Mouse brain cells live long and prosper

Mouse brain cells scamper close to eternal life: They can actually outlive their bodies. Mouse neurons transplanted into rat brains lived as long as the rats did, surviving twice as long as the mouse’s average life span, researchers report online February 25 in the Proceedings of the National Academy of Sciences.

The findings suggest that long lives might not mean deteriorating brains. “This could absolutely be true in other mammals — humans too,” says study author Lorenzo Magrassi, a neurosurgeon at the University of Pavia in Italy.

The findings are “very promising,” says Carmela Abraham, a neuroscientist at Boston University. “The question is: Can neurons live longer if we prolong our life span?” Magrassi’s experiment, she says, suggests the answer is yes.

One theory about aging, Magrassi says, is that every species has a genetically determined life span and that all the cells in the body wear out and die at roughly the same time. For the neurons his team studied, he says, “We have shown that this simple idea is certainly not true.”

Magrassi’s team surgically transplanted neurons from embryonic mice with an average life span of 18 months into rats. To do so, the researchers slipped a glass microneedle through the abdomens of anesthetized pregnant mice. Then, using a dissecting microscope and a tool to illuminate the corn-kernel-sized mouse embryos, the researchers scraped out tiny bits of brain tissue and injected the neurons into fetal rat brains. After the rat pups were born, Magrassi and colleagues waited as long as three years, until the animals were near death, to euthanize the rats and dissect their brains.

The transplanted mouse cells had linked up with the rat brain cells and developed into mature, working neurons, though they did retain their characteristic small size. Also, because Magrassi’s team had tagged the mouse cells to glow green, the researchers could distinguish between mouse and rat neurons. The mouse cells lived twice as long as they would have in a mouse brain, and they showed signs of aging similar to those of neighboring rat neurons.

Figuring out what’s helping the neurons survive could lead researchers to treatments for human neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, Magrassi says.

Blood marrow derived cells regulate appetite

Bone marrow cells that produce brain-derived eurotrophic factor (BDNF), known to affect regulation of food intake, travel to part of the hypothalamus in the brain where they “fine-tune” appetite, said researchers from Baylor College of Medicine and Shiga University of Medical Science in Otsu, Shiga, Japan, in a report that appears online in the journal Nature Communications.

"We knew that blood cells produced BDNF," said Dr. Lawrence Chan, professor of molecular and cellular biology and professor and chief of the division of diabetes, endocrinology & metabolism in the department of medicine and director of the federally funded Diabetes Research Center, all at BCM. The factor is produced in the brain and in nerve cells as well. "We didn’t know why it was produced in blood cells."

Fluorescent marker reveals surprise

Dr. Hiroshi Urabe and Dr. Hideto Kojima, current and former postdoctoral fellows in Chan’s laboratory respectively, looked for BDNF in the brains of mice who had not been fed for about 24 hours. The bone marrow-derived cells had been marked with a fluorescent protein that showed up on microscopy. To their surprise, they found cells producing BDNF in a part of the brain’s hypothalamus called the paraventricular nucleus.

"We knew that in embryonic development, some blood cells do go to the brain and become microglial cells," said Chan. (Microglial cells form part of the supporting structure of the central nervous system. They are characterized by a nucleus from which "branches" expand in all directions.) "This is the first time we have shown that this happens in adulthood. Blood cells can go to one part of the brain and become physically changed to become microglial-like cells."

However, these bone marrow cells produce a bone marrow-specific variant of BDNF, one that is different from that produced by the regular microglial cells already in the hypothalamus.

Only a few of these blood-derived cells actually reach the hypothalamus, said Chan.

"It’s not very impressive if you look casually under the microscope," he said. However, a careful scrutiny showed that the branching nature of these cells allow them to come into contact with a whole host of brain cells.

"Their effects are amplified," said Chan.

Curbing the urge

Mice that are born lacking the ability to produce blood cells that make BDNF overeat, become obese and develop insulin resistance (a lack of response to insulin that affects the ability to metabolize glucose). A bone marrow transplant that restores the gene for making the cells that produce BDNF can normalize appetite, said Chan. However, a transplant of bone marrow that does not contain this gene does not reverse overeating, obesity or insulin resistance.

When normal bone marrow cells that produce BDNF are injected into the third ventricle (a fluid-filled cavity in the brain) of mice that lack BDNF, they no longer have the urge to overeat, said Chan.

All in all, the studies represent a new mechanism by which these bone-marrow derived cells control feeding through BDNF and could provide a new avenue to attack obesity, said Chan.

He and his colleagues hypothesize that the bone marrow cells that produce BDNF fine tune the appetite response, although a host of different appetite-controlling hormones produced by the regular nerve cells in the hypothalamus do the lion’s share of the work.

"Bone marrow cells are so accessible," said Chan. “If these cells play a regulatory role, we could draw some blood, modify something in it or add something that binds to blood cells and give it back. We may even be able to deliver medication that goes to the brain," crossing the blood-brain barrier. Even a few of these cells can have an effect because their geometry means that they have contact with many different neurons or nerve cells.

Researchers find controlling element of Huntington’s disease: Molecular troika regulates production of harmful protein

A three molecule complex may be a target for treating Huntington’s disease, a genetic disorder affecting the brain. This finding by an international research team including scientists from the German Center for Neurodegenerative Diseases (DZNE) in Bonn and the University of Mainz was published in the online journal “Nature Communications”. The report states that the so-called MID1 complex controls the production of a protein which damages nerve cells.

The long DNA sequences in Huntington’s disease lead to changes in a certain protein called “Huntingtin”. The DNA is like an archive of blueprints for proteins. Errors in the DNA therefore result in defective proteins. “Huntingtin is essential for the organism’s survival. It is a multi-talent which is important for many processes,” emphasises Krauss. “If the protein is defective, brain cells may die.“

In the spotlight: protein synthesis
In the current study, the scientists around Sybille Krauss and the Mainz-based human geneticist Susann Schweiger took a closer look at a critical stage of protein production – translation. At this step, a copy of the DNA, the so-called messenger RNA, is processed by the cell’s protein factories. In patients with Huntington’s disease, the messenger RNA contains an unusually high number of consecutive CAG sequences – CAG representing the building plan for the amino acid glutamine.

These repetitive sequences have a direct consequence: more glutamine than normal is built into Huntingtin, which is therefore defective. Sybille Krauss and her colleagues have now identified a group of three molecules, which regulate the production of this protein. “We were able to show that this complex binds to the messenger RNA and controls the synthesis of defective Huntingtin,” says Krauss. When the scientists reduced the concentration of this so-called MID1 complex in the cell, production of the defective protein declined.

“If we could find a way of influencing this complex, for example with pharmaceuticals, it is quite possible that we could directly affect the production of defective Huntingtin. This kind of treatment would not just treat the symptoms but also the causes of Huntington’s disease,” says Krauss.

Background:Three molecules come together
The complex consists of MID1, from which it gets its name, and the proteins PP2Ac and S6K. “Every single one of these proteins is known to be important for translation. We have discovered that in the specific case of Huntington’s disease, they together bind to the CAG sequences. This was previously unknown. We also found that binding increases with repeat lengths,” says Krauss. “In sequences of normal length, we found only weak binding or none at all.”

The Bonn-based molecular biologist and her colleagues investigated the effect of the MID1 complex and the interaction between its components in a series of elaborate laboratory experiments. “This project took several years of research work,” says Krauss. Along with biochemical procedures, the scientists used cell cultures and analysed proteins from the brains of mice. The mice’s genetic code had been modified in such a way that it contained elongated CAG-repeats as it is typical for Huntington’s disease.

From previous studies it was already known that the protein MID1 tends to bind messenger RNAs. The scientists were now able to show that MID1 also attaches to messenger RNAs with excessively long CAG sequences. Furthermore, experiments showed that PP2Ac and S6K also bound the RNA in the presence of MID1. However, if the MID1 was depleted, this binding did not occur. “From this, we can conclude that these three proteins form a molecular complex, which binds to the RNA. MID1 is a key component. It actually seems to keep together its binding partners,” Krauss comments on the results of the experiments.

Complex controls protein production
The researchers were also able to prove that the MID1 complex controls the translation of RNA with excessively long CAG sequences. For this, they investigated various cell cultures. The cells produced either normal Huntingtin or – due to excessively long sequences in their DNA – a defective version of this protein. The scientists reduced the occurrence of MID1 inside the cells using a procedure known as “knock-down”. The elimination of this protein, which is a major part of the MID1 complex, had direct consequences: the production of defective Huntingtin declined. “However, it did not affect the production of normal Huntingtin,” emphazises Krauss. “This further proves that the MID1 complex specifically targets RNAs with excessively long CAG sequences.”

Highly specific
The Bonn-based molecular biologist sees this specific influence as a chance to treat Huntington’s disease: “The MID1 complex is a promising target for therapy. It indicates a possibility to suppress the production of defective Huntingtin only, while not affecting the production of normal Huntingtin. This is of particular significance, because the normal protein is also being produced in the patients’ bodies and it is important for the organism.”

A suitable active substance has yet to be found, says Krauss. However, the next developments are in sight: “We now want to test potential substances in the laboratory,” she says.

Now hear this: Researchers identify forerunners of inner-ear cells that enable hearing

Researchers at the Stanford University School of Medicine have identified a group of progenitor cells in the inner ear that can become the sensory hair cells and adjacent supporting cells that enable hearing. Studying these progenitor cells could someday lead to discoveries that help millions of Americans suffering from hearing loss due to damaged or impaired sensory hair cells.

“It’s well known that, in mammals, these specialized sensory cells don’t regenerate after damage,” said Alan Cheng, MD, assistant professor of otolaryngology. (In contrast, birds and fish are much better equipped: They can regain their sensory cells after trauma caused by noise or certain drugs.) “Identifying the progenitor cells, and the cues that trigger them to become sensory cells, will allow us to better understand not just how the inner ear develops, but also how to devise new ways to treat hearing loss and deafness.”

The research was published online Feb. 26 in Development. Cheng is the senior author. Former medical student Taha Jan, MD, and postdoctoral scholar Renjie Chai, PhD, share lead authorship of the study. Roel Nusse, PhD, a professor of developmental biology, is a co-senior author of the research.

The inner ear is a highly specialized structure for gathering and transmitting vibrations in the air. The auditory compartment, called the cochlea, is a snail-shaped cavity that houses specialized cells with hair-like projections that sense vibration, much like seaweed waving in the ocean current. These hair cells are responsible for both hearing and balance, and are surrounded by supporting cells that are also critical for hearing.

Twenty percent of all Americans, and up to 33 percent of those ages 65-74, suffer from hearing loss. Hearing aids and, in severe cases, cochlear implants can be helpful for many people, but neither address the underlying cause: the loss of hair cells in the inner ear. Cheng and his colleagues identified a class of cells called tympanic border cells that can give rise to hair cells and the cells that support them during a phase of cochlear maturation right after birth.

“Until now, these cells have had no clear function,” said Cheng. “We used several techniques to define their behavior in cell culture dishes, as well as in mice. I hope these findings will lead to new areas of research to better understand how our ears develop and perhaps new ways to stimulate the regeneration of sensory cells in the cochlea.”

Holographic Technique Could Lead to Bionic Vision

Researchers led by biomedical engineering Professor Shy Shoham of the Technion-Israel Institute of Technology are testing the power of holography to artificially stimulate cells in the eye, with hopes of developing a new strategy for bionic vision restoration.

Computer-generated holography, they say, could be used in conjunction with a technique called optogenetics, which uses gene therapy to deliver light-sensitive proteins to damaged retinal nerve cells. In conditions such as Retinitis Pigmentosa (RP) - a condition affecting about one in 4000 people in the United States - these light-sensing cells degenerate and lead to blindness.

“The basic idea of optogenetics is to take a light-sensitive protein from another organism, typically from algae or bacteria, and insert it into a target cell, and that photosensitizes the cell,” Shoham explained.

Intense pulses of light can activate nerve cells newly sensitized by this gene therapy approach. But Shoham said researchers around the world are still searching for the best way to deliver the light patterns so that the retina “sees” or responds in a nearly normal way.

The plan is to someday develop a prosthetic headset or eyepiece that a person could wear to translate visual scenes into patterns of light that stimulate the genetically altered cells.

In their paper in the February 26 issue of Nature Communications, the Technion researchers show how light from computer-generated holography could be used to stimulate these repaired cells in mouse retinas. The key, they say, is to use a light stimulus that is intense, precise, and can trigger activity across a variety of cells all at once.

Blueprint for an artificial brain

Scientists have long been dreaming about building a computer that would work like a brain. This is because a brain is far more energy-saving than a computer, it can learn by itself, and it doesn’t need any programming. Privatdozent [senior lecturer] Dr. Andy Thomas from Bielefeld University’s Faculty of Physics is experimenting with memristors – electronic microcomponents that imitate natural nerves. Thomas and his colleagues proved that they could do this a year ago. They constructed a memristor that is capable of learning. Andy Thomas is now using his memristors as key components in a blueprint for an artificial brain. He will be presenting his results at the beginning of March in the print edition of the prestigious Journal of Physics published by the Institute of Physics in London.

Memristors are made of fine nanolayers and can be used to connect electric circuits. For several years now, the memristor has been considered to be the electronic equivalent of the synapse. Synapses are, so to speak, the bridges across which nerve cells (neurons) contact each other. Their connections increase in strength the more often they are used. Usually, one nerve cell is connected to other nerve cells across thousands of synapses.

Like synapses, memristors learn from earlier impulses. In their case, these are electrical impulses that (as yet) do not come from nerve cells but from the electric circuits to which they are connected. The amount of current a memristor allows to pass depends on how strong the current was that flowed through it in the past and how long it was exposed to it.

Andy Thomas explains that because of their similarity to synapses, memristors are particularly suitable for building an artificial brain – a new generation of computers. ‘They allow us to construct extremely energy-efficient and robust processors that are able to learn by themselves.’ Based on his own experiments and research findings from biology and physics, his article is the first to summarize which principles taken from nature need to be transferred to technological systems if such a neuromorphic (nerve like) computer is to function. Such principles are that memristors, just like synapses, have to ‘note’ earlier impulses, and that neurons react to an impulse only when it passes a certain threshold.

Thanks to these properties, synapses can be used to reconstruct the brain process responsible for learning, says Andy Thomas.

Study shows human brain able to discriminate syllables three months prior to birth

A team of French researchers has discovered that the human brain is capable of distinguishing between different types of syllables as early as three months prior to full term birth. As they describe in their paper published in the Proceedings of the National Academy of Sciences, the team found via brain scans that babies born up to three months premature are capable of some language processing.

Many studies have been conducted on full term babies to try to understand the degree of mental capabilities at birth. Results from such studies have shown that babies are able to distinguish their mother’s voice from others, for example, and can even recognize the elements of short stories. Still puzzling however, is whether some of what newborns are able to demonstrate is innate, or learned immediately after birth. To learn more, the researchers enlisted the assistance of several parents of premature babies and their offspring. Babies born as early as 28 weeks (full term is 37 weeks) had their brains scanned using bedside functional optical imaging, while sounds (soft voices) were played for them.

Three months prior to full term, the team notes, neurons in the brain are still migrating to what will be their final destination locations and initial connections between the upper brain regions are still forming—also neural linkages between the ears and brain are still being created. All of this indicates a brain that is still very much in flux and in the process of becoming the phenomenally complicated mass that humans are known for, which would seem to suggest that very limited if any communication skills would have developed.

The researchers found, however, that even at a time when the brain hasn’t fully developed, the premature infants were able to tell the difference between female versus male voices, and to distinguish between the syllables “ba” and “ga”. They noted also that the same parts of the brain were used by the infants to process sounds as adults. This, the researchers conclude, shows that linguistic connections in the brain develop before birth and because of that do not need to be acquired afterwards, suggesting that at least some abilities are innate.

Researchers build robotic bat wing

Researchers at Brown University have developed a robotic bat wing that is providing valuable new information about dynamics of flapping flight in real bats.

The robot, which mimics the wing shape and motion of the lesser dog-faced fruit bat, is designed to flap while attached to a force transducer in a wind tunnel. As the lifelike wing flaps, the force transducer records the aerodynamic forces generated by the moving wing. By measuring the power output of the three servo motors that control the robot’s seven movable joints, researchers can evaluate the energy required to execute wing movements.

Testing showed the robot can match the basic flight parameters of bats, producing enough thrust to overcome drag and enough lift to carry the weight of the model species.

A paper describing the robot and presenting results from preliminary experiments is published in the journal Bioinspiration and Biomimetics. The work was done in labs of Brown professors Kenneth Breuer and Sharon Swartz, who are the senior authors on the paper. Breuer, an engineer, and Swartz, a biologist, have studied bat flight and anatomy for years.

The faux flapper generates data that could never be collected directly from live animals, said Joseph Bahlman, a graduate student at Brown who led the project. Bats can’t fly when connected to instruments that record aerodynamic forces directly, so that isn’t an option — and bats don’t take requests.

“We can’t ask a bat to flap at a frequency of eight hertz then raise it to nine hertz so we can see what difference that makes,” Bahlman said. “They don’t really cooperate that way.”

But the model does exactly what the researchers want it to do. They can control each of its movement capabilities — kinematic parameters — individually. That way they can adjust one parameter while keeping the rest constant to isolate the effects.

“We can answer questions like, ‘Does increasing wing beat frequency improve lift and what’s the energetic cost of doing that?’” Bahlman said. “We can directly measure the relationship between these kinematic parameters, aerodynamic forces, and energetics.”

Detailed experimental results from the robot will be described in future research papers, but this first paper includes some preliminary results from a few case studies.