Posts Tagged cell

[NEWS] Pill that reverses brain damage could be on the horizon

 

Researchers at the University of Pennsylvania have made important progress in designing a drug that could recover brain function in cases of severe brain damage due to injury or diseases such as Alzheimer’s.

brain cellsVitaly Sosnovskiy | Shutterstock

The work builds on a previous study where the team managed to convert human fetal glial cells called astrocytes into functional neurons. However, that required using a combination of nine molecules – too many for the formula to be translated into a clinically useful solution.

As reported in the journal Stem Cell Reports, the team has now successfully streamlined the process so that only four molecules are needed – an achievement that could lead to pill for repairing brain damage.

We identified the most efficient chemical formula among the hundreds of drug combinations that we tested. By using four molecules that modulate four critical signaling pathways in human astrocytes, we can efficiently turn human astrocytes — as many as 70 percent — into functional neurons.”

Jiu-Chao Yin, Study Author

The researchers report that the new neurons survived for more than seven months in the laboratory environment and that they functioned like normal brain cells, forming networks and communicating with one another using chemical and electrical signaling.

“The most significant advantage of the new approach is that a pill containing small molecules could be distributed widely in the world, even reaching rural areas without advanced hospital systems,” says Chen.

“My ultimate dream is to develop a simple drug delivery system, like a pill, that can help stroke and Alzheimer’s patients around the world to regenerate new neurons and restore their lost learning and memory capabilities,” he continued.

Now, the years of effort the team has put into simplifying the drug formula has finally paid off and taken the researchers a step closer towards realizing that dream.

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[WEB SITE] Neuroscientists unravel how two different types of brain plasticity work on synapses

 

The brain’s crucial function is to allow organisms to learn and adapt to their surroundings. It does this by literally changing the connections, or synapses, between neurons, strengthening meaningful patterns of neural activity in order to store information. The existence of this process – brain plasticity – has been known for some time.

But actually, there are two different types of brain plasticity at work on synapses. One is “Hebbian plasticity”; it is the one which effectively allows for the recording of information in the synapses, named after pioneering neuroscientist Donald Hebb. The other, more recently discovered, is “homeostatic synaptic plasticity” (HSP), and, like other “homeostatic” processes in the body such as maintaining a constant body temperature, its purpose is to keep things stable. In this case, HSP ensures that the brain doesn’t build up too much activity (as is the case in epilepsy) or become too quiet (as can happen when you lose synapses in Alzheimer’s Disease).

However, little is known about how these two types of plasticity actually interact in the brain. Now, a team of neuroscientists at the Champalimaud Centre for the Unknown, in Lisbon, Portugal, has begun to unravel the fundamental processes that happen in the synapse when the two mechanisms overlap. Their results were published in the journal iScience.

“In theory, the two types of plasticity act as opposing forces”, says Anna Hobbiss, first author of the new study, which was led by Inbal Israely. “Hebbian plasticity reacts to activity at the synapses by inciting them to get stronger while HSP reacts to it by making them weaker. We wanted to understand, on a cellular and molecular level, how the synapse deals with these two forces when they are present at the same time.”

In so doing, the authors have surprisingly shown that, contrary to what might be expected, HSP facilitates Hebbian plasticity, and thus influences memory formation and learning. This means that these two types of plasticity “may actually not be such distinct processes, but instead work together at the same synapses”, says Israely.

The team’s goal was to determine the changes in size of minute structures called dendritic spines, which are the “receiving end” of the synapse. The size of these spines changes to reflect the strength of the synaptic connection.

For this, they studied cells from the mouse hippocampus, a part of the brain which is crucial for learning. In their experiments, they blocked activity in the cells by introducing a potent neurotoxin called tetrodotoxin, thus simulating the loss of input to a certain part of the brain (“think about a person suddenly becoming blind, which leads to loss of input from the eyes to the brain”, says Hobbiss).

Forty eight hours later, they mimicked a small recovery of activity at only one synapse by releasing a few molecules of a neurotransmitter called glutamate on single spines of single neurons. This was possible thanks to a very high resolution, state-of-the-art laser technology, called two-photon microscopy, which allowed the scientists to very precisely visualize and target individual dendritic spines.

As this process evolved, the team closely watched what was happening to the spines – and they saw various anatomical changes. First, the silencing of all neural activity made the spines grow in size. “The spines are like little microphones, which, when there is silence, ramp up the ‘volume’ to try and catch even the faintest noise”, Hobbiss explains.

The scientists then activated individual spines with pulses of glutamate and watched them for two hours. One of the things they thought could happen was that the size of the spines would not grow further, since they had already turned up their ‘volume’ as far is it would go. But the opposite happened: the spines grew even more, with the smaller spines showing the biggest growth.

Finally, the authors also saw growth in neighboring spines, even though the experiment only targeted one spine. “We found that after a lack of activity, other spines in the vicinity also grew, further enhancing the cell’s sensitivity to restored neural transmission”, says Hobbiss. “The cells become more sensitive, more susceptible to encode information. It is as though the ‘gain’ has been turned up”, she adds.

“The fact that neighboring spines grew together with an active spine signifies that homeostatic plasticity changes one of the hallmark features of information storage, which is that plasticity is limited to the site of information entry”, Israely explains. “So, in this sense, the different plasticity mechanisms which are at work in the neuron can cooperate to change which and how many inputs respond to a stimulus. I think this is an exciting finding of our study.”

Taken together, these results show that homeostatic plasticity can actually rev up Hebbian plasticity, the type required for storing information. “Our work adds a piece to the puzzle of how the brain performs one of its fundamental tasks: being able to encode information while still keeping a stable level of activity”, concludes Hobbiss.

The misregulation of homeostatic plasticity – the stabilizing one – has started to be implicated in human health, specifically neurodevelopmental disorders such as Fragile X syndrome and Rett syndrome as well as neurodegenerative ones such as Alzheimer’s Disease. “Perhaps this balance is what allows us to be able to learn new information while retaining stability of that knowledge over a lifetime”, says Israely.

 

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[WEB SITE] Vagus nerve stimulation accelerates motor skill recovery after stroke

Researchers at The University of Texas at Dallas have demonstrated a method to accelerate motor skill recovery after a stroke by helping the brain reorganize itself more quickly.

In a preclinical study, the scientists paired vagus nerve stimulation (VNS) with a physical therapy task aimed at improving the function of an upper limb in rodents. The results showed a doubled long-term recovery rate relative to current therapy methods, not only in the targeted task but also in similar muscle movements that were not specifically rehabbed. Their work was recently published in the journal Stroke.

A clinical trial to test the technique in humans is underway in Dallas and 15 other sites across the country.

Dr. Michael Kilgard, associate director of the Texas Biomedical Device Center (TxBDC) and Margaret Forde Jonsson Professor of Neuroscience in the School of Behavioral and Brain Sciences, led the research team with Dr. Seth Hays, the TxBDC director of preclinical research and assistant professor of bioengineering in the Erik Jonsson School of Engineering and Computer Science, and postdoctoral researcher Eric Meyers PhD’17.

“Our experiment was designed to ask this new question: After a stroke, do you have to rehabilitate every single action?” Kilgard said. “If VNS helps you, is it only helping with the exact motion or function you paired with stimulation? What we found was that it also improves similar motor skills as well, and that those results were sustained months beyond the completion of VNS-paired therapy.”

Kilgard said the results provide an important step toward creating guidelines for standardized usage of VNS for post-stroke therapy.

“This study tells us that if we use this approach on complicated motor skills, those improvements can filter down to improve simpler movements,” he said.

Building Stronger Cell Connections

When a stroke occurs, nerve cells in the brain can die due to lack of blood flow. An arm’s or a leg’s motor skills fail because, though the nerve cells in the limb are fine, there’s no longer a connection between them and the brain. Established rehab methods bypass the brain’s damaged area and enlist other brain cells to handle the lost functions. However, there aren’t many neurons to spare, so the patient has a long-lasting movement deficit.

The vagus nerve controls the parasympathetic nervous system, which oversees elements of many unconscious body functions, including digestion and circulation. Electrical stimulation of the nerve is achieved via an implanted device in the neck. Already used in humans to treat depression and epilepsy, VNS is a well-documented technique for fine-tuning brain function.

The UT Dallas study’s application of VNS strengthens the communication path to the neurons that are taking over for those damaged by stroke. The experiments showed a threefold-to-fivefold increase in engaged neurons when adding VNS to rehab.

“We have long hypothesized that VNS is making new connections in the brain, but nothing was known for sure,” Hays said. “This is the first evidence that we are driving changes in the brain in animals after brain injury. It’s a big step forward in understanding how the therapy works — this reorganization that we predicted would underlie the benefits of VNS.”

In anticipation of the technique’s eventual use in humans, the team is working on an at-home rehab system targeting the upper limbs.

“We’ve designed a tablet app outlining hand and arm tasks for patients to interact with, delivering VNS as needed,” Meyers said. “We can very precisely assess their performance and monitor recovery remotely. This is all doable at home.”

Expanding the Possibilities for Therapy

The researchers are motivated in part by an understanding of the practical limitations of current therapeutic options for patients.

“If you have a stroke, you may have a limited time with a therapist,” Hays said. “So when we create guidelines for a therapist, we now know to advise doing one complex activity as many times as possible, as opposed to a variety of activities. That was an important finding — it was exciting that not only do we improve the task that we trained on, but also relatively similar tasks. You are getting generalization to related things, and you’re getting sustained improvement months down the line.”

For stroke patients, the opportunity to benefit from this technology may not be far off.

“A clinical trial that started here at UTD is now running nationwide, including at UT Southwestern,” Kilgard said. “They are recruiting patients. People in Dallas can enroll now — which is only fitting, because this work developed here, down to publishing this in a journal of the American Heart Association, which is based here in Dallas. This is a homegrown effort.

“The ongoing clinical trial is the last step in getting approved as an established therapy,” Kilgard said. “We’re hopefully within a year of having this be standard practice for chronic stroke.”

 

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[WEB SITE] Study uncovers genetic trigger that may help the brain to recover from stroke, other injuries

Scientists have found a genetic trigger that may improve the brain’s ability to heal from a range of debilitating conditions, from strokes to concussions and spinal cord injuries.

A new study in mice from UT Southwestern’s O’Donnell Brain Institute shows that turning on a gene inside cells called astrocytes results in a smaller scar and – potentially – a more effective recovery from injury.

The research examined spinal injuries but likely has implications for treating a number of brain conditions through gene therapy targeting astrocytes, said Dr. Mark Goldberg, Chairman of Neurology & Neurotherapeutics at UT Southwestern.

“We’ve known that astrocytes can help the brain and spinal cord recover from injury, but we didn’t fully understand the trigger that activates these cells,” Dr. Goldberg said. “Now we’ll be able to look at whether turning on the switch we identified can help in the healing process.”

The study published in Cell Reports found that the LZK gene of astrocytes can be turned on to prompt a recovery response called astrogliosis, in which these star-shaped cells proliferate around injured neurons and form a scar.

Scientists deleted the LZK gene in astrocytes of one group of injured mice, which decreased the cells’ injury response and resulted in a larger wound on the spinal cord. They overexpressed the gene in other injured mice, which stimulated the cells’ injury response and resulted in a smaller scar. Overexpressing the gene in uninjured mice also activated the astrocytes, confirming LZK as a trigger for astrogliosis.

Dr. Goldberg said a smaller scar likely aids the healing process by isolating the injured neurons, similar to how isolating a spreading infection can improve recovery. “But we don’t know under what circumstances this hypothesis is true because until now we didn’t have an easy way to turn the astrocyte reactivity on and off,” he said.

Further study is needed to analyze whether a compact scar tissue indeed improves recovery and how this process affects the neurons’ ability to reform connections with each other.

Dr. Goldberg’s lab will conduct more research to examine the effects of astrogliosis in stroke and spinal cord injuries. The researchers will determine whether turning up LZK in mice in advance of an injury affects its severity. They will then measure how the formation of the compact scar helps or hinders recovery.

“It has been a big mystery whether increasing astrocyte reactivity would be beneficial,” said Dr. Meifan Amy Chen, the study’s lead author and Instructor of Neurology at the Peter O’Donnell Jr. Brain Institute. “The discovery of LZK as an on switch now offers a molecular tool to answer this question.”

 

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[WEB SITE] New brain cells are added in elderly adult brains too

According to a new study from the Columbia University however, brain cells are continuously added to our brains even when we reach our 70s. This is a process called neurogenesis. Their work is published in a study that appeared in the latest issue of the journal Cell Stem Cell this week.

Neuron detailed anatomy illustrations. Neuron types, myelin sheath formation, organelles of the neuron body and synapse. Image Credit: Tefi / Shutterstock

Lead author Dr. Maura Boldrini, a research scientist at the department of psychiatry, Columbia University and her colleagues investigated the brains of 28 dead people aged between 14 and 79 years. They were studying the effects of aging on the brain’s neuron production. The team examined the brains that were donated by the families of the deceased at the time of death. The brains were frozen immediately at minus-112 degrees Fahrenheit before they could be examined. This preserved the tissues.

Neurogenesis has been shown to decline with age in lab mice and rats as well as in experimental primates. The team wanted to explore if same rates of decline are seen in human brains as well. So they checked the brains samples for developing neurons. These developmental stages included stem cells, intermediate progenitor cells, immature neuronal cells and finally new mature neurons. They focused on the hippocampus region of the brain that deals with memory and emotional control and behavior.

The results revealed that for all age groups, the hippocampus shows new developing neurons. The researchers concluded that even during old age, the hippocampus continues to make new neurons. The differences that they noted with age include reduction in the development of new blood vessels as people got older. The proteins that help the neurons to make new connections are reduced with age. This was a finding that differentiated ageing brains from younger ones, they explained. Boldrini said the new neurons are there in older brains but they make fewer connections than younger brains. This explains the memory losses and decrease in emotional resiliency in older adults she said.

An earlier study last month came from another set of researchers led by University of California San Francisco researcher Arturo Alvarez-Buylla. The study titled, “Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults,” was published first week of March this year in the journal Nature.

The team found that after adolescence there is little or no neurogenesis in the brain. They examined the brains of 17 deceased individuals and 12 patients with epilepsy part of whose brains had been surgically resected. The debate between the two teams continues. Boldrini explained that Buylla’s team had examined different types of samples that were not preserved as her samples had been.

Further the other team examined three to five sections of the hippocampus and not the whole of it she explained. More studies on this needed to make concrete conclusions regarding neurogenesis in the elderly say experts.

References

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[WEB SITE] Research could pave way for more effective and safer anti-epilepsy drugs

Columbia University Medical Center (CUMC) researchers have discovered how a new epilepsy drug works, which may lead the way to even more effective and safer medications.

The findings were published today in Neuron.

The most commonly used anti-epilepsy drugs are ineffective for about 30 percent of people with seizure disorders.

A new direction in the treatment of epilepsy is aimed at inhibiting AMPA receptors, which help transmit electrical signals in the brain and play a key role in propagating seizures. Currently, perampanel is the only FDA-approved drug that targets AMPA receptors. But because perampanel is associated with significant side effects, its clinical use has been limited.

“The problem is that AMPA receptors are heavily involved in the central nervous system, so if you inhibit their function, you cause an array of unwanted effects,” said study leader Alexander I. Sobolevsky, PhD, professor of biochemistry and molecular biophysics at CUMC. “If we hope to design better drugs for epilepsy, we need to learn more about the structure and function of these receptors.”

In this study, Dr. Sobolevsky employed a technique called crystallography to determine how perampanel and two other inhibitors interact with the AMPA receptors to stop transmission of electrical signals. The study was conducted using rat AMPA receptors, which are almost identical to human receptors.

In the new study, the researchers were able to pinpoint exactly where the drugs bind to AMPA receptors.

“Our data suggest that the inhibitors wedge themselves into the AMPA receptor, which prevents the opening of a channel within the receptor,” said Dr. Sobolevsky. When that channel is closed, ions cannot pass into the cell to trigger an electrical signal.

According to the researchers, these findings may allow drug makers to develop medications that are highly selective for the AMPA receptors, which could be safer and more effective than currently available anti-epilepsy drugs.

Source: Research could pave way for more effective and safer anti-epilepsy drugs

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[WEB SITE] Small device detects initial signal of epileptic attack and provides effective relief.

Published on August 23, 2016 

The results, from the Laboratory for Organic Electronics at LiU’s Campus Norrköping, have been published in the prestigious journal Proceedings of the National Academy of Sciences (PNAS), with Asst. Prof. Daniel Simon as main author.

According to a recently produced estimate, no less than six percent of the Earth’s population suffers from some type of neurological illness such as epilepsy or Parkinson’s. Some medicines are available, but when these are taken orally or injected into the bloodstream, they also end up where they aren’t needed and may cause serious problems. All medicines have more or less severe side effects, and no fully satisfactory treatment for neurological illnesses is available.

Neurons, or nerve cells, are the cells in the body that both transmit and receive nerve impulses. The small 20×20 µm device developed by the scientists can both capture signals and stop them in the exact area of nerve cells where they arise. No other part of the body needs to be involved.

“Our technology makes it possible to interact with both healthy and sick neurons. We can now start investigating opportunities for finding therapies for neurological illnesses that arise so rapidly and so locally that the patient doesn’t notice them,” says Daniel Simon.

The experiments were conducted in the laboratory on slices of brains from mice. The device consists of a sensor that detects nerve signals, and a small ion pump that doses an exact amount of the neurotransmitter GABA, a substance the body itself uses to inhibit stimuli in the central nervous system.

“The same electrode that registers the activity in the cell can also deliver the transmitter. We call it a bioelectronic ‘neural pixel’, since it imitates the functions of biological neurons,” says Daniel Simon.

“Signalling in biological systems is based on chemical signals in the form of cations, which are passed between transmitters and receptors, which consist of proteins. When a signal is transferred to another cell, the identification of the signal and the triggering of a new one occur within a very small distance – only a few nanometers. In certain cases, it happens at the same point. That’s why being able to combine electronic detection and release in the same electrode is a major advance,” says Professor Magnus Berggren.

The small ion pump, which was developed at the Laboratory for Organic Electronics, attracted a great deal of attention when it´s first application as a therapeutic device was published a year ago. The sensor that captures the nerve signal has subsequently been developed by the LiU researchers’ collaborators at the école Nationale Supérieure des Mines in Gardanne, France. The mouse experiments were performed at Aix-Marseille University. The entire device is manufactured from conductive, biocompatible plastic.

Source: Small device detects initial signal of epileptic attack and provides effective relief

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[Abstract] The Specific Requirements of Neural Repair Trials for Stroke.

Abstract

Novel molecular, cellular, and pharmacological therapies to stimulate repair of sensorimotor circuits after stroke are entering clinical trials. Compared with acute neuroprotection and thrombolysis studies, clinical trials for repair in subacute and chronic hemiplegic participants have a different time course for delivery of an intervention, different mechanisms of action within the milieu of the injury, distinct relationships to the amount of physical activity and skills practice of participants, and need to include more refined outcome measures.

This review examines the biological interaction of targeted rehabilitation with neural repair strategies to optimize outcomes. We suggest practical guidelines for the incorporation of inexpensive skills training and exercise at home. In addition, we describe some novel outcome measurement tools, including wearable sensors, to obtain the more detailed outcomes that may identify at least some minimal level of success from cellular and regeneration interventions.

Thus, proceeding in the shadow of acute stroke trial designs may unnecessarily limit the mechanisms of action of new repair strategies, reduce their impact on participants, and risk missing important behavioral outcomes.

Source: The Specific Requirements of Neural Repair Trials for Stroke

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