Scientists Show How A Neuron Gets Its Shape

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ScienceDaily (Apr. 13, 2009) — Ask a simple question, get a simple answer: When Abraham Lincoln was asked how long a man’s legs should be, he absurdly replied, “Long enough to reach the ground.” Now, by using a new microscopy technique to watch the growth of individual neurons in the microscopic roundworm Caenorhabditis elegans, Rockefeller University researchers are turning another deceptively simple question on its head. They asked, “How long should a worm’s neurons be?” And the worms fired back, “Long enough to reach their targets.”

The researchers’ surprising result: Rather than growing like the branches of a tree — extending outward — certain neurons work backward from their destination, dropping anchor and stretching their dendrites behind them as they crawl away. The work, led by Shai Shaham, head of the Laboratory of Developmental Genetics, and Maxwell Heiman, a research associate in the lab, not only addresses an age-old question of how neurons get their shape, but is also changing the way scientists think about the genetic program that wires the brain and allows it to grow throughout development.
“When I came to the lab, I thought that you would build a brain just like you would a house,” says Heiman. “The cell would measure the distance between its cell body and its target and then specify a dendrite of that length. Now, I’m not thinking about that kind of physical map at all. I think of a connectivity map, where what’s programmed are these connections among neurons and between neurons and their anchoring points.”
Since they were interested in how neurons get their shapes, Heiman and Shaham used a chemical to randomly mutate genes and then screened through thousands of animals for ones whose neurons were shaped abnormally. They specifically looked at a group of 12 sensory neurons whose dendritic tips converge at the worm’s nose in a sensory organ called the amphid. These dendritic tips collect information from the outside environment and give the worm cues on how to react to it.
Two genes, called dex-1 and dyf-7, caught their attention. If the animals had a mutation in either one of these genes, Heiman and Shaham saw that even though the cell migrated normally away from the tip of the nose, the dendrite didn’t stay anchored. Instead, it dragged along behind the cell body, resulting in an abnormally short dendrite. When they looked at the function of the proteins, the researchers found that they form a matrix to which the dendrites are anchored. Without the matrix to anchor the neuron, the dendrites didn’t form properly.
The two proteins, it turns out, are very similar to proteins that anchor the hair cells that detect sound waves in the human ear. “That was our second surprise,” says Heiman. “That there is this evolutionary relationship between a sensory organ in a worm and a sensory organ in humans. In the case of the worm, the anchor is being used to resist the force of cell migration. In our ear, it is the same anchor but it is being used for a completely different purpose.”
The scientists’ theory that the brain is wired based on connectivity (not absolute distance) provides an explanation of how the brain grows in proportion to the growth of an organism. “As the worm grows, its dendrites get longer and longer and the position of cell bodies change as they move farther away from a synapse,” says Shaham. “But what stays the same are these connections.”
Journal reference:
Maxwell G. Heiman and Shai Shaham. DEX-1 and DYF-7 Establish Sensory Dendrite Length by Anchoring Dendritic Tips during Cell Migration. Cell, 2009; DOI: 10.1016/j.cell.2009.01.057
Adapted from materials provided by Rockefeller University.

Medical Technology: 'SmartShunt' To Regulate Pressure In The Brain

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ScienceDaily (Apr. 12, 2009) — ETH Zurich researchers have simulated the motion of the cerebrospinal fluid in the human brain. They are using the results to develop a self-regulating system to treat hydrocephalus.

Cerebrospinal fluid is a colorless liquid surrounding the brain and the spinal cord and filling the cavities in the brain. It protects the brain from impact and vibrations, carries nutrients to it and harmful substances away from it, and acts as one of the brain’s communication routes. If too much of this fluid is produced or too little flows away, excessive pressure builds up in the head and hydrocephalus occurs.
The liquid flows into the abdomen
As a rule nowadays, hydrocephalus is treated by using a “shunt”: this involves implanting into the patient a thin tube that carries excess cerebrospinal fluid from the head into the abdomen via a pressure relief valve. However, this process often drains away too much or too little fluid. Most valves can no longer be adjusted after implantation. Although some valves have this option, the patient must visit the doctor for adjustments to be made.
ETH Zurich researchers led by Dimos Poulikakos, Professor of Thermodynamics, and Vartan Kurtcuoglu, Director of the Biofluidics group in the Laboratory for Thermodynamics in Emerging Technologies, want to go one step further. They are working on a “SmartShunt”, a self-regulating pressure relief device. To achieve their aim they must understand exactly how the cerebrospinal fluid flows within the skull. For this, they simulated the motion of the fluid in three dimensions on a computer. Initial results were published in the February issue of the Journal of Biomechanical Engineering. Its title page shows a graphic image of the results, the research group having already made the title page in the January issue with a publication on aortic aneurysms (see the Literature references).
A brain scan is the first step
The cerebrospinal fluid fills the space between the skull and the brain, called the sub-arachnoid space, in which it pulses in a cycle controlled indirectly by the heart. With each heartbeat, the heart pumps blood through the brain, causing the blood vessels to expand and the space available for the cerebrospinal fluid to decrease correspondingly. The blood flows away again before the next heartbeat, and the space for the cerebrospinal fluid increases.
The publication came into being in collaboration with Peter Bösiger, Professor at the Institute of Biomedical Technology of ETH Zurich. His group scanned the sub-arachnoid space of a healthy 25-year-old man by magnetic resonance imaging (MRI). They also used a special MRI technique to measure the velocity of the fluid in three planes to provide the boundary conditions for the calculations.
The scientists built a computer model based on the results of the measurements. They used a series of partial differential equations to describe the motion of the cerebrospinal fluid. At the same time, they had to take into account the fact that the sub-arachnoid space is criss-crossed by a sort of fine, networklike bar of tissues that retard the movement of the fluid. Instead of computing with the single bar, they represented the sub-arachnoid space in their model as a uniform porous medium similar to a sponge.
Valve for self-regulation
Based on the results, the researchers in the multi-disciplinary “SmartShunt” Project are now developing the basis for a shunt to control the outflow of cerebrospinal fluid automatically in accordance with the patient’s specific needs. The goal is a valve that controls the pressure in the patient’s head in real time, saving him or her regular visits to the doctor.
Dimos Poulikakos says, “We attach importance to the fact that definitereal medical problems are addressed in the continuation of basic research.” The researchers work in close collaboration with the medical staff of the University Hospital Zurich and with other ETH Zurich institutes. The Swiss National Science Foundation is funding the interdisciplinary project to the tune of approximately CHF 850,000. Poulikakos plans to start developing the actual product together with the industry in about three year’s time.
Knowledge of the cerebrospinal fluid motion will also be useful for other medical applications. The liquid plays a part in Alzheimer’s disease, in multiple sclerosis and in meningitis. In addition, drugs that cannot cross the blood-brain barrier can be injected into the cerebrospinal fluid, from where they reach the brain. In other cases, for example regarding painkillers, injection into the cerebrospinal fluid can allow the dose to be decreased to reduce side-effects.
Journal reference:
Gupta S, Soellinger M, Boesiger P, Poulikakos D & Kurtcuoglu V. Three-dimensional computational modelling of subject-specific cerebrospinal fluid flow in the sub-arachnoid space. Journal of Biomechanical Engineering, February 2009; Vol. 131, Issue 2 (020210) DOI: 10.1115/1.3005171
Adapted from materials provided by ETH Zurich.

How You Feel The World Impacts How You See It

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ScienceDaily (Apr. 10, 2009) — In the classic waterfall illusion, if you stare at the downward motion of a waterfall for some period of time, stationary objects — such as rocks — appear to drift upward. MIT neuroscientists have found that this phenomenon, called motion aftereffect, occurs not only in our visual perception but also in our tactile perception, and that these senses actually influence one another. Put another way, how you feel the world can actually change how you see it — and vice versa.

In a paper published in the April 9 online issue of Current Biology, researchers found that people who were exposed to visual motion in a given direction perceived tactile motion in the opposite direction. Conversely, tactile motion in one direction gave rise to the illusion of visual motion in the opposite direction.
"Our discovery suggests that the sensory processing of visual and tactile motion use overlapping neural circuits," explained Christopher Moore of the McGovern Institute for Brain Research at MIT and senior author of the paper. "The way something looks or feels can be influenced by a stimulus in the other sensory modality."
Volunteers watched visual motion on a computer screen while placing their right index fingertip on a tactile stimulator directly behind the screen. The stimulator consisted of a centimeter-square array composed of 60 pins to deliver precisely controlled vibrations to the fingertips. This stimulator, the only one of its kind in the world, was developed by Qi Wang, now at the Georgia Institute of Technology, and Vincent Hayward, now at the Université Pierre et Marie Curie in France.
To test the effect of visual motion on the subjects' perception of touch, the monitor displayed a pattern of horizontal stripes moving upward or downward for 10 seconds. After this visual pattern had disappeared, a single row of horizontal pins simultaneously vibrated the subjects' fingertips. Although the pins delivered a static burst of vibration, all eight subjects perceived that the row of pins was sweeping either upward or downward, in the direction opposite to the movement of the preceding visual pattern.
To test the effect of tactile motion on visual perception, adjacent rows of pins vibrated in rapid succession, creating the sensation of a tactile object sweeping up or down the subjects' fingertips. After 10 seconds of this stimulus, the monitor displayed a static pattern of horizontal stripes. Contrary to the prevailing assumption that vision always trumps touch, subjects perceived the stripes as moving in the opposite direction to the moving tactile stimulus.
Demos of the motion stimuli used in this study can be seen at http://web.mit.edu/~tkonkle/www/CrossmodalMAE.html.
"Aftereffects were once thought to reflect fatigue in the brain circuits," said Konkle, "but we now know that pools of neurons are continuously coding motion information and recalibrating the brain to its sensory environment. Our neurons are not tired, they are constantly adapting to the world around us."
Recent studies have found that a region of the visual cortex known as MT or V5 — long thought to play a major role in the perception of motion — may also process tactile motion. Moore's team intends to explore this brain region in future studies to determine whether it contributes to these cross-modal motion aftereffects.
"Neuroscientists study perceptual illusions because they help reveal how the brain gives rise to conscious experience," Moore said. "We don't experience the world through isolated senses, and our data support the emerging view that the brain is organized for cross talk among different sensory modalities."
The research was supported by the McGovern Institute for Brain Research at MIT, Mitsui Foundation, National Defense Science and Engineering Graduate Fellowship, Eric L. Adler Fellowship, Natural Sciences and Engineering Research Council.
Journal reference:
Talia Konkle, Qi Wang, Vincent Hayward, and Christopher I. Moore. Motion Aftereffects Transfer between Touch and Vision. Current Biology, 2009; DOI: 10.1016/j.cub.2009.03.035
Adapted from materials provided by Massachusetts Institute of Technology.

Rigorous Visual Training Teaches The Brain To See Again After Stroke

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ScienceDaily (Apr. 9, 2009) — By doing a set of vigorous visual exercises on a computer every day for several months, patients who had gone partially blind as a result of suffering a stroke were able to regain some vision, according to scientists who published their results in the April 1 issue of the Journal of Neuroscience.

Such rigorous visual retraining is not common for people who suffer blindness after a stroke. That’s in contrast to other consequences of stroke, such as speech or movement difficulties, where rehabilitation is common and successful.
“We were very surprised when we saw the results from our first patients,” said Krystel Huxlin, Ph.D., the neuroscientist and associate professor who led the study of seven patients at the University of Rochester Eye Institute. “This is a type of brain damage that clinicians and scientists have long believed you simply can’t recover from. It’s devastating, and patients are usually sent home to somehow deal with it the best they can.”
The results are a cause for hope for patients with vision damage from stroke or other causes, said Huxlin. The work also shows a remarkable capacity for “plasticity” in damaged, adult brains. It shows that the brain can change a great deal in older adults and that some brain regions are capable of covering for other areas that have been damaged.
Huxlin studied seven people who had suffered a stroke that damaged an area of the brain known as the primary visual cortex or V1, which serves as the gateway to the rest of the brain for all the visual information that comes through our eyes. V1 passes visual information along to dozens of other brain areas, which process and make sense of the information, ultimately allowing us to see.
Patients with damage to the primary visual cortex have severely impaired vision – they typically have a difficult or impossible time reading, driving, or getting out to do ordinary chores like grocery shopping. Patients may walk into walls, oftentimes cannot navigate stores without bumping into goods or other people, and they may be completely unaware of cars on the road coming toward them from the left or right.
Depending on where in the brain the stroke occurred, most patients will be blind in one-quarter to one-half of their normal field of view. Everything right or left of center, depending on the side of the stroke, might be gray or dark, for instance.
Adapted from materials provided by University of Rochester Medical Center.

Axons Necessary For Voluntary Movement Regenerated

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ScienceDaily (Apr. 9, 2009) — For the first time, researchers have clearly shown regeneration of a critical type of nerve fiber that travels between the brain and the spinal cord and which is required for voluntary movement. The regeneration was accomplished in a brain injury site in rats by scientists at the University of California, San Diego School of Medicine and is described in a study to be published in the April 6th early on-line edition of the Proceedings of the National Academy of Sciences (PNAS).

"This finding establishes a method for regenerating a system of nerve fibers called corticospinal motor axons. Restoring these axons is an essential step in one day enabling patients to regain voluntary movement after spinal cord injury," said Mark Tuszynski, MD, PhD, professor of neurosciences, director of the Center for Neural Repair at UC San Diego and neurologist at the Veterans Affairs San Diego Health System.
The corticospinal tract is a massive collection of nerve fibers called axons – long, slender projections of neurons that travel between the cerebral cortex of the brain and the spinal cord, carrying signals for movement from the brain to the body. Voluntary movement occurs through the activation of the upper motor neuron that resides in the frontal lobe of the brain and extends its axon down the spinal cord to the lower motor neuron. The lower motor neuron, in turn, sends its axon out to the muscle cells. In spinal cord injuries, the axons that run along the corticospinal tract are severed so that the lower motor neurons, below the site of injury, are disconnected from the brain.
"Previous spinal cord injury studies have shown regeneration of other nerve fiber systems that contribute to movement, but have not convincingly shown regeneration of the corticospinal system," said Tuszynski, theorizing this was due to a limited intrinsic ability of corticospinal neurons to turn on genes that allow regeneration after injury. He added that, without regeneration of corticospinal axons, it is questionable whether functional recovery would be attainable in humans.
The UC San Diego team achieved corticospinal regeneration by genetically engineering the injured neurons to over-express receptors for a type of nervous system growth factor called brain-derived neurotrophic factor (BDNF). The growth factor was delivered to a brain lesion site in injured rats. There, the axons – because they now expressed trkB, the receptor for BDNF– were able to respond to the growth factor and regenerate into the injury site. In the absence of overexpression of trkB, no regeneration occurred.
Although functional recovery in the animals was not assessed, the new study shows for the first time that regeneration of the corticospinal system – which normally does not respond to treatment – can be achieved in a brain lesion site.
"The next step will be to try this in a spinal cord injury site, once we get the injured neurons to send the growth factor receptor all the way down the axon and into the spinal cord," said Tuszynski, adding that the UC San Diego research team is now working on this. "We will then assess whether regeneration of corticospinal nerve fibers will lead to functional recovery and restored movement in animal models."
This work builds on another study from Tuszynski's laboratory, published in the February 8, 2009 issue of Nature Medicine, which reported that BDNF also exhibits potential as a therapy for reducing brain cell loss in Alzheimer's disease.
The lead author of the study was Edmund R. Hollis II, PhD. Additional contributors to the article included Pouya Jamshidi, Karin Low and Armin Blesch of the UC San Diego Department of Neurosciences. Their work was supported by grants from the National Institutes of Health, the Veterans Administration, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Bernard and Anne Spitzer Charitable Trust.
Journal reference:
Edmund R. Hollis II, Pouya Jamshidi, Karin Löw, Armin Blesch, Mark H. Tuszynski. Induction of corticospinal regeneration by lentiviral trkB-induced Erk activation. Proceedings of the National Academy of Sciences, 2009; DOI: 10.1073/pnas.0810624106
Adapted from materials provided by University of California - San Diego.