NS/ SARS-CoV-2 hijacks nanotubes between neurons to infect them, study finds
Neuroscience biweekly vol. 63, 20th July — 3rd August
TL;DR
- Scientists have used state-of-the-art electron microscopy approaches to demonstrate that SARS-CoV-2 hijacks nanotubes, tiny bridges that link infected cells with neurons. The virus is therefore able to penetrate neurons despite the fact that they are lacking the ACE2 receptor that the virus usually binds to when infecting cells.
- Your new apartment is just a couple of blocks down the street from the bus stop but today you are late and you see the bus roll past you. You break into a full sprint. Your goal is to get to the bus as fast as possible and then to stop exactly in front of the doors (which are never in exactly the same place along the curb) to enter before they close. To stop quickly and precisely enough, a new MIT study in mice finds, that the mammalian brain is niftily wired to implement principles of calculus.
- It may feel like an anvil hanging over your head, but that looming deadline stressing you out at work may actually be beneficial for your brain, according to new research. The study found that low to moderate levels of stress can help individuals develop resilience and reduce the risk of developing mental health disorders, like depression and antisocial behaviors. Low to moderate stress can also help individuals to cope with future stressful encounters.
- Researchers have produced definitive evidence that a specific region in the brain, called the subthalamic nucleus, is critical to governing the mind’s communication with the body’s motor control system. The findings, stemming from innovative experiments with humans, could yield advances in treatment for Parkinson’s disease.
- New research by Georgia State University’s TReNDS Center may lead to early diagnosis of conditions such as Alzheimer’s disease, schizophrenia and autism — in time to help prevent and more easily treat these disorders. In a new study published in Scientific Reports, a team of seven scientists from Georgia State built a sophisticated computer program that was able to comb through massive amounts of brain imaging data and discover novel patterns linked to mental health conditions. The brain imaging data came from scans using functional magnetic resonance imaging (fMRI), which measures dynamic brain activity by detecting tiny changes in blood flow.
- Researchers have identified the brain regions responsible for the increased aggression that occurs when male mice spend time with other male mice before an aggressive encounter — a concept known as social instigation. When social instigation occurs, cells in the lateral habenula signal to the dorsal raphe nucleus, which then communicates with the ventral tegmental area, leading to heightened aggression. These findings may have applications for socially provoked anger or violence.
- Non-invasive brain stimulation can restore optimal motor skill acquisition in people with diminished learning capabilities, e.g. due to age, according to a new study.
- What’s the best way to improve your memory as you age? Turns out, it depends, a new study comparing mnemonic and rehearsal-based memorization in people with mild cognitive impairment suggests.
- A new groundbreaking study from the University of Cincinnati shows promise that a new drug may help repair damage caused by strokes.
- CU Anschutz researchers have identified a new mechanism of how auditory sensitivity is regulated, making more sense of how our hearing is so precise — and providing insight into how we can better protect auditory sensitivity from damage.
- And more!
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Latest news and research
Tunneling nanotubes provide a route for SARS-CoV-2 spreading
by Anna Pepe, Stefano Pietropaoli, Matthijn Vos, Giovanna Barba-Spaeth, Chiara Zurzolo in Science Advances
COVID-19 often leads to neurological symptoms, such as a loss of taste or smell, or cognitive impairments (including memory loss and concentration difficulties), both during the acute phase of the disease and over the long term with “long COVID” syndrome. But the way in which the infection reaches the brain was previously unknown. Scientists from Institut Pasteur and CNRS laboratories have used state-of-the-art electron microscopy approaches to demonstrate that SARS-CoV-2 hijacks nanotubes, tiny bridges that link infected cells with neurons. The virus is therefore able to penetrate neurons despite the fact that they are lacking the ACE2 receptor that the virus usually binds to when infecting cells.
How does SARS-CoV-2 enter brain cells? A study published recently in Science Advances shows that the virus uses nanotubes that form between infected cells and neurons to gain access to neurons. These transient dynamic structures are a result of membrane fusion in distant cells. They enable the exchange of cellular material without the need for membrane receptors, the normal means of entering and exiting the cytoplasm. The Membrane Traffic and Pathogenesis Unit, led by Chiara Zurzolo at the Institut Pasteur, has already found that nanotubes play a role in degenerative diseases such as Alzheimer’s and Parkinson’s facilitating the transport of proteins responsible for these diseases.
Although the human cell receptor ACE2 serves as a gateway for SARS-CoV-2 to enter lung cells — the main target of the virus — and cells in the olfactory epithelium, it is not expressed by neurons. But viral genetic material has been found in the brains of some patients, which explains the neurological symptoms that characterize acute or long COVID. The olfactory mucosa has previously been suggested as a route to the central nervous system, but that does not explain how the virus is able to enter neuronal cells themselves.
According to this new study, SARS-CoV-2 is also thought to be capable of inducing the formation of nanotubes between infected cells and neurons, as well as among neurons, which would explain how the brain is infected from the epithelium. The research team revealed multiple viral particles located both inside and on the surface of nanotubes. Since the virus spreads more rapidly and directly from within nanotubes than by exiting one cell to move to the next via a receptor, this mode of transmission therefore contributes to the infectious capacity of SARS-CoV-2 and its spread to neuronal cells.
But the virus also moves on the external surface of nanotubes, where it can be guided more quickly to cells that express compatible receptors.
“Nanotubes can be seen as tunnels with a road on top,” suggests Chiara Zurzolo, Head of the Institut Pasteur’s Membrane Traffic and Pathogenesis Unit, “which enable the infection of nonpermissive cells like neurons but also facilitate the spread of infection between permissive cells.”
This publication combines research on in vitro cultures, showing that healthy neuronal cells are infected if they come into contact with infected cells, with the use of state-of-the-art microscopy tools. The Titan Krios microscope in the Institut Pasteur’s NanoImaging Core Facility offers unprecedented resolution of biological samples and nanomolecules that is closer to real biological conditions.
“With this instrument, novel imaging approaches have been developed to evaluate the structure of SARS-CoV-2 and the architecture of nanotubes,” explains Anna Pepe from the Institut Pasteur’s Membrane Traffic and Pathogenesis Unit, first author of the study.
Working in cooperation with the Institut Pasteur’s Ultrastructural BioImaging Core Facility, the research teams used precise investigative methods to detect structures in the nanotubes that were subsequently identified as “virus factories.” The nanotubes between neurons represent a propitious environment for SARS-CoV-2 to develop, since it is invisible to the immune system.
Chiara Zurzolo believes that “it may represent a mechanism for immune evasion and viral persistence that could be favorable to the virus.”
This study is an example of how basic interdisciplinary research, involving cellular biologists, virologists and state-of-the-art imaging techniques, can lead to new discoveries. It paves the way for further research on the role of cell-to-cell communication in the spread of SARS-CoV-2. It also encourages exploration of alternative therapeutic approaches to hinder the spread of SARS-CoV-2, alongside current projects that are mainly focused on blocking entry via the ACE2 receptor.
Is perceived stress linked to enhanced cognitive functioning and reduced risk for psychopathology? Testing the hormesis hypothesis
by Assaf Oshri, Zehua Cui, Cory Carvalho, Sihong Liu in Psychiatry Research
It may feel like an anvil hanging over your head, but that looming deadline stressing you out at work may actually be beneficial for your brain, according to new research from the Youth Development Institute at the University of Georgia.
Published in Psychiatry Research, the study found that low to moderate levels of stress can help individuals develop resilience and reduce the risk of developing mental health disorders, like depression and antisocial behaviors. Low to moderate stress can also help individuals to cope with future stressful encounters.
“If you’re in an environment where you have some level of stress, you may develop coping mechanisms that will allow you to become a more efficient and effective worker and organize yourself in a way that will help you perform,” said Assaf Oshri, lead author of the study and an associate professor in the College of Family and Consumer Sciences.
The stress that comes from studying for an exam, preparing for a big meeting at work or pulling longer hours to close the deal can all potentially lead to personal growth. Being rejected by a publisher, for example, may lead a writer to rethink their style. And being fired could prompt someone to reconsider their strengths and whether they should stay in their field or branch out to something new.
But the line between the right amount of stress and too much stress is a thin one.
“It’s like when you keep doing something hard and get a little callous on your skin,” continued Oshri, who also directs the UGA Youth Development Institute. “You trigger your skin to adapt to this pressure you are applying to it. But if you do too much, you’re going to cut your skin.”
The researchers relied on data from the Human Connectome Project, a national project funded by the National Institutes of Health that aims to provide insight into how the human brain functions. For the present study, the researchers analyzed the project’s data from more than 1,200 young adults who reported their perceived stress levels using a questionnaire commonly used in research to measure how uncontrollable and stressful people find their lives.
Participants answered questions about how frequently they experienced certain thoughts or feelings, such as “in the last month, how often have you been upset because of something that happened unexpectedly?” and “in the last month, how often have you found that you could not cope with all the things that you had to do?”
Their neurocognitive abilities were then assessed using tests that measured attention and ability to suppress automatic responses to visual stimuli; cognitive flexibility, or ability to switch between tasks; picture sequence memory, which involves remembering an increasingly long series of objects; working memory and processing speed.
The researchers compared those findings with the participants’ answers from multiple measures of anxious feelings, attention problems and aggression, among other behavioral and emotional problems.
The analysis found that low to moderate levels of stress were psychologically beneficial, potentially acting as a kind of inoculation against developing mental health symptoms.
“Most of us have some adverse experiences that actually make us stronger,” Oshri said. “There are specific experiences that can help you evolve or develop skills that will prepare you for the future.”
But the ability to tolerate stress and adversity varies greatly according to the individual.
Things like age, genetic predispositions and having a supportive community to fall back on in times of need all play a part in how well individuals handle challenges. While a little stress can be good for cognition, Oshri warns that continued levels of high stress can be incredibly damaging, both physically and mentally.
“At a certain point, stress becomes toxic,” he said. “Chronic stress, like the stress that comes from living in abject poverty or being abused, can have very bad health and psychological consequences. It affects everything from your immune system, to emotional regulation, to brain functioning. Not all stress is good stress.”
Dynamic control of visually guided locomotion through corticosubthalamic projections
by Elie M. Adam, Taylor Johns, Mriganka Sur in Cell Reports
Your new apartment is just a couple of blocks down the street from the bus stop but today you are late and you see the bus roll past you. You break into a full sprint. Your goal is to get to the bus as fast as possible and then to stop exactly in front of the doors (which are never in exactly the same place along the curb) to enter before they close. To stop quickly and precisely enough, a new MIT study in mice finds, the mammalian brain is niftily wired to implement principles of calculus.
One might think that coming to a screeching halt at a target after a flat out run would be as simple as a reflex, but catching a bus or running right up to a visually indicated landmark to earn a water reward (as the mice did), is a learned, visually guided, goal-directed feat. In such tasks, which are a major interest in the lab of senior author Mriganka Sur, Newton Professor of Neuroscience in The Picower Institute for Learning and Memory at MIT, the crucial decision to switch from one behavior (running) to another (stopping) comes from the brain’s cortex, where the brain integrates the learned rules of life with sensory information to guide plans and actions.
“The goal is where the cortex comes in,” said Sur, a faculty member of MIT’s Department of Brain and Cognitive Sciences. “Where am I supposed to stop to achieve this goal of getting on the bus.”
And that’s also where it gets complicated. The mathematical models of the behavior that postdoc and study lead author Elie Adam developed predicted that a “stop” signal going directly from the M2 region of the cortex to regions in the brainstem, which actually control the legs, would be processed too slowly.
“You have M2 that is sending a stop signal, but when you model it and go through the mathematics, you find that this signal, by itself, would not be fast enough to make the animal stop in time,” said Adam, whose work appears in the journal Cell Reports.
So how does the brain speed up the process? What Adam, Sur and co-author Taylor Johns found was that M2 sends the signal to an intermediary region called the subthalamic nucleus (STN), which then sends out two signals down two separate paths that re-converge in the brainstem. Why? Because the difference made by those two signals, one inhibitory and one excitatory, arriving one right after the other turns the problem from one of integration, which is a relatively slow adding up of inputs, to differentiation, which is a direct recognition of change. The shift in calculus implements the stop signal much more quickly.
Adam’s model employing systems and control theory from engineering — accurately — predicted the speed needed for a proper stop and that differentiation would be necessary to achieve it, but it took a series of anatomical investigations and experimental manipulations to confirm the model’s predictions.
First, Adam confirmed that indeed M2 was producing a surge in neural activity only when the mice needed to achieve their trained goal of stopping at the landmark. He also showed it was sending the resulting signals to the STN. Other stops for other reasons did not employ that pathway. Moreover, artificially activating the M2-STN pathway compelled the mice to stop and artificially inhibiting it caused mice overrun the landmark somewhat more often.
The STN certainly then needed to signal the brainstem — specifically the pedunculopontine nucleus (PPN) in the mesenecephalic locomotor region. But when the scientists looked at neural activity starting in the M2 and then quickly resulting in the PPN, they saw that different types of cells in the PPN responded with different timing. Particularly, before the stop, excitatory cells were active and their activity reflected the speed of the animal during stops. Then, looking at the STN, they saw two kinds of surges of activity around stops — one slightly slower than the other — that were conveyed either directly to PPN through excitation or indirectly via the substantia nigra pars reticulata (SNr) through inhibition. The net result of the interplay of these signals in the PPN was an inhibition sharpened by excitation. That sudden change could be quickly found by differentiation to implement stopping.
“An inhibitory surge followed by excitation can create a sharp [change of] signal,” Sur said.
The study dovetails with other recent papers. Working with Picower Institute investigator Emery N. Brown, Adam recently produced a new model of how deep brain stimulation in the STN quickly corrects motor problems that result from Parkinson’s disease. And last year members of Sur’s lab, including Adam, published a study showing how the cortex overrides the brain’s more deeply ingrained reflexes in visually guided motor tasks. Together such studies contribute to understanding how the cortex can consciously control instinctually wired motor behaviors but also how important deeper regions, such as the STN, are to quickly implementing goal-directed behavior. A recent review from the lab expounds on this.
Adam speculated that the “hyperdirect pathway” of cortex-to-STN communications may have a role broader than quickly stopping action, potentially expanding beyond motor control to other brain functions such as interruptions and switches in thinking or mood.
Dissecting motor skill acquisition: Spatial coordinates take precedence
by Pablo Maceira-Elvira, Jan E. Timmermann, Traian Popa, Anne-Christine Schmid, John W. Krakauer, Takuya Morishita, Maximilian J. Wessel, Friedhelm C. Hummel in Science Advances
Even though we don’t think about it, every movement we make in our daily life essentially consists of a sequence of smaller actions in a specific order. The only time we realize this is when we have to learn a new motor skill, like a sport, a musical instrument, a new dance routine or even a new electronic device such as a smart phone or videogame controller.
Perhaps unsurprisingly, there is a lot of research invested in figuring out how humans acquire sequential motor skills, with a majority of studies in healthy young adults. Studies involving older individuals (and common experience) show that the older we get, the harder it is and the longer it takes to learn new motor skills, suggesting an age-related decrease in learning ability.
“As learning is crucial for continuously adapting and staying integrated in daily life, improving these impaired functions will help to maintain the quality of life as we age, especially in view of the constant increase in life expectancy seen worldwide,” says Professor Friedhelm Hummel who holds the Defitech Chair of Clinical Neuroengineering at EPFL’s School of Life Sciences.
In a new study, Hummel and his PhD student Pablo Maceira-Elvira have found that transcranial brain stimulation can improve the age-related impairment in learning new motor skills.
The study used a common way of evaluating how well a person learns new motor skills called the “finger-tapping task.” It involves typing a sequence of numbers as fast and as accurately as possible. The task is popular in studies because it simulates activities that require high dexterity — such as playing the piano or typing on a keyboard — while providing an objective measure of “improvement,” defined as a person increasing their speed without losing accuracy.
Scientists refer to this as a “shift in the speed-accuracy tradeoff,” and it constitutes a key feature of learning. One of the ways the brain achieves this shift is by grouping individual motor actions into so called “motor chunks”: spontaneously emerging brain structures that reduce a person’s mental load, while optimizing the mechanical execution of the motor sequence.
“Motor chunks emerge reliably when young adults train on the finger-tapping task, but previous studies show either lacking or deficient motor chunks in older adults,” says Pablo Maceira-Elvira.
The study first trained and tested groups of younger and older adults on learning a new sequence of finger-tapping task, and revealed fundamental differences between the two. Young adults learned the finger-tapping task most efficiently by prioritizing the improvement of the accuracy during their first training session and by focusing on improving their speed thereafter. This led to a shift in the speed-accuracy tradeoff, which allowed efficient motor chunks to emerge early on.
“Older adults showed decreased fast online learning and absent offline learning,” says Maceira-Elvira. “In other words, while young adults show sharp performance increases early in training and improve overnight, older adults improve at a more moderate pace and even worsen overnight.”
In contrast, older adults improved their accuracy gradually over the course of training, generating efficient motor chunks only after more extensive practice.
Extensive research has been carried out on novel neurotechnologies that may restore learning impairment in older people.
“Recent studies have shown we can enhance motor skill acquisition by applying non-invasive brain stimulation to the motor cortex, with anodal transcranial direct current stimulation (atDCS) attracting both academic and commercial interest in recent years due to its unobtrusiveness, portability and affordability,” says Hummel.
In the current study, the researchers applied atDCS to the participants and found that it helped older adults to improve their accuracy sharply earlier on in training and in a pattern similar to that seen in young adults.
“Stimulation accelerated the shift in the speed-accuracy tradeoff and enabled an earlier emergence of efficient motor chunks, with 50% of older adults generating these structures during the first training session,” says Maceira-Elvira.
He adds:
“The study suggests that atDCS can at least partially restore motor skill acquisition in individuals with diminished learning mechanisms, by facilitating the storage of task-relevant information, quickly reducing mental load and allowing the optimization of the mechanical execution of the sequence.”
“These studies add to the better understanding of age-related deficits in motor skill acquisition and offer a novel strategy to non-invasively restore these deficits,” says Hummel. “These findings open novel opportunities of interventional strategies adjusted to the specific learning phase to restore deficits due to healthy aging or neurological disorder such as stroke.”
A causal role for the human subthalamic nucleus in non-selective cortico-motor inhibition
by Jan R. Wessel, Darcy A. Diesburg, Nathan H. Chalkley, Jeremy D.W. Greenlee in Current Biology
University of Iowa researchers have confirmed in a new study that a specific region in the brain is critical to governing the mind’s communication with the body’s motor control system. The findings could yield advances in treatment for Parkinson’s disease, as declining motor coordination is a central symptom of the disorder.
In experiments with humans, the researchers pinpointed the subthalamic nucleus as the region in the brain that communicates with the motor system to help the body stop an action. This communication is vital because it helps humans avoid surprises and react to potentially dangerous or unforeseen circumstances.
The subthalamic nucleus is a tiny grouping of cells that is part of the basal ganglia, which is a key circuit in controlling movement. The basal ganglia takes initial motor commands generated in the brain and either amplify or halt specific parts of those commands as they pass from the central nervous system to the spinal cord.
“You can think of the subthalamic nucleus as the core region in this ‘halting’ of extra, unwanted components of compound movements, as it is the last relay station before the output nuclei of the basal ganglia, which then communicates these commands to the wider motor system,” says Jan Wessel, associate professor in the Department of Psychological and Brain Sciences at Iowa and the corresponding author on the study.
Previous research had indicated the subthalamic nucleus’ role in this stage of brain-motor control communication, but the hypothesis had not been directly tested in humans until now. To do that, the researchers used some ingenious techniques. First, they recruited 20 patients who have Parkinson’s disease, which affects motor control. These patients had implanted deep-brain stimulators, which the researchers used to activate or deactivate the subthalamic nucleus. They then tracked those changes to motor-control activity through a simple stop-action task, monitoring the brain-motor control responses through a technique called transcranial magnetic stimulation.
Parkinson’s disease patients are treated regularly with deep-brain stimulation, but the addition of transcranial magnetic stimulation allowed the researchers to confirm the subthalamic nucleus’ definitive role. Wessel partnered on the experiments with Jeremy Greenlee, professor and the Arnold H. Menezes Chair in the Department of Neurosurgery, who cares for patients with Parkinson’s disease.
“Deep-brain stimulation is the only method to causally and systematically influence the activity of deeply embedded brain nuclei like the subthalamic nucleus in awake, behaving humans,” says Wessel, also an associate professor in the Department of Neurology. “However, combining deep-brain stimulation with transcranial magnetic stimulation is a highly complicated and novel technical endeavor, especially in awake, behaving humans.”
The subthalamic nucleus-motor control link is important, Wessel says, because it puts to rest a central question in the brain’s communication with the body’s motor system, especially how an initiated action is suddenly halted. But it has potential benefits to patients, too.
“The subthalamic nucleus is a key therapeutic target in Parkinson’s disease,” Wessel says. “Indeed, just like it was done for the patient sample in our study, implantation of stimulation electrodes into the subthalamic nucleus is a highly successful treatment option for the motoric symptoms of Parkinson’s disease. Our study provides some mechanistic insights into this potential patient-care benefit.”
Toward rational use of cognitive training in those with mild cognitive impairment
by Benjamin M. Hampstead, Anthony Y. Stringer, Alexandru D. Iordan, Robert Ploutz‐Snyder, K. Sathian in Alzheimer’s & Dementia
What’s the best way to improve your memory as you age? Turns out, it depends, a new study suggests. But your fourth-grade math teacher may have been onto something with that phrase to help you remember how to work out a complicated problem: Please Excuse My Dear Aunt Sally.
A new study led by researchers from the University of Michigan and Penn State College of Medicine compared two approaches for people with an early form of memory loss.
The two are mnemonic strategy training, which aims to connect what someone is trying to remember to something else like a word, phrase or song (such as the Dear Aunt Sally mnemonic), and spaced retrieval training, which gradually increases the amount of time between tests of remembering something.
People with mild cognitive impairment, which can but does not always lead to a later Alzheimer’s disease diagnosis, were better able to remember information when using one of these cognitive training approaches. However, the data, and brain scans that revealed which areas of the brain were more active, showed each activity works differently.
“Our research shows that we can help people with mild cognitive impairment improve the amount of information they learn and remember; however, different cognitive training approaches engage the brain in distinct ways,” said lead and corresponding author Benjamin Hampstead, Ph.D. Hampstead is a professor of psychiatry at Michigan Medicine and the VA Ann Arbor Healthcare System. He directs the Research Program on Cognition and Neuromodulation Based Interventions and leads the Clinical Core and co-leads the Neuroimaging Core at the federally funded Michigan Alzheimer’s Disease Research Center.
“Mnemonic strategy training increased activity in brain areas often affected by Alzheimer’s disease, which likely explains why this training approach helped participants remember more information and for longer,” Hampstead said “In contrast, those completing rehearsal-based training showed reduced brain activity, which suggests they were processing the information more efficiently.”
Hampstead and his team worked with Krish Sathian, MBBS, Ph.D., professor and chair of Penn State’s Department of Neurology and director of Penn State Neuroscience Institute. Sathian noted that cognitive training approaches are likely to become increasingly important in synergy with the new pharmacological treatments on the horizon for those with neurodegenerative disorders.
Moving forward, Hampstead said researchers and clinicians can use this type of information to help identify the best-fit non-pharmacologic treatments for their patients with memory impairment.
Inhibition of CSPG receptor PTPσ promotes migration of newly born neuroblasts, axonal sprouting, and recovery from stroke
by Fucheng Luo, Jiapeng Wang, Zhen Zhang, Zhen You, Alicia Bedolla, FearGod Okwubido-Williams, L. Frank Huang, Jerry Silver, Yu Luo in Cell Reports
A new groundbreaking study from the University of Cincinnati shows promise that a new drug may help repair damage caused by strokes.
Currently, there are no FDA approved drugs to repair the damage caused by a stroke. The study found a drug called NVG-291-R enables nervous system repair and significant functional recovery in an animal model of severe ischemic stroke. Genetic deletion of the molecular target of the drug also shows similar effect on neural stem cells.
“We are very excited about the data showing significant improvement in motor function, sensory function, spatial learning and memory,” said Agnes (Yu) Luo, PhD, associate professor in the Department of Molecular Genetics and Biochemistry in UC’s College of Medicine and the study’s senior author.
Luo said the drug would be a “substantial breakthrough” if the early results translate into clinical settings. Further study and validation of results from independent groups will be needed to determine if the drug is similarly effective to repair the damage of ischemic strokes in human patients. Additional studies will be needed to research if NVG-291-R effectively repairs damage caused by hemorrhagic strokes in both animal models and human patients.
“Most therapies being researched today primarily focus on reducing the early damage from stroke,” Luo said. “However, our group has focused on neurorepair as an alternative and now has shown that treatment with NVG-291-R not only results in neuroprotection to reduce neuronal death but also robust neuroreparative effects.”
The study also found the drug was effective even when treatment began as late as seven days after the stroke’s onset.
“The only current FDA-approved drug for treatment of stroke does not repair damage and must be administered within 4.5 hours of stroke onset.” Luo said. “Most therapies being researched need to be applied within 24–48 hours of a stroke’s onset. A product that works to repair damage from stroke even a week after symptom onset would change the paradigm for stroke treatment.”
Jerry Silver, PhD, co-author of the study and professor of neurosciences at CWRU’s School of Medicine, said the study showed the drug repaired damage through at least two avenues: creating new neuronal connections and enhancing migration of newly born neurons derived from neuronal stem cells to the site of the damage.
“NVG-291-R’s ability to enhance plasticity was demonstrated by using staining techniques that clearly showed an increase in axonal sprouting to the damaged part of the brain,” Silver said. “This enhanced plasticity is an excellent validation of the same powerful mechanisms that we and other researchers were able to demonstrate using NVG-291-R in spinal cord injury.”
NervGen Pharma Corp. holds the exclusive worldwide rights to NVG-291, and the drug is also currently being tested in a Phase 1 clinical trial in healthy human subjects. NervGen plans to initiate patient safety and efficacy trials in spinal cord injury, Alzheimer’s disease and multiple sclerosis in 2022 and 2023.
cAMP and voltage modulate rat auditory mechanotransduction by decreasing the stiffness of gating springs
by Andrew A. Mecca, Giusy A. Caprara, Anthony W. Peng in Proceedings of the National Academy of Sciences
A new study published in PNAS highlights a newly identified mechanism of how auditory sensitivity is regulated that could temporarily reduce sensitivity of the auditory system to protect itself from loud sounds that can cause irreversible damage.
The study, led by CU Anschutz researchers Andrew Mecca and Giusy Caprara in the laboratory of Anthony Peng, tested a decades-old hypothesis which proposed that the gating spring, a tiny, nanometer-scale protein structure which mechanically opens and closes an ion channel in sensory hair cell cells in response to sound vibrations, can act directly as a controller of the channel’s activity.
Previous work in the auditory field has focused mostly on understanding mechanisms which target the ion channel. This study provides the first evidence that the gating spring itself has the capacity to modulate the sensitivity of the channel.
“This study documents the first time we understand a mechanism that regulates auditory sensitivity on both the molecular and mechanical levels,” says Peng, Ph.D., associate professor at the University of Colorado School of Medicine and senior author of the study. “We uncovered a new mechanism of modulating sensitivity, which opens the door to discovering more about how the auditory system functions generally and uses this to both maximize the range of sounds that we can detect and protect the vital sensory cells from potential damage.”
The mechanism discussed in the study works by modifying a physical property of the gating spring, its stiffness, which is responsible for controlling how much the channel opens and closes in response to sound vibrations that enter the inner ear. The researchers studied the properties of the gating spring and the resulting activity of the channel in single sensory hair cells, and found that cyclic adenosine monophosphate (cAMP), a specific type of signaling molecule, reduced the stiffness of the gating spring and decreased the channel’s sensitivity — which is the first time a physiological mechanism for controlling gating spring stiffness has been identified.
“Identifying the underlying mechanism of this process — how it works physiologically and mechanically, provides an avenue for future research and provides an opportunity for the field to develop a new type of drug that can be used to prevent a type of hearing loss that occurs from exposure to very loud sound,” says Peng.
Ultimately, they aim to learn more about how the ear can detect such a large range of sounds and how the system protects itself, and this represents a huge step forward for the field.
Interpreting models interpreting brain dynamics
by Md. Mahfuzur Rahman, Usman Mahmood, Noah Lewis, Harshvardhan Gazula, Alex Fedorov, Zening Fu, Vince D. Calhoun, Sergey M. Plis in Scientific Reports
New research by Georgia State University’s TReNDS Center may lead to early diagnosis of conditions such as Alzheimer’s disease, schizophrenia and autism — in time to help prevent and more easily treat these disorders. In a new study published in Scientific Reports a team of seven scientists from Georgia State built a sophisticated computer program that was able to comb through massive amounts of brain imaging data and discover novel patterns linked to mental health conditions. The brain imaging data came from scans using functional magnetic resonance imaging (fMRI), which measures dynamic brain activity by detecting tiny changes in blood flow.
“We built artificial intelligence models to interpret the large amounts of information from fMRI,” said Sergey Plis, associate professor of computer science and neuroscience at Georgia State, and lead author on the study.
He compared this kind of dynamic imaging to a movie — as opposed to a snapshot such as an x-ray or, the more common structural MRI — and noted “the available data is so much larger, so much richer than a blood test or a regular MRI. But that’s the challenge — that huge amount of data is hard to interpret.”
In addition, fMRI’s on these specific conditions are expensive, and not easy to obtain. Using an artificial intelligence model, however, regular fMRI’s can be data mined. And those are available in large numbers.
“There are large datasets available in individuals without a known clinical disorder,” explains Vince Calhoun, Founding Director of the TReNDS Center, and one of the study’s authors. Using these large but unrelated available datasets improved the model’s performance on smaller specific datasets.
“New patterns emerged that we could definitively link to each of the three brain disorders,” Calhoun said.
The AI models were first trained on a dataset including over 10,000 individuals to learn to understand basic fMRI imaging and brain function. The researchers then used multi-site data sets of over 1200 individuals including those with autism spectrum disorder, schizophrenia, and Alzheimer’s disease.
How does it work? It’s a bit like Facebook, YouTube or Amazon learning about you from your online behavior, and beginning to be able to predict future behavior, likes and dislikes. The computer software was even able to home in on the “moment” when the brain imaging data was most likely linked to the mental disorder in question.
To make these findings clinically useful, they will need to be applied before a disorder manifests.
“If we can find markers for and predict Alzheimer’s risk in a 40-year-old,” Calhoun said, “we might be able to do something about it.”
Similarly, if schizophrenia risks can be predicted before there are actual changes in brain structure, there may be ways to offer better or more effective treatments.
“Even if we know from other testing or family history that someone is at risk of a disorder such as Alzheimer’s, we are still unable to predict when exactly it will occur,” Calhoun said. “Brain imaging could narrow down that time window, by catching the relevant patterns when they do show up before clinical disease is apparent.”
“The vision is that we collect a large imaging dataset, our AI models pore over it, and show us what they learned about certain disorders,” Plis said. “We are building systems to discover new knowledge we could not discover on our own.”
“Our goal,” said Md Mahfuzur Rahman, first author on the study and a doctoral student in computer science at Georgia State, “is to bridge big worlds and big datasets with small worlds and disease-specific datasets and move towards markers relevant for clinical decisions.”
Lateral habenula glutamatergic neurons projecting to the dorsal raphe nucleus promote aggressive arousal in mice
by Aki Takahashi, Romain Durand-de Cuttoli, Meghan E. Flanigan, Emi Hasegawa, Tomomi Tsunematsu, Hossein Aleyasin, Yoan Cherasse, Ken Miya, Takuya Okada, Kazuko Keino-Masu, Koshiro Mitsui, Long Li, Vishwendra Patel, Robert D. Blitzer, Michael Lazarus, Kenji F. Tanaka, Akihiro Yamanaka, Takeshi Sakurai, Sonoko Ogawa, Scott J. Russo in Nature Communications
When male animals spend time around other males of the same species, subsequent aggressive behavior tends to be amplified — this type of priming is known as social instigation. However, the pathway in the brain that leads to this increased aggression was, until recently, relatively unknown. In a study published in Nature Communications, researchers from the University of Tsukuba have revealed that the lateral habenula, a small and relatively primitive region located deep within the brain, is important for this behavior in mice.
Aggressive behavior, especially between males, is important in many animal species and can be promoted in a number of different ways, including by social instigation. Although this behavioral effect is well characterized, the brain pathway that is responsible for it is less understood. The dorsal raphe nucleus is a brain region that controls aggressive behaviors, and it receives glutamate (a molecule that acts as a signal between brain cells) when social instigation occurs. However, the source of this glutamate was a mystery. Researchers from the University of Tsukuba decided to address this gap in the knowledge.
“Many different brain regions release glutamate into the dorsal raphe nucleus,” explains lead author of the study Professor Aki Takahashi. “Because our initial experiments suggested that glutamate release from the lateral habenula might be responsible for aggression induced by social instigation, we conducted more experiments to see if this was the case.”
The research team used two different techniques to block communication between the lateral habenula and dorsal raphe nucleus in mice, and found that this also blocked the increased aggression caused by social instigation — but it didn’t affect normal levels of aggression, suggesting that this pathway is not important for aggressive behavior in general.
“We then wanted to look at the pathway beyond the dorsal nucleus,” says Professor Takahashi. “We found that social instigation caused signals to travel through the brain from the lateral habenula to the dorsal raphe nucleus and then on to the ventral tegmental area — a highly connected region in the midbrain — leading to heightened aggression.”
Although there are many differences in aggression between humans and mice, the results of this new study may have applications when investigating socially provoked anger or violence. There is currently a lack of effective preventative measures against socially provoked aggression, and any information that increases our understanding of these aggressive behaviors will be useful.
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