Brain Connections Break Down as We Age, Study Suggests

http://www.sciencedaily.com/releases/2010/08/100818151822.htm


The circled portion of the older adult' brain on the left indicates the cross-talk between the two hemispheres that is not apparent in the younger brain on the right. Click above image for higher resolution. (Credit: Rachael Seidler)
ScienceDaily (Aug. 19, 2010) — It's unavoidable: breakdowns in brain connections slow down our physical response times as we age, a new study suggests.

This slower reactivity is associated with an age-related breakdown in the corpus callosum, a part of the brain that acts as a dam during one-sided motor activities to prevent unwanted connectivity, or cross-talk, between the two halves of the brain, said Rachael Seidler, associate professor in the University of Michigan School of Kinesiology and Department of Psychology, and lead study author.

At other times the corpus callosum acts at a bridge and cross-talk is helpful, such as in certain cognitive functions or two-sided motor skills.

The U-M study is the first known to show that this cross-talk happens even while older adults are at rest, said Seidler, who also has appointments in the Institute of Gerontology and the Neuroscience Graduate Program. This resting cross-talk suggests that it is not helpful or compensatory for the two halves of the brain to communicate during one-sided motor movements because the opposite side of the brain controls the part of the body that is moving. So, when both sides of the brain talk simultaneously while one side of the body tries to move, confusion and slower responses result, Seidler said.

Previous studies have shown that cross-talk in the brain during certain motor tasks increases with age but it wasn't clear if that cross-talk helped or hindered brain function, said Seidler.

"Cross-talk is not a function of task difficulty, because we see these changes in the brain when people are not moving," Seidler said.

In some diseases where the corpus callosum is very deteriorated, such as in people with multiple sclerosis, you can see "mirror movements" during one sided-motor tasks, where both sides move in concert because there is so much communication between the two hemispheres of the brain, Seidler said. These mirror movements also happen normally in very young children before the corpus callosum is fully developed.

In the study, researchers gave joysticks to adults between the ages of 65 and 75 and measured and compared their response times against a group approximately 20-25 years old.

Researchers then used a functional MRI to image the blood-oxygen levels in different parts of the brain, a measurement of brain activity.

"The more they recruited the other side of the brain, the slower they responded," Seidler said.

However there is hope, and just because we inevitably age doesn't mean it's our fate to react more slowly. Seidler's group is working on developing and piloting motor training studies that might rebuild or maintain the corpus callosum to limit overflow between hemispheres, she said.

A previous study done by another group showed that doing aerobic training for three months helped to rebuild the corpus callosum, she said, which suggests that physical activity can help to counteract the effects of the age-related degeneration.

Seidler's group also has a study in review that uses the same brain imaging techniques to examine disease related brain changes in Parkinson's patients.

The study appeared in the journal Frontiers in Systems Neuroscience.

Newts' ability to regenerate tissue replicated in mouse cells

Found at: http://www.physorg.com/news200224844.html

August 5, 2010
Tissue regeneration a la salamanders and newts seems like it should be the stuff of science fiction. But it happens routinely. Why can't we mammals just re-grow a limb or churn out a few new heart muscle cells as needed? New research suggests there might be a very good reason: Restricting our cells' ability to pop in and out of the cell cycle at will -- a prerequisite for the cell division necessary to make new tissue -- reduces the chances that they'll run amok and form potentially deadly cancers.


Now scientists at the Stanford University School of Medicine have taken a big step toward being able to confer this regenerative capacity on mammalian muscle cells; they accomplished this feat in experiments with laboratory mice in which they blocked the expression of just two tumor-suppressing proteins. The finding may move us closer to future regenerative therapies in humans — surprisingly, by sending us shimmying back down the evolutionary tree.

"Newts regenerate tissues very effectively," said Helen Blau, PhD, the Donald E. and Delia B. Baxter Professor and a member of Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "In contrast, mammals are pathetic. We can regenerate our livers, and that's about it. Until now it's been a mystery as to how they do it."

Blau is the senior author of the research, which will be published in Cell Stem Cell on Aug. 6. Kostandin Pajcini, PhD, a former graduate student, and Jason Pomerantz, MD, a former postdoctoral scholar in Blau's laboratory, are primarily responsible for the work and are first author and co-senior author, respectively.

Although there's been a lot of discussion about using adult or embryonic stem cells to repair or revitalize tissues throughout the body, in this case the researchers weren't studying stem cells. Instead they were investigating whether myocytes, run-of-the mill muscle cells that normally don't divide, can be induced to re-enter the cell cycle and begin proliferating. This is important because most specialized, or differentiated, cells in mammals are locked into a steady state that does not allow cell division. And without cell division, it is not possible to get regeneration.

In contrast, the cells of some types of amphibians are able to replace lost or damaged tissue by entering the cell cycle to give rise to more muscle cells. While doing so, the cells maintain their muscle identity, which prevents them from straying from the beaten path and becoming other, less useful cell types.


Pomerantz and Blau wondered if it could be possible to coax mammalian cells to follow a similar path. To do so, though, they needed to pinpoint what was different between mammalian and salamander cells when it comes to cell cycle control. One aspect involves a class of proteins called tumor suppressors that block inappropriate cell division.
Previous research had shown that a tumor suppressor called retinoblastoma, or Rb, plays an important role in preventing many types of specialized mammalian cells, including those found in muscle, from dividing willy-nilly. But the effect of blocking the expression of Rb in mammalian cells has been inconsistent: In some cases it has allowed the cells to hop back into the cell cycle; in others, it hasn't.

The researchers employed some evolutionary detective work to figure out that another tumor suppressor called ARF might be involved. Like Rb, ARF works to throw the brakes on the cell cycle in response to internal signals. An examination of the evolutionary tree provided a key clue. They saw that ARF first arose in chickens. It is found in other birds and mammals, but not in animals like salamanders nestled on the lower branches. Tellingly, it's also missing in cell lines that begin cycling when Rb is lost, and it is expressed at lower-than-normal levels in mammalian livers — the only organ that we humans can regenerate.

Based on previous investigators' work with newts, Blau said it "seemed to us that they don't have the same limitations on growth. We hypothesized that maybe, during evolution, humans gained a tumor suppressor not present in lower animals at the expense of regeneration."

Sure enough, Pajcini and Pomerantz found that blocking the expression of both Rb and ARF allowed individual myocytes isolated from mouse muscle to dedifferentiate and begin dividing. When they put the cells back into the mice, they were able to merge with existing muscle fibers — as long as Rb expression was restored. Without Rb the transplanted cells proliferated excessively and disrupted the structure of the original muscle.

"These myocytes have reached the point of no return," said Blau. "They can't just start dividing again. But here we show that temporarily blocking the expression of just two proteins can restore an ancient ability to contribute to mammalian muscle."
The key word here is "temporarily." As is clear from the mouse experiments, blocking the expression of tumor suppressors in mammalian cells can be a tricky gambit. Permanently removing these proteins can lead to uncontrolled cell division. But, a temporary and well-controlled loss — as the researchers devised here — could be a useful therapeutic tool.

The research required some sophisticated technology to separate individual myocytes from one another for study. To do so, Pajcini traveled to Munich to learn how to optimize a technique normally used on cryopreserved and fixed tissue sections — "laser micro-dissection catapulting" — for use with living cells. But the effort paid off when he was able to prove conclusively that once the expression of the two proteins was blocked, individual live cells were, in fact, dividing in culture.

Next, the researchers would like to see if the technique works in other cell types, like those of the pancreas or the heart, and whether they can induce it to happen in tissue at sites of injury. If so, it may be possible to trigger temporary cell proliferation as a means of therapy for a variety of ailments.
Provided by Stanford University Medical Center