Posts tagged neuroscience

A team of researchers at The New York Stem Cell Foundation Research Institute led by Scott Noggle, PhD, Director of the NYSCF Laboratory and the NYSCF – Charles Evans Senior Research Fellow for Alzheimer’s Disease, and Michael W. Nestor, PhD, a NYSCF Postdoctoral Research Fellow, has developed a technique to produce three-dimensional cultures of induced pluripotent stem (iPS) cells called embryoid bodies, amenable to live cell imaging and to electrical activity measurement. As reported in their Stem Cell Research study, these cell aggregates enable scientists to both model and to study diseases such as Alzheimer’s and Parkinson’s disease.

The NYSCF Alzheimer’s disease research team aims to better understand and to find treatments to this disease through stem cell research. For such disorders in which neurons misfire or degenerate, the NYSCF team creates “disease in a dish” models by reprogramming patients’ skin and or blood samples into induced pluripotent stem (iPS) cells that can become neurons and the other brain cells affected in the diseases.

The cells in our body form three-dimensional networks, essential to tissue function and overall health; however, previous techniques to form complex brain tissue resulted in structures that, while similar in form to naturally occurring neurons, undermined imaging or electrical recording attempts.

In the current study, the Noggle and Nestor with NYSCF scientists specially adapted two-dimensional culture methods to grow three-dimensional neuron structures from iPS cells. The resultant neurons were “thinned-out,” enabling calcium-imaging studies, which measure the electrical activity of cells like neurons.

"Combining the advantages of iPS cells grown in a 3D environment with those of a 2D system, our technique produces cells that can be used to observe electrical activity of putative networks of biologically active neurons, while simultaneously imaging them," said Nestor. "This is key to modeling and studying neurodegenerative diseases."

Neural networks, thought to underlie learning and memory, become disrupted in Alzheimer’s disease. By generating aggregates from iPS cells and comparing these to an actual patient’s brain tissue, scientists may uncover how disease interferes with these cell-to-cell interactions and understand how to intervene to slow or stop Alzheimer’s disease.

"This critical new tool developed by our Alzheimer’s team will accelerate Alzheimer’s research, enabling more accurate manipulation of cells to find a cure to this disease," said Susan L. Solomon, CEO of NYSCF.

(Source: eurekalert.org)

Clumps of proteins that accumulate in brain cells are a hallmark of neurological diseases such as dementia, Parkinson’s disease and Alzheimer’s disease. Over the past several years, there has been much controversy over the structure of one of those proteins, known as alpha synuclein.

MIT computational scientists have now modeled the structure of that protein, most commonly associated with Parkinson’s, and found that it can take on either of two proposed states — floppy or rigid. The findings suggest that forcing the protein to switch to the rigid structure, which does not aggregate, could offer a new way to treat Parkinson’s, says Collin Stultz, an associate professor of electrical engineering and computer science at MIT.

“If alpha synuclein can really adopt this ordered structure that does not aggregate, you could imagine a drug-design strategy that stabilizes these ordered structures to prevent them from aggregating,” says Stultz, who is the senior author of a paper describing the findings in a recent issue of the Journal of the American Chemical Society.

For decades, scientists have believed that alpha synuclein, which forms clumps known as Lewy bodies in brain cells and other neurons, is inherently disordered and floppy. However, in 2011 Harvard University neurologist Dennis Selkoe and colleagues reported that after carefully extracting alpha synuclein from cells, they found it to have a very well-defined, folded structure.

That surprising finding set off a scientific controversy. Some tried and failed to replicate the finding, but scientists at Brandeis University, led by Thomas Pochapsky and Gregory Petsko, also found folded (or ordered) structures in the alpha synuclein protein.

Stultz and his group decided to jump into the fray, working with Pochapsky’s lab, and developed a computer-modeling approach to predict what kind of structures the protein might take. Working with the structural data obtained by the Brandeis researchers, Stultz created a model that calculates the probabilities of many different possible structures, to determine what set of structures would best explain the experimental data.

The calculations suggest that the protein can rapidly switch among many different conformations. At any given time, about 70 percent of individual proteins will be in one of the many possible disordered states, which exist as single molecules of the alpha synuclein protein. When three or four of the proteins join together, they can assume a mix of possible rigid structures, including helices and beta strands (protein chains that can link together to form sheets).

“On the one hand, the people who say it’s disordered are right, because a majority of the protein is disordered,” Stultz says. “And the people who would say that it’s ordered are not wrong; it’s just a very small fraction of the protein that is ordered.”

“This paper seems to bridge the gap” between the two camps, says Trevor Creamer, an associate professor of molecular and cellular biochemistry at the University of Kentucky who was not involved in this research. Also important is the model’s prediction of new structures for the protein that experimental biologists can now look for, Creamer adds.

The MIT researchers also found that when alpha synuclein adopts an ordered structure, similar to that described by Selkoe and co-workers, the portions of the protein that tend to aggregate with other molecules are buried deep within the structure, explaining why those ordered forms do not clump together.

Stultz is now working to figure out what controls the protein’s configuration. There is some evidence that other molecules in the cell can modify alpha synuclein, forcing it to assume one conformation or another.

“If this structure really does exist, we have a new way now of potentially designing drugs that will prevent aggregation of alpha synuclein,” he says.

(Source: web.mit.edu)

Scientists have known for some time that the human brain’s ability to stay calm and focused is limited and can be overwhelmed by the constant noise and hectic, jangling demands of city living, sometimes resulting in a condition informally known as brain fatigue.

With brain fatigue, you are easily distracted, forgetful and mentally flighty — or, in other words, me.

But an innovative new study from Scotland suggests that you can ease brain fatigue simply by strolling through a leafy park.

The idea that visiting green spaces like parks or tree-filled plazas lessens stress and improves concentration is not new. Researchers have long theorized that green spaces are calming, requiring less of our so-called directed mental attention than busy, urban streets do. Instead, natural settings invoke “soft fascination,” a beguiling term for quiet contemplation, during which directed attention is barely called upon and the brain can reset those overstretched resources and reduce mental fatigue.

But this theory, while agreeable, has been difficult to put to the test. Previous studies have found that people who live near trees and parks have lower levels of cortisol, a stress hormone, in their saliva than those who live primarily amid concrete, and that children with attention deficits tend to concentrate and perform better on cognitive tests after walking through parks or arboretums. More directly, scientists have brought volunteers into a lab, attached electrodes to their heads and shown them photographs of natural or urban scenes, and found that the brain wave readouts show that the volunteers are more calm and meditative when they view the natural scenes.

But it had not been possible to study the brains of people while they were actually outside, moving through the city and the parks. Or it wasn’t, until the recent development of a lightweight, portable version of the electroencephalogram, a technology that studies brain wave patterns.

For the new study, published this month in The British Journal of Sports Medicine, researchers at Heriot-Watt University in Edinburgh and the University of Edinburgh attached these new, portable EEGs to the scalps of 12 healthy young adults. The electrodes, hidden unobtrusively beneath an ordinary looking fabric cap, sent brain wave readings wirelessly to a laptop carried in a backpack by each volunteer.

The researchers, who had been studying the cognitive impacts of green spaces for some time, then sent each volunteer out on a short walk of about a mile and half that wound through three different sections of Edinburgh.

The first half mile or so took walkers through an older, historic shopping district, with fine, old buildings and plenty of pedestrians on the sidewalk, but only light vehicle traffic.

The walkers then moved onto a path that led through a park-like setting for another half mile.

Finally, they ended their walk strolling through a busy, commercial district, with heavy automobile traffic and concrete buildings.

The walkers had been told to move at their own speed, not to rush or dawdle. Most finished the walk in about 25 minutes.

Throughout that time, the portable EEGs on their heads continued to feed information about brain wave patterns to the laptops they carried.

Afterward, the researchers compared the read-outs, looking for wave patterns that they felt were related to measures of frustration, directed attention (which they called “engagement”), mental arousal and meditativeness or calm.

What they found confirmed the idea that green spaces lessen brain fatigue.

When the volunteers made their way through the urbanized, busy areas, particularly the heavily trafficked commercial district at the end of their walk, their brain wave patterns consistently showed that they were more aroused, attentive and frustrated than when they walked through the parkland, where brain-wave readings became more meditative.

While traveling through the park, the walkers were mentally quieter.

Which is not to say that they weren’t paying attention, said Jenny Roe, a professor in the School of the Built Environment at Heriot-Watt University, who oversaw the study. “Natural environments still engage” the brain, she said, but the attention demanded “is effortless. It’s called involuntary attention in psychology. It holds our attention while at the same time allowing scope for reflection,” and providing a palliative to the nonstop attentional demands of typical, city streets.

Of course, her study was small, more of a pilot study of the nifty new, portable EEG technology than a definitive examination of the cognitive effects of seeing green.

But even so, she said, the findings were consistent and strong and, from the viewpoint of those of us over-engaged in attention-hogging urban lives, valuable. The study suggests that, right about now, you should consider “taking a break from work,” Dr. Roe said, and “going for a walk in a green space or just sitting, or even viewing green spaces from your office window.” This is not unproductive lollygagging, Dr. Roe helpfully assured us. “It is likely to have a restorative effect and help with attention fatigue and stress recovery.”

-by Gretchen Reynolds, The New York Times

Focusing on the present rather than letting the mind drift may help to lower levels of the stress hormone cortisol, suggests new research from the Shamatha Project at the University of California, Davis.

The ability to focus mental resources on immediate experience is an aspect of mindfulness, which can be improved by meditation training.

"This is the first study to show a direct relation between resting cortisol and scores on any type of mindfulness scale," said Tonya Jacobs, a postdoctoral researcher at the UC Davis Center for Mind and Brain and first author of a paper describing the work, published this week in the journal Health Psychology.

High levels of cortisol, a hormone produced by the adrenal gland, are associated with physical or emotional stress. Prolonged release of the hormone contributes to wide-ranging, adverse effects on a number of physiological systems.

The new findings are the latest to come from the Shamatha Project, a comprehensive long-term, control-group study of the effects of meditation training on mind and body.

Led by Clifford Saron, associate research scientist at the UC Davis Center for Mind and Brain, the Shamatha Project has drawn the attention of both scientists and Buddhist scholars including the Dalai Lama, who has endorsed the project.

In the new study, Jacobs, Saron and their colleagues used a questionnaire to measure aspects of mindfulness among a group of volunteers before and after an intensive, three-month meditation retreat. They also measured cortisol levels in the volunteers’ saliva.

During the retreat, Buddhist scholar and teacher B. Alan Wallace of the Santa Barbara Institute for Consciousness Studies trained participants in such attentional skills as mindfulness of breathing, observing mental events, and observing the nature of consciousness. Participants also practiced cultivating benevolent mental states, including loving kindness, compassion, empathic joy and equanimity.

At an individual level, there was a correlation between a high score for mindfulness and a low score in cortisol both before and after the retreat. Individuals whose mindfulness score increased after the retreat showed a decrease in cortisol.

"The more a person reported directing their cognitive resources to immediate sensory experience and the task at hand, the lower their resting cortisol," Jacobs said.

The research did not show a direct cause and effect, Jacobs emphasized. Indeed, she noted that the effect could run either way — reduced levels of cortisol could lead to improved mindfulness, rather than the other way around. Scores on the mindfulness questionnaire increased from pre- to post-retreat, while levels of cortisol did not change overall.

According to Jacobs, training the mind to focus on immediate experience may reduce the propensity to ruminate about the past or worry about the future, thought processes that have been linked to cortisol release.

"The idea that we can train our minds in a way that fosters healthy mental habits and that these habits may be reflected in mind-body relations is not new; it’s been around for thousands of years across various cultures and ideologies," Jacobs said. "However, this idea is just beginning to be integrated into Western medicine as objective evidence accumulates. Hopefully, studies like this one will contribute to that effort."

Saron noted that in this study, the authors used the term “mindfulness” to refer to behaviors that are reflected in a particular mindfulness scale, which was the measure used in the study.

"The scale measured the participants’ propensity to let go of distressing thoughts and attend to different sensory domains, daily tasks, and the current contents of their minds. However, this scale may only reflect a subset of qualities that comprise the greater quality of mindfulness, as it is conceived across various contemplative traditions," he said.

Previous studies from the Shamatha Project have shown that the meditation retreat had positive effects on visual perception, sustained attention, socio-emotional well-being, resting brain activity and on the activity of telomerase, an enzyme important for the long-term health of body cells.

(Source: news.ucdavis.edu)

Johns Hopkins scientists say they have evidence from animal studies that a type of central nervous system cell other than motor neurons plays a fundamental role in the development of amyotrophic lateral sclerosis (ALS), a fatal degenerative disease. The discovery holds promise, they say, for identifying new targets for interrupting the disease’s progress.

In a study described online in Nature Neuroscience, the researchers found that, in mice bred with a gene mutation that causes human ALS, dramatic changes occurred in oligodendrocytes — cells that create insulation for the nerves of the central nervous system — long before the first physical symptoms of the disease appeared. Oligodendrocytes located near motor neurons — cells that govern movement — died off at very high rates, and new ones regenerated in their place were inferior and unhealthy.

The researchers also found, to their surprise, that suppressing an ALS-causing gene in oligodendrocytes of mice bred with the disease — while still allowing the gene to remain in the motor neurons — profoundly delayed the onset of ALS. It also prolonged survival of these mice by more than three months, a long time in the life span of a mouse. These observations suggest that oligodendrocytes play a very significant role in the early stage of the disease.

“The abnormalities in oligodendrocytes appear to be having a negative impact on the survival of motor neurons,” says Dwight E. Bergles, Ph.D., a co-author and a professor of neuroscience at the Johns Hopkins University School of Medicine. “The motor neurons seem to be dependent on healthy oligodendrocytes for survival, something we didn’t appreciate before.”

“These findings teach us that cells we never thought had a role in ALS not only are involved but also clearly contribute to the onset of the disease,” says co-author Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology at Johns Hopkins and director of the Johns Hopkins Medicine Brain Science Institute.

Scientists have long believed that oligodendrocytes functioned only as structural elements of the central nervous system. They wrap around nerves, making up the myelin sheath that provides the “insulation” that allows nerve signals to be transmitted rapidly and efficiently. However, Rothstein and others recently discovered that oligodendrocytes also deliver essential nutrients to neurons, and that most neurons need this support to survive.

The Johns Hopkins team of Bergles and Rothstein published a paper in 2010 that described in mice with ALS an unexpected massive proliferation of oligodendrocyte progenitor cells in the spinal cord’s motor neurons, and that these progenitors were being mobilized to make new oligodendrocytes. The researchers believed that these cells were multiplying because of an injury to oligodendrocytes, but they weren’t sure what was happening. Using a genetic method of tracking the fate of oligodendrocytes, in the new study, the researchers found that cells present in young mice with ALS were dying off at an increasing rate in concert with advancing disease. Moreover, the development of the newly formed oligodendrocytes was stalled and they were not able to provide motor neurons with a needed source of cell nutrients.

To determine whether the changes to the oligodendrocytes were just a side effect of the death of motor neurons, the scientists used a poison to kill motor neurons in the ALS mice and found no response from the progenitors, suggesting, says Rothstein, that it is the mutant ALS gene that is damaging oligodendrocytes directly.

Meanwhile, in separate experiments, the researchers found similar changes in samples of tissues from the brains of 35 people who died of ALS. Rothstein says it may be possible to see those changes early on in the disease and use MRI technology to follow progression.

“If our research is confirmed, perhaps we can start looking at ALS patients in a different way, looking for damage to oligodendrocytes as a marker for disease progression,” Rothstein says. “This could not only lead to new treatment targets but also help us to monitor whether the treatments we offer are actually working.”

ALS, also known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, affects nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary.

There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival.

Even though myelin loss has not previously been thought to occur in the gray matter, a region in the brain where neurons process information, the researchers in the new study found in ALS patients a significant loss of myelin in one of every three samples of human tissue taken from the brain’s gray matter, suggesting that the oligodendrocytes were abnormal. It isn’t clear if the oligodendrocytes that form this myelin in the gray matter play a different role than in white matter — the region in the brain where signals are relayed.

The findings further suggest that clues to the treatment of other diseases long believed to be focused in the brain’s gray matter — such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease — may be informed by studies of diseases of the white matter, such as multiple sclerosis (MS). Bergles says ALS and MS researchers never really thought their diseases had much in common before.

Oligodendrocytes have been under intense scrutiny in MS, Bergles says. In MS, the disease over time can transform from a remitting-relapsing form — in which myelin is attacked but then is regenerated when existing progenitors create new oligodendrocytes to re-form myelin — to a more chronic stage in which oligodendrocytes are no longer regenerated. MS researchers are working to identify new ways to induce the creation of new oligodendrocytes and improve their survival. “It’s possible that we may be able to dovetail with some of the same therapeutics to slow the progression of ALS,” Bergles says.

(Source: newswise.com)