Do viruses make us smarter? 

Public Release: 12-Jan-2015

A new study from Lund University in Sweden indicates that inherited viruses that are millions of years old play an important role in building up the complex networks that characterise the human brain.

Researchers have long been aware that endogenous retroviruses constitute around five per cent of our DNA. For many years, they were considered junk DNA of no real use, a side-effect of our evolutionary journey.

In the current study, Johan Jakobsson and his colleagues show that retroviruses seem to play a central role in the basic functions of the brain, more specifically in the regulation of which genes are to be expressed, and when. The findings indicate that, over the course of evolution, the viruses took an increasingly firm hold on the steering wheel in our cellular machinery. The reason the viruses are activated specifically in the brain is probably due to the fact that tumours cannot form in nerve cells, unlike in other tissues. Continue reading “Do viruses make us smarter? “

BPA may affect the developing brain by disrupting gene regulation

Contact: Rachel Harrison 919-419-5069 Duke University Medical Center

             IMAGE:   Exposure to BPA may disrupt development of the central nervous system by slowing down the removal of chloride from neurons. As an organism matures and the brain develops, chloride levels…

Click here for more information.     

DURHAM, N.C. — Environmental exposure to bisphenol A (BPA), a widespread chemical found in plastics and resins, may suppress a gene vital to nerve cell function and to the development of the central nervous system, according to a study led by researchers at Duke Medicine.

The researchers published their findings – which were observed in cortical neurons of mice, rats and humans – in the journal Proceedings of the National Academy of Sciences on Feb. 25, 2013.

“Our study found that BPA may impair the development of the central nervous system, and raises the question as to whether exposure could predispose animals and humans to neurodevelopmental disorders,” said lead author Wolfgang Liedtke, M.D., PhD, associate professor of medicine/neurology and neurobiology at Duke.

BPA, a molecule that mimics estrogen and interferes with the body’s endocrine system, can be found in a wide variety of manufactured products, including thermal printer paper, some plastic water bottles and the lining of metal cans. The chemical can be ingested if it seeps into the contents of food and beverage containers.

Research in animals has raised concerns that exposure to BPA may cause health problems such as behavioral issues, endocrine and reproductive disorders, obesity, cancer and immune system disorders. Some studies suggest that infants and young children may be the most vulnerable to the effects of BPA, which led the U.S. Food and Drug Administration to ban the use of the chemical in baby bottles and cups in July 2012.

While BPA has been shown to affect the developing nervous system, little is understood as to how this occurs. The research team developed a series of experiments in rodent and human nerve cells to learn how BPA induces changes that disrupt gene regulation.

During early development of neurons, high levels of chloride are present in the cells. These levels drop as neurons mature, thanks to a chloride transporter protein called KCC2, which churns chloride ions out of the cells. If the level of chloride within neurons remains elevated, it can damage neural circuits and compromise a developing nerve cell’s ability to migrate to its proper position in the brain.

Exposing neurons to minute amounts of BPA alters the chloride levels inside the cells by somehow shutting down the Kcc2 gene, which makes the KCC2 protein, thereby delaying the removal of chloride from neurons.

MECP2, another protein important for normal brain function, was found to be a possible culprit behind this change. When exposed to BPA, MECP2 is more abundant and binds to the Kcc2 gene at a higher rate, which might help to shut it down. This could contribute to problems in the developing brain due to a delay in chloride being removed.

These findings raise the question of whether BPA could contribute to neurodevelopmental disorders such as Rett syndrome, a severe autism spectrum disorder that is only found in girls and is characterized by mutations in the gene that produces MECP2.

While both male and female neurons were affected by BPA in the studies, female neurons were more susceptible to the chemical’s toxicity. Further research will dig deeper into the sex-specific effects of BPA exposure and whether certain sex hormone receptors are involved in BPA’s effect on KCC2.

“Our findings improve our understanding of how environmental exposure to BPA can affect the regulation of the Kcc2 gene. However, we expect future studies to focus on what targets aside from Kcc2 are affected by BPA,” Liedtke said. “This is a chapter in an ongoing story.”



In addition to Liedtke, study authors include Michele Yeo and Ken Berglund of the Liedtke Lab in the Division of Neurology at Duke Medicine; Michael Hanna, Maria D. Torres and Jorge Busciglio of the University of California, Irvine; Junjie U. Guo and Yuan Gao of the Lieber Institute for Brain Development and Johns Hopkins University in Baltimore, Md.; and Jaya Kittur, Joel Abramowitz and Lutz Birnbaumer of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C.

The research received funding from Duke University, the Klingenstein Fund, the National Institutes of Health (R21NS066307, HD38466 and AG16573), and intramural funds from the National Institute of Environmental Health Sciences

Blueprint for an artificial brain

Published 26. February 2013, 15:18 h



Bielefeld physicist Andy Thomas takes nature as his model


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.



Lernfähiges Nano-Bauelement: 600 Mal dünner als das Haar eines Menschen ist der Bielefelder Memristor, hier eingebaut in einen Chip. Foto: Universität Bielefeld

Lernfähiges Nano-Bauelement: 600 Mal dünner als das Haar eines Menschen ist der Bielefelder Memristor, hier eingebaut in einen Chip. Foto: Universität Bielefeld

A nanocomponent that is capable of learning: The Bielefeld memristor built into a chip here is 600 times thinner than a human hair.

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.


Dr. Andy Thomas has summarized the technological principles that need to be met when constructing a processor based on the brain.

Thanks to these properties, synapses can be used to reconstruct the brain process responsible for learning, says Andy Thomas. He takes the classic psychological experiment with Pavlov’s dog as an example. The experiment shows how you can link the natural reaction to a stimulus that elicits a reflex response with what is initially a neutral stimulus – this is how learning takes place. If the dog sees food, it reacts by salivating. If the dog hears a bell ring every time it sees food, this neutral stimulus will become linked to the stimulus eliciting a reflex response. As a result, the dog will also salivate when it hears only the bell ringing and no food is in sight. The reason for this is that the nerve cells in the brain that transport the stimulus eliciting a reflex response have strong synaptic links with the nerve cells that trigger the reaction.


If the neutral bell-ringing stimulus is introduced at the same time as the food stimulus, the dog will learn. The control mechanism in the brain now assumes that the nerve cells transporting the neutral stimulus (bell ringing) are also responsible for the reaction – the link between the actually ‘neutral’ nerve cell and the ‘salivation’ nerve cell also becomes stronger. This link can be trained by repeatedly bringing together the stimulus eliciting a reflex response and the neutral stimulus. ‘You can also construct such a circuit with memristors – this is a first step towards a neuromorphic processor,’ says Andy Thomas.


‘This is all possible because a memristor can store information more precisely than the bits on which previous computer processors have been based,’ says Thomas. Both a memristor and a bit work with electrical impulses. However, a bit does not allow any fine adjustment – it can only work with ‘on’ and ‘off’. In contrast, a memristor can raise or lower its resistance continuously. ‘This is how memristors deliver a basis for the gradual learning and forgetting of an artificial brain,’ explains Thomas.


Original publication:

Andy Thomas, ‘Memristor-based neural networks’, Journal of Physics D: Applied Physics,, released online on 5 February 2013, published in print on 6 March 2013.


For further information in the Internet, go to:



Dr. Andy Thomas, Bielefeld University

Faculty of Physics

Telephone: 0049 521 106-2540



Gesendet von MBorchert in General Tags: hp

Brain-like chip outstrips normal computers

COMPUTER chips that mimic the human brain are outstripping conventional chips in crucial ways. They could also revolutionise our understanding of how the brain functions.Attempts to simulate the brain usually involve programming software to behave like groups of neurons. A new “neuromorphic” design instead tries to recreate the brain’s hardware, using analogue components last seen in the early days of computing. “On our system, you can physically point to the neuron,” says Karlheinz Meier of the University of Heidelberg in Germany.

The Spikey chip contains 400 “neurons”, or printed circuits. Real neurons have a voltage across their outer membrane, which Spikey mimics using capacitors: components that store charge. Just as in a real neuron, when the applied voltage reaches a certain level, the capacitor becomes conductive, firing a “nerve signal”.

Spikey also mimics synapses – the connections between neurons. In a normal chip, every process is digital and so can only take the value 0 or 1. Meier’s team instead used analogue components with variable levels of resistance to simulate the way connections between neurons become stronger or weaker depending on how much they are used. “Analogue circuits died after digital computers became more powerful,” says Meier, but they are now finding new roles.

The team connected the neurons in the Spikey chip in different ways to mimic various brain circuits. They have now modelled six neural networks, including one found in the insect olfactory system. By measuring patterns of activity, they found Spikey’s artificial networks behave much like the real thing (

“This is as good as you can get in simulating neural architecture,” says Massimiliano Versace of Boston University, Massachusetts.

Neuromorphic chips do already exist, though until now each chip could only mimic one particular brain circuit. Spikey, on the other hand, can recreate any pattern.

Neuromorphics have advantages over conventional chips that makes them useful in certain situations. For example, they do not separate memory and computation – information is stored in the synaptic strength – so they can run faster using less power. They also cope better with damage. Knocking out a few bits of a normal chip often breaks it altogether, but neuromorphics keep working, albeit slowly.

Companies like IBM and HP are looking into neuromorphics (see “Compute like a human“), and some medical devices already use them. Versace is working with NASA to develop a neuromorphic system to control a Mars rover, and says that the chips’ fault tolerance may make them better suited to surviving the intense radiation of space. The chips also allow theories of how the brain functions to be tested, in experiments that systematically change how each neuron and network behaves.

The team is now scaling up Spikey as part of a project called BrainScales. “Instead of 400 neurons we have 200,000,” says team member Thomas Pfeil. The researchers have printed all the circuits onto a single silicon wafer, 20 centimetres across, which allowed them to incorporate many more connections. Next year, they will use it to simulate part of the cortex of a rat brain. From there, they plan to connect six wafers in parallel, simulating over a million neurons, and eventually model a rat’s entire visual cortex.

“The idea is to develop a new computing architecture,” says Pfeil.

First evidence that chitosan could repair spinal damage

2010 study posted for filing

Contact: Kathryn Knight 44-078-763-44333 The Company of Biologists

Chitosan offers hope for spinal injury patients

This release is available in Chinese.

Richard Borgens and his colleagues from the Center for Paralysis Research at the Purdue School of Veterinary Medicine have a strong record of inventing therapies for treating nerve damage. From Ampyra, which improves walking in multiple sclerosis patients to a spinal cord simulator for spinal injury victims, Borgens has had a hand in developing therapies that directly impact patients and their quality of life. Another therapy that is currently undergoing testing is the use of polyethylene glycol (PEG) to seal and repair damaged spinal cord nerve cells. By repairing the damaged membranes of nerve cells, Borgens and his team can restore the spinal cord’s ability to transmit signals to the brain. However, there is one possible clinical drawback: PEG’s breakdown products are potentially toxic. Is there a biodegradable non-toxic compound that is equally effective at targeting and repairing damaged nerve membranes? Borgens teamed up with physiologist Riyi Shi and chemist Youngnam Cho, who pointed out that some sugars are capable of targeting damaged membranes. Could they find a sugar that restored spinal cord activity as effectively as PEG? Borgens and his team publish their discovery that chitosan can repair damaged nerve cell membranes in The Journal of Experimental Biology on 16 April 2010 at

Having initially tested mannose and found that it did not repair spinal cord nerve membranes, Cho decided to test a modified form of chitin, one of the most common sugars that is found in crustacean shells. Converting chitin into chitosan, Cho isolated a segment of guinea pig spinal cord, compressed a section, applied the modified chitin and then added a fluorescent dye that could only enter the cells through damaged membranes. If the chitosan repaired the crushed membranes then the spinal cord tissue would be unstained, but if the chitosan had failed, the spinal cord neurons would be flooded with the fluorescent dye. Viewing a section of the spinal cord under the microscope, Cho was amazed to see that the spinal cord was completely dark. None of the dye had entered the nerve cells. Chitosan had repaired the damaged cell membranes.

Next Cho tested whether a dose of chitosan could prevent large molecules from leaking from damaged spinal cord cells. Testing for the presence of the colossal enzyme lactate dehydrogenase (LDH), Borgens admits he was amazed to see that levels of LDH leakage from chitosan treated spinal cord were lower than from undamaged spinal cords. Not only had the sugar repaired membranes at the compression site but also at other sites where the cell membranes were broken due to handling. And when the duo tested for the presence of harmful reactive oxygen species (ROS), released when ATP generating mitochondria are damaged, they found that ROS levels also fell after applying chitosan to the damaged tissue: chitosan probably repairs mitochondrial membranes as well as the nerve cell membranes.

But could chitosan restore the spinal cord’s ability to transmit electrical signals to the brain through a damaged region? Measuring the brain’s response to nerve signals generated in a guinea pig’s hind leg, the duo saw that the signals were unable to reach the brain through a damaged spinal cord. However, 30·min after injecting chitosan into the rodents, the signals miraculously returned to the animals’ brains. Chitosan was able to repair the damaged spinal cord so that it could carry signals from the animal’s body to its brain.

Borgens is extremely excited by this discovery that chitosan is able to locate and repair damaged spinal cord tissue and is even more enthusiastic by the prospect that nanoparticles of chitosan could also target delivery of neuroprotective drugs directly to the site of injury ‘giving us a dual bang for our buck,’ says Borgens.



REFERENCE: Cho, Y., Shi, R. and Borgens, R. B. (2010). Chitosan produces potent neuroprotection and physiological recovery following traumatic spinal cord injury. J. Exp. Biol. 213, 1513-1520.

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Specific kind of vitamin E can prevent nerve cells from dying after a stroke, new research suggests

2010 study posted for filing

Contact: Chandan Sen
Ohio State University



COLUMBUS, Ohio – Blocking the function of an enzyme in the brain with a specific kind of vitamin E can prevent nerve cells from dying after a stroke, new research suggests.

In a study using mouse brain cells, scientists found that the tocotrienol form of vitamin E, an alternative to the popular drugstore supplement, stopped the enzyme from releasing fatty acids that eventually kill neurons.

The Ohio State University researchers have been studying how this form of vitamin E protects the brain in animal and cell models for a decade, and intend to pursue tests of its potential to both prevent and treat strokes in humans.

“Our research suggests that the different forms of natural vitamin E have distinct functions. The relatively poorly studied tocotrienol form of natural vitamin E targets specific pathways to protect against neural cell death and rescues the brain after stroke injury,” said Chandan Sen, professor and vice chair for research in Ohio State’s Department of Surgery and senior author of the study.

“Here, we identify a novel target for tocotrienol that explains how neural cells are protected.”

The research appears online and is scheduled for later print publication in the Journal of Neurochemistry.

Vitamin E occurs naturally in eight different forms. The best-known form of vitamin E belongs to a variety called tocopherols. The form of vitamin E in this study, tocotrienol or TCT, is not abundant in the American diet but is available as a nutritional supplement. It is a common component of a typical Southeast Asian diet.

Sen’s lab discovered tocotrienol vitamin E’s ability to protect the brain 10 years ago. But this current study offers the most specific details about how that protection works, said Sen, who is also a deputy director of Ohio State’s Heart and Lung Research Institute.

“We have studied an enzyme that is present all the time, but one that is activated after a stroke in a way that causes neurodegeneration. We found that it can be put in check by very low levels of tocotrienol,” he said. “So what we have here is a naturally derived nutrient, rather than a drug, that provides this beneficial impact.”

Sen and colleagues had linked TCT’s effects to various substances that are activated in the brain after a stroke before they concluded that this enzyme could serve as an important therapeutic target. The enzyme is called cystolic calcium-dependent phospholipase A2, or cPLA2.

Following the trauma of blocked blood flow associated with a stroke, an excessive amount of glutamate is released in the brain. Glutamate is a neurotransmitter that, in tiny amounts, has important roles in learning and memory. Too much of it triggers a sequence of reactions that lead to the death of brain cells, or neurons – the most damaging effects of a stroke.

Sen and colleagues used cells from the hippocampus region of developing mouse brains for the study. They introduced excess glutamate to the cells to mimic the brain’s environment after a stroke.

With that extra glutamate present, the cPLA2 enzyme releases a fatty acid called arachidonic acid into the brain. Under normal conditions, this fatty acid is housed within lipids that help maintain cell membrane stability.

But when it is free-roaming, arachidonic acid undergoes an enzymatic chemical reaction that makes it toxic – the final step before brain cells are poisoned in this environment and start to die. Activation of the cPLA2 enzyme is required to release the damaging fatty acid in response to insult caused by high levels of glutamate.

Sen and colleagues introduced the tocotrienol vitamin E to the cells that had already been exposed to excess glutamate. The presence of the vitamin decreased the release of fatty acids by 60 percent when compared to cells exposed to glutamate alone.

Brain cells exposed to excess glutamate followed by tocotrienol fared much better, too, compared to those exposed to only the damaging levels of glutamate. Cells treated with TCT were almost four times more likely to survive than were cells exposed to glutamate alone.

Though cPLA2 exists naturally in the body, blocking excessive function of this enzyme is not harmful, Sen explained. Scientists have already determined that mice genetically altered so they cannot activate the enzyme achieve their normal life expectancy and carry a lower risk for stroke.

Sen also noted that the amount of tocotrienol needed to achieve these effects is quite small – just 250 nanomolar, a concentration about 10 times lower than the average amount of tocotrienol circulating in humans who consume the vitamin regularly.

“So you don’t have to gobble up a lot of the nutrient to see these effects,” he said.

The National Institutes of Health supported this work.

Long-term effects of statin therapy could lead to transient or permanent cognitive impairment

2009 study posted for filing

Contact: Nick Zagorski
American Society for Biochemistry and Molecular Biology

Statins show dramatic drug and cell dependent effects in the brain

Besides their tremendous value in treating high cholesterol and lowering the risk of heart disease, statins have also been reported to potentially lower the risks of other diseases, such as dementia. However, a study in the October Journal of Lipid Research finds that similar statin drugs can have profoundly different effects on brain cells –both beneficial and detrimental. These findings reinforce the idea that great care should be taken when deciding on the dosage and type of statin given to individuals, particularly the elderly.

John Albers and colleagues compared the effects of two commercially used statins, simvastatin and pravastatin, on two different types of brain cells, neurons and astrocytes (support cells that help repair damage). By directly applying the drugs to cells as opposed to administering them to animals, they could eliminate differences in the drugs’ ability to cross the blood-brain barrier as a reason for any differing effects. Albers and colleagues looked at the expression of genes related to neurodegeneration, and found that indeed, despite using biologically equivalent drug concentrations, differences were seen both between cells, and between drugs; for example, simvastatin reduced the expression of the cholesterol transporter ABCA1 by approximately 80% in astrocytes, while pravastatin lowered expression by only around 50%. Another interesting difference was that while both statins decreased expression of the Tau protein –associated with Alzheimer’s disease—in astrocytes, they increased Tau expression in neurons; pravastatin also increased the expression of another Alzheimer’s hallmark, amyloid precursor protein (APP).

While increased levels of these two proteins may account for potential risks of disease, Albers and colleagues also note that large decreases in cholesterol proteins like ABCA1 should be considered. Brain cholesterol levels tend to be reduced in elderly people, and in such individuals the long-term effects of statin therapy could lead to transient or permanent cognitive impairment.


From the article: “Differential effects of simvastatin and pravastatin on expression of Alzheimer’s disease-related genes in human astrocytes and neuronal cells” by Weijiang Dong, Simona Vuletic and John J. Albers
Corresponding Author: John J Albers, Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington

Active ingredients in marijuana found to spread and prolong pain : Transforms transient normal pain into persistent chronic pain

2009 study posted for filing

Contact: Jim Kelly
University of Texas Medical Branch at Galveston

Research has implications for medical use of drug and concepts of chronic pain

GALVESTON, Texas — Imagine that you’re working on your back porch, hammering in a nail. Suddenly you slip and hit your thumb instead — hard. The pain is incredibly intense, but it only lasts a moment. After a few seconds (and a few unprintable words) you’re ready to start hammering again.

How can such severe pain vanish so quickly? And why is it that other kinds of equally terrible pain refuse to go away, and instead torment their victims for years?

University of Texas Medical Branch at Galveston researchers think they’ve found at least part of the answer—and believe it or not, it’s in a group of compounds that includes the active ingredients in marijuana, the cannabinoids. Interestingly enough, given recent interest in the medical use of marijuana for pain relief, experiments with rodents and humans described in a paper published in the current issue of Science suggest these “endocannabinoids,” which are made within the human body, can actually amplify and prolong pain rather than damping it down.

“In the spinal cord there’s a balance of systems that control what information, including information about pain, is transmitted to the brain,” said UTMB professor Volker Neugebauer, one of the authors of the Science article, along with UTMB senior research scientist Guangchen Ji and collaborators from Switzerland, Hungary, Japan, Germany, France and Venezuela. “Excitatory systems act like a car’s accelerator, and inhibitory ones act like the brakes. What we found is that in the spinal cord endocannabinoids can disable the brakes.”

To get to this conclusion, the researchers began by studying what happened when they applied a biochemical mimic of an endocannabinoid to inhibitory neurons (the brakes, in Neugebauer’s analogy) on slices of mouse spinal cord. Electrical signals that would ordinarily have elicited an inhibitory response were ignored. They then repeated the procedure using slices of spinal cord from mice genetically engineered to lack receptors where the endocannabinoid molecules could dock, and found that in that case, the “brakes” worked. Finally, using electron microscopy, they confirmed that the receptors were in fact on inhibitory, not excitatory neurons. Endocannabinoids docking with them would suppress the inhibitor neurons, and leave pain signals with a straight shot to the brain.

“The next step was to make the leap from spinal slices to test whether this really had anything to do with pain,” Neugebauer said. Using anesthetized rats, he recorded the spinal cord electrical activity produced by an injection in the hindpaw of capsaicin– a chemical found in hot peppers that produces a level of pain he compared to a severe toothache. Although the rats were unconscious, pain impulses could be detected racing up their spinal cords. What’s more, formerly benign stimuli now generated a significant pain response — a response that stopped when the rats were treated with an endocannabinoid receptor blocker.

“Why was this non-painful information now gaining access to the spinal “pain” neurons?” Neugebauer said. “The capsaicin produced an overstimulation that led to the peripheral nerves releasing endocannabinoids, which activated receptors that shut down the inhibitor neurons, leaving the gates wide open.”

Finally, the researchers recruited human volunteers to determine whether a compound that blocked endocannabinoid receptors would have an effect on the increased sensitivity to pain (hyperalgesia) and tendency for normally non-painful stimuli to induce pain (allodynia) often reported in areas of the body near where acute pain had been inflicted. In this case, the researchers induced pain by passing electricity through the volunteers’ left forearms, with the intensity of the current set by each volunteer to a 6 on a scale of 1 to 10. At a second session a month later, the volunteers who had received the receptor blocker showed no reduction in perceived acute pain, but had significantly less hyperalgesia and allodynia — a result that matched up well with the endocannabinoid hypothesis.

“To sum up, we’ve discovered a novel mechanism that can transform transient normal pain into persistent chronic pain,” Neugebauer said. “Persistent pain is notoriously difficult to treat, and this study offers insight into new mechanisms and possibly a new target in the spinal cord.”

It also raises questions about the efficacy of marijuana in relieving acute pain, given that endocannabinoids and the cannabinoids found in marijuana are so biochemically similar. “If you had a toothache, you probably wouldn’t want to treat it with marijuana, because you could actually make it worse,” Neugebauer said. “Now, for more pathological conditions like neuropathic pain, where the problem is a dysfunction within the nerves themselves and a subsequent disturbance throughout the nervous system that’s not confined to the pain system, marijuana may be beneficial. There are studies that seem to show that. But our model shows cannabinoids over-activating the pain system, and it just doesn’t seem like a good idea to further increase this effect.”

Are downloadable memories just around the corner? ( Using light repsonse as a Binary Code model )

By Daily Mail Reporter

PUBLISHED:18:49 EST, 26  October 2012| UPDATED:18:49 EST, 26 October 2012

A scientist at MIT could be on track to  uncovering how to restore lost memories in the brain.

Using light stimulation to control neurons  and map out brain activity, scientists could repair neuron functionality in  cases where a stroke, Alzheimer’s and other degenerative diseases have caused  reduced brain functionality.

Dr Ed Boyden, a researcher at the  Massachusetts university, is studying how to code brain pathways and eventually  could discover how to code memories and re-upload that information to restore  neuron functionality.

Scroll down  for video.

Image concept of a network of neurons in the human brain.

Brain science: There are approximately 100 billion  neurons in the human brain, which scientists are attempting to map and control  (stock image)

Ray of light:

Ray of light: A protein, channelrhodopsin (ChR) which is  actually extracted from algae, can be inserted into neurons to convert light  into electricity

The human brain has approximately 100 billion  neurons that pass along information.

Dr Boyden, who leads the Synthetic  Neurobiology Group at the MIT Media  Lab, is studying how to use light to  control neuron activity and to decode brain patterns.

He has identified a protein,  channelrhodopsin (ChR) which is actually extracted from algae, that can  convert light into electricity.

Ed Boyden

Dr Ed Boyden leads the Synthetic Neurobiology Group at  the MIT Media Lab

When this protein is inserted into neurons it  prompts neurons to respond to flashing lights and send an electrical signal.

With this inserted protein in place, Boyden  and his team could begin mapping out electrical signals sent in the brain triggered by light, using a specially  designed computer program.

The impact of light could become an ‘on-off’  switch for neuron activity.

Additionally, the light sensitive  protein  could allow the brain to be translated into a binary code that  allows for the  mapping of these complex pathways.

If brain pathways could be coded, it would  allow for that information to be converted and stored.

Memories could be coded and that code saved,  available to be re-introduced should neuron functionality diminish over time.

Testing in mice has proved successful in  treating brain disorders and as the experiments continue, it  could greatly  impact treatments for debilitating brain degeneration

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Stem Cells Not Needed for Cancer

Fully developed neurons can revert to stem cell-like states and give rise to brain tumors.

By Ruth Williams |October 18, 2012

The prevailing view that stem cells are the principle originators of brain cancer may be incorrect, according to a report out today (October 18) in Science.The new study suggests that terminally differentiated brain cells, including neurons, can be reprogrammed by oncogenic factors to become progenitor-like cells that then develop into brain tumors, or gliomas.

“What’s provocative about these experiments is that they challenge the notion that only stem cells can give rise to cancers of the brain,” said David Gutmann, a professor of neurology at Washington University in St Louis, Missouri, who did not participate in the study. “While we were all very excited 10 years ago when the cancer stem cell hypothesis came out, I think it was perhaps wishful thinking for us to believe that that was the only path to cancer.” The researchers were “able to demonstrate that you can get gliomas from these terminally differentiated neurons,” agreed Ronald DePinho, president of the MD Anderson Cancer Center at the University of Texas, Houston. “[The finding] is very exciting and basically teaches us that cells maintain an extraordinary level of plasticity.”

The potential for multiple cell types to give rise to brain cancer may also account for the variety of glioma subclasses observed, Gutmann added.

Inder Verma, a geneticist at the Salk Institute in La Jolla, California made the discovery as part of a larger effort to create mouse models of glioma. The team had injected lentiviral vectors that activated Ras signaling—a pathway that promotes cell growth and division—into the brains of mice that were deficient in the cell cycle protein p53 to induce gliomas.

The cellular origin of these gliomas was unknown, but the researchers assumed the most likely candidates were neural progenitor cells, because such cells are more easily reprogrammable and share many features with cancer cells. In the latest study, however, Verma’s team used an approach to specifically target mature neurons and astrocytes, and found both cell types were able to produce gliomas.

The neuron and astrocyte-derived gliomas expressed high levels of stem and progenitor cell marker proteins. And in vitro studies confirmed that the lentiviral vectors induced differentiated adult brain cells to adopt progenitor like features—similar to those found in neural and induced pluripotent stem cells. Transplanting these reprogrammed cells into receptive mice resulted in tumor growth, confirming the cells were cancerous.

“What we’re saying is, any cell in the brain that gets an oncogenic insult has the ability to dedifferentiate [and form tumors],” said Verma. This might seem a rather bleak outlook, but “by knowing the mechanism, we at least have a handle to start thinking about [treatments],” Verma said.

Of course, just because differentiated neurons can be induced to give rise to tumors experimentally doesn’t mean the process occurs in human patients, Gutmann pointed out. But Verma and colleagues found evidence to suggest that it might.  An analysis of the molecular profiles of the tumors derived from adult neurons revealed a striking similarity to that of a particularly aggressive subtype of human glioma.  “It is possible that these human tumors might also have originated from neurons,” said Verma.

The finding also suggested that different cells-of-origin give rise to different types of glioma. “It’s like German Americans and Italian Americans,” said Gutmann. “They’re both American citizens but still retain their heritage.” Importantly, he added, those subtle ancestral differences “may make a huge difference in terms of response to therapy and outcome.”

D. Friedmann-Morvinski et al., “Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice,” Science, doi: 10.1126/science.1226929, 2012


Reprogramming of Pericyte-Derived Cells of the Adult Human Brain into Induced Neuronal Cells

  • Reprogramming of somatic cells into neurons provides a new approach toward cell-based therapy of neurodegenerative diseases (Vierbuchen and Wernig, 2011). Previous studies have shown that postnatal astroglia from the mouse cerebral cortex can be directly converted into functional neuronal cells in vitro by forced expression of a single transcription factor (Heinrich et al., 2010, Heinrich et al., 2011; Heins et al., 2002) and that the synergistic action of three or four transcription factors can induce neurogenesis from rodent and human fibroblasts (Caiazzo et al., 2011; Pang et al., 2011; Qiang et al., 2011; Son et al., 2011; Vierbuchen et al., 2010; Yoo et al., 2011). However, a major challenge for the translation of neuronal reprogramming into therapy is whether direct conversion of somatic cells into neuronal cells can be achieved from cells residing within the adult human brain. To address this question, we prepared adherent cultures from 30 human specimens that were derived from surgical approaches through the cerebral cortex to deep-seated nontraumatic nonmalignant lesions, i.e., epileptic foci and nonruptured vascular lesions. In order to characterize the cellular composition of the cultures obtained from these specimens, we performed immunocytochemistry and fluorescence-activated cell sorting (FACS) analyses at different stages of culturing. Intriguingly, the majority of cells expressed platelet-derived growth factor receptor-β (PDGFRβ) (Daneman et al., 2010) (Figures 1C and 1D and Figure S1A available online), which is detected within the human brain tissue exclusively on microvessel-associated pericytes (Figure 1A), a cell type involved in the establishment and maintenance of the blood-brain barrier and regulation of local blood flow (Armulik et al., 2011). Consistent with a pericyte identity, we also observed expression of NG2 (Karram et al., 2005) (Figure 1B and S1B), smooth muscle actin (SMA) (Figures S1A and S1B) (Hellström et al., 1999), CD146 (Crisan et al., 2008), and CD13 (Crisan et al., 2008) (Figure 1E), though with some heterogeneity with regard to coexpression of these markers (Figures 1E, S1A, and SB). In contrast, the number of glial acidic fibrillary protein (GFAP)-positive cells was extremely low in these cultures (<1%), although astrocytes were readily detected within the human tissue (data not shown). Quantitative RT-PCR experiments confirmed the enriched expression of pericytic marker genes and the virtual absence of astroglial (gfap) and oligodendroglial cells (olig2) in these cultures compared to human brain tissue from which the cells had been isolated (Figure S1C). Importantly, βIII-tubulin could not be detected at any stage of culturing (assessed from 2 days to 8 weeks after plating), demonstrating that these cultures were devoid of neuroblasts or surviving neurons (data not shown). Furthermore, these cultures were completely devoid of expression of neural stem cell markers such as sox2 or prom1 or neurogenic fate determinants such as ascl1 or pax6 (Figure S1C). Moreover, Sox2, Mash1, Olig2, and Pax6 were also not detected on the protein level by immunocytochemistry (data not shown). The few CD34-positive cells (Figures 1D and S1C) of hematopoietic or endothelial origin were lost upon passaging. Thus, these cultures are enriched for cells exhibiting pericyte characteristics.
    • Figure 1 Characterization and In Vitro Conversion into Induced Neuronal Cells of Human and Mouse Adult Brain Pericyte-like Cells (A) PDGFRβ expression in microvessel-associated cells in the adult human cerebral cortex. Scale bar: 100 μm. (B) NG2 expression in microvessel-associated cells in the adult human cerebral cortex. Microvessels were visualized by CD31 (green) immunoreactivity and DAPI (blue). Scale bar: 100 μm. (C) Immunocytochemical analysis for pericyte marker PDGFRβ (red) in cell cultures obtained from human cerebral tissue; DAPI is in blue. Scale bar: 100 μm. See also Figures S1A and S1D. Scale bar: 100 μm. (D) Example of FACS analysis from an adult human brain culture. Depicted are the isotype controls (ctrl, left and middle panel) for establishing the gating conditions for sorting the PDGFRβ- and CD34-positive populations. See also Figure S1I. (E) Relative coexpression of pericyte markers as analyzed by FACS analysis. Each data point represents the relative coexpression of PDGFRβ and CD146 (mean 40.7% ± 28.1%) or CD13 (mean 46.4% ± 29.1%). (F) Quantification of the effect on βIII-tubulin expression and morphology following DsRed only for control, Sox2, Mash1, and combined Sox2 and Mash1 expression. Cells were categorized for exhibiting a flat polygonal morphology, round morphology without processes, or neuronal morphology with processes. Each value represents the mean of βIII-tubulin-positive cells from six different patients. For each patient and treatment, at least three experimental replicates were analyzed. For each condition >1,000 cells were analyzed. Error bars are SEM. (G) Live imaging of the conversion of a PDGFRβ-positive FACS-sorted cell (blue arrow, see also Figure S1I) into an induced neuronal cell following coexpression of Sox2 and Mash1. Pictures show phase contrast and fluorescence (Mash1-DsRed and Sox2-GFP) images at different time points (Days-Hours:Minutes) during the reprogramming process. Note the change of the cotransduced cell from a protoplasmic to a neuron-like morphology. See also Movie S1Download (20.51 MB)Movie S1. Direct Observation of Neuronal Reprogramming of PDGFRβ- Sorted Pericyte-Derived Cells from the Adult Human Brain by Continuous Live Imaging in Culture Note the change in morphology of a cell coexpressing Sox2 and Mash1 (blue arrow) during reprogramming. Postimaging immunocytochemistry for βIII-tubulin (white) confirms the neuronal identity of the reprogrammed cell at the end of live imaging (see also Figure 1F).. (G′) Depicted is the last recorded time point in phase contrast (LT) and the postimmunocytochemistry (Post IC) of the reprogrammed cell for GFP (green), DsRed (red), and βIII-tubulin (white). (H) Example of MAP2 and βIII-tubulin coexpression after 5 weeks following transduction. See also Figure S1G. (I) Specific β-galactosidase expression associated with CD31-positive blood vessels in the cerebral cortex of Tg:TN-AP-CreERT2:R26RNZG mice. β-galactosidase-positive cells express the pericyte marker PDGFRβ. Note the restricted expression around microvessels. β-galactosidase, green; PDGFRβ, red; CD31, blue. Scale bars: left panel, 50 μm; right panels, 10 μm. (J) Reprogramming of EYFP-positive cells isolated from the cerebral cortex of adult Tg:TN-AP-CreERT2:R26REYFP mice into induced neuronal cells. EYFP-positive cells (green) transduced with Mash1 (red) and Sox2 (without reporter) display a neuronal morphology and express βIII-tubulin; 14 days postinfection. Scale bar: 100 μm. For the efficiency of reprogramming of mouse pericytic cells, see Figures S1J–S1K.
  • Previous work has identified Mash1 (mammalian achaete-scute homolog 1, encoded by the gene ascl1) as a powerful reprogramming factor for direct conversion of somatic cells into neuronal cells (Berninger et al., 2007; Caiazzo et al., 2011; Vierbuchen et al., 2010). When we assessed the response of our cultures to retrovirus-mediated expression of Mash1 (CAG-ascl1-IRES-dsred), we observed the reduction of PDGFRβ expression to 23% (n[cells] = 219), indicating a loss of pericyte-specific protein expression (Figure S1D). Moreover, a subset of Mash1-transduced cells responded with the induction of βIII-tubulin, suggesting some degree of neuronal respecification (Figure 1F). Previous work has suggested that Sox2 expression may facilitate neuronal reprogramming of postnatal astrocytes by neurogenic fate determinants (Heinrich et al., 2010). As there was no endogenous Sox2 expression in these cultures (Figure S1C), we hypothesized that forced expression of sox2 may enhance the efficiency of neuronal reprogramming by Mash1. Expression of Sox2 (CAG-sox2-IRES-gfp) alone had no overt effect on βIII-tubulin expression (Figure 1F) or morphology of pericyte-like cells (Figure S1F). In contrast, coexpression of Sox2 and Mash1 significantly increased the proportion of βIII-tubulin-expressing cells to 48% ± 9% SEM (n[cells] = 1,500, analyzed after 4–5 weeks following transduction, cultures from six different patients; compared to 10% ± 4% SEM after Mash1 transduction alone, p = 0.0038, Figure 1F). Most strikingly, many of the double-transduced cells (28% ± 5% SEM) exhibited neuronal morphology (Figure S1F) and induced expression of MAP2 (46% ± 11% SEM, n[cells] = 296 from three different patients, analyzed after 5–6 weeks; Figures 1H and S1G) and NeuN (Figure S1H), indicating a high degree of reprogramming efficiency of cells from adult human tissue. Consistent with the acquisition of a neuronal phenotype and a loss of pericyte identity, Sox2- and Mash1-coexpressing cells downregulated PDGFRβ (Figure S1E). Of note, some cultures contained virtually only (97%) PDGFRβ-positive cells (Figure 1D), of which 46% of the Mash1 and Sox2 cotransduced cells differentiated into βIII-tubulin-positive cells, with 26% exhibiting neuronal morphology (n[cells] = 203). In the following we refer to these neuronal cells derived from human pericyte-like cells as human pericyte-derived induced neuronal cells (hPdiNs).
  • Despite the high frequency of PDGFRβ-positive cells infected by the retroviral vectors, the remainder of PDGFRβ-negative cells may still act as the main source of induced neuronal cells upon Mash1 and Sox2 transduction. Thus, we proceeded to follow the fate conversion of pericytes by live imaging (Rieger et al., 2009). Cultured cells were FACS-sorted for surface expression of PDGFRβ (Figure S1I), transduced 48 hr later with retroviral vectors encoding sox2 and ascl1, and subsequently imaged by time-lapse video microscopy (Movie S1Download (20.51 MB)Movie S1. Direct Observation of Neuronal Reprogramming of PDGFRβ- Sorted Pericyte-Derived Cells from the Adult Human Brain by Continuous Live Imaging in Culture Note the change in morphology of a cell coexpressing Sox2 and Mash1 (blue arrow) during reprogramming. Postimaging immunocytochemistry for βIII-tubulin (white) confirms the neuronal identity of the reprogrammed cell at the end of live imaging (see also Figure 1F).). Figure 1G shows an example of an anti-PDGFRβ FACS-sorted cell undergoing Sox2- and Mash1-induced neurogenesis. The cell acquired a polarized morphology within 12 days following transduction and could be shown to express βIII-tubulin at the end of the live imaging (Figure 1G′). Intriguingly, following the onset of reporter expression, this PDGFRβ-sorted cell did not undergo any cell division, providing evidence for direct conversion from an adult human nonneuronal somatic cell into an hPdiN. Likewise, only 1 of 36 (3%) Sox2- and Mash1-coexpressing cells that we followed over time underwent cell division, in sharp contrast to untransduced (n[cells] = 11/30; 36%], Mash1-only (n[cells] = 8/30; 26%), and Sox2-only transduced cells (n[cells] = 13/30; 46%), indicating that Sox2- and Mash1-induced reprogramming does not only not require cell division, but is accompanied by immediate cell cycle exit. Of all the tracked cells coexpressing Sox2 and Mash1, 36% endured cell death. This percentage was considerably higher than that of untransduced cells (3%) and Sox2-only transduced cells (7%). Of note, Mash1-only transduced cells also exhibited a higher rate of cell death (33%), suggesting that Mash1 or Sox2 and Mash1 coexpression can induce a catastrophic conflict of cell fates in pericyte-derived cells. Counting of βIII-tubulin-positive cells after imaging revealed that none of the Sox2-only cells (n[cells] > 300), 7% of Mash1-only (n[cells] = 88) cells, and 25% of double-positive cells (n[cells] = 786; two independent experiments) expressed βIII-tubulin. In an additional experiment, in which cells had been sorted simultaneously for PDGFRβ and CD146 and had been time-lapsed, a reprogramming efficiency of 37% was observed (n[cells] = 209). Combining all time-lapse experiments, the overall reprogramming efficiency was 19% of the coinfected cells, taking proliferation and cell death into account.
  • To unequivocally determine the origin of the reprogrammed cells from pericytes in vivo, we turned to genetic fate-mapping in mice. We took advantage of a transgenic mouse that expresses an inducible Cre recombinase (CreERT2) under control of the tissue-nonspecific alkaline phosphatase (TN-AP) promoter for genetic fate mapping of pericytes (Dellavalle et al., 2011). These mice were crossed to reporter lines (Tg:TN-AP-CreERT2:R26RNZG and Tg:TN-AP-CreERT2:R26REYFP) to aid identification of cells of pericytic origin either by β-galactosidase or yellow fluorescent protein (YFP) immunoreactivity following tamoxifen-induced Cre-mediated excision of the stop cassette. As expected β-galactosidase expression was confined to microvessel-associated cells coexpressing PDGFRβ (Figure 1I) and NG2 (data not shown) (Dellavalle et al., 2011) in the cerebral cortex of young adult mice following induction at postnatal stages, indicating that the TN-AP promoter allows reliable fate-mapping of pericyte-derived cells in the adult brain. Next we prepared cultures from the adult cerebral cortex of Tg:TN-AP-CreERT2:R26REYFP mice under the same culture conditions as used for human samples. As in the adult cerebral cortex, reporter-positive cells coexpressed the pericytic markers PDGFRβ, NG2, and CD146 and could be expanded in vitro (data not shown). In contrast to control vector-transduced reporter-positive pericyte-derived cells (data not shown), Sox2- and Mash1-expressing cells gave rise to βIII-tubulin-positive PdiNs (Figure 1J). Neuronal reprogramming of wild-type mouse pericyte-derived cells occurred at an even higher frequency compared to adult human pericyte-derived cells: coexpression of Sox2 and Mash1 significantly increased the proportion of βIII-tubulin-positive cells to 92% ± 3% SEM (compared to 41% ± 10% SEM after Mash1 transduction alone, p = 0.0028) (Figure S1K), and most of the double-transduced cells (73% ± 7% SEM) exhibited neuronal morphology (Figure S1J) and were capable of repetitive action potential firing (Figure S2F and Table S1).
  • We next analyzed whether the hPdiNs expressing neuron-specific proteins also acquire the functional membrane properties of neurons. In Mash1 (n[cells] = 7) and Sox2 (n[cells] = 6) singly transduced cells, step-current injection failed to elicit any action potentials (Figures S2A, S2A′, S2B, and S2B′), indicating that neither transcription factor alone induces neuronal electrical properties. In sharp contrast, a substantial proportion of cells (71% of 17 cells tested, cultures from five different patients) coexpressing both factors responded typically with the generation of a single action potential that could be blocked by the sodium channel antagonist tetrodotoxin (TTX) (Figures S2C and S2C′). Moreover, in voltage-clamp these cells exhibited clearly discernible sodium (Figure S2C″) and potassium (data not shown) currents. However, these hPdiNs exhibited immature properties, as reflected by the relatively high input resistances, low action potential, and peak sodium current amplitudes, even after prolonged time in culture, consistent with the slow maturation of human neurons (Table S1). In order to further promote maturation and to investigate whether hPdiNs can integrate into a neuronal network, we cocultured hPdiNs with neurons from the mouse embryonic neocortex. Under these conditions hPdiNs exhibited a more complex morphology (Figures 2A, 2B, and 2E) and were capable of repetitive action potential firing (Figure 2C), although input resistances were still high (Table S1). Importantly, hPdiNs were found to receive functional glutamatergic input from cocultured neurons (4 out of 12 cells analyzed, Figures 2D–2D″), demonstrating that they express functional transmitter receptors, are capable of assembling a postsynaptic compartment, and can be recognized by other neurons as functional targets. Consistent with functional glutamatergic input, dendrites of hPdiNs were decorated with presynaptic terminals containing vesicular glutamate transporters (Figure 2F). Of note, hPdiNs exhibited immunoreactivity for the inhibitory neurotransmitter β-aminobutyric acid (GABA, 14/14 hPdiNs analyzed) (Figure S2D). Moreover, qRT-PCR showed the expression of the interneuron calcium binding protein pvalb (Figure S2E), pointing toward acquisition of an interneuron-like phenotype. In contrast, none of the Sox2 and Mash1 cotransduced cells expressed the glutamatergic lineage marker tbr1 (T-box brain gene 1; data not shown) or slc17a7 (encoding the vesicular glutamate transporter [vGluT]-1; Figure S2E). However, a definitive proof for a GABAergic interneuron-like identity awaits the demonstration of functional GABAergic transmission.
    • Figure 2 Neuronal Morphology and Membrane Properties of hPdiNs (A) Bright-field micrograph depicts an hPdiN (red arrowhead) after 26 days of coculture with E14 mouse cerebral cortical neurons, 46 days following retroviral transduction. (B) DsRed fluorescence indicating transduction with ascl1 and dsred-encoding retroviruses. Inset: GFP fluorescence indicating transduction with sox2– and gfp-encoding retrovirus. (C) Step current injection in current-clamp results in repetitive action potential firing. For comparison with cells transduced with a single transcription factor or cotransduced, but cultured without mouse cortical neurons, see Figures S2A–S2C″. (D) The graph depicts spontaneous synaptic events recorded from the same hPdiN as shown in (C). The enlarged trace shows individual synaptic events. (D′) The synaptic events are blocked by the application of CNQX (10 μM). (D″) Recovery of spontaneous synaptic input following washout of CNQX. For a summary of the electrophysiological properties, see Table S1. (E) Micrograph depicting an hPdiN stained for DsRed and GFP, after 22 days of coculture with E14 neurons, 42 days following retroviral transduction. (F) High-magnification view of a single dendrite (magenta, GFP) from the same hPdiN as shown in (E), illustrating the high density and the distribution of vGluT1-immunoreactive puncta (green, Cy5).
  • Here we provide evidence for high-efficiency reprogramming of pericyte-derived cells of the adult human cerebral cortex into induced neuronal cells by coexpression of only two transcription factors. The fact that only coexpressing cells convert into neuronal cells provides direct evidence for a cell-autonomous effect. Different scenarios may account for the synergism of these two transcription factors. Sox2 may facilitate Mash1-induced reprogramming by rendering the somatic genome more susceptible to the neurogenic activity exerted by Mash1. Alternatively, Sox2 may be required to directly interact with Mash1 on common target genes. While we can currently not discern between these two modes of action, the fact that Neurog2 failed to reprogram cells in culture from the adult human cerebral cortex (data not shown) argues partially against the first mechanism as the solely important one. Recent studies on the role of Mash1 and Neurog2 during cortical development suggest that these factors activate distinct programs in neural progenitors (Castro et al., 2011). Mash1 also has been found as a key transcription factor in the direct reprogramming of fibroblasts (Pang et al., 2011; Vierbuchen et al., 2010) and hepatocytes (Marro et al., 2011) where it synergizes with Brn2 and Myt1l. This may suggest that Mash1 acts as a core factor in direct neuronal reprogramming. Interestingly, we observed a very slight induction of endogenous ascl1 mRNA expression (Figure S2E). It is noteworthy that, while fibroblasts coexpressing different combinations of transcription factors have been shown to give rise to induced neuronal cells of glutamatergic identity (Pang et al., 2011; Vierbuchen et al., 2010), dopaminergic (Caiazzo et al., 2011; Kim et al., 2011; Pfisterer et al., 2011) and cholinergic motor neuron identity (Son et al., 2011), the combination of Sox2 and Mash1 appears to favor a GABAergic phenotype in hPdiNs. It will be important to understand whether this is largely dependent on the factor combination used or the cellular context determined by the origin and nature of the reprogrammed cell.
  • Local CNS pericytes have been recently recognized as a major source of proliferating scar-forming cells following CNS injury (Göritz et al., 2011). A key finding of the present study is that progeny of brain pericytes represent a potential target for direct reprogramming. While much needs to be learned about adapting a direct neuronal reprogramming strategy to meaningful repair in vivo, e.g., by using a noninvasive approach to activate these transcription factors (Kormann et al., 2011), our data provide strong support for the notion that neuronal reprogramming of cells of pericytic origin within the damaged brain may become a viable approach to replace degenerated neurons

Slices of brain tissue can store patterns of activity for short periods of time: scientists

By Mo Costandi, The Guardian Sunday, September 16, 2012 5:44 EDT

Laboratory pipette with drop of red liquid over Petri dishes via Shutterstock

It sounds like the plot of a science fiction film, or like something from a transhumanist fantasy: researchers from Case Western Reserve University in Cleveland, Ohio, report that they can induce memory-like patterns of activity in slices of brain tissue, and that the slices can store these activity patterns for short periods of time.

The brain can encode information about the outside world and retrieve it later on, and the mechanisms underlying this ability are of great interest to neuroscientists. The general consensus among researchers is that memories are formed by the strengthening of connections within networks of nerve cells, and recalled by reactivation of the electrical signals generated by these networks. The new work, published in the journal Nature Neuroscience, contributes to our understanding of these processes.

Robert Hyde and Ben Strowbridge dissected horizontal slices of brain tissue from the hippocampus of rats, placed them into Petri dishes, and used electrodes to manipulate and measure the activity of individual neurons in the slices. The hippocampus is well known to be critical for long-term memory formation and, together with the prefrontal cortex, also plays an important role in working memory, which stores information for short periods of time so that it can be used to perform the task at hand.

In the 1940s, Donald Hebb proposed that working memories are maintained by reverberating patterns of neuronal activity, and subsequent research suggests that this is the case. For example, training monkeys to remember visual information and respond to it after a short delay increases the activity of neurons in the prefrontal cortex. This activity persists until the animal has executed its response and, crucially, is weaker in the seconds preceding an incorrect response than a correct one, indicating that it is associated with the working memory of the stimulus.

In the new study, Hyde and Strowbridge inserted electrodes into four individual neurons at one end the hippocampal slices, so that each cell could be stimulated independently. They then used the electrodes to stimulate each cell on its, or all of them, one after the other, in different sequences. These ‘inputs’ generated activity patterns that reverberated within the neuronal networks. At the same time, they measured the ‘output’ of the networks, using more electrodes to record the activity of three neurons at the other end of the slices.

The researchers found that each type of input produced a unique output. When stimulated alone, each input neuron produced an output that differed from that of the others. Similarly, when the neurons were stimulated one after the other, each sequence produced a distinct output. Each input consistently produced the same output, and the outputs accurately predicted not only individual inputs, but also the sequences of inputs.

They also found that the activity patterns generated by each input reverberated within the slices for periods of up to 15 seconds – the accuracy of their predictions remained high within this time window, but rapidly decreased thereafter.

This shows that networks of neurons in the hippocampus encode different types of information as distinct patterns of activity. These activity patterns persisted for seconds, and resembled those associated with working memory storage in the monkey experiments. The activity also encoded contextual information – during the experiments involving sequences of inputs, each input in a given sequence triggered a pattern that depended upon the input that came before it, and which differed from the pattern triggered by that input on its own.

This does not mean that the researchers have “invented a method to create new memories in brains.” The activity patterns generated by the inputs looked something like those observed in prefrontal cortex neurons while monkeys perform working memory tasks, but they are not memories as such. The information that they stored is essentially meaningless, and it’s not clear how similar the patterns are to those evoked by real stimuli, if at all.

What’s more, the study tells us very little about what happens between the input and output stages, or how the neuronal networks encode the information. In the future, automated methods of stimulating and recording from multiple neurons, such as those being developed by Ed Boyden and his colleagues, will probably be very useful in helping researchers to unravel these cellular mechanisms even further.


Hyde, R. A. & Strowbridge, B. W. (2012). Mnemonic representations of transient stimuli and temporal sequences in the rodent hippocampus in vitro. Nat. Neurosci. DOI: 10.1038/nn.3208

Statins have unexpected effect on pool of powerful brain cells : Reduces Glial progenitor cells

Re-post 34th HRR 2008

Contact: Tom Rickey
University of Rochester Medical Center

Cholesterol-lowering drugs known as statins have a profound effect on an elite group of cells important to brain health as we age, scientists at the University of Rochester Medical Center have found. The new findings shed light on a long-debated potential role for statins in the area of dementia.

Neuroscientists found that statins, one of the most widely prescribed classes of medication ever used, have an unexpected effect on brain cells. Researchers looked at the effects of statins on glial progenitor cells, which help the brain stay healthy by serving as a crucial reservoir of cells that the brain can customize depending on its needs. The team found that the compounds spur the cells, which are very similar to stem cells, to shed their flexibility and become one particular type of cell.

The new findings come at a time of increasing awareness among neurologists and cardiologists of the possible effects of statins on the brain. Several studies have set out to show that statins provide some protection against dementia, but the evidence has been inconclusive at best. Meanwhile, there is some debate among physicians about whether statins might actually boost the risk of dementia. The new research published in the July issue of the journal Glia by Steven Goldman, M.D., Ph.D., and first author Fraser Sim, Ph.D., provides direct evidence for an effect of statins on brain cells.

“There has been a great deal of discussion about a link between statins and dementia, but evidence either way has been scant,” said Goldman, a neurologist who led the team. “This new data provides a basis for further exploration.

“These findings were made through experiments done in cell culture using human brain cells and exposing them to doses of statins used widely in patients. But this research was not done in people. There are a great number of questions that need to be explored further before anyone considers changing the way statins are used,” Goldman added.

Goldman’s team is recognized as a leader identifying and directing the molecular signals that direct the development of stem cells and their daughter cells, known as progenitor cells. In this study, Sim ran a genomic screen to see which genes are more active in these cells compared to other brain cells. Sim and Goldman found several related to cholesterol, including the enzyme HMG-CoA reductase, which is central to making cholesterol and is the main target of statins.

“It was quite surprising that the cholesterol-signaling pathways are so active in these cells,” Goldman said. “Since such signaling is blocked with compounds used literally by millions of patients every day, we decided to take a closer look.”

The team measured the effects of two widely used statins, simvastatin and pravastatin, on glial progenitor cells, which can become either astrocytes or oligodendrocytes. The team looked at progenitor cells from 16 patients who had brain tissue removed during surgery to treat epilepsy, tumors, or vascular problems.

Scientists found that both compounds, when used at doses that mimic those that patients take, spur glial progenitor cells to develop into oligodendrocytes. For example, in one experiment, they found about five times as many oligodendrocytes in cultures of human progenitor cells exposed to pravastatin compared to cultures not exposed to the substance. Similarly, they found that the number of progenitor cells was just about one-sixth the level in cultures exposed to simvastatin compared to cultures not exposed to the compound.

To understand the process, think of a baseball team raising a group of great young prospects. They run fast, they throw hard, they hit well. Most teams will tailor their players to the positions the team needs – a few pitchers, for instance, and several batters. Any team that suddenly found itself with all pitchers or all hitters would be ill prepared to compete.

The Rochester team discovered that statins essentially push most of the raw talent in one direction.

Scientists don’t really know the long-term effects of such a shift. Physicians are looking at statins as a possible treatment for multiple sclerosis, where the myelin coating that covers nerve cells in the central nervous system is damaged. Myelin is produced by oligodendrocytes – so spurring the development of oligodendrocytes might provide one way to reduce or repair the damage seen in M.S.

But the body maintains a pool of uncommitted glial progenitor cells for a reason. The body normally turns to that reservoir of cells when it needs to repair damage from a variety of causes, such as an infection, hemorrhage, a serious blow to the head, or inflammation within the brain, such as in patients with multiple sclerosis. No one knows the consequences if such cells weren’t available when needed, though increased cognitive impairment might be one possibility.

“These are the cells ready to respond if you have a region of the brain that is damaged due to trauma, or lack of blood flow like a mini-stroke,” said Sim, assistant professor of Neurology. “Researchers need to look very carefully at what happens if these cells have been depleted prematurely.”

Glial progenitor cells are distributed throughout the brain and, according to Sim, make up about 3 percent of our brain cells. While true stem cells that can become any type of cell are very rare in the brain, their progeny, progenitor cells, are much more plentiful. They are slightly more specialized than stem cells but can still develop into different cell types.

The work may be relevant to drugs commonly used by diabetics as well. That’s because the team discovered that a signaling molecule called PPAR gamma is central to the effect of statins on glial progenitor cells. When PPAR gamma was blocked, the statins no longer had the effect. Since PPAR gamma is the main target of diabetes medications such as Avandia and Actos, which trigger the molecule, Goldman said it’s likely that those medications have the same effect on progenitor cells. He also noted that many patients are on both diabetes drugs and statins, which could increase the effect.

“Our results suggest the need for awareness of the possible toxicities accruing to long-term statin use, and identify one such potential toxicity, the premature differentiation and attendant long-term depletion of oligodendrocyte progenitor cells of the adult brain,” conclude the authors in their Glia paper.


Besides Sim and Goldman, other authors include medical student Jennifer Lang, technical associate Tracy Ali, Cornell scientist Neeta Roy, and neurosurgeons Edward Vates, M.D., and Webster Pilcher, M.D. The National Institute of Neurological Disorders and Stroke and the National Multiple Sclerosis Society funded the work

Neuroengineers silence brain cells with multiple colors of light

For Immediate Release:January 6, 2010 * Reposted for Filing

contact: Jen Hirsch, MIT News Office email: phone: 617-253-2700
New tools show potential for treating brain disorders

CAMBRIDGE, Mass. — Neuroscientists at MIT have developed a powerful new class of tools to reversibly shut down brain activity using different colors of light. When targeted to specific neurons, these tools could potentially lead to new treatments for the abnormal brain activity associated with disorders such as chronic pain, epilepsy, brain injury, and Parkinson’s disease.
The tools work on the principle that such disorders might be best treated by silencing, rather than stimulating, brain activity. These “super silencers” exert exquisite control over the timing of the shutdown of overactive neural circuits — an effect that’s impossible with existing drugs or other conventional therapies. “Silencing different sets of neurons with different colors of light allows us to understand how they work together to implement brain functions,” explains Ed Boyden, senior author of the study, to be published in the Jan. 7 issue of Nature. “Using these new tools, we can look at two neural pathways and study how they compute together. These tools will help us understand how to control neural circuits, leading to new understandings and treatments for brain disorders — some of the biggest unmet medical needs in the world.” Boyden is the Benesse Career Development Professor in the MIT Media Lab and an associate member of the McGovern Institute for Brain Research at MIT.
Boyden’s super silencers are developed from two genes found in different natural organisms such as bacteria and fungi. These genes, called Arch and Mac, encode for light-activated proteins that help the organisms make energy. When neurons are engineered to express Arch and Mac, researchers can inhibit their activity by shining light on them. Light activates the proteins, which lowers the voltage in the neurons and safely and effectively prevents them from firing. In this way, light can bathe the entire brain and selectively affect only those neurons sensitized to specific colors of light. Neurons engineered to express Arch are specifically silenced by yellow light, while those expressing Mac are silenced by blue light.
“In this way the brain can be programmed with different colors of light to identify and possibly correct the corrupted neural computations that lead to disease,” explains co-author Brian Chow, postdoctoral associate in Boyden’s lab.

In 2005, Boyden, in collaboration with investigators at Stanford University and the Max Planck Institute, introduced the first such “optogenetic” technique, so called because it combines the use of optics with gene delivery. The 2005 tool, now widely used, involves a light-activated ion channel, ChR2, which allows light to selectively turn on neurons in the brain.
Two years later, Boyden demonstrated that halorhodopsin, another light-sensitive protein, could inhibit the activity of neurons when illuminated. “But the genomic diversity of the world suggested that more powerful tools were out there waiting to be discovered,” Boyden says. His group accordingly screened a diverse set of microbial light-sensitive proteins, and found the new multicolor silencers. The newly discovered tools are much better than the old. Arch-expressing neurons were switched off with greater precision and recovered faster than halorhodopsin-expressing neurons, allowing researchers to manipulate different neurons with different colors of light.
“Multicolor silencing dramatically increases the complexity with which you can study neural circuits,” says co-author Xue Han, postdoctoral researcher in Boyden’s lab. “We will use these tools to parse out the neural mechanisms of cognition.”
How they did it: MIT researchers loaded the Arch and Mac genes into viruses that inserted their genetic cargo into mouse neurons. Optical fibers attached to lasers flashed light onto the neurons, and electrodes measured the resulting neural activity.
Next steps: Boyden’s team recently demonstrated the efficacy of ChR2 in monkeys with no apparent side effects. Determining whether Arch and Mac are safe and effective in monkeys will be a critical next step toward the potential use of these optical silencing tools in humans. Boyden plans to use these super silencers to examine the neural circuits of cognition and emotion and to find targets in the brain that, when shut down, could relieve pain and treat epilepsy. His group continues to mine the natural world for new and even more powerful tools to manipulate brain cell activity – tools that, he hopes, will empower scientists to explore neural circuits in ways never before possible.
Source: “High-Performance Genetically-Targetable Optical Neural Silencing by Light-Driven Proton Pumps,” Chow BY, Han X, Dobry AS, Qian X, Chuong AS, Li M, Henninger MA, Belfort GM, Lin Y, Monahan PE, Boyden ES. Nature Jan. 7 2010.
Funding: NIH, NSF, McGovern Institute Neurotechnology (MINT) Program at MIT, Department of Defense, NARSAD, Alfred P. Sloan Foundation, Jerry and Marge Burnett, Society for Neuroscience, MIT Media Lab, Benesse Foundation, Wallace H. Coulter Foundation, and the Helen Hay Whitney Foundation

* Reposted for Filing

Green tea may protect brain cells against Parkinson’s disease

Philadelphia, PA, December 13, 2007 – Does the consumption of green tea, widely touted to have beneficial effects on health, also protect brain cells” Authors of a new study being published in the December 15th issue of Biological Psychiatry share new data that indicates this may be the case. The authors investigated the effects of green tea polyphenols, a group of naturally occurring chemical substances found in plants that have antioxidant properties, in an animal model of Parkinson’s disease.

Parkinson’s disease is a progressive, degenerative disorder of the central nervous system, resulting from the loss of dopamine-producing brain cells, and there is presently no cure. According to Dr. Baolu Zhao, corresponding and senior author on this article, current treatments for Parkinson’s are associated with serious and important side effects. Their previous research has indicated that green tea possesses neuroprotective effects, leading Guo and colleagues to examine its effects specifically in Parkinson’s. The authors discovered that green tea polyphenols protect dopamine neurons that increases with the amount consumed. They also show that this protective effect is mediated by inhibition of the ROS-NO pathway, a pathway that may contribute to cell death in Parkinson’s.

Dr. Zhao’s hope is that eventually “green tea polyphenols may be developed into a safe and easily administrable drug for Parkinson’s disease.” Dr. Krystal agrees, that “if green tea consumption can be shown to have meaningful neuroprotective actions in patients, this would be an extremely important advance.”

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Long-term methadone treatment can affect nerve cells in brain

Long-term methadone treatment can cause changes in the brain, according to recent studies from the Norwegian Institute of Public Health. The results show that treatment may affect the nerve cells in the brain. The studies follow on from previous studies where methadone was seen to affect cognitive functioning, such as learning and memory.


Since it is difficult to perform controlled studies of methadone patients and unethical to attempt in healthy volunteers, rats were used in the studies. Previous research has shown that methadone can affect cognitive functioning in both humans and experimental animals.

Sharp decrease in key signaling molecule

Rats were given a daily dose of methadone for three weeks. Once treatment was completed, brain areas which are central for learning and memory were removed and examined for possible neurobiological changes or damage.
In one study, on the day after the last exposure to methadone, there was a significant reduction (around 70 per cent) in the level of a signal molecule which is important in learning and memory, in both the hippocampus and in the frontal area of the brain. This reduction supports findings from a previous study (Andersen et al., 2011) where impaired attention in rats was found at the same time. At this time, methadone is no longer present in the brain. This indicates that methadone can lead to cellular changes that affect cognitive functioning after the drug has left the body, which may be cause for concern.

No effect on cell generation

The second study, a joint project with Southwestern University in Texas, investigated whether methadone affects the formation of nerve cells in the hippocampus. Previous research has shown that new nerve cells are generated in the hippocampus in both adult humans and rats, and that this formation is probably important for learning and memory. Furthermore, it has been shown that other opiates such as morphine and heroin can inhibit this formation. It was therefore reasonable to assume that methadone, which is also an opiate, would have the same effect.
However, the researchers did not find any change in the generation of new nerve cells after long-term methadone treatment. If the same is true in humans, this is probably more positive for methadone patients than continuing with heroin. However, the researchers do not know what effect methadone has on nerve cells that have previously been exposed to heroin.

Large gaps in knowledge

Since the mid-1960s, methadone has been used to treat heroin addiction. This is considered to be a successful treatment but, despite extensive and prolonged use, little is known about possible side effects. There are large knowledge gaps in this field.
Our studies show that prolonged methadone treatment can affect the nerve cells, and thus behaviour, but the results are not always as expected. Many more pre-clinical and clinical studies are needed to understand methadone’s effect on the brain, how this can result in altered cognitive function, and, if so, how long these changes last. Knowledge of this is important – both for the individual methadone patient and the outcome of treatment.


  • Andersen JM, Klykken C, Mørland J. (2012) Long-term methadone treatment reduces phosphorylation of CaMKII in rat brain. J Pharm Pharmacol. 64(6):843-7.
  • Sankararaman A, Masiulis I, Richardson DR, Andersen JM, Mørland J, Eisch AJ. (2012) Methadone does not alter key parameters of adult hippocampal neurogenesis in the heroin-naïve rat. Neurosci Lett. 516(1):99-104.