and his colleagues simultaneously stimulated the whiskers of mice and the nucleus basalis of Meynert (NBM), a basal forebrain structure containing neurons that synthesize acetylcholine and project widely to the cortex. Using electrodes and an imaging technique called two-photon microscopy, performed through a ‘cranial window’, they monitored the responses of cells in the barrel cortex, which receives inputs from the whiskers.

Recordings from the electrodes showed that repeated co-stimulation of the whiskers and NBM induced plasticity in the barrel cortex. This plasticity depended on two types of receptors—muscarinic acetylcholine receptors (mAChRs) and N-methyl-D-aspartic acid receptors (NMDARs). Two-photon imaging microscopy further revealed that activation of the mAChRs during co-stimulation elevated the concentration of calcium ions within astrocytes of the barrel cortex.

The researchers repeated these experiments in mutant mice lacking the receptor that controls the release of calcium ions in astrocytes. Since co-stimulation of whiskers and NBM did not induce plasticity in the mutants, Hirase and colleagues concluded that calcium signaling in astrocytes acts as a ‘gate’ linking the changes in global brain state induced by acetylcholine to activity in local cortical circuits.

Furthermore, the researchers found that stimulation of the NBM led to an increase in the extracellular concentration of the amino acid D-serine in the normal, but not the mutant, mice. D-serine is secreted by astrocytes and activates NMDARs. Hirase’s team had previously shown that astrocytes are electrically silent in living rodents even in the presence of neural activity2. The new findings showed that the biochemical, as opposed to electrical, activation of astrocytes induces them to release the transmitter that modulates synaptic plasticity in the neuronal circuitry.

“Our study is probably the first to show that calcium signaling in astrocytes is related to neuronal circuit plasticity in living animals,” says Hirase. “We are now studying if this type of calcium signaling occurs in all parts of an astrocyte or is restricted to some parts of the cell.”

Provided by RIKEN

Source: medicalxpress.com

May 11, 2012

Even mild head injuries can cause significant abnormalities in brain function that last for several days, which may explain the neurological symptoms experienced by some individuals who have experienced a head injury associated with sports, accidents or combat, according to a study by Virginia Commonwealth University School of Medicine researchers.

These findings, published in the May issue of the Journal of Neuroscience, advance research in the field of traumatic brain injury (TBI), enabling researchers to better understand what brain structural or functional changes underlie posttraumatic disorders – a question that until now has remained unclear.

Previous research has shown that even a mild case of TBI can result in long-lasting neurological issues that include slowing of cognitive processes, confusion, chronic headache, posttraumatic stress disorder and depression.

The VCU team, led by Kimberle M. Jacobs, Ph.D., associate professor in the Department of Anatomy and Neurobiology, demonstrated for the first time, using sophisticated bioimaging and electrophysiological approaches, that mild injury can cause structural disruption of axons in the brain while also changing the way the neurons fire in areas where they have not been structurally altered. Axons are nerve fibers in the brain responsible for conducting electrical impulses. The team used models of mild traumatic brain injury and followed morphologically identified neurons in live cortical slices.

“These findings should help move the field forward by providing a unique bioimaging and electrophysiological approach to assess the evolving changes evoked by mild TBI and their potential therapeutic modulation,” said co-investigator, John T. Povlishock, Ph.D., professor and chair of the VCU School of Medicine’s Department of Anatomy and Neurobiology and director of the Commonwealth Center for the Study of Brain Injury.

According to Povlishock, additional benefit may also derive from the use of this model system with repetitive injuries to determine if repeated insults exacerbate the observed abnormalities.

Provided by Virginia Commonwealth University

Source: medicalxpress.com

May 11th, 2012

Babies born to women with sensitivity to gluten appear to be at increased risk for certain psychiatric disorders later in life, according to research by scientists at Karolinska Institutet in Sweden and Johns Hopkins Children’s Center in Baltimore.

The team’s findings, published in The American Journal of Psychiatry, add to a growing body of evidence that many “adult” diseases may take root before and shortly after birth.

“Lifestyle and genes are not the only factors that shape disease risk, and factors and exposures before, during and after birth can help pre-program much of our adult health,” said investigator Robert Yolken, M.D., a neuro-virologist at Johns Hopkins Children’s Center. “Our study is an illustrative example suggesting that a dietary sensitivity before birth could be a catalyst in the development of schizophrenia or a similar condition 25 years later.”

Maternal infections and other inflammatory disorders during pregnancy have long been linked to greater risk for schizophrenia in the offspring but, the Swedish and U.S. investigators say, this is the first study that points to maternal food sensitivity as a possible culprit in the development of such disorders. The findings establish a strong link but do not mean that gluten sensitivity will invariably cause schizophrenia, the investigators caution. The research, however, does suggest an intriguing new mechanism that may drive up risk and illuminate possible prevention strategies.

“Our research not only underscores the importance of maternal nutrition during pregnancy and its lifelong effects on the offspring, but also suggests one potential cheap and easy way to reduce risk if we were to find further proof that gluten sensitivity exacerbates or drives up schizophrenia risk,” said study lead investigator Håkan Karlsson, M.D., Ph.D., a neuroscientist at Karolinska Institutet and former neuro-virology fellow at Johns Hopkins.

The team’s findings are based on an examination of 764 birth records and neonatal blood samples of Swedes born between 1975 and 1985. Some 211 of them subsequently developed non-affective psychoses, such as schizophrenia and delusional disorders.

Using stored neonatal blood samples, the investigators measured levels of IgG antibodies to milk and wheat. IgG antibodies are markers of immune system reaction triggered by the presence of certain proteins. Because a mother’s antibodies cross the placenta during pregnancy to confer immunity to the baby, a newborn’s elevated IgG levels are proof of protein sensitivity in the mother.

Children born to mothers with abnormally high levels of antibodies to the wheat protein gluten had nearly twice the risk of developing schizophrenia later in life, compared with children who had normal levels of gluten antibodies. The link persisted even after researchers accounted for other factors known to increase schizophrenia risk, including maternal age, gestational age, mode of delivery and the mother’s immigration status. The risk for psychiatric disorders was not increased among those with elevated levels of antibodies to milk protein.

The researchers say the suspicion that food sensitivity in the mother can affect her child’s risk for psychiatric disorders stems from an observation made in the wake of the World War II by U.S. Army researcher F. Curtis Dohan, M.D. Dohan noted that food scarcity in post-war Europe and wheat-poor diets led to notably fewer hospital admissions for schizophrenia.  The link was merely observational, but it has piqued the curiosity of scientists ever since.

Researchers in the past also have observed that people diagnosed with schizophrenia have disproportionately high rates celiac disease, a rare autoimmune disorder characterized by gluten sensitivity. Although it is a hallmark of the condition, gluten sensitivity alone is not enough to diagnose celiac disease. Other studies have found that some people with schizophrenia have gluten sensitivity without other signs of celiac disease, the researchers note.

Yolken and Karlsson say the team already is conducting follow-up studies to clarify how gluten or sensitivity to it increases schizophrenia risk and whether it does so only in those genetically predisposed.

Source: Neuroscience News

ScienceDaily (May 10, 2012) — Researchers at the Medical Research Council (MRC) Toxicology Unit at the University of Leicester have identified a major pathway leading to brain cell death in mice with neurodegenerative disease. The team was able to block the pathway, preventing brain cell death and increasing survival in the mice.

Scientists have identified a major pathway leading to brain cell death in mice with neurodegenerative disease. The team was able to block the pathway, preventing brain cell death and increasing survival in the mice. (Credit: © pressmaster / Fotolia)

In human neurodegenerative diseases, including Alzheimer’s, Parkinson’s and prion diseases, proteins “mis-fold” in a variety of different ways resulting in the build up of mis-shapen proteins. These form the plaques found in Alzheimer’s and the Lewy bodies found in Parkinson’s disease.

The researchers studied mice with neurodegeneration caused by prion disease. These mouse models currently provide the best animal representation of human neurodegenerative disorders, where it is known that the build up of mis-shapen proteins is linked with brain cell death.

They found that the build up of mis-folded proteins in the brains of these mice activates a natural defense mechanism in cells, which switches off the production of new proteins. This would normally switch back ‘on’ again, but in these mice the continued build-up of mis-shapen protein keeps the switch turned ‘off’. This is the trigger point leading to brain cell death, as those key proteins essential for nerve cell survival are not made.

By injecting a protein that blocks the ‘off’ switch of the pathway, the scientists were able to restore protein production, independently of the build up of mis-shapen proteins,and halt the neurodegeneration. The brain cells were protected, protein levels and synaptic transmission (the way in which brain cells signal to each other) were restored and the mice lived longer, even though only a very small part of their brain had been treated.

Mis-shapen proteins in human neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, also over-activate this fundamental pathway controlling protein synthesis in the brains of patients, which represents a common target underlying these different clinical conditions. The scientists’ results suggest that treatments focused on this pathway could be protective in a range of neurodegenerative disease in which mis-shapen proteins are building up and causing neurons to die.

Professor Giovanna Mallucci, who led the team, said, “What’s exciting is the emergence of a common mechanism of brain cell death, across a range of different neurodegenerative disorders, activated by the different mis-folded proteins in each disease. The fact that, in mice with prion disease, we were able to manipulate this mechanism and protect the brain cells means we may have a way forward in how we treat other disorders. Instead of targeting individual mis-folded proteins in different neurodegenerative diseases, we may be able to target the shared pathways and rescue brain cell degeneration irrespective of the underlying disease.”

Professor Hugh Perry, chair of the MRC’s Neuroscience and Mental Health Board, said, “Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are debilitating and largely untreatable conditions. Alzheimer’s disease and related disorders affect over seven million people in Europe, and this figure is expected to double every 20 years as the population ages across Europe. The MRC believes that research such as this, which looks at the fundamental mechanisms of these devastating diseases, is absolutely vital. Understanding the mechanism that leads to neuronal dysfunction prior to neuronal loss is a critical step in finding ways to arrest disease progression.”

Source: Science Daily