Mechanism that repairs brain after stroke discovered

A stroke is caused by a blood clot blocking a blood vessel in the brain, which leads to an interruption of blood flow and therefore a shortage of oxygen. Many nerve cells die, resulting in motor, sensory and cognitive problems.

The researchers have shown that following an induced stroke in mice, support cells, so-called astrocytes, start to form nerve cells in the injured part of the brain. Using genetic methods to map the fate of the cells, the scientists could demonstrate that astrocytes in this area formed immature nerve cells, which then developed into mature nerve cells.

”This is the first time that astrocytes have been shown to have the capacity to start a process that leads to the generation of new nerve cells after a stroke”, says Zaal Kokaia, Professor of Experimental Medical Research at Lund University.

The scientists could also identify the signalling mechanism that regulates the conversion of the astrocytes to nerve cells. In a healthy brain, this signalling mechanism is active and inhibits the conversion, and, consequently, the astrocytes do not generate nerve cells. Following a stroke, the signalling mechanism is suppressed and astrocytes can start the process of generating new cells.

”Interestingly, even when we blocked the signalling mechanism in mice not subjected to a stroke, the astrocytes formed new nerve cells”, says Zaal Kokaia.

“This indicates that it is not only a stroke that can activate the latent process in astrocytes. Therefore, the mechanism is a potentially useful target for the production of new nerve cells, when replacing dead cells following other brain diseases or damage.”

The new nerve cells were found to form specialized contacts with other cells. It remains to be shown whether the nerve cells are functional and to what extent they contribute to the spontaneous recovery that is observed in a majority of experimental animals and patients after a stroke.

A decade ago, Kokaia’s and Lindvall’s research group was the first to show that stroke leads to the formation of new nerve cells from the adult brain’s own neural stem cells. The new findings further underscore that when the adult brain suffers a major blow such as a stroke, it makes a strong effort to repair itself using a variety of mechanisms.

The major advancement with the new study is that it demonstrates for the first time that self-repair in the adult brain involves astrocytes entering a process by which they change their identity to nerve cells.

”One of the major tasks now is to explore whether astrocytes are also converted to neurons in the human brain following damage or disease. Interestingly, it is known that in the healthy human brain, new nerve cells are formed in the striatum. The new data raise the possibility that some of these nerve cells derive from local astrocytes. If the new mechanism also operates in the human brain and can be potentiated, this could become of clinical importance not only for stroke patients, but also for replacing neurons which have died, thus restoring function in patients with other disorders such as Parkinson’s disease and Huntington’s disease”, says Olle Lindvall, Senior Professor of Neurology.

Memory relies on astrocytes, the brain’s lesser known cells

When you’re expecting something—like the meal you’ve ordered at a restaurant—or when something captures your interest, unique electrical rhythms sweep through your brain.

These waves are called gamma oscillations and they reflect a symphony of cells—both excitatory and inhibitory—playing together in an orchestrated way. Though their role has been debated, gamma waves have been associated with higher-level brain function, and disturbances in the patterns have been tied to schizophrenia, Alzheimer’s disease, autism, epilepsy and other disorders.

Now, new research from the Salk Institute shows that little known supportive cells in the brain known as astrocytes may in fact be major players that control these waves.

In a study published July 28 in the Proceedings of the National Academy of Sciences, Salk researchers report a new, unexpected strategy to turn down gamma oscillations, by disabling not neurons but astrocytes—cells type traditionally thought to provide more of a support role in the brain. In the process, the team showed that astrocytes, and the gamma oscillations they help shape, are critical for some forms of memory.

"This is what could be called a smoking gun," says co-author Terrence Sejnowski, head of the Computational Neurobiology Laboratory at the Salk Institute for Biological Sciences and a Howard Hughes Medical Institute investigator. "There are hundreds of papers linking gamma oscillations with attention and memory, but they are all correlational. This is the first time we have been able to do a causal experiment, where we selectively block gamma oscillations and show that it has a highly specific impact on how the brain interacts with the world."

A collaboration among the labs of Salk professors Sejnowski, Inder Verma and Stephen Heinemann found that activity in the form of calcium signaling in astrocytes immediately preceded gamma oscillations in the brains of mice. This suggested that astrocytes, which use many of the same chemical signals as neurons, could be influencing these oscillations.

To test their theory, the group used a virus carrying tetanus toxin to disable the release of chemicals released selectively from astrocytes, effectively eliminating the cells’ ability to communicate with neighboring cells. Neurons were unaffected by the toxin.

After adding a chemical to trigger gamma waves in the animals’ brains, the researchers found that brain tissue with disabled astrocytes produced shorter gamma waves than in tissue containing healthy cells. And after adding three genes that would allow the researchers to selectively turn on and off the tetanus toxin in astrocytes at will, they found that gamma waves were dampened in mice whose astrocytes were blocked from signaling. Turning off the toxin reversed this effect.

The mice with the modified astrocytes seemed perfectly healthy. But after several cognitive tests, the researchers found that they failed in one major area: novel object recognition. A healthy mouse spent more time with a new item placed in its environment than it did with familiar items, as expected.

In contrast, the group’s new mutant mouse treated all objects the same. “That turned out to be a spectacular result in the sense that novel object recognition memory was not just impaired, it was gone—as if we were deleting this one form of memory, leaving others intact,” Sejnowski says.

The results were surprising, in part because astrocytes operate on a seconds- or longer timescale whereas neurons signal far faster, on the millisecond scale. Because of that slower speed, no one suspected astrocytes were involved in the high-speed brain activity needed to make quick decisions.

"What I thought quite unique was the idea that astrocytes, traditionally considered only guardians and supporters of neurons and other cells, are also involved in the processing of information and in other cognitive behavior," says Verma, a professor in the Laboratory of Genetics and American Cancer Society Professor.

It’s not that astrocytes are quick—they’re still slower than neurons. But the new evidence suggests that astrocytes are actively supplying the right environment for gamma waves to occur, which in turn makes the brain more likely to learn and change the strength of its neuronal connections.

Sejnowski says that the behavioral result is just the tip of the iceberg. “The recognition system is hugely important,” he says, adding that it includes recognizing other people, places, facts and things that happened in the past. With this new discovery, scientists can begin to better understand the role of gamma waves in recognition memory, he adds.

How the brain stabilizes its connections in order to learn better

Throughout our lives, our brains adapt to what we learn and memorise. The brain is indeed made up of complex networks of neurons and synapses that are constantly re-configured. However, in order for learning to leave a trace, connections must be stabilized. A team at the University of Geneva (UNIGE) discovered a new cellular mechanism involved in the long-term stabilization of neuron connections, in which non-neuronal cells, called astrocytes, play a role unidentified until now. These results, published in Current Biology, will lead to a better understanding of neurodegenerative and neurodevelopmental diseases.

The central nervous system excitatory synapses – points of contact between neurons that allow them to transmit signals – are highly dynamic structures, which are continuously forming and dissolving. They are surrounded by non-neuronal cells, or glial cells, which include the distinctively star-shaped astrocytes. These cells form complex structures around synapses, and play a role in the transmission of cerebral information which was widely unknown before.

Plasticity and Stability

By increasing neuronal activity through whiskers stimulation of adult mice, the scientists were able to observe, in both the somatosensory cortex and the hippocampus, that this increased neuronal activity provokes an increase in astrocytes movements around synapses. The synapses, surrounded by astrocytes, re-organise their architecture, which protects them and increases their longevity. The team of researchers led by Dominique Muller, Professor in the Department of Fundamental Neuroscience of the Faculty of Medicine at UNIGE, developed new techniques that allowed them to specifically “control” the different synaptic structures, and to show that the phenomenon took place exclusively in the connections between neurons involved in learning. “In summary, the more the astrocytes surround the synapses, the longer the synapses last, thus allowing learning to leave a mark on memory,” explained Yann Bernardinelli, the lead author on this study.

This study identifies a new, two-way interaction between neurons and astrocytes, in which the learning process regulates the structural plasticity of astrocytes, who in turn determine the fate of the synapses. This mechanism indicates that astrocytes apparently play an important role in the processes of learning and memory, which present abnormally in various neurodegenerative and neurodevelopmental diseases, among which Alzheimer’s, autism, or Fragile X syndrome.

This discovery highlights the until now underestimated importance of cells which, despite being non-neuronal, participate in a crucial way in the cerebral mechanisms that allow us to learn and retain memories of what we have learned.

Blame it on the astrocytes

In the brains of all vertebrates, information is transmitted through synapses, a mechanism that allows an electric or chemical signal to be passed from one brain cell to another. Chemical synapses, which are the most abundant type of synapse, can be either excitatory or inhibitory. Synapse formation is crucial for learning, memory, perception and cognition, and the balance between excitatory and inhibitory synapses critical for brain function. For instance, every time we learn something, the new information is transformed into memory through synaptic plasticity, a process in which synapses are strengthened and become more responsive to different stimuli or environmental cues. Synapses may change their shape or function in a matter of seconds or over an entire lifetime. In humans, a number of disorders are associated with dysfunctional synapses, including autism, epilepsy, substance abuse and depression.

Astrocytes, named for their star-like shape, are ubiquitous brain cells known for regulating excitatory synapse formation through cells. Recent studies have shown that astrocytes also play a role in forming inhibitory synapses, but the key players and underlying mechanisms have remained unknown until now.

A new study just published in the journal Glia and available online on July 11th, details the newly discovered mechanism by which astrocytes are involved in inhibitory synapse formation and presents strong evidence that Transforming Growth Factor Beta 1 (TGF β1), a protein produced by many cell types (including astrocytes) is a key player in this process. The team led by Flávia Gomes of the Rio de Janeiro Institute of Biomedical Sciences at the Federal University of Rio de Janeiro investigated the process in both mouse and human tissues, first in test tubes, then in living brain cells.

Previous evidence has shown that TGF β1, a molecule associated with essential functions in nervous system development and repair, modulates other components responsible for normal brain function. In this study, the authors were able to show that TGF β1 triggers N-methyl-D-aspartate receptor (NMDA), a molecule controlling memory formation and maintenance through synaptic plasticity. In the study, the group also shows that TGF β1-induction of inhibitory synapses depends on activation of another molecule - Ca2+/calmodulin-dependent protein kinase II (CaMK2)-, which works as a mediator for learning and memory. “Our study is the first to associate this complex pathway of molecules, of which TGF β1 seems to be a key player, to astrocytes’ ability to modulate inhibitory synapses”, says Flávia Gomes.

The idea that the balance between excitatory and inhibitory inputs depends on astrocyte signals gains strong support with this new study and suggests a pivotal role for astrocytes in the development of neurological disorders involving impaired inhibitory synapse transmission. Knowing the players and mechanisms underlying inhibitory synapses may improve our understanding of synaptic plasticity and cognitive processes and may help develop new drugs for treating these diseases.

(Image credit)

Discovery of New Drug Targets for Memory Impairment in Alzheimer’s Disease

We are now a step closer to having a drug that can cure dementia and memory loss. Research team in Korea has discovered that reactive astrocytes, which have been commonly observed in Alzheimer’s patients, aberrantly and abundantly produce the chief inhibitory neurotransmitter GABA and release it through the Best1 channel. The released GABA strongly inhibits neighboring neurons to cause impairment in synaptic transmission, plasticity and memory. This discovery will open a new chapter in the development of new drugs for treating such diseases.

Alzheimer’s disease, which is the most common cause of dementia, is fatal and currently, there is no cure. In Alzheimer’s disease, brain cells are damaged and destroyed, leading to devastating memory loss. It is reported that 1 in 8 Americans aged 65 or over have Alzheimer’s disease. In 2011, 7,600 elderly people with dementia lost their way back home and became homeless in Korea. However, to date, there has been no clear understanding of the mechanisms underlying dementia in Alzheimer’s disease. So far, neuronal death is the only proposed mechanism available in scientific literature.

The research team discovered that reactive astrocytes in the brains of Alzheimer’s disease model mice produce the inhibitory transmitter GABA by the enzyme Monoamine oxidase B(MAO-B) and release GABA through the Bestrophin-1 channel to suppress normal information flow during synaptic transmission. Based on this discovery, the team was able to reduce the production and release of GABA by inhibiting MAO-B or Bestrophin-1, and successfully ameliorate impairments in neuronal firing, synaptic transmission and memory in Alzheimer’s disease model mice.

In the behavioral test, the team used the fact that mice tend to prefer dark places. If a mouse experiences an electric shock in a dark place, it will remember this event and avoid dark places from then on. However, a mouse with modeled Alzheimer’s disease cannot remember if such shock is related to dark places and keeps going back to dark places. The team demonstrated that treating these mice with a MAO-B inhibitor fully recovered the mice’s memory. The selegiline is currently used in Parkinson’s disease as an adjunct therapy and considered as a one of best promising medicine for MAO-B inhibitor. But it has been previously shown to be less effective in Alzheimer’s disease.

The team proved that selegiline is effective for a short time, but when it is used in long term, it loses its efficacy in Alzheimer’s disease model mice. When treated for 1 week, selegiline brought the neuronal firing to a normal level. But when it was treated for 2 and 4 weeks, neuronal firing came back to the levels of untreated mice. From these results, the team proposed that there is a pressing need for a new drug that has long lasting effects.

Dr. C. Justin Lee said, “From this study, we reveal the novel mechanism of how Alzheimer’s patients might lose their memory. We also propose new therapeutic targets, which include GABA production and release mechanisms in reactive astrocytes for treatment of Alzheimer’s disease. Furthermore, we provide a stepping stone for the development of MAO-B inhibitors with long lasting efficacy.”

Neurons Get Their Neighbors To Take Out Their Trash

Biologists have long considered cells to function like self-cleaning ovens, chewing up and recycling their own worn out parts as needed. But a new study challenges that basic principle, showing that some nerve cells found in the eye pass off their old energy-producing factories to neighboring support cells to be “eaten.” The find, which may bear on the roots of glaucoma, also has implications for Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS) and other diseases that involve a buildup of “garbage” in brain cells.

The study was led by Nicholas Marsh-Armstrong, Ph.D., a research scientist at the Kennedy Krieger Institute and an associate professor in the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience, together with Mark H. Ellisman, Ph.D., a neuroscience professor at the University of California, San Diego. In a previous study, the two had seen hints that retinal ganglion cells, which transmit visual information from the eye to the brain, might be handing off bits of themselves to astrocytes, cells that surround and support the eye’s signal-transmitting neurons. They appeared to pass them to astrocytes at the optic nerve head, the beginning of the long tendril that connects retinal ganglion cells from the eye to the brain. Specifically, they suspected that the neuronal bits being passed on were mitochondria, which are known as the powerhouses of the cell.

To find out whether this was really the case, Marsh-Armstrong’s research group genetically modified mice so that they produced indicators that glowed in the presence of chewed up mitochondria. Ellisman’s group then used cutting-edge electron microscopy to reconstruct 3-D images of what was happening at the optic nerve head. The researchers saw that astrocytes were, indeed, breaking down large numbers of mitochondria from neighboring retinal ganglion cells.

“This was a very surprising study for us, because the findings go against the common understanding that each cell takes care of its own trash,” says Marsh-Armstrong. It is particularly interesting that the newly discovered process occurs at the optic nerve head, he notes, as that is the site thought to be at fault in glaucoma. He plans to investigate whether the mitochondria disposal process is relevant to this disease, the second leading cause of blindness worldwide.

But the implications of the results go beyond the optic nerve head, Marsh-Armstrong says, as a buildup of “garbage” inside cells causes neurodegenerative diseases such as Parkinson’s, Alzheimer’s and ALS. “By showing that this type of alternative disposal happens, we’ve opened up the door for others to investigate whether similar processes might be happening with other cell types and cellular parts other than mitochondria,” he says.

(Image caption: Astrocyte activity is shown in green in this slice of tissue from the brain region that controls movement in mice. Internal, structural elements of the astrocytes are shown in magenta; cell bodies are in red. Credit: Amit Agarwal and Dwight Bergles, courtesy of Cell Press)

Fight-Or-Flight Chemical Prepares Cells to Shift the Brain From Subdued to Alert State

A new study from The Johns Hopkins University shows that the brain cells surrounding a mouse’s neurons do much more than fill space. According to the researchers, the cells, called astrocytes because of their star-shaped appearance, can monitor and respond to nearby neural activity, but only after being activated by the fight-or-flight chemical norepinephrine. Because astrocytes can alter the activity of neurons, the findings suggest that astrocytes may help control the brain’s ability to focus.

The study involved observing the cells in the brains of living, active mice over long periods of time. A combination of genetically engineered mice and advanced microscopy allowed the researchers to visualize the activity of astrocyte networks in different regions of the brain to learn how these abundant supporting cells are controlled.

The scientists monitored astrocytes in the area of the brain responsible for controlling movement and saw that the cells often increased their activity as the mice walked on treadmills — but not always, and sometimes astrocytes became active when the animals were not moving. This lack of consistency suggested to the researchers that the astrocytes were not responding to nearby neurons, as had been thought.

Similarly, astrocytes in the vision processing area of the brain did not necessarily become active when the mice were stimulated with light, but they were sometimes active, even in the dark. The team solved both mysteries when they tested the idea that the astrocytes needed a signal to “wake them up” before they could respond to nearby neurons. That is how they found that norepinephrine, the brain’s broadly distributed fight-or-flight signal, primes the astrocytes in both locations to “listen in” on nearby neuronal activity.

“Astrocytes are among the most abundant cells in the brain, but we know very little about how they are controlled and how they contribute to brain function,” says Dwight Bergles, Ph.D., professor of neuroscience, who led the study. “Since memory formation and other important functions of the brain require a state of attention, we’re interested in learning more about how astrocytes help create that state.”

For example, Bergles says, “We know that astrocytes can regulate local blood flow, provide energy to neurons and release signaling molecules that alter neuronal activity. They could be doing any or all of those things in response to being activated. It is also possible that they act as a sort of megaphone to broadcast local norepinephrine signals to every neuron in the brain.” Whatever the case may be, researchers now know that astrocytes are not idle loiterers. This ability to study astrocyte network activity in animals as they do different things will help to reveal how these cells contribute to brain function.

This research was published in the journal Neuron on June 18.

Rescue of Alzheimer’s Memory Deficit Achieved by Reducing ‘Excessive Inhibition’

A new drug target to fight Alzheimer’s disease has been discovered by a research team led by Gong Chen, a Professor of Biology and the Verne M. Willaman Chair in Life Sciences at Penn State University. The discovery also has potential for development as a novel diagnostic tool for Alzheimer’s disease, which is the most common form of dementia and one for which no cure has yet been found. A scientific paper describing the discovery will be published in Nature Communications on 13 June 2014. 

Chen’s research was motivated by the recent failure in clinical trials of once-promising Alzheimer’s drugs being developed by large pharmaceutical companies. “Billions of dollars were invested in years of research leading up to the clinical trials of those Alzheimer’s drugs, but they failed the test after they unexpectedly worsened the patients’ symptoms,” Chen said. The research behind those drugs had targeted the long-recognized feature of Alzheimer’s brains: the sticky buildup of the amyloid protein known as plaques, which can cause neurons in the brain to die. “The research of our lab and others now has focused on finding new drug targets and on developing new approaches for diagnosing and treating Alzheimer’s disease,” Chen explained.

"We recently discovered an abnormally high concentration of one inhibitory neurotransmitter in the brains of deceased Alzheimer’s patients," Chen said. He and his research team found the neurotransmitter, called GABA (gamma-aminobutyric acid), in deformed cells called "reactive astrocytes" in a structure in the core of the brain called the dentate gyrus. This structure is the gateway to hippocampus, an area of the brain that is critical for learning and memory.  

Chen’s team found that the GABA neurotransmitter was drastically increased in the deformed versions of the normally large, star-shaped “astrocyte” cells which, in a healthy individual, surround and support individual neurons in the brain. “Our research shows that the excessively high concentration of the GABA neurotransmitter in these reactive astrocytes is a novel biomarker that we hope can be targeted in further research as a tool for the diagnosis and treatment of Alzheimer’s disease,” Chen said. 

Chen’s team developed new analysis methods to evaluate neurotransmitter concentrations in the brains of normal and genetically modified mouse models for Alzheimer’s disease (AD mice). “Our studies of AD mice showed that the high concentration of the GABA neurotransmitter in the reactive astrocytes of the dentate gyrus correlates with the animals’ poor performance on tests of learning and memory,” Chen said. His lab also found that the high concentration of the GABA neurotransmitter in the reactive astrocytes is released through an astrocyte-specific GABA transporter, a novel drug target found in this study, to enhance GABA inhibition in the dentate gyrus. With too much inhibitory GABA neurotransmitter, the neurons in the dentate gyrus are not fired up like they normally would be when a healthy person is learning something new or remembering something already learned.

Importantly, Chen said, “After we inhibited the astrocytic GABA transporter to reduce GABA inhibition in the brains of the AD mice, we found that they showed better memory capability than the control AD mice. We are very excited and encouraged by this result because it might explain why previous clinical trials failed by targeting amyloid plaques alone. One possible explanation is that while amyloid plaques may be reduced by targeting amyloid proteins, the other downstream alterations triggered by amyloid deposits, such as the excessive GABA inhibition discovered in our study, cannot be corrected by targeting amyloid proteins alone. Our studies suggest that reducing the excessive GABA inhibition to the neurons in the brain’s dentate gyrus may lead to a novel therapy for Alzheimer’s disease. An ultimate successful therapy may be a cocktail of compounds acting on several drug targets simultaneously.”