TL;DR
- Research has led to the development of the MeshCODE theory, a revolutionary new theory for understanding brain and memory function. This discovery may be the beginning of a new understanding of brain function and in treating brain diseases such as Alzheimer’s.
- Tohoku University scientists have shown that neuronal and glial circuits form a loosely coupled super-network within the brain. Activation of the metabotropic glutamate receptors in neurons was shown to be largely influenced by the state of the glial cells. Therefore, artificial control of the glial state could potentially be used to enhance the memory function of the brain.
- Neurodegenerative diseases, such as various forms of senile dementia or amyotrophic lateral sclerosis (ALS), have one thing in common: large amounts of certain RNA-protein complexes (snRNPs) are produced and deposited in the nerve cells of those affected — and this hinders the function of the cells. The overproduction is possibly caused by a malfunction in the assembly of the protein complexes.
- Intravenous injection of bone marrow derived stem cells (MSCs) in patients with spinal cord injuries led to significant improvement in motor functions, researchers report.
- Researchers have mapped the physical organization of the brain of a microscopic soil-living nematode worm called Caenorhabditis elegans, creating a new model for the architecture of the animal’s brain and how it processes information. The scientists say the worms’ brains might have a lot more in common with larger animals than previously thought.
- A computer network closely modelled on part of the human brain is enabling new insights into the way our brains process moving images — and explains some perplexing optical illusions.
- As people get older, their neural stem cells lose the ability to proliferate and produce new neurons, leading to a decline in memory function. Researchers have now discovered a mechanism linked to stem cell aging — and how the production of neurons can be reactivated.
- A study of spatial learning in mice shows that exposure to new experiences dampens established representations in the brain’s hippocampus and prefrontal cortex, allowing the mice to learn new navigation strategies.
- Three decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, researchers report. The finding could offer an alternative to opioid-based painkillers, addictive prescription medications that are responsible for an epidemic of abuse in the US.
- Scientists have identified the first compound that eliminates the ongoing degeneration of upper motor neurons that become diseased and are a key contributor to ALS (amyotrophic lateral sclerosis), a swift and fatal neurodegenerative disease that paralyzes its victims. In ALS, movement-initiating nerve cells in the brain and muscle-controlling nerve cells in the spinal cord die. After administering the new compound,, the diseased brain neurons stopped degenerating so much that they became similar to healthy control neurons after 60 days of treatment.
- Propranolol, a drug that is efficacious against infantile haemangiomas (‘strawberry naevi’, resembling birthmarks), can also be used to treat cerebral cavernous malformations, a condition characterized by misshapen blood vessels in the brain and elsewhere.
- …And more!
Neuroscience market
The global neuroscience market size was valued at USD 28.4 billion in 2016 and it is expected to reach USD 38.9 billion by 2027.
Latest news and researches
The Mechanical Basis of Memory — the MeshCODE Theory
by Benjamin T. Goult in Frontiers in Molecular Neuroscience
Research from the University of Kent has led to the development of the MeshCODE theory, a revolutionary new theory for understanding brain and memory function. This discovery may be the beginning of a new understanding of brain function and in treating brain diseases such as Alzheimer’s.
In a paper, Dr Ben Goult from Kent’s School of Biosciences describes how his new theory views the brain as an organic supercomputer running a complex binary code with neuronal cells working as a mechanical computer. He explains how a vast network of information-storing memory molecules operating as switches is built into each and every synapse of the brain, representing a complex binary code. This identifies a physical location for data storage in the brain and suggests memories are written in the shape of molecules in the synaptic scaffolds.
The theory is based on the discovery of protein molecules, known as talin, containing “switch-like” domains that change shape in response to pressures in mechanical force by the cell. These switches have two stable states, 0 and 1, and this pattern of binary information stored in each molecule is dependent on previous input, similar to the Save History function in a computer. The information stored in this binary format can be updated by small changes in force generated by the cell’s cytoskeleton.
In the brain, electrochemical signalling between trillions of neurons occurs between synapses, each of which contains a scaffold of the talin molecules. Once assumed to be structural, this research suggests that the meshwork of talin proteins actually represent an array of binary switches with the potential to store information and encode memory.
This mechanical coding would run continuously in every neuron and extend into all cells, ultimately amounting to a machine code coordinating the entire organism. From birth, the life experiences and environmental conditions of an animal could be written into this code, creating a constantly updated, mathematical representation of its unique life.
Dr Goult, a reader in biochemistry, said: ‘This research shows that in many ways the brain resembles the early mechanical computers of Charles Babbage and his Analytical Engine. Here, the cytoskeleton serves as the levers and gears that coordinate the computation in the cell in response to chemical and electrical signalling. Like those early computation models, this discovery may be the beginning of a new understanding of brain function and in treating brain diseases.’
Architectural similarities of memory storage in silico and in vivo. (A) A high-capacity SSD storage device is incredibly complicated, but its general architecture is arranged into a logical repeating structure of pages, arranged into blocks that are arranged into memory modules (NAND Flash). These hierarchical structures are linked to channels that connect each memory module to a memory controller that controls the data coming in and out of the drive and directs current to the relevant pages and transistors for data read-write. (B) The cortex shares a similar logical architecture. Three cortical columns are shown that are equivalent to the SSD channels. These columns contain layers (I–VI) that are comprised of minicolumns (the memory modules equivalent to the NAND Flash), which are comprised of circuits of pyramidal neurons (the blocks) that contain tens of thousands of MeshCODEs in the synapses and dendritic spines (the pages). Each column is linked with read and write channels back to the hippocampus.
Glial amplification of synaptic signals
by Kaoru Beppu, Naoko Kubo, Ko Matsui in The Journal of Physiology
Tohoku University scientists have shown that neuronal and glial circuits form a loosely coupled super-network within the brain. Activation of the metabotropic glutamate receptors in neurons was shown to be largely influenced by the state of the glial cells. Therefore, artificial control of the glial state could potentially be used to enhance the memory function of the brain.
Although the glial cells occupy more than half of the brain, they were thought to act as glue — merely filling the gap between neurons. However, recent findings show that the concentration of intracellular ions in glia, such as calcium and proton, can fluctuate over time.
“Glial cells appear to have the capacity of coding information,” says professor Ko Matsui of the Super-network Brain Physiology lab at Tohoku University, who led the research. “However, the role of the added layer of signals encoded in the glial circuit has always been an enigma.”
Using patch clamp electrophysiology techniques in acute brain slices from mice, Dr. Kaoru Beppu, Matsui, and their team show that glial cells in the cerebellum react to excitatory transmitter glutamate released from synapses of neurons. The glial cells then release additional glutamate in return. Therefore, these glial cells effectively function as excitatory signal amplifiers.
The additional glutamate released from glial cells efficiently activate metabotropic glutamate receptors on Purkinje neurons — essential for cerebellar motor learning. The amount of feedforward excitation was controlled by the intracellular pH of the glia cells.
“Depending on the state of our mind, the same experience could become a lasting memory or could fade away,” says Matsui. “It is possible that the pH of the glial cells at the time of the experience could have a pivotal role on memory formation.”
In this study, light-sensitive proteins were genetically expressed in glial cells to control their pH at will. Such optogenetics technology would be difficult to apply in human patients. “Although it would take a long time for clinical use, it is possible to imagine a future where a therapeutic strategy is designed to target glial cells to control their pH for memory enhancement to treat dementia,” added Matsui.
Interaction of 7SK with the Smn complex modulates snRNP production
by Changhe Ji, Jakob Bader, Pradhipa Ramanathan, Luisa Hennlein, Felix Meissner, Sibylle Jablonka, Matthias Mann, Utz Fischer, Michael Sendtner, Michael Briese in Nature Communications
Neurodegenerative diseases, such as various forms of senile dementia or amyotrophic lateral sclerosis (ALS), have one thing in common: large amounts of certain RNA-protein complexes (snRNPs) are produced and deposited in the nerve cells of those affected — and this hinders the function of the cells. The overproduction is possibly caused by a malfunction in the assembly of the protein complexes.
How the production of these protein complexes is regulated was unknown until now. Researchers from Martinsried and Würzburg in Bavaria, Germany, have solved the puzzle. They describe in detail a signaling pathway that prevents the overproduction of snRNPs when they are not needed. The results should make it possible to better understand the processes in motor neuron diseases and senile dementia.
The research group led by Professor Michael Sendtner and Dr. Michael Briese from the Institute of Clinical Neurobiology at Julius-Maximilians-Universität Würzburg (JMU) was in charge of the publication. Professor Utz Fischer and Pradhipa Ramanathan from the JMU Institute of Biochemistry were also involved, as was a team from the Max Planck Institute of Biochemistry in Martinsried.
a Volcano plot of the 7SK interaction proteome following pulldown with Biotin-pd7SK and scr control from NSC-34 cell lysate. Smn complex proteins are highlighted in green, the 7SK core interactors Mepce and Larp7 are marked in red. b Western blot analysis of proteins co-immunoprecipitated from NSC-34 cells by an anti-Larp7 antibody directed against the C-terminus of Larp7. Immunoprecipitation with rabbit-IgG antibody was used as control. In, input; IP, immunoprecipitation. c Co-immunoprecipitation of proteins by an anti-Larp7 antibody directed against the N-terminal half of Larp7. d Co-immunoprecipitation of proteins by anti-Smn from NSC-34 cells. Lack of Gapdh co-precipitation serves as specificity control. e Sucrose gradient fractionation of NSC-34 cell lysate. Individual fractions were probed by Western blotting for proteins indicated on the right. Lower panel: Detection of 7SK in each fraction by qPCR. a.u., arbitrary units. f Co-immunoprecipitation of proteins by anti-SmB/B’ from NSC-34 cells. g qPCR analysis of 7SK co-precipitated by anti-SmB/B’ from NSC-34 cells. Data are mean ± standard deviation (s.d.); ***P ≤ 0.001; unpaired two-tailed t-test (n = 3). h Co-immunoprecipitation of proteins by anti-SmD1 from NSC-34 cells. Source data are provided as a Source Data file.
The next steps in research
Further investigations shall now show how the synthesis and degradation of excess snRNPs are regulated in nerve cells. The scientists hope that in the end they will be able to identify new therapeutic options for neurodegenerative diseases.
Intravenous Infusion of Auto Serum-expanded Autologous Mesenchymal Stem Cells in Spinal Cord Injury Patients: 13 Case Series
by Osamu Honmou, Toshihiko Yamashita, Tomonori Morita, Tsutomu Oshigiri, Ryosuke Hirota, Satoshi Iyama, Junji Kato, Yuichi Sasaki, Sumio Ishiai, Yoichi M. Ito, Ai Namioka, Takahiro Namioka, Masahito Nakazaki, Yuko Kataoka-Sasaki, Rie Onodera, Shinichi Oka, Masanori Sasaki, Stephen G. Waxman, Jeffery D. Kocsis in Clinical Neurology and Neurosurgery
Intravenous injection of bone marrow derived stem cells (MSCs) in patients with spinal cord injuries led to significant improvement in motor functions, researchers from Yale University and Japan report.
For more than half of the patients, substantial improvements in key functions — such as ability to walk, or to use their hands — were observed within weeks of stem cell injection, the researchers report. No substantial side effects were reported.
The patients had sustained, non-penetrating spinal cord injuries, in many cases from falls or minor trauma, several weeks prior to implantation of the stem cells. Their symptoms involved loss of motor function and coordination, sensory loss, as well as bowel and bladder dysfunction. The stem cells were prepared from the patients’ own bone marrow, via a culture protocol that took a few weeks in a specialized cell processing center. The cells were injected intravenously in this series, with each patient serving as their own control. Results were not blinded and there were no placebo controls.
Yale scientists Jeffery D. Kocsis, professor of neurology and neuroscience, and Stephen G. Waxman, professor of neurology, neuroscience and pharmacology, were senior authors of the study, which was carried out with investigators at Sapporo Medical University in Japan. Key investigators of the Sapporo team, Osamu Honmou and Masanori Sasaki, both hold adjunct professor positions in neurology at Yale.
Kocsis and Waxman stress that additional studies will be needed to confirm the results of this preliminary, unblinded trial. They also stress that this could take years. Despite the challenges, they remain optimistic.
“Similar results with stem cells in patients with stroke increases our confidence that this approach may be clinically useful,” noted Kocsis. “This clinical study is the culmination of extensive preclinical laboratory work using MSCs between Yale and Sapporo colleagues over many years.”
“The idea that we may be able to restore function after injury to the brain and spinal cord using the patient’s own stem cells has intrigued us for years,” Waxman said. “Now we have a hint, in humans, that it may be possible.”
A multi-scale brain map derived from whole-brain volumetric reconstructions
by Christopher A. Brittin, Steven J. Cook, David H. Hall, Scott W. Emmons, Netta Cohen in Nature
Researchers have mapped the physical organization of the brain of a microscopic soil-living nematode worm called Caenorhabditis elegans, creating a new model for the architecture of the animal’s brain and how it processes information.
In a surprise twist, they found a large degree of variation in the structure of some neural circuits or pathways in individual worms which complemented a core set of neural circuits common to different animals.
The scientists say the worms’ brains might have a lot more in common with larger animals than previously thought.
Created by neuroscientists at the University of Leeds in collaboration with researchers in New York’s Albert Einstein College of Medicine, the brain map reveals that different spatial regions support different specialised circuits for routing information in the brain, where information is integrated before being acted upon.
C. elegans are nematodes that feed on bacteria found in rotting vegetation in your garden. They are only around a millimetre in length and as thin as a human hair.
An adult worm has exactly 302 cells in its nervous system — by comparison, the human brain has around 100 billion cells. But almost two thirds of the worm’s nerve cells form a ring in the head region, where they make thousands of connections with each other.
This ‘brain’ is the control centre of the animal, where much of the sensing and decision-making takes place.
Even though the brain is very compact, the animal displays a range of complex behaviours, and neuroscientists have been interested in understanding its brain for decades. Previous studies have created ‘wiring diagrams’ for the connections between nerve cells.
This latest study, though, is the first to provide the complete spatial coordinates to those circuit diagrams.
Professor Netta Cohen, Computational Neuroscientist at the University of Leeds, who supervised the research, said: “The brain needs to organise information flow to control the animal’s behaviour. But how the structure and function of the brain are related is an open question. Providing the spatial representation of the circuitry has allowed us to uncover the modular structure of this animal’s brain.”
Creating the brain map
The researchers used a legacy collection of electron microscope images of the brain of an adult and juvenile nematode worm. Those images revealed individual brain cells or neurons, allowing the researchers to map the organisation of the worms’ neural circuits, from the level of individual cells through to the large scale architecture of the entire brain.
Structure-function of the brain
The scientists identified known neural circuits and pathways within the brain such as a navigation neural circuit which an animal would use to follow smells and tastes to forage for food. Another circuit is thought to facilitate mechano-sensation, so it would feel its way as it wriggles through the soil — or sense if it is surrounded by bacteria.
Their theory is that information is processed in the worm’s brain through a number of ‘layers’. In fact, a similar layered architecture is found in the human brain. Information flow starts in sensory cells, which respond to the environment. For example, cells may sense bacteria but are they the right bacteria to feed on — do they smell like the ‘right’ bacteria? The answer requires information to be integrated from multiple senses before being sent to the command area of the brain for action.
Professor Cohen said: “The brain map reveals a very elegant structure to support information flow through a worm’s brain and it is more sophisticated than the traditional view that simple animals follow a stimulus-response path.
“The map suggests a convergence of different neural circuits — and this allows the worm to integrate all of the different cues it is receiving through its sensory cells and to coordinate the response.”
Variation in brain structure
During their study, the researchers were surprised to discover the extent of individual variation in the worms’ brains.
C elegans is one of the most studied animals in biology. During the life of the worm, the way its cells divide and grow follows a strict blueprint which is observed across the entire species. But when it comes to the brain cells, there seemed to be a high degree of variation in the way the brain cells formed contacts with neighbouring cells to create neural circuits.
Using mathematical and computer models, the scientists were able to discern between those connections that are likely to form the ‘core’ circuit across a large population of animals, and those that appear to be variable between individuals.
Dr. Christopher Brittin, a former PhD student at the University of Leeds and first author on the paper said: “This work raises interesting questions about how even seemingly simple nervous systems are able to accommodate both core and individualized brain circuitry.”
The scientists found that only around half the wiring in the worms’ brains is similar — the other half showed variation.
Professor Cohen added: “This finding was really exciting for us. First, this suggests that worm brains have a lot more in common with the brains of higher animals than we knew or expected, and the lessons learned about worms can help us learn about brains more generally.”
The variable connectivity may support individuality, redundancy and adaptability of brains as the animals face challenging, dangerous and ever-changing environments.
Exploring and explaining properties of motion processing in biological brains using a neural network
by Reuben Rideaux, Andrew E. Welchman in Journal of Vision
A computer network closely modelled on part of the human brain is enabling new insights into the way our brains process moving images — and explains some perplexing optical illusions.
By using decades’ worth of data from human motion perception studies, researchers have trained an artificial neural network to estimate the speed and direction of image sequences.
The new system, called MotionNet, is designed to closely match the motion-processing structures inside a human brain. This has allowed the researchers to explore features of human visual processing that cannot be directly measured in the brain.
Their study, uses the artificial system to describe how space and time information is combined in our brain to produce our perceptions, or misperceptions, of moving images.
The brain can be easily fooled. For instance, if there’s a black spot on the left of a screen, which fades while a black spot appears on the right, we will ‘see’ the spot moving from left to right — this is called ‘phi’ motion. But if the spot that appears on the right is white on a dark background, we ‘see’ the spot moving from right to left, in what is known as ‘reverse-phi’ motion.”
The researchers reproduced reverse-phi motion in the MotionNet system, and found that it made the same mistakes in perception as a human brain — but unlike with a human brain, they could look closely at the artificial system to see why this was happening. They found that neurons are ‘tuned’ to the direction of movement, and in MotionNet, ‘reverse-phi’ was triggering neurons tuned to the direction opposite to the actual movement.
The artificial system also revealed new information about this common illusion: the speed of reverse-phi motion is affected by how far apart the dots are, in the reverse to what would be expected. Dots ‘moving’ at a constant speed appear to move faster if spaced a short distance apart, and more slowly if spaced a longer distance apart.
“We’ve known about reverse-phi motion for a long time, but the new model generated a completely new prediction about how we experience it, which no-one has ever looked at or tested before,” said Dr Reuben Rideaux, a researcher in the University of Cambridge’s Department of Psychology and first author of the study.
Humans are reasonably good at working out the speed and direction of a moving object just by looking at it. It’s how we can catch a ball, estimate depth, or decide if it’s safe to cross the road. We do this by processing the changing patterns of light into a perception of motion — but many aspects of how this happens are still not understood.
“It’s very hard to directly measure what’s going on inside the human brain when we perceive motion — even our best medical technology can’t show us the entire system at work. With MotionNet we have complete access,” said Rideaux.
Thinking things are moving at a different speed than they really are can sometimes have catastrophic consequences. For example, people tend to underestimate how fast they are driving in foggy conditions, because dimmer scenery appears to be moving past more slowly than it really is.
The researchers showed in a previous study that neurons in our brain are biased towards slow speeds, so when visibility is low they tend to guess that objects are moving more slowly than they actually are.
Revealing more about the reverse-phi illusion is just one example of the way that MotionNet is providing new insights into how we perceive motion. With confidence that the artificial system is solving visual problems in a very similar way to human brains, the researchers hope to fill in many gaps in current understanding of how this part of our brain works.
Predictions from MotionNet will need to be validated in biological experiments, but the researchers say that knowing which part of the brain to focus on will save a lot of time.
Declining lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity
by Muhammad Khadeesh bin Imtiaz, Baptiste N. Jaeger, Sara Bottes, Raquel A.C. Machado, Mojca Vidmar, Darcie L. Moore, Sebastian Jessberger in Cell Stem Cell
The stem cells in our brain generate new neurons throughout life, for example in the hippocampus. This region of the brain plays a key role for a range of memory processes. With increasing age, and in patients suffering from Alzheimer’s disease, the hippocampus’ ability to create new neurons declines steadily — and with it, its memory functions.
Distribution of age-dependent cell damage
A study conducted by the research group of Sebastian Jessberger, a professor at the Brain Research Institute of the University of Zurich, shows how the formation of new neurons is impaired with advancing age. Protein structures in the nuclei of neural stem cells make sure that harmful proteins accumulating over time are unevenly distributed onto the two daughter cells during cell division. This seems to be an important part of the cells’ ability to proliferate over a long time in order to maintain the supply of neurons. With advancing age, however, the amounts of nucleic proteins change, resulting in defective distribution of harmful proteins between the two daughter cells. This results in a decrease in the numbers of newly generated neurons in the brains of older mice.
The central element in this process is a nuclear protein called lamin B1, the levels of which decrease as people age. When the researchers increased lamin B1 levels in experiments in aging mice, stem cell division improved and the number of new neurons grew. “As we get older, stem cells throughout the body gradually lose their ability to proliferate. Using genetic engineering and cutting-edge microscope technology, we were able to identify a mechanism that is associated with this process,” says doctoral candidate and first author Khadeesh bin Imtiaz.
Halting the aging process of stem cells
The research is part of several ongoing projects aiming to reactivate aging stem cells. The ability to regenerate damaged tissue generally declines with age, thus affecting almost all types of stem cells in the body. “While our study was limited to brain stem cells, similar mechanisms are likely to play a key role when it comes to the aging process of other stem cells,” says Sebastian Jessberger.
These latest findings are an important step towards exploring age-dependent changes in the behavior of stem cells. “We now know that we can reactivate aging stem cells in the brain. Our hope is that these findings will one day help increase levels of neurogenesis, for example in older people or those suffering from degenerative diseases such as Alzheimer’s. Even if this may still be many years in the future,” says Jessberger.
Reset of hippocampal–prefrontal circuitry facilitates learning
by Alan J. Park, Alexander Z. Harris, Kelly M. Martyniuk, Chia-Yuan Chang, Atheir I. Abbas, Daniel C. Lowes, Christoph Kellendonk, Joseph A. Gogos, Joshua A. Gordon in Nature
A study of spatial learning in mice shows that exposure to new experiences dampens established representations in the brain’s hippocampus and prefrontal cortex, allowing the mice to learn new navigation strategies.
“The ability to flexibly learn in new situations makes it possible to adapt to an ever-changing world,” noted Joshua A. Gordon, M.D., Ph.D., a senior author on the study and director of the National Institute of Mental Health, part of NIH. “Understanding the neural basis of this flexible learning in animals gives us insight into how this type of learning may become disrupted in humans.”
Dr. Gordon co-supervised the research project with Joseph A. Gogos, M.D., Ph.D., and Alexander Z. Harris, M.D., Ph.D., both of Columbia University, New York City.
Whenever we encounter new information, that information must be consolidated into a stable, lasting memory for us to recall it later. A key mechanism in this memory consolidation process is long-term potentiation, which is a persistent strengthening of neural connections based on recent patterns of activity. Although this strengthening of neural connections may be persistent, it can’t be permanent, or we wouldn’t be able to update memory representations to accommodate new information. In other words, our ability to remember new experiences and learn from them depends on information encoding that is both enduring and flexible.
To understand the specific neural mechanisms that make this plasticity possible, the research team, led by Alan J. Park, Ph.D., of Columbia, examined spatial learning in mice.
Spatial learning depends on a key circuit between the ventral hippocampus (a structure located in the middle of the brain) and the medial prefrontal cortex (located just behind the forehead). Connectivity between these brain structures strengthens over the course of spatial learning. If the connectivity remains at maximum strength, however, it impairs later adaptation to new tasks and rules. The researchers hypothesized that exposure to a new experience may serve as an environmental trigger that dampens established hippocampal-prefrontal connectivity, enabling flexible spatial learning.
In the first task, the researchers trained mice to navigate a maze in a certain way to receive a reward. Some of the mice were then allowed to explore a space they hadn’t seen before, while others explored a familiar space. The mice then engaged in a second spatial task, which required that they switch to a new navigation strategy to get a reward.
As expected, all of the mice favored their original navigation strategy at first. But the mice that had explored a new space gradually overcame this bias and successfully learned the new navigation strategy about halfway through the 40-trial training session. When the researchers tested a subset of the mice on the first task again, they found that the novelty-exposed mice were able to switch back to the original strategy, indicating that they updated and chose their strategy according to the task demands.
Additional findings showed that the effects of novelty extended beyond new spaces: Encountering new mice before the second task also enhanced learning of the new reward strategy.
Changes in brain activity throughout training revealed the neuronal mechanisms that drive this novelty-enhanced learning. In rodents, there is a well-defined firing pattern in the hippocampus known as the theta wave, which is thought to play a central role in learning and memory. When Park and coauthors examined recordings from the ventral hippocampus, they found that the theta wave became stronger during exploration of the novel arena and the hour that followed; the theta wave decreased as the mice became familiar with the arena over the next two days. The researchers found that novelty exposure also disrupted encoding of the original navigation strategy, reorganizing the firing pattern of individual neurons in the ventral hippocampus to bring them in sync with the theta wave.
At the same time, neurons in the medial prefrontal cortex showed decreased theta wave synchrony, and correlations between hippocampal activity and prefrontal activity weakened. These and other findings suggest that novelty exposure dampened the synaptic connections between the ventral hippocampus and medial prefrontal cortex, resetting the circuit to allow for subsequent strengthening of connectivity associated with learning.
By triggering this reset, novelty appears to facilitate strategy updating in response to the task’s specific reward structure. Machine learning analyses indicated that, following novelty exposure, ventral hippocampal neurons switched encoding from a strategy that predicted reward on the first task to one that predicted reward on the second task. The task-specific information was then relayed to the medial prefrontal neurons, which updated encoding accordingly.
On a chemical level, the neurotransmitter dopamine acts as a key mediator of this plasticity. Several experiments showed that activating dopamine D1-receptors in the ventral hippocampus led to novelty-like effects, including dampened hippocampal-prefrontal connectivity and enhanced learning. Blocking D1-receptors prevented these novelty-induced effects.
Together, these findings shed light on some of the brain mechanisms that play a role in flexible information encoding.
“Our study points to novelty as one way to trigger the circuitry reset that facilitates spatial learning in mice,” said Park. “The next step is to build on these findings and explore whether novelty plays a similar role in human memory and learning.”
Three decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, researchers report. The finding could offer an alternative to opioid-based painkillers, addictive prescription medications that are responsible for an epidemic of abuse in the US.
Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain
by Mahmoud S. Ahmed, Ping Wang, Ngoc Uyen Nhi Nguyen, Yuji Nakada, Ivan Menendez-Montes, Muhammad Ismail, Robert Bachoo, Mark Henkemeyer, Hesham A. Sadek, Enas S. Kandil in Proceedings of the National Academy of Sciences
Three decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, UT Southwestern researchers report. The finding, published online today in PNAS, could offer an alternative to opioid-based painkillers, addictive prescription medications that are responsible for an epidemic of abuse in the U.S.
Over 100 million Americans are affected by chronic pain, and a quarter of these experience pain on a daily basis, a burden that costs an estimated $600 billion in lost wages and medical expenses each year. For many of these patients — those with cancer, diabetes, or trauma, for example — their pain is neuropathic, meaning it’s caused by damage to pain-sensing nerves.
To treat chronic pain, prescriptions for opioid painkillers have increased exponentially since the late 1990s, leading to a rise in abuse and overdoses. Despite the desperate need for safer pain medications, development of a new prescription drug typically takes over a decade and more than $2 billion according to a study by the Tufts Center for the Study of Drug Development, explains study leader Enas S. Kandil, M.D., associate professor of anesthesiology and pain management at UTSW.
Seeking an alternative to opioids, Kandil and her UT Southwestern colleagues — including Hesham A. Sadek, M.D., Ph.D., professor of internal medicine, molecular biology, and biophysics; Mark Henkemeyer, Ph.D., professor of neuroscience; Mahmoud S. Ahmed, Ph.D., instructor of internal medicine; and Ping Wang, Ph.D., a postdoctoral researcher — explored the potential of drugs already approved by the Food and Drug Administration (FDA).
The team focused on EphB1, a protein found on the surface of nerve cells, which Henkemeyer and his colleagues discovered during his postdoctoral training nearly three decades ago. Research has shown that this protein is key for producing neuropathic pain. Mice genetically altered to remove all EphB1 don’t feel neuropathic pain, he explains. Even mice with half the usual amount of this protein are resistant to neuropathic pain, suggesting EphB1’s promise as a target for pain-relieving drugs. Unfortunately, no known drugs inactivate EphB1.
Exploring this angle further, Ahmed used computer modeling to scan a library of FDA-approved drugs, testing if their molecular structures had the right shape and chemistry to bind to EphB1. Their search turned up three tetracyclines, members of a family of antibiotics used since the 1970s. These drugs — demeclocycline, chlortetracycline, and minocycline — have a long history of safe use and minimal side effects, Ahmed says.
To investigate whether these drugs could bind to and inactivate EphB1, the team combined the protein and these drugs in petri dishes and measured EphB1’s activity. Sure enough, each of these drugs inhibited the protein at relatively low doses. Using X-ray crystallography, Wang imaged the structure of EphB1 with chlortetracycline, showing that the drug fits neatly into a pocket in the protein’s catalytic domain, a key portion necessary for EphB1 to function.
In three different mouse models of neuropathic pain, injections of these three drugs in combination significantly blunted reactions to painful stimuli such as heat or pressure, with the triplet achieving a greater effect at lower doses than each drug individually. When the researchers examined the brains and spinal cords of these animals, they confirmed that EphB1 on the cells of these tissues had been inactivated, the probable cause for their pain resistance. A combination of these drugs might be able to blunt pain in humans too, the next stage for this research, says Kandil.
“Unless we find alternatives to opioids for chronic pain, we will continue to see a spiral in the opioid epidemic,” she says. “This study shows what can happen if you bring together scientists and physicians with different experience from different backgrounds. We’re opening the window to something new.”
In silico molecular modeling simulations. (A) Staurosporine structure was selected as query for molecular similarity simulations. (B) A schematic flowchart for the in silico molecular virtual screening, starting with energy minimized FDA-approved small molecules using MMFF94 force field to be checked for degree of superimposition based on Staurosporine. This was followed by selecting the top 100 hits based on their Tanimoto coefficient ratio to undergo a semiflexible docking study using MOE to end up with the top 10 drug candidates. (C )A Space-filling representation for EphB1 tyrosine kinase domain, where the red circle refer to the binding domain of identified small molecules. (D) The 2D chemical structures of demeclocycline (blue), chlortetracycline (gray), and minocycline (orange) and their structural superimposition, along with Staurosporine (green). (E) A visual representation of demeclocycline docked with EphB1 Kinase domain, showing hydrophobic interaction, and dotted green lines represent hydrogen bonding along with Met-700:A and Thr-697:A; chlortetracycline (gray), where hydrogen bonds situated along with MET 700:A and GLN 711:A, and minocycline (orange), where hydrogen bonds along with MET 700:A and GLU 668:A.
Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP‐43 pathology
by Barış Genç, Mukesh Gautam, Öge Gözütok, Ina Dervishi, Santana Sanchez, Gashaw M. Goshu, Nuran Koçak, Edward Xie, Richard B. Silverman, P. Hande Özdinler in Clinical and Translational Medicine
Northwestern University scientists have identified the first compound that eliminates the ongoing degeneration of upper motor neurons that become diseased and are a key contributor to ALS (amyotrophic lateral sclerosis), a swift and fatal neurodegenerative disease that paralyzes its victims.
In addition to ALS, upper motor neuron degeneration also results in other motor neuron diseases, such as hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS).
In ALS, movement-initiating nerve cells in the brain (upper motor neurons) and muscle-controlling nerve cells in the spinal cord (lower motor neurons) die. The disease results in rapidly progressing paralysis and death.
So far, there has been no drug or treatment for the brain component of ALS, and no drug for HSP and PLS patients.
“Even though the upper motor neurons are responsible for the initiation and modulation of movement, and their degeneration is an early event in ALS, so far there has been no treatment option to improve their health,” said senior author Hande Ozdinler, associate professor of neurology at Northwestern University Feinberg School of Medicine. “We have identified the first compound that improves the health of upper motor neurons that become diseased.”
Ozdinler collaborated on the research with study author Richard B. Silverman, the Patrick G. Ryan/Aon Professor of Chemistry at Northwestern.
The study was initiated after Silverman identified a compound, NU-9, developed in his lab for its ability to reduce protein misfolding in critical cell lines. The compound is not toxic and crosses the blood brain barrier.
The NU-9 compound addresses two of the important factors that cause upper motor neurons to become diseased in ALS: protein misfolding and protein clumping inside the cell. Proteins fold in a unique way to function; when they misfold they become toxic to the neuron. Sometimes proteins aggregate inside the cell and cause pathology as in the TDP-43 protein pathology. This happens in about 90% of all ALS patient brains and is one of the most common problems in neurodegeneration.
The research team began to investigate whether NU-9 would be able to help repair upper motor neurons that become diseased due to increased protein misfolding in ALS. The results in mice were positive. Scientists next performed experiments to reveal how and why the diseased upper motor neurons regained their health.
New compound restores neurons to robust health
After administering NU-9, both the mitochondria (the cell’s energy producer) and the endoplasmic reticulum (the cell’s protein producer) began to regain their health and integrity resulting in improved neuron health. The upper motor neurons were more intact, their cell bodies were larger and the dendrites were not riddled with holes. They stopped degenerating so much that the diseased neurons became similar to healthy control neurons after 60 days of NU-9 treatment.
Commanders-in-chief of movement
“Improving the health of brain neurons is important for ALS and other motor neuron diseases,” Ozdinler said.
Upper motor neurons are the brain’s commanders-in-chief of movement. They carry the brain’s input to spinal cord targets to initiate voluntary movement. The degeneration of these neurons impairs the connection from the brain to the spinal cord and leads to paralysis in patients.
Lower motor neurons have direct connections with the muscle, contracting muscle to execute movement. Thus, the lower motor neuron activity is in part controlled by the upper motor neurons.
Ozdinler and colleagues will now complete more detailed toxicology and pharmacokinetic studies prior to initiating a Phase 1 clinical trial. Ozdinler and Silverman are members of the Chemistry of Life Processes Institute at Northwestern.
Upper motor neurons (UMNs) display ultrastructural defects in amyotrophic lateral sclerosis (ALS) patients, and in the mouse models that are diseased due to different underlying causes. (A) Representative electron microscopic (EM) image of UMN of normal control appears intact while (B) UMN of ALS patient showing cytoarchitectural defects. (C )EM image of UMN of WT mouse. (D) Representative EM image of UMN of hSOD1G93A, and (E) prpTDP‐43A315T mouse displaying massive ultrastructural disintegration. (F) The mitochondria in a normal control showing intact inner mitochondrial membranes (arrows), as opposed to (G) mitochondria in ALS patient that displays disintegration of inner mitochondrial membrane (arrowheads). (H) Mitochondria in WT mouse appears to be structurally intact with distinct inner and outer mitochondrial membranes (arrow), whereas (I) mitochondria in UMN in a hSOD1G93A and (J) prpTDP‐43A315T mouse displaying severe disintegration of inner mitochondrial membranes (arrowheads). (K) Electron micrographs of UMN endoplasmic reticulum (ER) in a normal control display properly stacked long cisternae (arrows), but (L) ER in ALS patient shows distension and ballooning of ER cisternae (arrowheads). Similarly, (M) ER in a WT mouse (arrows) looks structurally intact in contrast to (N) ER in UMN of hSOD1G93A and (O) prpTDP‐43A315T mouse that displaying broken, short, and disintegrated ER cisternae (arrowheads). (P) Quantification of average percentage of ER with cytoarchitectural defects/UMN in ALS patients. ****p < .0001, Student’s t‐test. (Q) Quantification of average percentage of ER with cytoarchitectural defects/UMN in hSOD1G93A. ****p < .0001, and prpTDP‐43A315T mice. ****p < .0001, One‐way ANOVA followed by Tukey’s post hoc multiple‐comparison test. (R) Quantification of average length of ER cisternae/UMN in ALS patients. **p < .001, Student’s t‐test. (S) Quantification of average length of ER cisternae/UMN in hSOD1G93A **** p < .0001, and prpTDP‐43A315T mice. ****p < .0001, One‐way ANOVA followed by Tukey’s post hoc multiple‐comparison test. Scale bars: A–E = 2 µm; F–O = 200 nm
Propranolol Reduces the Development of Lesions and Rescues Barrier Function in Cerebral Cavernous Malformations
by Joppe Oldenburg, Matteo Malinverno, Maria Ascencion Globisch, Claudio Maderna, Monica Corada, Fabrizio Orsenigo, Lei Liu Conze, Charlotte Rorsman, Veronica Sundell, Maximiliano Arce, Ross O. Smith, Anthony C.Y. Yau, Gry Hulsart Billström, Caroline Öhman Mägi, Galina V. Beznoussenko, Alexander A. Mironov, Dinesh Fernando, Geoffrey Daniel, Davide Olivari, Francesca Fumagalli, Maria Grazia Lampugnani, Elisabetta Dejana, Peetra U. Magnusson in Stroke
Propranolol, a drug that is efficacious against infantile haemangiomas (“strawberry naevi,” resembling birthmarks), can also be used to treat cerebral cavernous malformations, a condition characterised by misshapen blood vessels in the brain and elsewhere.
“Up to now, there’s been no drug treatment for these patients, so our results may become hugely important for them,” says Peetra Magnusson of the University’s Department of Immunology, Genetics and Pathology, who headed the study.
Cerebral cavernous malformations (CCMs, also called cavernous angiomas or cavernomas) are vascular lesions on blood vessels in the brain and elsewhere, caused by genetic changes that may be hereditary or arise spontaneously. Today, an operation to remove these lesions is the only possible treatment. However, surgical interventions in the brain are highly risky. Since the vascular malformations, moreover, recur in the hereditary form of the condition, a drug treatment for CCMs is urgently required instead.
The uses of propranolol, a beta blocker, include treating cardiovascular diseases and conditions, such as high blood pressure. But it can also be used to treat a haemangioma (“strawberry naevus”), a common blood-vessel malformation in children. There are some indications that the preparation might work against CCMs as well.
The new study is a collaboration involving researchers at Uppsala University, the Swedish University of Agricultural Sciences and, in Italy, IFOM — The FIRC Institute of Molecular Oncology and the Mario Negri Institute of Pharmacological Research. The researchers have been investigating how propranolol affects the emergence of vascular lesions in the form of CCMs.
“We examined mice with vascular malformations in the brain — cavernomas or CCMs, as they’re called — that corresponded to the hereditary form of the condition in humans. The mice were given propranolol in their drinking water, and we were able to see that the cavernomas were becoming fewer and smaller. The blood vessels functioned better, too, with less leaking and improved contacts between their cells,” Magnusson says.
The propranolol dose administered to the animals was equivalent to the dose used to treat diseases in humans. Using an electron microscope, the researchers were able to study in detail how the drug affected the cavernomas.
The results show that propranolol can be used to shrink and stabilise vascular lesions, and may be a potential medicine for treating CCMs.
“What makes the study especially interesting is that right now, in Italy, a clinical study is under way in which CCM patients are to get two years’ treatment with propranolol. During this period, they’re being monitored by means of magnetic resonance imaging of the blood vessels, to see how the malformations are developing,” says Professor Elisabetta Dejana of Uppsala University’s Department of Immunology, Genetics and Pathology and IFOM in Italy.
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