Posts tagged brain

Article Date: 20 Feb 2012 - 2:00 PST

New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study published in Nature on February 19 (advance online publication). Led by researchers at the University of California, Santa Cruz, the study reveals details of how brain circuits are rewired during the formation of new motor memories.

The researchers studied mice as they learned new behaviors, such as reaching through a slot to get a seed. They observed changes in the motor cortex, the brain layer that controls muscle movements, during the learning process. Specifically, they followed the growth of new “dendritic spines,” structures that form the connections (synapses) between nerve cells.

“For the first time we are able to observe the spatial distribution of new synapses related to the encoding of memory,” said Yi Zuo, assistant professor of molecular, cell and developmental biology at UC Santa Cruz and corresponding author of the paper.

In a previous study, Zuo and others documented the rapid growth of new dendritic spines on pyramidal neurons in the motor cortex during the learning process. These spines form synapses where the pyramidal neurons receive input from other brain regions involved in motor memories and muscle movements. In the new study, first author Min Fu, a postdoctoral researcher in Zuo’s lab, analyzed the spatial distribution of the newly formed synapses.

Initial results of the spatial analysis showed that one third of the newly formed synapses were located next to another new synapse. These clustered synapses tended to form over the course of a few days during the learning period, when the mouse was repeatedly performing the new behavior. Compared to non-clustered counterparts, the clustered synapses were more likely to persist through the learning sessions and after training stopped.

In addition, the researchers found that after formation of the second spine in a cluster, the first spine grew larger. The size of the spine head correlates with the strength of the synapse. “We found that formation of a second connection is correlated with a strengthening of the first connection, which suggests that they are likely to be involved in the same circuitry,” Zuo said. “The clustering of synapses may serve to magnify the strength of the connections.”

Another part of the study also supported the idea that the clustered synapses are involved in neural circuits specific to the task being learned. The researchers studied mice trained first in one task and then in a different task. Instead of grabbing a seed, the mice had to learn how to handle a piece of capellini pasta. Both tasks induced the formation of clustered spines, but spines formed during the learning of different tasks did not cluster together.

The researchers also looked at mice that were challenged with new motor tasks every day, but did not repeat the same task over and over like the ones trained in seed-grabbing or capellini-handling. These mice also grew lots of new dendritic spines, but few of the new spines were clustered.

“Repetitive activation of the same cortical circuit is really important in learning a new task,” Zuo said. “But what is the optimal frequency of repetition? Ultimately, by studying the relationship between synapse formation and learning, we want to find out the best way to induce new memories.”

The study used mice that had been genetically altered to make a fluorescent protein within certain neurons in the motor cortex. The researchers used a special microscopy technique (two-photon microscopy) to obtain images of those neurons near the surface of the brain. The noninvasive imaging technique enabled them to view changes in individual brain cells of the mice before, during, and after learning a new behavior.  

Source: Medical News Today

ScienceDaily (Feb. 19, 2012) — New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study published in Nature on February 19 (advance online publication). Led by researchers at the University of California, Santa Cruz, the study reveals details of how brain circuits are rewired during the formation of new motor memories.

Rendering of neural network. New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study. (Credit: © nobeastsofierce / Fotolia)

The researchers studied mice as they learned new behaviors, such as reaching through a slot to get a seed. They observed changes in the motor cortex, the brain layer that controls muscle movements, during the learning process. Specifically, they followed the growth of new “dendritic spines,” structures that form the connections (synapses) between nerve cells.

"For the first time we are able to observe the spatial distribution of new synapses related to the encoding of memory," said Yi Zuo, assistant professor of molecular, cell and developmental biology at UC Santa Cruz and corresponding author of the paper.

In a previous study, Zuo and others documented the rapid growth of new dendritic spines on pyramidal neurons in the motor cortex during the learning process. These spines form synapses where the pyramidal neurons receive input from other brain regions involved in motor memories and muscle movements. In the new study, first author Min Fu, a postdoctoral researcher in Zuo’s lab, analyzed the spatial distribution of the newly formed synapses.

Initial results of the spatial analysis showed that one third of the newly formed synapses were located next to another new synapse. These clustered synapses tended to form over the course of a few days during the learning period, when the mouse was repeatedly performing the new behavior. Compared to non-clustered counterparts, the clustered synapses were more likely to persist through the learning sessions and after training stopped.

In addition, the researchers found that after formation of the second spine in a cluster, the first spine grew larger. The size of the spine head correlates with the strength of the synapse. “We found that formation of a second connection is correlated with a strengthening of the first connection, which suggests that they are likely to be involved in the same circuitry,” Zuo said. “The clustering of synapses may serve to magnify the strength of the connections.”

Another part of the study also supported the idea that the clustered synapses are involved in neural circuits specific to the task being learned. The researchers studied mice trained first in one task and then in a different task. Instead of grabbing a seed, the mice had to learn how to handle a piece of capellini pasta. Both tasks induced the formation of clustered spines, but spines formed during the learning of different tasks did not cluster together.

The researchers also looked at mice that were challenged with new motor tasks every day, but did not repeat the same task over and over like the ones trained in seed-grabbing or capellini-handling. These mice also grew lots of new dendritic spines, but few of the new spines were clustered.

"Repetitive activation of the same cortical circuit is really important in learning a new task," Zuo said. "But what is the optimal frequency of repetition? Ultimately, by studying the relationship between synapse formation and learning, we want to find out the best way to induce new memories."

The study used mice that had been genetically altered to make a fluorescent protein within certain neurons in the motor cortex. The researchers used a special microscopy technique (two-photon microscopy) to obtain images of those neurons near the surface of the brain. The noninvasive imaging technique enabled them to view changes in individual brain cells of the mice before, during, and after learning a new behavior.

Source: Science Daily

February 16, 2012

(Medical Xpress) — Gene therapy not only helps injured brain cells to live longer and regenerate, but also changes the shape of the cells, according to researchers The University of Western Australia. 

The study, published in the international science and medicine journal PLoS One, was led by Winthrop Professor Alan Harvey from UWA’s School of Anatomy, Physiology and Human Biology, and Associate Professor Jennifer Rodger, NHMRC Research Fellow in Experimental and Regenerative Neurosciences at UWA’s School of Animal Biology.  The research was funded primarily by the WA Neurotrauma Research Program.

Professor Harvey said gene therapy was a relatively new strategy that attempted to help injured brain cells survive and regrow.

"Our previous work has shown that when growth-promoting genes are introduced into injured brain cells for long periods of time (up to nine months), the cells’ capacity for survival and regeneration is significantly increased," he said.

"We have now shown that these same neurons have also changed shape in response to persistent over-expression of the growth factors.  Importantly, it is not just neurons containing the introduced growth-promoting gene that are affected, but neighbouring "bystander" neurons."

Professor Harvey said neural morphology was very important in determining how a cell communicated with other cells and formed the circuits that allowed the brain to function.

"Any changes in morphology are therefore likely to alter the way neurons receive and transmit information.  These changes may be beneficial but could also interfere with normal brain circuits, reducing the benefits of improved survival and regeneration."

Professor Harvey said the results were significant for those involved in designing gene therapy-based protocols to treat brain and spinal cord injury and degeneration.

"These new results suggest that we may need to be careful about the types of genes we use in neurotherapy and how long we continue the therapy.  While it may be beneficial for these genes to move around and cause changes in other cells, we need to be able to switch them off once the change has taken place."

Provided by University of Western Australia

Source: medicalxpress.com

February 16th, 2012

Researchers have created a living 3-D model of a brain tumor and its surrounding blood vessels. In experiments, the scientists report that iron-oxide nanoparticles carrying the agent tumstatin were taken by blood vessels, meaning they should block blood vessel growth. The living-tissue model could be used to test the effectiveness of nanoparticles in fighting other diseases. Results appear in Theranostics.

Brown University scientists have created the first three-dimensional living tissue model, complete with surrounding blood vessels, to analyze the effectiveness of therapeutics to combat brain tumors. The 3-D model gives medical researchers more and better information than Petri dish tissue cultures.

The researchers created a glioma, or brain tumor, and the network of blood vessels that surrounds it. In a series of experiments, the team showed that iron-oxide nanoparticles ferrying the chemical tumstatin penetrated the blood vessels that sustain the tumor with oxygen and nutrients. The iron-oxide nanoparticles are important, because they are readily taken up by endothelial cells and can be tracked by magnetic resonance imaging.

Previous experiments have shown that tumstatin was effective at blocking endothelial cell growth in gliomas. The tests by the Brown researchers took it to another level by confirming, in a 3-D, living environment, the iron-oxide nanoparticles’ ability to reach blood vessels surrounding a glioma as well as tumstatin’s ability to penetrate endothelial cells.

“The 3-D glioma model that we have developed offers a facile process to test diffusion and penetration into a glioma that is covered by a blood vessel-like coating of endothelial cells,” said Don Ho, a graduate student in the lab of chemistry professor Shouheng Sun and the lead author of the paper in the journal Theranostics. “This assay would save time and money, while reducing tests in living organisms, to examine an agent’s 3-D characteristics such as the ability for targeting and diffusion.”

The tissue model concept comes from Jeffrey Morgan, a bioengineer at Brown and a corresponding author on the paper. Building on that work, Ho and others created an agarose hydrogel mold in which rat RG2-cell gliomas roughly 200 microns in diameter formed. The team used endothelial cells derived from cow respiratory vessels, which congregated around the tumor and created the blood vessel architecture. The advantage of a 3-D model rather than Petri-dish-type analyses is that the endothelial cells attach to the tumor, rather than being separated from the substrate. This means the researchers can study their formation and growth, as well as the action of anti-therapeutic agents, just as they would in a living organism.

“You want to see nanoparticles that diffuse through the endothelial cells, which is lost in 2-D because you just have diffusion into media,” Ho said.

Other 3-D tissue models have been “forced cell arrangements,” Ho said. The 3-D glioma model, in contrast, allowed the glioma and the endothelial cells to assemble naturally, just as they would in real life. “It more clearly mimics what would actually happen,” Ho explained.

The group then attached tumstatin, part of a naturally occurring protein found in collagen, to iron-oxide nanoparticles and dosed the mold. True to form, the nanoparticles were gobbled up by the endothelial cells. In a series of in vitro experiments, the team reported the tumstatin iron-oxide nanoparticles decreased vasculature growth 2.7 times more than under normal conditions over eight days. “The growth is pretty much flat,” Ho said. “There’s no new growth of endothelial cells.” The next step is to test the tumstatin nanoparticles’ performance in the 3-D environment.

“This model has significant potential to help in the testing and optimization of the design of therapeutic/diagnostic nanocarriers and determine their therapeutic capabilities,” the researchers write.

Source: Neuroscience News

Article Date: 16 Feb 2012 - 1:00 PST

Scientists at Emory University School of Medicine have identified a new group of compounds that may protect brain cells from inflammation linked to seizures and neurodegenerative diseases.

The compounds block signals from EP2, one of the four receptors for prostaglandin E2, which is a hormone involved in processes such as fever, childbirth, digestion and blood pressure regulation. Chemicals that could selectively block EP2 were not previously available. In animals, the EP2 blockers could markedly reduce the injury to the brain induced after a prolonged seizure, the researchers showed.

The results were published online this week in the Proceedings of the National Academy of Sciences Early Edition.

“EP2 is involved in many disease processes where inflammation is showing up in the nervous system, such as epilepsy, stroke and neurodegenerative diseases,” says senior author Ray Dingledine, PhD, chairman of Emory’s Department of Pharmacology. “Anywhere that inflammation is playing a role via EP2, this class of compounds could be useful. Outside the brain, EP2 blockers could find uses in other diseases with a prominent inflammatory component such as cancer and inflammatory bowel disease.”

Prostaglandins are the targets for non-steroid anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen. NSAIDSs inhibit enzymes known as cyclooxygenases, the starting point for generating prostaglandins in the body. Previous research indicates that drugs that inhibit cyclooxygenases can have harmful side effects. For example, sustained use of aspirin can weaken the stomach lining, coming from prostaglandins’ role in the stomach. Even drugs designed to inhibit only cyclooxygenases involved in pain and inflammation, such as Vioxx, have displayed cardiovascular side effects.

Dingledine’s team’s strategy was to bypass cyclooxygenase enzymes and go downstream, focusing on one set of molecules that relay signals from prostaglandins. Working with Yuhong Du in the Emory Chemical Biology Discovery Center, postdoctoral fellows Jianxiong Jiang, Thota Ganesh and colleagues sorted through a library of 262,000 compounds to find those that could block signals from the EP2 prostaglandin receptor but not related receptors. One of the compounds could prevent damage to neurons in mice after “status epilepticus,” a prolonged drug-induced seizure used to model the neurodegeneration linked to epilepsy. The team found that a family of related compounds had similar protective effects.

Dingledine says that the compounds could become valuable tools for exploring new ways to treat neurological diseases. However, given the many physiological processes prostaglandins regulate, more tests are needed, he says. Prostaglandin E2 is itself a drug used to induce labor in pregnant women, and female mice engineered to lack the EP2 receptor are infertile, so the compounds would need to be tested for effects on reproductive organs, for example.

View drug information on Vioxx.

Source: Medical News Today

ScienceDaily (Feb. 15, 2012) — Brain scans of two strains of mice imbibing significant quantities of alcohol reveal serious shrinkage in some brain regions — but only in mice lacking a particular type of receptor for dopamine, the brain’s “reward” chemical. The study, conducted at the U.S. Department of Energy’s Brookhaven National Laboratory and published in the May 2012 issue of Alcoholism: Clinical and Experimental Research, now online, provides new evidence that these dopamine receptors, known as DRD2, may play a protective role against alcohol-induced brain damage.

"This study clearly demonstrates the interplay of genetic and environmental factors in determining the damaging effects of alcohol on the brain, and builds upon our previous findings suggesting a protective role of dopamine D2 receptors against alcohol’s addictive effects," said study author Foteini Delis, a neuroanatomist with the Behavioral Neuropharmacology and Neuroimaging Lab at Brookhaven, which is funded through the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Coauthor and Brookhaven/NIAA neuroscientist Peter Thanos stated that, "These studies should help us better understand the role of genetic variability in alcoholism and alcohol-induced brain damage in people, and point the way to more effective prevention and treatment strategies."

The current study specifically explored how alcohol consumption affects brain volume — overall and region-by-region — in normal mice and a strain of mice that lack the gene for dopamine D2 receptors. Half of each group drank plain water while the other half drank a 20 percent ethanol solution for six months. Then scientists performed magnetic resonance imaging (MRI) scans on all the mice and compared the scans of those drinking alcohol with those from the water drinkers in each group.

The scans showed that chronic alcohol drinking induced significant overall brain atrophy and specific shrinkage of the cerebral cortex and thalamus in the mice that lacked dopamine D2 receptors, but not in mice with normal receptor levels. Mice in both groups drank the same amount of alcohol.

"This pattern of brain damage mimics a unique aspect of brain pathology observed in human alcoholics, so this research extends the validity of using these mice as a model for studying human alcoholism," Thanos said.

In humans, these brain regions are critically important for processing speech, sensory information, and motor signals, and for forming long-term memories. So this research helps explain why alcohol damage can be so widespread and detrimental.

"The fact that only mice that lacked dopamine D2 receptors experienced brain damage in this study suggests that DRD2 may be protective against brain atrophy from chronic alcohol exposure," Thanos said. "Conversely, the findings imply that lower-than-normal levels of DRD2 may make individuals more vulnerable to the damaging effects of alcohol."

That would in effect deal people with low DRD2 levels a double whammy of alcohol vulnerability: Previous studies conducted by Thanos and collaborators suggest that individuals with low DRD2 levels may be more susceptible to alcohol’s addictive effects.

"The increased addictive liability and the potentially devastating increased susceptibility to alcohol toxicity resulting from low DRD2 levels make it clear that the dopamine system is an important target for further research in the search for better understanding and treatment of alcoholism," Thanos said.

Source: Science Daily

ScienceDaily (Feb. 14, 2012) — Curcumin, a substance extracted from turmeric, prolongs life and enhances activity of fruit flies with a nervous disorder similar to Alzheimers, according to new research. The study conducted at Linköping University, indicates that it is the initial stages of fibril formation and fragments of the amyloid fibrils that are most toxic to neurons.

Above left are the survival curves for “Alzheimer flies” treated (dashed line) and those not treated with curcumin. The flies that were administered curcumin lived longer and were more active. The scientists identified an accelerated formation of amyloid plaque in the treated flies, which seemed to protect the nerve cells. On the right we see microscopic images of neurons (blue) and plaque (green) in the fruit fly’s brain. The study strengthens the hypothesis that a curcumin-based drug can contribute to toxic fibrils being encapsulated (bottom left of the figure). (Credit: Per Hammarström, Ina Caesar)

Ina Caesar, as the lead author, has published the results of the study in the journal PLoS ONE.

For several years curcumin has been studied as a possible drug candidate to combat Alzheimer’s disease, which is characterized by the accumulation of sticky amyloid-beta and Tau protein fibres. Linköping researchers wanted to investigate how the substance affected transgenic fruit flies (Drosophila melanogaster), which developed evident Alzheimer’s symptoms. The fruit fly is increasingly used as a model for neurodegenerative diseases.

Five groups of diseased flies with different genetic manipulations were administered curcumin. They lived up to 75 % longer and maintained their mobility longer than the sick flies that did not receive the substance.

However, the scientists saw no decrease of amyloid in the brain or eyes. Curcumin did not dissolve the amyloid plaque; on the contrary it accelerated the formation of fibres by reducing the amount of their precursor forms, known as oligomers.

"The results confirm our belief that it is the oligomers that are most harmful to the nerve cells," says Professor Per Hammarstrom, who led the study.

"We now see that small molecules in an animal model can influence the amyloid form. To our knowledge the encapsulation of oligomers is a new and exciting treatment strategy," he said.

Several theories have been established about how oligomers can instigate the disease process. According to one hypothesis, they become trapped at synapses, inhibiting nerve impulse signals. Others claim that they cause cell death by puncturing the cell membrane.

Curcumin is extracted from the root of herbaceous plant turmeric and has been used as medicine for thousands of years. More recently, it has been tested against pain, thrombosis and cancer.

Source: Science Daily