Overlooked cells hold keys to brain organization and disease

Scientists studying brain diseases may need to look beyond nerve cells and start paying attention to the star-shaped cells known as “astrocytes,” because they play specialized roles in the development and maintenance of nerve circuits and may contribute to a wide range of disorders, according to a new study by UC San Francisco researchers.

In a study published online April 28, 2014 in Nature, the researchers report that malfunctioning astrocytes might contribute to neurodegenerative disorders such as Lou Gehrig’s disease (ALS), and perhaps even to developmental disorders such as autism and schizophrenia.

David Rowitch, MD, PhD, UCSF professor of pediatrics and neurosurgery and a Howard Hughes Medical Institute investigator, led the research.

The researchers discovered in mice that a particular form of astrocyte within the spinal cord secretes a protein needed for survival of the nerve circuitry that controls reflexive movements. This discovery is the first demonstration that different types of astrocytes exist to support development and survival of distinct nerve circuits at specific locations within the central nervous system.

Astrocytes vastly outnumber signal-conducting neurons, and make up the majority of cells in the brain. But where neuroscientists are accustomed to seeing only vanilla when it comes to astrocytes – viewing all of them as similar despite their different locations in brain and spinal cord — they now will have to imagine “31 flavors” or more.

There might even be hundreds of distinctive varieties of astrocytes performing specific functions in different locations, according to Rowitch, chief of neonatology for UCSF Benioff Children’s Hospital San Francisco.

"Our study shows roles for specialized astrocytes that function to support particular kinds of neurons in their neighborhood," Rowitch said.

Led by Rowitch lab postdoctoral fellow Anna Molofsky, MD, PhD, the researchers studied the spinal cord sensory motor circuit, which allows both mice and humans to react without thought – to jerk a limb away from something hot, for instance.

The team discovered that a protein called Sema3a is produced much more abundantly by astrocytes close to motor neurons than by astrocytes from other regions in the spinal cord. They concluded that motor neurons required this source of Sema3a from the local astrocytes, because when Sema3a production was blocked, the motor neurons failed to form normal connections, and half of them died.

Motor neurons also die in ALS, a fatal neurodegenerative disease, and in spinal muscular atrophy, a disease that can affect newborn infants. In other studies, scientists have found that abnormal astrocytes can have toxic effects on motor neurons.

Molofsky is a psychiatrist who studies how astrocytes organize nerve circuits, and how disruptions of these nerve circuits during development or disease may involve abnormal astrocyte function. Disrupted neural circuits are believed to be responsible for certain psychiatric disorders.

"The immediate implications of this study are for diseases of motor neurons, like ALS, but I think our findings might also apply more generally to diseases of neural-circuit formation in the brain such as autism, schizophrenia and epilepsy," Molofsky said. "To achieve a comprehensive understanding of how neural circuits form and are maintained, it seems important that we integrate knowledge of how astrocytes support that process."

Rowitch agrees. “To the extent that psychiatric or neurological disease is localized to a specific part of the brain, we should now be considering the potentially specialized type of astrocytes regulating nerve connections in that region and their contributions to disease,” he said.

(Image: Astrocytes surround neuronal sysnapses and form networks physically coupled by gap-junctions. Credit: Dr. Takahiro Takano)

(Image caption: Adult neurons are seen without (top) and following (below) treatment to inactivate Rb. Following treatment, the neurons show an increase in growth (branching) of axons. Credit: Bhagat Singh)

Scientists discover a new way to enhance nerve growth following injury

New research published today by researchers at the University of Calgary’s Hotchkiss Brain Institute uncovers a mechanism to promote growth in damaged nerve cells.

Dr. Doug Zochodne, a professor in the Department of Clinical Neurosciences, and his team have discovered a key molecule that directly regulates nerve cell growth in the damaged nervous system. This surprising discovery was published in the prestigious journal Nature Communications, with lead authors Kim Christie and Anand Krishnan.

“We have discovered that a protein called Retinoblastoma (Rb) is present in adult neurons,” explains Zochodne. “This protein appears to normally act as a brake – preventing nerve growth. What we have shown is that by inactivating Rb, we can release the brake and coax nerves to grow much faster.”

Clues from cancer

Zochodne and his team decided to look for Rb in nerve cells because of its known role in regulating cell growth elsewhere in the body.

“We know that cancer is characterized by excessive cell growth and we also know that Rb is often functioning abnormally in cancer,” says Zochodne. “So if cancer is able to release this brake and increase cell growth, we thought we’d try to mimic this same action in nerve cells and encourage growth where we want it.”

The key to this methodology, as Zochodne explains, is shutting down the brake for a very short, controlled period of time in order to avoid adverse effects such as excessive cell growth that could lead to cancer.

“In our tests, we were able to do this for a short amount of time,” says Zochodne. “We didn’t see any negative results, which leaves us optimistic that this could one day be used as a safe treatment for patients suffering from nerve damage.”

Peripheral nerve injuries and illnesses  

So far, Zochodne is only investigating this technique in the peripheral nervous system. Peripheral nerves connect the brain and spinal cord to the body and without them, there is no movement or sensation. Peripheral nerve damage can be incredibly debilitating, with patients experiencing symptoms like pain, tingling, numbness or difficulty co-ordinating hands, feet, arms or legs.

As Zochodne explains, “peripheral nerve damage is surprisingly common. We see patients with cut or crushed nerves from motor vehicle accidents and we also see patients that suffer from conditions called neuropathies – a range of disorders that damage peripheral nerves.”

For example, diabetic neuropathy is more common than multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) combined. More than half of all diabetics have some form of nerve pain and currently there is no treatment to stop damage or reverse it.

Facility a one-stop shop for translating discoveries from the lab into the clinic

Developing safe and effective therapies for conditions such as peripheral nerve disorders requires the ability to take investigations from cells in a petri dish to patients in a clinic. Zochodne and his team have been able to do that thanks in part to a preclinical facility that opened at the Hotchkiss Brain Institute (HBI) in 2010. The Regeneration Unit in Neurobiology (RUN) was created through a partnership between the HBI, the University of Calgary and the Canada-Alberta Western Economic Partnership Agreement.
 
“The RUN facility has been critical for this research,” says Zochodne. “It provides the resources and cutting-edge equipment that we need all in one facility. RUN has allowed us to take this idea from nerve cells, to animal models and eventually will help us investigate whether it could be a feasible treatment in humans. It’s an incredible asset.”

Brain activity drives dynamic changes in neural fiber insulation

The brain is a wonderfully flexible and adaptive learning tool. For decades, researchers have known that this flexibility, called plasticity, comes from selective strengthening of well-used synapses — the connections between nerve cells.

Now, researchers at the Stanford University School of Medicine have demonstrated that brain plasticity also comes from another mechanism: activity-dependent changes in the cells that insulate neural fibers and make them more efficient. These cells form a specialized type of insulation called myelin.

“Myelin plasticity is a fascinating concept that may help to explain how the brain adapts in response to experience or training,” said Michelle Monje, MD, PhD, assistant professor of neurology and neurological sciences.

The researchers’ findings are described in a paper published online April 10 in Science Express.

“The findings illustrate a form of neural plasticity based in myelin, and future work on the molecular mechanisms responsible may ultimately shed light on a broad range of neurological and psychiatric diseases,” said Monje, senior author of the paper. The lead authors of the study are Stanford postdoctoral scholar Erin Gibson, PhD, and graduate student David Purger.

Sending neural impulses quickly down a long nerve fiber requires insulation with myelin, which is formed by a cell called an oligodendrocyte that wraps itself around a neuron. Even small changes in the structure of this insulating sheath, such as changes in its thickness, can dramatically affect the speed of neural-impulse conduction. Demyelinating disorders, such as multiple sclerosis, attack these cells and degrade nerve transmission, especially over long distances.

Myelin-insulated nerve fibers make up the “white matter” of the brain, the vast tracts that connect one information-processing area of the brain to another. “If you think of the brain’s infrastructure as a city, the white matter is like the roads, highways and freeways that connect one place to another,” Monje said.

In the study, Monje and her colleagues showed that nerve activity prompts oligodendrocyte precursor cell proliferation and differentiation into myelin-forming oligodendrocytes. Neuronal activity also causes an increase in the thickness of the myelin sheaths within the active neural circuit, making signal transmission along the neural fiber more efficient. It’s much like a system for improving traffic flow along roadways that are heavily used, Monje said. And as with a transportation system, improving the routes that are most productive makes the whole system more efficient.

In recent years, researchers have seen clues that nerve cell activity could promote the growth of myelin insulation. There have been studies that showed a correlation between experience and myelin dynamics, and studies of isolated cells in a dish suggesting a relationship between neuronal activity and myelination. But there has been no way to show that neuronal activity directly causes myelin changes in an intact brain. “You can’t really implant an electrode in the brain to answer this question because the resulting injury changes the behavior of the cells,” Monje said.

The solution was a relatively new and radical technique called optogenetics. Scientists insert genes for a light-sensitive ion channel into a specific group of neurons. Those neurons can be made to fire when exposed to particular wavelengths of light. In the study, Monje and her colleagues used mice with light-sensitive ion channels in an area of their brains that controls movement. The scientists could then turn on and off certain movement behaviors in the mice by turning on and off the light. Because the light diffuses from a source placed at the surface of the brain down to the neurons being studied, there was no need to insert a probe directly next to the neurons, which would have created an injury.

By directly stimulating the neurons with light, the researchers were able to show it was the activation of the neurons that prompted the myelin-forming cells to respond.

Further research could reveal exactly how activity promotes oligodendrocyte-precursor-cell proliferation and maturation, as well as dynamic changes in myelin. Such a molecular understanding could help researchers develop therapeutic strategies that promote myelin repair in diseases in which myelin is degraded, such as multiple sclerosis, the leukodystrophies and spinal cord injury.

“Conversely, when growth of these cells is dysregulated, how does that contribute to disease?” Monje said. One particular area of interest for her is a childhood brain cancer called diffuse intrinsic pontine glioma. The cancer, which usually strikes children between 5 and 9 years old and is inevitably fatal, occurs when the brain myelination that normally takes place as kids become more physically coordinated goes awry, and the brain cells grow out of control.

Stumbling Fruit Flies Lead Scientists to Discover Gene Essential for Sensing Joint Position

Scientists at The Scripps Research Institute (TSRI) have discovered an important mechanism underlying sensory feedback that guides balance and limb movements.

The finding, which the TSRI team uncovered in fruit flies, centers on a gene and a type of nerve cell required for detection of leg-joint angles. “These cells resemble human nerve cells that innervate joints,” said team leader Professor Boaz Cook, who is an assistant professor at TSRI, “and they encode joint-angle information in the same way.”

If the findings can be fully replicated in humans, they could lead to a better understanding of, as well as treatments for, disorders arising from faulty proprioception, the detection of body position.

A report of the findings appears in the March 14, 2014 issue of the journal Science.

A Mystery of Sensation

The proprioceptive sense of how the limbs are positioned is what enables a person, even with eyes closed, to touch the tip of the nose with the tip of a finger—an ability easily impaired by alcohol, which is why traffic police often test suspected drunk drivers this way.

Scientists have known that proprioceptive signals originate from so-called mechanosensory neurons, whose nerve ends are embedded in muscles, skin and other tissues. The stretching or compression of these tissues opens ion channels in the nerve membrane, which results in a signal to the brain.

What hasn’t been clear is how such a neuron can specialize in sensing just one type of membrane-distorting stimulus—such as the angle of a limb joint—yet exclude others, such as impact pressures.

In the new study, Cook and two members of his laboratory, first author Bela S. Desai, a postdoctoral fellow, and graduate student Abhishek Chadha, sought to shed some light on this mystery with a study of Drosophila fruit flies. Quickly maturing and easily studied, Drosophila often are analyzed for clues to the genetic underpinnings of basic animal behaviors.

Following the Trail

Cook and his colleagues began with a special collection of Drosophila containing a variety of uncatalogued mutations. The scientists sifted through the collection looking for mutant flies with walking impairments and soon zeroed in on several impaired walkers that turned out to have mutations in the same gene.

The scientists named the gene stumble (stum for short) for the abnormality caused by its absence.

Using a fluorescent tracer, they then localized the expression of stum in normal flies to neurons that lay close to the three main leg joints. Each neuron’s input-sensing tendril (dendrite) grew right up to the joints—a sign that its evolved function is to detect joint angle.

The researchers also found that the protein specified by the stum gene normally migrates to the tip of each dendrite. With high-resolution microscopy, they imaged each of these tips and observed an extra length branching more or less sideways at the joint.

At ordinary, at-rest joint angles, the relative positions of the main dendrite tip and its side branch stayed more or less the same; however, at extreme joint angles, the pair stretched out. As they did, the level of calcium ions in the neuron rose sharply, suggesting that ion channels had opened and the neuron was becoming active.

Cook noted the results show how a seemingly general mechanosensory, membrane-stretch-sensitive neuron can evolve a specificity for a particular type of proprioceptive signal. “It’s a nice example of how you can create that specificity from something that only stretches mechanically,” he said.

The team is now trying to nail down the specific role of stum proteins in Drosophila and to determine whether the human version of stum—which has never been characterized—also works in joint angle sensing. Some sensory role for the human version of stum is likely, as the stum gene has been remarkably well conserved throughout animal evolution. Cook and his colleagues were even able to restore some normal walking ability to stum-mutant flies by adding the mouse version of the stum gene. “Stum is probably doing the same thing in all animals,” he said.

A sparse memory is a precise memory

Particular smells can be incredibly evocative and bring back very clear, vivid memories.

Maybe you find the smell of freshly baked apple pie is forever associated with warm memories of grandma’s kitchen. Perhaps cut grass means long school holidays and endless football kickabouts. Or maybe catching the scent of certain medicines sees you revisit a bout of childhood illness.

What’s remarkable about the power of these ‘associative memories’ – connecting sensory information and past experiences – is just how precise they are. How do we and other animals attach distinct memories to the millions of possible smells we encounter?

There’s a clear advantage in doing so: accurately discriminating smells indicating dangers while making no mistakes in following those that are advantageous. But it’s a huge information processing challenge.

Researchers at Oxford University’s Centre for Neural Circuits and Behaviour have discovered that a key to forming distinct associative memories lies in how information from the senses is encoded in the brain.

Their study in fruit flies for the first time gives experimental confirmation of a theory put forward in the 1960s which suggested sensory information is encoded ‘sparsely’ in the brain.

The idea is that we have a huge population of nerve cells in many of our higher brain centres. But only a very few neurons fire in response to any particular sensation – be it smell, sound or vision. This would allow the brain to discriminate accurately between even very similar smells and sensations.

'This “sparse” coding means that neurons that respond to one odour don't overlap much with neurons that respond to other odours, which makes it easier for the brain to tell odours apart even if they are very similar,' explains Dr Andrew Lin, the lead author of the study published in Nature Neuroscience.

While previous studies have indicated that sensory information is encoded sparsely in the brain, there’s been no evidence that this arrangement is beneficial to storing distinct memories and acting on them.

'Sparse coding has been observed in the brains of other organisms, and there are compelling theoretical arguments for its importance,' says Professor Gero Miesenböck, in whose laboratory the research was performed. 'But until now it hasn’t been possible experimentally to link sparse coding with behaviour.'

In their new work, the researchers demonstrated that if they interfered with the sparse coding in fruit flies – if they ‘de-sparsened’ odour representations in the neurons that store associative memories – the flies lost the ability to form distinct memories for similar smells.

The flies are normally able to discriminate between two very similar odours, learning to avoid one and head for the other. This is controlled by the neurons that store associative memories, called Kenyon cells. There’s a separate nerve cell that acts as a control system to dampen down the activity the Kenyon cells, preventing too many of them from firing for any particular odour.

Dr Lin and colleagues showed that if this single nerve cell is blocked, the odour coding in Kenyon cells becomes less sparse and less able to discriminate between smells. The flies end up attaching the same memory to similar, yet different, odours.

Sparse coding does turn out to be important for sensory memories and our ability to act on them. Although the research was carried out in fruit flies, the scientists say sparse coding is likely to play a similar role in human memory.

Although sparse coding in the brain would seem to require much greater numbers of nerve cells, that cost appears to be worth it in being able to form distinct associative memories and act on them – thankfully. A life of experiences and memories is so much more full as a result.