‘Robot’ cells answer call to arms

By thinking of cells as programmable robots, researchers at Rice University hope to someday direct how they grow into the tiny blood vessels that feed the brain and help people regain functions lost to stroke and disease.

Rice bioengineer Amina Qutub and her colleagues simulate patterns of microvasculature cell growth and compare the results with real networks grown in their lab. Eventually, they want to develop the ability to control the way these networks develop.

The results of a long study are the focus of a new paper in the Journal of Theoretical Biology.

“We want to be able to design particular capillary structures,” said Qutub, an assistant professor of bioengineering based at Rice’s BioScience Research Collaborative. “In our computer model, the cells are miniature adaptive robots that respond to each other, respond to their environment and pattern into unique structures that parallel what we see in the lab.”

When brain cells are deprived of oxygen – a condition called hypoxia that can lead to strokes – they pump out growth factor proteins that signal endothelial cells. Those cells, which line the interior of blood vessels, are prompted to branch off as capillaries in a process called angiogenesis to bring oxygen to starved neurons.

How these new vessels form networks and the shapes they take are of great interest to bioengineers who want to improve blood flow to parts of the brain by regenerating the microvasculature.

“The problem, especially as we age, is that we become less able to grow these blood vessels,” Qutub said. “At the same time, we’re at higher risk for strokes and neurodegenerative diseases. If we can understand how to guide the vessel structures and help them self-repair, we are a step closer to aiding treatment.”

Green tea and red wine extracts interrupt Alzheimer’s disease pathway in cells

Natural chemicals found in green tea and red wine may disrupt a key step of the Alzheimer’s disease pathway, according to new research from the University of Leeds.

In early-stage laboratory experiments, the researchers identified the process which allows harmful clumps of protein to latch on to brain cells, causing them to die. They were able to interrupt this pathway using the purified extracts of EGCG from green tea and resveratrol from red wine.

The findings, published in the Journal of Biological Chemistry, offer potential new targets for developing drugs to treat Alzheimer’s disease, which affects some 800,000 people in the UK alone, and for which there is currently no cure.

"This is an important step in increasing our understanding of the cause and progression of Alzheimer’s disease," says lead researcher Professor Nigel Hooper of the University’s Faculty of Biological Sciences. "It’s a misconception that Alzheimer’s is a natural part of ageing; it’s a disease that we believe can ultimately be cured through finding new opportunities for drug targets like this."

Alzheimer’s disease is characterised by a distinct build-up of amyloid protein in the brain, which clumps together to form toxic, sticky balls of varying shapes. These amyloid balls latch on to the surface of nerve cells in the brain by attaching to proteins on the cell surface called prions, causing the nerve cells to malfunction and eventually die.

"We wanted to investigate whether the precise shape of the amyloid balls is essential for them to attach to the prion receptors, like the way a baseball fits snugly into its glove," says co-author Dr Jo Rushworth. "And if so, we wanted to see if we could prevent the amyloid balls binding to prion by altering their shape, as this would stop the cells from dying."

The team formed amyloid balls in a test tube and added them to human and animal brain cells. Professor Hooper said: “When we added the extracts from red wine and green tea, which recent research has shown to re-shape amyloid proteins, the amyloid balls no longer harmed the nerve cells. We saw that this was because their shape was distorted, so they could no longer bind to prion and disrupt cell function.

"We also showed, for the first time, that when amyloid balls stick to prion, it triggers the production of even more amyloid, in a deadly vicious cycle," he added.

Professor Hooper says that the team’s next steps are to understand exactly how the amyloid-prion interaction kills off neurons.

"I’m certain that this will increase our understanding of Alzheimer’s disease even further, with the potential to reveal yet more drug targets," he said.

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, which part-funded the study, said: “Understanding the causes of Alzheimer’s is vital if we are to find a way of stopping the disease in its tracks. While these early-stage results should not be a signal for people to stock up on green tea and red wine, they could provide an important new lead in the search for new and effective treatments. With half a million people affected by Alzheimer’s in the UK, we urgently need treatments that can halt the disease – that means it’s crucial to invest in research to take results like these from the lab bench to the clinic.”

With Identical Neurons, Two Worm Species Live Very Different Lives

Two species of worms have the same set of 20 neurons that control their foregut (a digestive organ located, naturally, near the front end of the worm). The way those neurons are wired, though, completely changes their behavior.

Caenorhabditis elegans eats bacteria, while its worm cousin Pristionchus pacificus, while able to subsist on bacteria, also eats other worms. While C. elegans uses a grinder to break up bacteria, P. pacificus develops teeth-like denticles to puncture its prey.

"These species are separated by 200 to 300 million years, but have the same cells," researcher Ralf Sommer told New Scientist. However, they found the synapses were wired vastly differently, leading to a substantial change in the way information flows through their neural system.

In P. pacificus, neural signals pass through more cells before reaching the muscles. That suggests that it’s perfuming more complex motor functions, according to the European Molecular Biology Lab’s Detlev Arendt.

The paper can be found in the January 17 issue of Cell.

Chemical reaction keeps stroke-damaged brain from repairing itself

Nitric oxide, a gaseous molecule produced in the brain, can damage neurons. When the brain produces too much nitric oxide, it contributes to the severity and progression of stroke and neurodegenerative diseases such as Alzheimer’s. Researchers at Sanford-Burnham Medical Research Institute recently discovered that nitric oxide not only damages neurons, it also shuts down the brain’s repair mechanisms. Their study was published by the Proceedings of the National Academy of Sciences the week of February 4.

“In this study, we’ve uncovered new clues as to how natural chemical reactions in the brain can contribute to brain damage—loss of memory and cognitive function—in a number of diseases,” said Stuart A. Lipton, M.D., Ph.D., director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center and a clinical neurologist.

Lipton led the study, along with Sanford-Burnham’s Tomohiro Nakamura, Ph.D., who added that these new molecular clues are important because “we might be able to develop a new strategy for treating stroke and other disorders if we can find a way to reverse nitric oxide’s effect on a particular enzyme in nerve cells.”

Nitric oxide inhibits the neuroprotective ERK1/2 signaling pathway

Learning and memory are in part controlled by NMDA-type glutamate receptors in the brain. These receptors are linked to pores in the nerve cell membrane that regulate the flow of calcium and sodium in and out of the nerve cells. When these NMDA receptors get over-activated, they trigger the production of nitric oxide. In turn, nitric oxide attaches to other proteins via a reaction called S-nitrosylation, which was first discovered by Lipton and colleagues. When those S-nitrosylated proteins are involved in cell survival and lifespan, nitric oxide can cause brain cells to die prematurely—a hallmark of neurodegenerative disease.

In their latest study, Lipton, Nakamura and colleagues used cultured neurons as well as a living mouse model of stroke to explore nitric oxide’s relationship with proteins that help repair neuronal damage. They found that nitric oxide reacts with the enzyme SHP-2 to inhibit a protective cascade of molecular events known as the ERK1/2 signaling pathway. Thus, nitric oxide not only damages neurons, it also blocks the brain’s ability to self-repair.

Researcher uncovers potential cause, biomarker for autism and proposes study to investigate theory

A New York-based physician-researcher from Touro College of Osteopathic Medicine, best known for his research into fertility and twinning, has uncovered a potential connection between autism and a specific growth protein that could eventually be used as a way to predict an infant’s propensity to later develop the disease. The protein, called insulin-like growth factor (IGF), is especially involved in the normal growth and development of babies’ brain cells. Based on findings of prior published studies, Touro researcher Gary Steinman, MD, PhD, proposes that depressed levels of this protein in the blood of newborns could potentially serve as a biomarker for the later development of autism. However, this connection, described below in greater detail, has never been directly studied. Steinman presents his exciting theory in the journal Medical Hypotheses.

IGF stimulates special cells in the brain to provide an essential insulating material, called myelin, around the developing nerves that is needed to efficiently transmit important messages about everything the brain controls — from physical functions such as movement to mental functions such as sensory perception, thinking and emotions. In the developing fetal and pediatric brain, myelin is also important for nerve fibers in one area of the brain to form proper pathways to other regions, allowing the body to hone functions over time. Insufficient IGF results in insufficient insulating material, as has been seen in brain biopsies of autistic individuals, and may impede proper pathway development. Steinman is proposing that this potential relationship between neonatal IGF levels and autism be directly studied.

"Autism is on the rise, especially in the last two decades — either because of environmental factors, expanded diagnostic criteria, or both. Yet almost nothing is currently known about the predisposing molecular and histological changes that differentiate a newborn destined to be neurologically normal from an autistic one," said Steinman.

Because no effective treatment or prevention for autism exists, research examining Steinman’s idea is critical, as it may hold the key to understanding the cause of this often devastating illness. In his article, Steinman proposes a study to investigate this hypothesis, and if this study supports his theory that identification of reduced IGF at birth is later followed by the appearance of autistic characteristics, then the subsequent development of a simple biomarker blood test is equally critical.

Research Institute Study Shows How Brain Cells Shape Temperature Preferences

While the wooly musk ox may like it cold, fruit flies definitely do not. They like it hot, or at least warm. In fact, their preferred optimum temperature is very similar to that of humans—76 degrees F.

Scientists have known that a type of brain cell circuit helps regulate a variety of innate and learned behavior in animals, including their temperature preferences. What has been a mystery is whether or not this behavior stems from a specific set of neurons (brain cells) or overlapping sets.

Now, a new study from The Scripps Research Institute (TSRI) shows that a complex set of overlapping neuronal circuits work in concert to drive temperature preferences in the fruit fly Drosophila by affecting a single target, a heavy bundle of neurons within the fly brain known as the mushroom body. These nerve bundles, which get their name from their bulbous shape, play critical roles in learning and memory.

The study, published in the January 30, 2013 edition of the Journal of Neuroscience, shows that dopaminergic circuits—brain cells that synthesize dopamine, a common neurotransmitter—within the mushroom body do not encode a single signal, but rather perform a more complex computation of environmental conditions.

“We found that dopamine neurons process multiple inputs to generate multiple outputs—the same set of nerves process sensory information and reward-avoidance learning,” said TSRI Assistant Professor Seth Tomchik. “This discovery helps lay the groundwork to better understand how information is processed in the brain. A similar set of neurons is involved in behavior preferences in humans—from basic rewards to more complex learning and memory.”

Using imaging techniques that allow scientists to visualize neuron activity in real time, the study illuminated the response of dopaminergic neurons to changes in temperature. The behavioral roles were then examined by silencing various subsets of these neurons. Flies were tested using a temperature gradient plate; the flies moved from one place to another to express their temperature preferences.

As it turns out, genetic silencing of dopaminergic neurons innervating the mushroom body substantially reduces cold avoidance behavior. “If you give the fly a choice, it will pick San Diego weather every time,” Tomchik said, “but if you shut down those nerves, they suddenly don’t mind being in Minnesota.”

The study also showed dopaminergic neurons respond to cooling with sudden a burst of activity at the onset of a drop in temperature, before settling down to a lower steady-state level. This initial burst of dopamine could function to increase neuronal plasticity—the ability to adapt—during periods of environmental change when the organism needs to acquire new associative memories or update previous associations with temperature changes.

(Image: ALAMY)

Chance finding reveals new control on blood vessels in developing brain

Zhen Huang freely admits he was not interested in blood vessels four years ago when he was studying brain development in a fetal mouse.

Instead, he wanted to see how changing a particular gene in brain cells called glia would affect the growth of neurons.

The result was hemorrhage, caused by deteriorating veins and arteries, and it begged for explanation.

"It was a surprising finding," says Huang, an assistant professor of neuroscience and neurology at the University of Wisconsin-Madison. "I was mainly interested in the neurological aspect, how the brain develops and wires itself to prepare for all the wonderful things it does."

But chance favors the prepared mind, as Louis Pasteur said, and Huang knew he needed to follow up on the suggestion that glia, normally considered “helpers” for the neurons, would affect the growth of blood vessels. For one thing, blood flow is a big deal in the brain, says Huang, whose collaborators included Shang Ma, in the graduate program in cellular and molecular biology at UW-Madison. “We know the brain is very energy-intensive. Per unit of volume, it consumes 10 times as much oxygen as the rest of the body.”

Although it makes intuitive sense that blood vessel development should be guided by neuronal development in some fashion, Huang spent years making sure he wasn’t being mislead by his experiment. Now, he’s satisfied himself, and his scientific reviewers, and the journal PLOS Biology has just published his study.

New Brain Circuit Sheds Light on Development of Voluntary Movements

All parents know the infant milestones: turning over, learning to crawl, standing, and taking that first unassisted step. Achieving each accomplishment presumably requires the formation of new connections among subsets of the billions of nerve cells in the infant’s brain. But how, when and where those connections form has been a mystery.

Now researchers at Duke Medicine have begun to find answers. In a study reported Jan. 23, 2013, in the scientific journal Neuron, the research team describes the entire network of brain cells that are connected to specific motor neurons controlling whisker muscles in newborn mice.

A better understanding of such motor control circuits could help inform how human brains develop, potentially leading to new ways of restoring movement in people who suffer paralysis from brain injuries, or to the development of better prosthetics for limb replacement.

“Whiskers to mice are like fingers to humans, in that both are moving touch sensors,” said lead investigator Fan Wang, PhD, associate professor of cell biology and member of the Duke Institute for Brain Sciences. “Understanding how the mouse’s brain controls whisker movements may tell us about neural control of finger movements in people.”

Mice are active at night, so they rely heavily on whiskers to detect and discriminate objects in the dark, brushing their whiskers against objects in a rhythmic back-and-forth sweeping pattern referred to as “whisking”. But this whisking behavior does not appear until about two weeks after birth, when young mice start to explore the world outside their nest.

To learn how motor control of whiskers takes place, Wang and postdoctoral fellow Jun Takatoh used a new technique that takes advantage of the rabies virus’ ability to spread through connected nerve cells. A disabled form of the virus used to vaccinate pets was created with the ability to express a fluorescent protein. The researchers were able to trace its path through a network of brain cells directly connected to the motor neurons controlling whisker movement.

“The precision of this mapping method allowed us to ask a key question, namely are parts of the whisker motor control circuitry not yet connected in newborn mice, and are such missing links added later to enable whisking?” Wang said.

By taking a series of pictures in the fluorescently labeled brains during the first two weeks after birth, the research team chronicled the developing circuits before and after mice start whisking.

“When we traced the circuit it was stunning in the sense that we didn’t realize there are so many pools of neurons located throughout the brainstem that are connected to whisker motor neurons,” said Wang. “It’s remarkable that a single motor neuron receives so many inputs, and somehow is able to integrate them.”

At the same time whisking movements emerge, motor neurons receive a new set of inputs from a region of the brainstem called the LPGi. A single LPGi neuron is connected to motor neurons on both sides of the face, putting them in perfect position to synchronize the movements of left and right whiskers.

To learn more about the new circuit formed between LPGi and motor neurons, Wang and Takatoh drew on the expertise of Duke colleague Richard Mooney, PhD, professor of neurobiology, and his student Anders Nelson. Together, the researchers were able to record the labeled neurons and found the LPGi neurons communicate with motor neurons using glutamate, the main neurotransmitter that stimulates the brain. They further discovered that LPGi neurons receive direct inputs from the motor cortex.

“This makes sense because exploratory whisking is a voluntary movement under control of the motor cortex,” Wang said. “Excitatory input is needed for initiating such movements, and LPGi may be critical for relaying signals from the motor cortex to whisker motor neurons.”

The researchers will next explore the connectivity by using genetic, viral and optical tools to see what happens when certain components of the circuits are activated or silenced during various motor tasks.

Astrocytes Identified as Target for New Depression Therapy

Neuroscience researchers from Tufts University have found that our star-shaped brain cells, called astrocytes, may be responsible for the rapid improvement in mood in depressed patients after acute sleep deprivation. This in vivo study, published in the current issue of Translational Psychiatry, identified how astrocytes regulate a neurotransmitter involved in sleep. The researchers report that the findings may help lead to the development of effective and fast-acting drugs to treat depression, particularly in psychiatric emergencies.

Drugs are widely used to treat depression, but often take weeks to work effectively. Sleep deprivation, however, has been shown to be effective immediately in approximately 60% of patients with major depressive disorders. Although widely-recognized as helpful, it is not always ideal because it can be uncomfortable for patients, and the effects are not long-lasting.

During the 1970s, research verified the effectiveness of acute sleep deprivation for treating depression, particularly deprivation of rapid eye movement sleep, but the underlying brain mechanisms were not known.

Most of what we understand of the brain has come from research on neurons, but another type of largely-ignored cell, called glia, are their partners. Although historically thought of as a support cell for neurons, the Phil Haydon group at Tufts University School of Medicine has shown in animal models that a type of glia, called astrocytes, affect behavior.  

Haydon’s team had established previously that astrocytes regulate responses to sleep deprivation by releasing neurotransmitters that regulate neurons. This regulation of neuronal activity affects the sleep-wake cycle. Specifically, astrocytes act on adenosine receptors on neurons. Adenosine is a chemical known to have sleep-inducing effects.

During our waking hours, adenosine accumulates and increases the urge to sleep, known as sleep pressure. Chemicals, such as caffeine, are adenosine receptor antagonists and promote wakefulness. In contrast, an adenosine receptor agonist creates sleepiness.

“In this study, we administered three doses of an adenosine receptor agonist to mice over the course of a night that caused the equivalent of sleep deprivation. The mice slept as normal, but the sleep did not reduce adenosine levels sufficiently, mimicking the effects of sleep deprivation. After only 12 hours, we observed that mice had decreased depressive-like symptoms and increased levels of adenosine in the brain, and these results were sustained for 48 hours,” said first author Dustin Hines, Ph.D., a post-doctoral fellow in the department of neuroscience at Tufts University School of Medicine (TUSM).

“By manipulating astrocytes we were able to mimic the effects of sleep deprivation on depressive-like symptoms, causing a rapid and sustained improvement in behavior,” continued Hines.

“Further understanding of astrocytic signaling and the role of adenosine is important for research and development of anti-depressant drugs. Potentially, new drugs that target this mechanism may provide rapid relief for psychiatric emergencies, as well as long-term alleviation of chronic depressive symptoms,” said Naomi Rosenberg, Ph.D., dean of the Sackler School of Graduate Biomedical Sciences and vice dean for research at Tufts University School of Medicine. “The team’s next step is to further understand the other receptors in this system and see if they, too, can be affected.”

(Image: Paul De Koninck)