Homer prevents stress-induced cognitive deficits

Before examinations and in critical situations, we need to be particularly receptive and capable of learning. However, acute exam stress and stage fright causes learning blockades and reduced memory function. Scientists from the Max Planck Institute of Psychiatry in Munich have now discovered a mechanism responsible for these cognitive deficits, which functions independently of stress hormones. In animal studies, the researchers show that social stress reduces the volume of Homer-1 in the hippocampus – a region of the brain that plays a central role in learning. This specific protein deficiency leads to altered neuronal activity followed by deterioration in the animals’ learning performance. In the experiments, it was possible to prevent the cognitive deficit by administering additional volumes of the protein to the mice. This suggests that Homer-1 could provide a key molecule for the development of drugs for the treatment of stress-induced cognitive deficits.

Klaus Wagner, a scientist at the Max Planck Institute of Psychiatry, studied the learning behaviour of mice that had been subjected to severe stress. He exposed the animals to social stress – a pressure also frequently experienced by humans today. A male mouse was placed in the cage of an aggressive member of the same species for five minutes. The latter tried to banish the “intruder” by attacking it. Unlike in nature, the test mouse was unable to flee from the cage and was under severe stress, as substantiated by measurements of the stress hormones in its blood.

Following a period of eight hours in which the animal was able to recover in its own cage, its behaviour was examined. While the mouse’s motivation, activity and sensory functions were not impaired at this time, it displayed clear deficits in its learning behaviour. A single five-minute situation of social stress was sufficient, therefore, to impair the animal’s learning performance hours later.

The researchers at the Max Planck Institute then tried to establish which mechanisms were responsible for these cognitive deficits. They identified the protein Homer-1, the concentration of which declines specifically in the hippocampus after exposure to stress. Through its interaction with the neuronal messenger substance glutamate and its receptors, Homer-1 modulates the communication in the neuronal synapses. When the volume of Homer-1 in the hippocampus falls after exposure to stress, the natural receptor activity is severely disrupted and learning capacity declines. The researchers were able to prevent this effect by increasing the Homer-1 concentration again.

Mathias Schmidt, Research Group Leader at the Max Planck Institute of Psychiatry interprets the results as follows: “With our study, we demonstrated the regulation of glutamate-mediated communication in the hippocampus, which directly controls learning behaviour. This mechanism functions independently of stress hormones for the most part. The molecule Homer-1 assumes a key role in this process and will hopefully provide new possibilities in future for targeted pharmaceutical intervention for the avoidance of cognitive deficits.”

The great illusion of the self

As you wake up each morning, hazy and disoriented, you gradually become aware of the rustling of the sheets, sense their texture and squint at the light. One aspect of your self has reassembled: the first-person observer of reality, inhabiting a human body.

As wakefulness grows, so does your sense of having a past, a personality and motivations. Your self is complete, as both witness of the world and bearer of your consciousness and identity. You.

This intuitive sense of self is an effortless and fundamental human experience. But it is nothing more than an elaborate illusion. Under scrutiny, many common-sense beliefs about selfhood begin to unravel. Some thinkers even go as far as claiming that there is no such thing as the self.

In these articles, discover why “you” aren’t the person you thought you were.

Linking insulin to learning: Important insights in research with worms

Recent work by Harvard researchers demonstrates how the signaling pathway of insulin and insulinlike peptides plays a critical role in helping to regulate learning and memory.

The research, led by Yun Zhang, associate professor of organismic and evolutionary biology, is described in a Feb. 6 paper in Neuron.

“People think of insulin and diabetes, but many metabolic syndromes are associated with some types of cognitive defects and behavioral disorders, like depression or dementia,” Zhang said. “That suggests that insulin and insulinlike peptides may play an important role in neural function, but it’s been very difficult to nail down the underlying mechanism, because these peptides do not have to function through synapses that connect different neurons in the brain.”

To get at that mechanism, Zhang and colleagues turned to an organism whose genome and nervous system are well described and highly accessible by genetics: C. elegans.

Using genetic tools, researchers altered the transparent worms by removing their ability to create individual insulinlike compounds. These new “mutant” worms were then tested to see whether they would learn to avoid eating a particular type of bacteria that is known to infect the worms. Tests showed that although some worms did learn to steer clear of the bacteria, others didn’t — suggesting that removing a specific insulinlike compound halted the worms’ ability to learn.

Researchers were surprised to find, however, that it wasn’t just removing the molecules that could make the animals lose the ability to learn — some peptides were found to inhibit learning.

“We hadn’t predicted that we would find both positive and negative regulators from these peptides,” Zhang said. “Why does the animal need this bidirectional regulation of learning? One possibility is that learning depends on context. There are certain things you want to learn — for example, the worms in these experiments wanted to learn that they shouldn’t eat this type of infectious bacteria. That’s a positive regulation of the learning. But if they needed to eat, even if it is a bad food, to survive, they would need a way to suppress this type of learning.”

Even more surprising for Zhang and her colleagues was evidence that the various insulinlike molecules could regulate each other.

“Many animals, including humans, have multiple insulinlike molecules, and it appears that these molecules can act like a network,” she said. “Each of them may play a slightly different role in the nervous system, and they function together to coordinate the signaling related to learning and memory. By changing the way the molecules interact, the brain can fine-tune learning in a host of different ways.”

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.