Mechanism behind the activation of dormant memory cells discovered

The electrical stimulation of the hippocampus in in-vivo experiments activates precisely the same receptor complexes as learning or memory recall. This has been discovered for the first time and the finding has now been published in the highly respected journal “Brain Structure Function”. “This may form the basis for the use of medications aimed at powering up dormant or less active memory cells,” says Gert Lubec, Head of Fundamental Research / Neuroproteomics at the University Department of Paediatrics and Adolescent Medicine at the MedUni Vienna. 

“This discovery has far-reaching consequences both for the molecular understanding of memory formation and the understanding of the clinical electrical stimulation, which is already possible, of areas of the brain for therapeutic purposes,” says the MedUni Vienna researcher.  Similar principles are currently already being used in the field of deep brain stimulation. With this technology, an implanted device delivers electronic impulses to the patient’s brain. This physical stimulation allows neuronal circuits to be influenced that control both behaviour and memory.

The latest findings very much form part of the highly controversial subject of “cognitive enhancement”. Scientists are currently discussing the possibility of improving mental capacity through the use of drugs - including in healthy subjects of all age groups, but especially in patients with age-related impairments of cognitive processes.

With regard to the study design, two electrodes were implanted into the brain in an animal model. One transferred electrical impulses to stimulate the hippocampus, while the other transferred the electrical signals away. “These electrical potentials are the electrical equivalent of memory and are known as LTP (Long Term Potentiation),” explains Lubec. The generation of LTP in an in-vivo experiment was accompanied by specific changes in the receptor complexes - the same receptor complexes that are also activated during learning and memory formation.

A circuit for change

To answer the seemingly simple question “Have I been here before?” we must use our memories of previous experiences to determine if our current location is familiar or novel. In a new study published in the Journal of Neuroscience researchers from the RIKEN Brain Science Institute have identified a region of the hippocampus, called CA2, which is sensitive to even small changes in a familiar context. The results provide the first clue to the contributions of CA2 to memory and may help shed light on why this area is often found to be abnormal in the schizophrenic brain.

Image caption: New details about how motor neurons die in ALS have been uncovered by a new cell-culture system that combines spinal cord or brain cells from ALS patients with human motor neurons. The culture system shows that patient astrocytes (shown here with a blue-stained nucleus) release a toxin that kills motor neurons via a recently discovered process described as a “controlled cellular explosion.” Image: Diane Re.

Toxin from Brain Cells Triggers Neuron Loss in Human ALS Model

In most cases of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, a toxin released by cells that normally nurture neurons in the brain and spinal cord can trigger loss of the nerve cells affected in the disease, Columbia researchers reported today in the online edition of the journal Neuron.

The toxin is produced by star-shaped cells called astrocytes and kills nearby motor neurons. In ALS, the death of motor neurons causes a loss of control over muscles required for movement, breathing, and swallowing. Paralysis and death usually occur within 3 years of the appearance of first symptoms.

The report follows the researchers’ previous study, which found similar results in mice with a rare, genetic form of the disease, as well as in a separate study from another group that used astrocytes derived from patient neural progenitor cells. The current study shows that the toxins are also present in astrocytes taken directly from ALS patients.

“I think this is probably the best evidence we can get that what we see in mouse models of the disease is also happening in human patients,” said the study’s senior author, Serge Przedborski, MD, PhD, the Page and William Black Professor of Neurology (in Pathology and Cell Biology), Vice Chair for Research in the department of Neurology, and co-director of Columbia’s Motor Neuron Center.

The findings also are significant because they apply to the most common form of ALS, which affects about 90 percent of patients. Scientists do not know why ALS develops in these patients; the other 10 percent of patients carry one of 27 genes known to cause the disease.

“Now that we know that the toxin is common to most patients, it gives us an impetus to track down this factor and learn how it kills the motor neurons,” Dr. Przedborski said. “Its identification has the potential to reveal new ways to slow down or stop the destruction of the motor neurons.”

In the study, Dr. Przedborski and study co-authors Diane Re, PhD, and Virginia Le Verche, PhD, associate research scientists, removed astrocytes from the brain and spinal cords of six ALS patients shortly after death and placed the cells in petri dishes next to healthy motor neurons. Because motor neurons cannot be removed from human subjects, they had been generated from human embryonic stem cells in the Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, also at CUMC.

Within two weeks, many of the motor neurons had shrunk and their cell membranes had disintegrated; about half of the motor neurons in the dish had died. Astrocytes removed from people who died from causes other than ALS had no effect on the motor neurons. Nor did other types of cells taken from ALS patients.

The researchers confirmed that the cause of the motor neurons’ death was a toxin released into the environment by immersing healthy motor neurons in the astrocytes’ culture media. The presence of the media, even without astrocytes, killed the motor neurons.

 How the Toxin Triggers Motor Neuron Death

The researchers have not yet identified the toxin released by the astrocytes. But they did discover the nature of the neuronal death process triggered by the toxin.The toxin triggers a biochemical cascade in the motor neurons that essentially causes them to undergo a controlled cellular explosion.

Drs. Przedborski, Re, and Le Verche found that they could prevent astrocyte-triggered motor neuron death by inhibiting one of the key components of this molecular cascade.

These findings may lead to a way to prevent motor neuron death in patients and potentially prolong life. But the therapeutic potential of such inhibition is far from clear. “For example, we don’t know if this would leave patients with living but dysfunctional neurons,” Dr. Przedborski said. The researchers are now testing the idea of inhibition in animal models of ALS.

New Human Cell Model of ALS Will Speed Identification of Potential Therapies

The development of new therapies for ALS has been disappointing, with more than 30 clinical trials ending with no new treatments since the 1995 FDA approval of riluzole.

The lack of progress may be partly because animal models used to study ALS do not completely recreate the human disease. The new all-human cell model of ALS created for the current study may improve scientists’ ability to identify useful drug targets, particularly for the most common form of the disease.

“Although there are many neurodegenerative disorders, only for a handful do we have access to a simplified model that is relevant to the disease and can therefore potentially be used for high-throughput drug screening. So this model is quite special,” Dr. Przedborski said. “Here we have a spontaneous disease phenotype triggered by the relevant tissue that causes human illness. That’s one important thing. The other important thing is that this model is derived entirely from human elements. This is probably the closest, most natural model of human ALS that we can get in a dish.”

Sociable receptors: in pairs, in groups or in a crowd

When cells migrate in the body, for instance, during development, or when neurons establish new connections, cells need to know where they are going. A ‘wrong turn’ will generally cause disease or developmental disorders. The cells take direction cues from other cells with which they interact, and which they then repel after a short period of contact. Among those direction cues are ephrin ligands, recognized by Eph receptors on the cell. Together with colleagues from the Max Planck Institute of Molecular Physiology in Dortmund, scientists at the Max Planck Institute of Neurobiology in Martinsried have discovered that Eph receptors must form groups of three or four in order to become active and transmit the signal. Furthermore, the ratio of such multimers to inactive dimers determines the strength of the cellular repulsion response. The new findings help scientists understand how cells communicate and offer a point of departure for studying diseases related to breakdowns in this guidance system.

When people get together, there is usually a lot of interaction. Our cells behave similarly. When cells grow close to each other during development, they need to communicate with the surrounding cells to establish whether they are in the right place in the organism and which cells they should connect with. This communication is especially critical in the brain, where adhesion and repulsion processes between neurons occur continuously. It is only when the right cells connect that something new can be learned, for example. Emerging tumours also must exchange information with the cells around them to be able to grow. “It is of fundamental importance to understand how cells communicate with one another”, says Rüdiger Klein, Director at the Max Planck Institute of Neurobiology. He has been studying the language of the cells for years together with colleagues in his department. Their research focuses on the so-called Eph receptors and their ephrin ligands.

Cell communication via ephrin/Eph receptors comes into play in most encounters between cells. As a result of this communication, one cell usually repels the other, which continues to grow in another direction. Many such instances of interaction guide the cell to the right place. The guidance system itself – the ephrins and Eph receptors – are found on the cell surface. When the ephrin and the Eph receptor of two opposing cells meet, they form an ephrin/Eph complex. This triggers cellular processes in one or both of the cells, which eventually cause the detachment of the ephrin/Eph complex and the repulsion of the two cells from one another.

“Many receptor systems have developed a security mechanism to prevent false alarms from triggering the cellular processes”, explains Rüdiger Klein. “A signal is only transmitted to the cell if two receptor/ligand pairs form a dimer.” However, in the case of ephrins and Eph receptors, things are different. Ephrin/Eph complexes form dimers, but often also larger groups on the cell membranes. Scientists were previously not sure how this affects repulsion and repulsive signalling strength.

The neurobiologists in Martinsried and their colleagues from the Max Planck Institute of Molecular Physiology in Dortmund have now been able to artificially trigger and study the formation of groups of Eph receptors in cell culture. The results show that the otherwise usual dimers are inactive when made up of Eph receptors. Only trimers and tetramers triggered the signals that caused cell repulsion. However, the scientists’ working hypothesis that a larger group would trigger a stronger signal turned out to be too simple. “It took us quite some time to figure out the system”, says Andreas Schaupp, first author of the study. “In fact, it is not the size of each individual group that matters, but the composition of the entire population of groups.”

The more trimers and tetramers and the fewer dimers present in the cell membrane, the stronger the repulsion signal. In contrast, a higher abundance of dimers and a smaller number of multimers produce a weaker reaction or none at all. “Thanks to this mechanism, a cell can grade its response from forcing another cell to make a U-turn to simply guiding it past at close range”, Rüdiger Klein says. This is an important step in understanding how migrating and growing cells navigate, and why this guidance system breaks down in some diseases.

Image caption: When adult mice were kept in the dark for about a week, neural networks in the auditory cortex, where sound is processed, strengthened their connections from the thalamus, the midbrain’s switchboard for sensory information. As a result, the mice developed sharper hearing. This enhanced image shows fibers (green) that link the thalamus to neurons (red) in the auditory cortex. Cell nuclei are blue. Image by Emily Petrus and Amal Isaiah

A Short Stay in Darkness May Heal Hearing Woes

Call it the Ray Charles Effect: a young child who is blind develops a keen ability to hear things others cannot. Researchers have known this can happen in the brains of the very young, which are malleable enough to re-wire some circuits that process sensory information. Now researchers at the University of Maryland and Johns Hopkins University have overturned conventional wisdom, showing the brains of adult mice can also be re-wired, compensating for a temporary vision loss by improving their hearing.

The findings, published Feb. 5 in the peer-reviewed journal Neuron, may lead to treatments for people with hearing loss or tinnitus, said Patrick Kanold, an associate professor of biology at UMD who partnered with Hey-Kyoung Lee, an associate professor of neuroscience at JHU, to lead the study.

"There is some level of interconnectedness of the senses in the brain that we are revealing here," Kanold said.

"We can perhaps use this to benefit our efforts to recover a lost sense," said Lee. "By temporarily preventing vision, we may be able to engage the adult brain to change the circuit to better process sound."

Kanold explained that there is an early “critical period” for hearing, similar to the better-known critical period for vision. The auditory system in the brain of a very young child quickly learns its way around its sound environment, becoming most sensitive to the sounds it encounters most often. But once that critical period is past, the auditory system doesn’t respond to changes in the individual’s soundscape.

"This is why we can’t hear certain tones in Chinese if we didn’t learn Chinese as children," Kanold said. "This is also why children get screened for hearing deficits and visual deficits early. You cannot fix it after the critical period."

Kanold, an expert on how the brain processes sound, and Lee, an expert on the same processes in vision, thought the adult brain might be flexible if it were forced to work across the senses rather than within one sense. They used a simple, reversible technique to simulate blindness: they placed adult mice with normal vision and hearing in complete darkness for six to eight days.

After the adult mice were returned to a normal light-dark cycle, their vision was unchanged. But they heard much better than before.

The researchers played a series of one-note tones and tested the responses of individual neurons in the auditory cortex, a part of the brain devoted exclusively to hearing. Specifically, they tested neurons in a middle layer of the auditory cortex that receives signals from the thalamus, a part of the midbrain that acts as a switchboard for sensory information. The neurons in this layer of the auditory cortex, called the thalamocortical recipient layer, were generally not thought to be malleable in adults.

But the team found that for the mice that experienced simulated blindness these neurons did, in fact, change. In the mice placed in darkness, the tested neurons fired faster and more powerfully when the tones were played, were more sensitive to quiet sounds, and could discriminate sounds better. These mice also developed more synapses, or neural connections, between the thalamus and the auditory cortex.

The fact that the changes occurred in the cortex, an advanced sensory processing center structured about the same way in most mammals, suggests that flexibility across the senses is a fundamental trait of mammals’ brains, Kanold said.

"This makes me hopeful that we would see it in higher animals too," including humans, he said. "We don’t know how many days a human would have to be in the dark to get this effect, and whether they would be willing to do that. But there might be a way to use multi-sensory training to correct some sensory processing problems in humans."

The mice that experienced simulated blindness eventually reverted to normal hearing after a few weeks in a normal light-dark cycle. In the next phase of their five-year study, Kanold and Lee plan to look for ways to make the sensory improvements permanent, and to look beyond individual neurons to study broader changes in the way the brain processes sounds.

In the brain, the number of neurons in a network may not matter

Last spring, President Obama established the federal BRAIN Initiative to give scientists the tools they need to get a dynamic picture of the brain in action.

To do so, the initiative’s architects envision simultaneously recording the activity of complete neural networks that consist of thousands or even millions of neurons. However, a new study indicates that it may be possible to accurately characterize these networks by recording the activity of properly selected samples of 50 neurons or less – an alternative that is much easier to realize.

The study was performed by a team of cognitive neuroscientists at Vanderbilt University and reported in a paper published the week of Feb. 3 in the online Early Edition of the Proceedings of the National Academy of Sciences.

The paper describes the results of an ambitious computer simulation that the team designed to understand the behavior of the networks of hundreds of thousands of neurons that initiate different body movements: specifically, how the neurons are coordinated to trigger a movement at a particular point in time, called the response time.

The researchers were surprised to discover that the range of response times produced by the simulated population of neurons did not change with size: A network of 50 simulated neurons responded with the same speed as a network with 1,000 neurons.

For decades, response time has been a core measurement in psychology. “Psychologists have developed powerful models of human responses that explain the variation of response time based on the concept of single accumulators,” said Centennial Professor of Psychology Gordon Logan. In this model, the brain acts as an accumulator that integrates incoming information related to a given task and produces a movement when the amount of information reaches a preset threshold. The model explains random variations in response times by how quickly the brain accumulates the information it needs to act.

Meanwhile, neuroscientists have related response time to measurements of single neurons. “Twenty years ago we discovered that the activity of particular neurons resembles the accumulators of psychology models. We haven’t understood until now how large numbers of these neurons can act collectively to initiate movements,” said Ingram Professor of Neuroscience Jeffrey Schall.

No one really knows the size of the neural networks involved in initiating movements, but researchers estimated that about 100,000 neurons are involved in launching a simple eye movement.

“One of the main questions we addressed is how ensembles of 100,000 neuron accumulators can produce behavior that is also explained by a single accumulator,” Schall said.

“The way that the response time of these ensembles varies with ensemble size clearly depends on the ‘stopping rules’ that they follow,” explained co-author Thomas Palmeri, associate professor of psychology. For example, if an ensemble doesn’t respond until all of its member neurons have accumulated enough activity, then its response time would be slower for larger networks. On the other hand, if the response time is determined by the first neurons that react, then the response time in larger networks would be shorter than those of smaller networks.

Another important factor is the degree to which the ensemble is coordinated. “The more the ensemble is coordinated, the more the collective resembles a single accumulator. What has been unknown is how much coordination is necessary for the ensemble to act in unison, ” said Bram Zandbelt, a post-doctoral fellow and lead author on the paper.

To address this problem, the researchers developed a new type of computer simulation, one that models the collective behavior of different numbers of accumulators given different amounts of variation in the rates of accumulation. The simulation took a tremendous amount of computer power. Even using Vanderbilt’s in-house supercomputer at the Advanced Computing Center for Research & Education, Zandbelt was limited to modeling networks containing 1,000 neurons.

The researchers found that the networks did not produce realistic response times if responses were initiated when only a few or almost all of the simulated neurons finished accumulating, or if the simulated neurons had very different accumulation rates. However, the networks produced realistic response times over a broad range of stopping rules and similarity in accumulation rates, showing that within these broad constraints, size doesn’t matter. “We were surprised to discover that the networks behaved with a remarkable uniformity except under extreme assumptions,” said Schall.

“As far as the response time goes, the bottom line is that we found that the size of the neural network doesn’t matter under a large set of conditions. If this is true for networks ranging from 10 to 1,000 neurons, it should also hold for networks of 10,000 to 100,000 neurons,” Palmeri said.

Making your brain social

In many people with autism and other neurodevelopmental disorders, different parts of the brain don’t talk to each other very well. Scientists have now identified, for the first time, a way in which this decreased functional connectivity can come about. In a study published online today in Nature Neuroscience, scientists at the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, and collaborators at the Istituto Italiano di Tecnologia (IIT), in Rovereto, and La Sapienza University in Rome, demonstrate that it can be caused by cells called microglia failing to trim connections between neurons.

“We show that a deficit in microglia during development can have widespread and long-lasting effects on brain wiring and behaviour,” says Cornelius Gross, who led the study. “It leads to weak brain connectivity, decreased social behaviour, and increased repetitive behaviour, all hallmarks of autism.”

The findings indicate that, by trimming surplus connections in the developing brain, microglia allow the remaining links to grow stronger, like high-speed fibre-optic cables carrying strong signals between brain regions. But if these cells fail to do their job at that crucial stage of development, those brain regions are left with a weaker communication network, which in turn has lifelong effects on behaviour.

Yang Zhan, a postdoctoral fellow in Gross’ lab at EMBL, analysed the strength of connections between different areas of brain in mice that were genetically engineered to have fewer microglia during development. Working with Alessandro Gozzi’s lab at IIT and Davide Ragozzino at La Sapienza University, the EMBL scientists combined this approach with high-resolution fMRI (functional Magnetic Resonance Imaging) scans of the mice’s brains, taking full advantage of a novel technique developed at IIT, which enables scientists to obtain detailed, three-dimensional maps of the brain’s functional connections. The team found that mice with fewer microglia had weaker connections between neurons, and less cross-talk between different brain regions. When Rosa Paolicelli, a PhD student in Gross’ lab, studied the mice’s behaviour, she discovered that mice with fewer microglia and decreased connectivity displayed behaviours commonly associated with autism spectrum disorders. These mice spent more time repeatedly grooming themselves, and avoided social interactions.

“This is an exciting time to be studying microglia,” Gross concludes:  “they’re turning out to be major players in how our brain gets wired up.”