Category: Neurology

Categories : NeurologyTags :

Getting Vital Creatine into the Brain is a Weighty Problem

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Photo by Jonathan Borba on Unsplash

Creatine is popularly known as a muscle-building supplement, but its influence on human muscle function can be a matter of life or death. But getting it to one particular organ that needs it – the brain – is challenging.

“Creatine is very crucial for energy-consuming cells in skeletal muscle throughout the body, but also in the brain and in the heart,” said Chin-Yi Chen, a research scientist at Virginia Tech’s Fralin Biomedical Research Institute at VTC.

Chen is part of a research team working to develop a technique that uses focused ultrasound to deliver creatine directly to the brain. The work, being conducted in the lab of Fralin Biomedical Research Institute Assistant Professor Cheng-Chia “Fred” Wu, will be supported by a $30 000 grant from the Association for Creatine Deficiencies.

Creatine plays a vital role in the brain, where it interacts with phosphoric acid to help create the key energy molecule adenosine triphosphate (ATP). In addition to its role in energy production, creatine also influences neurotransmitter systems.

For example, creatine influences the brain’s major inhibitory pathways that use the neurotransmitter gamma-aminobutyric acid (GABA), which limits neuronal excitability in the central nervous system. It may play a role in a variety of functions, including seizure control, learning, memory, and brain development.

A growing body of research suggests that creatine may itself function as a neurotransmitter, as it is delivered to neurons from glial cells in the brain and can influence signalling processes between other neurons. While creatine deficiency disorders can weaken the skeletal muscle and the heart, they can also severely affect the brain. Many patients see increased muscle mass and body weight with creatine supplements, but they often continue to face neurodevelopmental challenges that can hinder their ability to speak, read, or write.

This is largely caused by the brain’s protective blood-brain barrier preventing creatine entry.

Wu studies therapeutic focused ultrasound, which precisely directs sound waves to temporarily accessed areas of the brain. The process allows drugs to reach diseased tissue without harming surrounding healthy cells. While Wu is investigating this method as a potential treatment for paediatric brain cancer, he also sees potential in applying it to creatine deficiency.

“Through the partnership between Virginia Tech and Children’s National Hospital, I was able to present our work in focused ultrasound at the Children’s National Research & Innovation Campus,” Wu said. “There, I met Dr Seth Berger, a medical geneticist, who introduced me to creatine transporter deficiency. Together, we saw the promise that focused ultrasound had to offer.”

The Focused Ultrasound Foundation has recognised Virginia Tech and Children’s National as Centers of Excellence. Wu said the two organisations bring together clinical specialists, trial experts, and research scientists who can design experiments that could inform future clinical trials.

“It was a moment that made me really excited – that I had found a lab where I could move from basic research to something that could help patients,” Chen said. “When Fred asked me, ‘Are you interested in this project?’ I said, ‘Yes, of course.’”

Because creatine deficiencies can impair brain development, the early stages of Chen’s project will concentrate on using focused ultrasound to deliver creatine across the blood-brain barrier. Chen hopes the technique will restore normal brain mass in models of creatine deficiency.

Source: Virginia Tech

Categories : NeurologyTags :

Scientists Grow Novel ‘Whole-brain’ Organoid

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Image from Pixabay.

Johns Hopkins University researchers have grown a novel whole-brain organoid, complete with neural tissues and rudimentary blood vessels, in an advance that could usher in a new era of research into neuropsychiatric disorders such as autism.

“We’ve made the next generation of brain organoids,” said senior author Annie Kathuria, an assistant professor in JHU’s Department of Biomedical Engineering who studies brain development and neuropsychiatric disorders. “Most brain organoids that you see in papers are one brain region, like the cortex or the hindbrain or midbrain. We’ve grown a rudimentary whole-brain organoid; we call it the multi-region brain organoid (MRBO).”

The research, published in Advanced Science, marks one of the first times scientists have been able to generate an organoid with tissues from each region of the brain connected and acting in concert. Having a human cell-based model of the brain will open possibilities for studying schizophrenia, autism, and other neurological diseases that affect the whole brain – work that typically is conducted in animal models.

To generate a whole-brain organoid, Kathuria and members of her team first grew neural cells from the separate regions of the brain and rudimentary forms of blood vessels in separate lab dishes. The researchers then stuck the individual parts together with sticky proteins that act as a biological superglue and allowed the tissues to form connections. As the tissues began to grow together, they started producing electrical activity and responding as a network.

Much smaller compared to a real brain – weighing in at 6 million to 7 million neurons compared with tens of billions in adult brains – these organoids provide a unique platform on which to study whole-brain development.

The researchers also saw the creation of an early blood–brain barrier formation, a layer of cells that surround the brain and control which molecules can pass through.

“We need to study models with human cells if you want to understand neurodevelopmental disorders or neuropsychiatric disorders, but I can’t ask a person to let me take a peek at their brain just to study autism,” Kathuria said. “Whole-brain organoids let us watch disorders develop in real time, see if treatments work, and even tailor therapies to individual patients.”

Using whole-brain organoids to test experimental drugs may also help improve the rate of clinical trial success, researchers said. Roughly 85% to 90% of drugs fail during Phase 1 clinical trials. For neuropsychiatric drugs, the fail rate is closer to 96%. This is because scientists predominantly study animal models during the early stages of drug development. Whole-brain organoids more closely resemble the natural development of a human brain and likely will make better test subjects.

“Diseases such as schizophrenia, autism, and Alzheimer’s affect the whole brain, not just one part of the brain. If you can understand what goes wrong early in development, we may be able to find new targets for drug screening,” Kathuria said. “We can test new drugs or treatments on the organoids and determine whether they’re actually having an impact on the organoids.”

Source: Johns Hopkins Medicine

Categories : Neurology UrogenitalTags :

New Discovery Reveals the Spinal Cord’s Role in Bladder Control

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Urinary incontinence. Credit: Scientific Animations CC4.0

Urinary incontinence is a devastating condition, leading to significant adverse impacts on patients’ mental health and quality of life. Disorders of urination are also a key feature of all neurological disorders.

A USC research team has now made major progress in understanding how the human spinal cord triggers the bladder emptying process. The discovery could lead to exciting new therapies to help patients regain control of this essential function.

In the pioneering study, a team from USC Viterbi School of Engineering and Keck School of Medicine of USC has harnessed functional ultrasound imaging to observe real-time changes in blood flow dynamics in the human spinal cord during bladder filling and emptying.

The work was published in Nature Communications and was led by Charles Liu, the USC Neurorestoration Center director at Keck School of Medicine of USC and professor of biomedical engineering at USC Viterbi, and Vasileios Christopoulos, assistant professor at the Alfred E. Mann Department of Biomedical Engineering.

The spinal cord regulates many essential human functions, including autonomic processes like bladder, bowel, and sexual function. These processes can break down when the spinal cord is damaged or degenerated due to injury, disease, stroke, or aging. However, the spinal cord’s small size and intricate bony enclosure have made it notoriously challenging to study directly in humans.

Unlike in the brain, routine clinical care does not involve invasive electrodes and biopsies in the spinal cord due to the obvious risks of paralysis.

Furthermore, fMRI imaging, which comprises most of human functional neuroimaging, does not exist in practical reality for the spinal cord, especially in the thoracic and lumbar regions where much of the critical function localises.

“The spinal cord is a very undiscovered area,” Christopoulos said. “It’s very surprising to me because when I started doing neuroscience, everybody was talking about the brain. And Dr. Liu and I asked, “What about the spinal cord?”

“For many, it was just a cable that transfers information from the brain to the peripheral system. The truth was that we didn’t know how to go there—how to study the spinal cord in action, visualize its dynamics and truly grasp its role in physiological functions.”

Functional ultrasound imaging: A new window into the spinal cord

To overcome these barriers, the USC team employed functional ultrasound imaging (fUSI), an emerging neuroimaging technology that is minimally invasive. The fUSI process allowed the team to measure where changes in blood volume occur on the spinal cord during the cycle of urination.

However, fUSI requires a “window” through the bone to image the spinal cord. The researchers found a unique opportunity by working with a group of patients undergoing standard-of-care epidural spinal cord stimulation surgery for chronic low back pain.

“During the implantation of the spinal cord stimulator, the window we create in the bone through which we insert the leads gives us a perfect and safe opportunity to image the spinal cord using fUSI with no risk or discomfort to the study volunteers,” said co-first author Darrin Lee, associate director of the USC Neurorestoration Center, who performed the surgeries.

“While the surgical team was preparing the stimulator, we gently filled and emptied the bladder with saline to simulate a full urination cycle under anaesthesia while the research team gathered the fUSI data,” added Evgeniy Kreydin from the Rancho Los Amigos National Rehabilitation Center and the USC Institute of Urology, who was already working closely with Liu to study the brain of stroke patients during micturition using fMRI.

“This is the first study where we’ve shown that there are areas in the spinal cord where activity is correlated with the pressure inside the bladder,” Christopoulos said.

“Nobody had ever shown a network in the spinal cord correlated with bladder pressure. What this means is I can look at the activity of your spinal cord in these specific areas and tell you your stage of the bladder cycle – how full your bladder is and whether you’re about to urinate.”

Christopoulos said the experiments identified that some spinal cord regions showed positive correlation, meaning their activity increased as bladder pressure rose, while others showed negative (anti-correlation), with activity decreasing as pressure increased. This suggests the involvement of both excitatory and inhibitory spinal cord networks in bladder control.

“It was extremely exciting to take data straight from the fUSI scanner in the OR to the lab, where advanced data science techniques quickly revealed results that have never been seen before, even in animal models, let alone in humans,” said co-first author Kofi Agyeman, biomedical engineering postdoc.

New hope for patients

Liu has worked for two decades at the intersection of engineering and medicine to develop transformative strategies to restore function to the nervous system. Christopoulos has spent much of his research career developing neuromodulation techniques to help patients regain motor control.

Together, they noted that for patients, retaining control of the autonomic processes that many of us take for granted is more fundamental than even walking.

“If you ask these patients, the most important function they wanted to restore was not their motor or sensory function. It was things like sexual function and bowel and bladder control,” Christopoulos said, noting that urinary dysfunction often leads to poor mental health. “It’s a very dehumanising problem to deal with.”

Worse still, urinary incontinence leads to more frequent urinary tract infections (UTIs) because patients must often be fitted with a catheter. Due to limited sensory function, they may not be able to feel that they have an infection until it is more severe and has spread to the kidneys, resulting in hospitalisation.

This study offers a tangible path toward addressing this critical need for patients suffering from neurogenic lower urinary tract dysfunction. The ability to decode bladder pressure from spinal cord activity provides proof-of-concept for developing personalised spinal cord interfaces that could warn patients about their bladder state, helping them regain control.

Currently, almost all neuromodulation strategies for disorders of micturition are focused on the lower urinary tract, largely because the neural basis of this critical process remains unclear.

“One has to understand a process before one can rationally improve it,” Liu said.

This latest research marks a significant step forward, opening new avenues for precision medicine interventions that combine invasive and noninvasive neuromodulation with pharmacological therapeutics to make neurorestoration of the genitourinary system a clinical reality for millions worldwide.

Source: University of Southern Carolina

Categories : Mental Health NeurologyTags :

Astrocytes Identified as Hidden Culprit Behind PTSD

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Excessive astrocytic GABA impairs fear extinction in PTSD, new drug target offers hope for treatment

Figure 1. Astrocyte-Derived GABA and Therapeutic Effects of KDS2010 in PTSD. Brain imaging of PTSD patients revealed unusually high levels of GABA and reduced cerebral blood flow in the prefrontal cortex, showing that changes strongly correlated with symptom severity. In animal models, this excess GABA was traced to reactive astrocytes producing it abnormally due to increased MAOB and reduced levels of the GABA-degrading enzyme ABAT. This disrupted normal brain function and impaired the ability to extinguish fear. Treatment with KDS2010, a selective MAOB inhibitor, successfully lowered astrocytic GABA, restored brain activity, and rescued fear extinction, highlighting its potential as a therapeutic option. Credit: Institute for Basic Science

Why do patients with post traumatic stress disorder (PTSD) often struggle to forget traumatic memories, even long after the danger has passed? This failure to extinguish fear memories has long puzzled scientists and posed a major hurdle for treatment, especially since current medications targeting serotonin receptors offer limited relief for only a subset of patients.

In a new discovery, scientists at the Institute for Basic Science (IBS) and Ewha Womans University have uncovered a new brain mechanism driving PTSD – and a promising drug that may counteract its effects. The research is reported in Signal Transduction and Target Therapy.

Led by Dr C. Justin Lee at the IBS Center for Cognition and Sociality and Professor Lyoo In Kyoon at Ewha Womans University, the team has shown that excessive GABA (gamma-aminobutyric acid) produced by astrocytes, which are star-shaped support cells in the brain, impairs the brain’s ability to extinguish fear memories. This deficit is a core feature of PTSD and helps explain why traumatic memories can persist long after the threat has passed.

Crucially, the researchers found that a brain-permeable drug called KDS2010, which selectively blocks the monoamine oxidase B enzyme responsible for this abnormal GABA production, can reverse PTSD-like symptoms in mice. The drug has already passed Phase 1 safety trials in humans, making it a strong candidate for future PTSD treatments.

PTSD remains difficult to treat, with current medications targeting serotonin pathways providing limited relief for many patients. The new study focused on the medial prefrontal cortex (mPFC), a region of the brain critical for regulating fear, and found that PTSD patients had unusually high levels of GABA and reduced cerebral blood flow in this area. These findings emerged from brain imaging studies of more than 380 participants. Importantly, GABA levels decreased in patients who showed clinical improvement, pointing to the chemical’s central role in recovery.

To uncover the origin of this excess GABA, the researchers examined postmortem human brain tissue and used PTSD-like mouse models. They discovered that astrocytes, not neurons, were producing abnormal amounts of GABA via the enzyme monoamine oxidase B (MAOB). This astrocyte-derived GABA impaired neural activity, blocking the brain’s ability to forget traumatic memories.

When the researchers administered KDS2010, a highly selective, reversible MAOB inhibitor developed at IBS, the mice showed normalized brain activity and were able to extinguish fear responses. The drug reduced GABA levels, restored blood flow in the mPFC, and re-enabled memory extinction mechanisms. The study thus confirms astrocytic MAOB as a central driver of PTSD symptoms, and MAOB inhibition as a viable therapeutic path.

A major challenge of the study was linking clinical findings in humans with cellular mechanisms in the lab. The researchers addressed this by applying a “reverse translational” strategy: they began with clinical brain scans and moved backward to identify the cellular source of dysfunction, then confirmed the mechanism and tested drug effects in animal models. This approach led to a new understanding of how glial cells – long thought to be passive – actively shape psychiatric symptoms.

“This study is the first to identify astrocyte-derived GABA as a key pathological driver of fear extinction deficit in PTSD,” said Dr Won Woojin, a postdoctoral researcher and co-first author of the study. “Our findings not only uncover a novel astrocyte-based mechanism underlying PTSD, but also provide preclinical evidence for a new therapeutic approach using an MAOB inhibitor.”

Director C. Justin LEE, who led the study, emphasized that “This work represents a successful example of reverse translational research, where clinical findings in human guided the discovery of underlying mechanisms in animal models. By identifying astrocytic GABA as a pathological driver in PTSD and targeting it via MAOB inhibition, the study opens a completely new therapeutic paradigm not only for PTSD but also for other neuropsychiatric disorders such as panic disorder, depression, and schizophrenia.”

The researchers plan to further investigate astrocyte-targeted therapies for various neuropsychiatric disorders. With KDS2010 currently undergoing Phase 2 clinical trials, this discovery may soon lead to new options for patients whose symptoms have not responded to conventional treatments.

Source: Institute for Basic Science

Categories : NeurologyTags :

How the Brain Controls Its Blood Volume

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Inhibitory neurons and astrocytes hold the key to sharper functional brain imaging –

Image of an astrocyte, a subtype of glial cells. Glial cells are the most common cell in the brain. Credit: Pasca Lab, Stanford University NIH support from: NINDS, NIMH, NIGMS, NCATS

Researchers at the Center for Neuroscience Imaging Research within the Institute for Basic Science (IBS) have uncovered a two-step mechanism by which the brain regulates blood volume – a breakthrough with significant implications for how scientists understand and interpret functional magnetic resonance imaging (fMRI).

At the core of this study are somatostatin-expressing interneurons (SST neurons), a specialised type of inhibitory neuron. Among all neurons in the brain, approximately 15% are inhibitory neurons, but the role of these neurons in regulating cerebral blood volume has not been clearly elucidated in previous studies, with most of earlier research mainly focusing on the excitatory neurons. The new study by the IBS team sheds light on how inhibitory neurons interact with astrocytes, a type of support cell, to precisely control blood vessel dilation in the brain.

To unravel this complex process, the research team developed mouse models (e.g., SST-ChR2, SST-hM4Di) that allowed selective activation or inhibition of SST neurons. The researchers also used advanced neuroscience techniques in these mice. Specifically, they applied optogenetics and chemogenetics to precisely control the activity of these neurons. To observe the cellular and vascular responses, the team employed calcium imaging to visualise astrocyte activity, electrophysiology to measure neural signals, and intrinsic optical imaging (OIS) alongside ultra-high-field functional MRI (fMRI) to track blood volume dynamics with high spatial and temporal resolution.

Through these experiments, the team uncovered a two-step mechanism of vasodilation. In the early phase, SST neurons, when activated, released nitric oxide (NO) – a powerful vasodilator that triggered rapid and widespread expansion of nearby blood vessels. This was followed by a late phase, in which astrocytes became activated and induced slower, more localised vasodilation, especially during periods of prolonged sensory stimulation.

Figure 1. Somatostatin neurons regulate astrocytes surrounding cerebral blood vessels, enabling more precise delivery of blood volume to specific brain regions, thereby enhancing the spatial accuracy of neurovascular responses. Credit: Institute for Basic Science

Notably, when SST neurons were silenced, the layer-specific precision of blood volume signals observed in fMRI was lost – a finding that links cellular activity directly to spatial specificity in imaging data.

“This two-step mechanism involving inhibitory neurons and astrocytes helps explain why high-resolution fMRI can distinguish activity between different layers of the brain cortex,” the researchers explained. “Our study fills a major gap in understanding how neural signals are translated into the blood volume changes we measure in brain imaging.”

The team also overcame several technical challenges – including distinguishing overlapping signals and timing differences – by integrating multiple imaging techniques and running extensive repeat experiments to validate the causal link between SST neuron activity and vascular responses.

Their findings not only advance basic knowledge of neurovascular coupling, but also open new avenues for investigating neurological and psychiatric conditions in which SST neuron function is impaired, such as Alzheimer’s disease, depression, and autism. The group plans to study disease-model mice to identify how disruptions in this neuron–astrocyte–vascular pathway affect blood volume, brain function, and fMRI signals.

Ultimately, this research lays the groundwork for improving the accuracy of brain imaging interpretation and may lead to better diagnostic and therapeutic strategies for brain disorders.

Source: Institute for Basic Science

Categories : NeurologyTags :

Why Do We Need Sleep? Oxford Researchers Find the Answer May Lie in Mitochondria

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New study uncovers how a metabolic “overload” in specialised brain cells triggers the need to sleep.

Photo by Cottonbro on Pexels

Sleep may not just be rest for the mind – it may be essential maintenance for the body’s power supply. A new study by University of Oxford researchers, published in Nature, reveals that the pressure to sleep arises from a build-up of electrical stress in the tiny energy generators inside brain cells.

The discovery offers a physical explanation for the biological drive to sleep and could reshape how scientists think about sleep, ageing, and neurological disease.

Led by Professor Gero Miesenböck from the Department of Physiology, Anatomy and Genetics (DPAG), and Dr Raffaele Sarnataro at Oxford’s Centre for Neural Circuits and Behaviour, the team found that sleep is triggered by the brain’s response to a subtle form of energy imbalance. The key lies in mitochondria – microscopic structures inside cells that use oxygen to convert food into energy.

When the mitochondria of certain sleep-regulating brain cells (studied in fruit flies) become overcharged, they start to leak electrons, producing potentially damaging byproducts known as reactive oxygen species. This leak appears to act as a warning signal that pushes the brain into sleep, restoring equilibrium before damage spreads more widely.

‘You don’t want your mitochondria to leak too many electrons,’ said Dr Sarnataro. ‘When they do, they generate reactive molecules that damage cells.’

The researchers found that specialised neurons act like circuit breakers – measuring this mitochondrial electron leak and triggering sleep when a threshold is crossed. By manipulating the energy handling in these cells – either increasing or decreasing electron flow – the scientists could directly control how much the flies slept.

Even replacing electrons with energy from light (using proteins borrowed from microorganisms) had the same effect: more energy, more leak, more sleep.

Professor Miesenböck said: ‘We set out to understand what sleep is for, and why we feel the need to sleep at all. Despite decades of research, no one had identified a clear physical trigger. Our findings show that the answer may lie in the very process that fuels our bodies: aerobic metabolism. In certain sleep-regulating neurons, we discovered that mitochondria – the cell’s energy producers – leak electrons when there is an oversupply. When the leak becomes too large, these cells act like circuit breakers, tripping the system into sleep to prevent overload.’

The findings help explain well-known links between metabolism, sleep, and lifespan. Smaller animals, which consume more oxygen per gram of body weight, tend to sleep more and live shorter lives. Humans with mitochondrial diseases often experience debilitating fatigue even without exertion, now potentially explained by the same mechanism.

‘This research answers one of biology’s big mysteries,’ said Dr Sarnataro.

‘Why do we need sleep? The answer appears to be written into the very way our cells convert oxygen into energy.’

The paper, ‘Mitochondrial origins of the pressure to sleep‘, is published in Nature.

Source: University of Oxford

Categories : Implants and Prostheses NeurologyTags :

Building Better Cerebrospinal Fluid Shunts for the Brain

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Schematic of approach to simulating brain shunt fluid dynamics. Credit: Harvard SEAS

Millions of people worldwide suffer from hydrocephalus, a condition which recently received greater attention when Billy Joel announced his diagnosis. Treatment usually involves surgical placement of shunts to divert cerebrospinal fluid away, but this procedure often leads to complications, infections, and multiple re-treatments.  

Bioengineers in the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have now developed a new computational model to aid the creation of shunts tailored to individual patients’ anatomy and needs. The model combines brain anatomy, fluid flow, and biomolecular transport dynamics to simulate shunt performance with pinpoint accuracy.

The work was supported by federal funding from the National Science Foundation and published in Proceedings of the National Academy of Sciences. It was led by SEAS postdoctoral fellow Haritosh Patel, who works in the labs of Joanna Aizenberg, Professor of Materials Science at SEAS and Professor of Chemistry and Chemical Biology; and Venkatesh Murthy, Professor of Molecular and Cellular Biology and Director of the Center for Brain Science.

Repeat surgeries due to infection or obstruction

Tens of thousands of shunt procedures are performed annually in the U.S. — many of which are repeat surgeries due to the inserted devices becoming blocked or obstructed, or the patient suffering an infection.

“Some elderly patients told me they had had over 10 surgeries — one every two to three years,” Patel said. “We really wanted to understand why this was happening, and we realised that many of these obstructions and infections were tied to shunt designs that didn’t fully consider fluid dynamics as a fundamental part of their geometry. We noticed that the tubing geometry used in shunts closely resembles the kind of piping we rely on in household plumbing. While that simplicity has its advantages, we saw an opportunity to explore more creative, biomimetic solutions that better suit the complexity of the brain’s environment.”

Pursuing the problem from both a material and design perspective, the team quickly realized there was no universally accepted fluid flow model for the brain ventricle space to guide them. “Okay, well, we can’t test our devices in a model, so why don’t we first make a better model?” Patel said.

Computational tool simulates fluid flow in brain

The result is their computational tool, called BrainFlow, which combines detailed anatomical and physiological features of the brain to simulate the flow of cerebrospinal fluid flow in the presence of shunt implants.

 The model incorporates patient-specific medical imaging data along with pulse-induced flow to mimic a patient’s cerebrospinal fluid dynamics, all to offer insight into optimal shunt design, placement, and even choice of materials.

“We believe that our model, combined with novel geometries and materials improvements such as anti-biofouling coatings developed in my lab, could lead to smoother integration of optimized, patient-specific medical devices into patients’ brains, with less likelihood of complications, and a better quality of life,” Aizenberg said.

The Harvard team is currently conducting studies that use the model to test different designs of shunts and calculate their efficacy.

Source: Harvard John A. Paulson School of Engineering and Applied Sciences

Categories : NeurologyTags :

New Discovery Reveals Dopamine Operates with Surgical Precision

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Neurotransmitters at a synapse. Credit: Scientific Animations CC4.0

A new study from the University of Colorado Anschutz Medical Campus has upended decades of neuroscience dogma by revealing that the neurotransmitter dopamine communicates in the brain with extraordinary precision – not broad diffusion as previously believed. This groundbreaking research offers fresh hope for millions of people living with dopamine-related disorders, marking a significant advance in the quest for precision-based neuroscience and medicine.

For years, scientists thought of dopamine as a kind of chemical “broadcast system,” flooding large areas of the brain to influence behaviour. But new research, published in Science, found that dopamine acts more like a finely-tuned postal service, delivering highly localised messages to specific nerve cell branches at exact moments in time.

“Our current research found that dopamine signaling and transmission in the brain is much more complex than we thought,” said Christopher Ford, PhD, professor at the University of Colorado School of Medicine and lead author. “We knew that dopamine plays a role in many different behaviours, and our work gives the beginning of a framework for understanding how all those different behaviours could all be regulated by dopamine.”

‘We are really only at the tip of the iceberg in trying to understand how dysfunctions in dopamine contribute to diseases like Parkinson’s disease, schizophrenia or addiction.’

– Christopher Ford, PhD

Using advanced microscopy techniques, researchers found that dopamine is released in concentrated hotspots which enable targeted, rapid responses in nearby brain cells, while broader signals activate slower, widespread effects. This dual signaling system allows dopamine to simultaneously fine-tune individual neural connections and orchestrate complex behaviours like movement, decision-making, and learning.

The implications are far-reaching: dopamine system dysfunction plays a central role in a wide range of brain disorders, including Parkinson’s disease, addiction, schizophrenia, ADHD and depression. Current treatments largely focus on restoring overall dopamine levels – but this research suggests that the precision of dopamine signalling may be just as crucial.

“We are really only at the tip of the iceberg in trying to understand how dysfunctions in dopamine contribute to diseases like Parkinson’s disease, schizophrenia or addiction,” said Ford. “More work is needed to grasp how these specific changes in dopamine signalling are affected in these different neurological and psychiatric diseases. The goal, of course, would then be to build on those findings to come up with new and improved treatments for those disorders.”

Source: University of Colorado Anschutz Medical Campus

Categories : Neurology Regenerative MedicineTags :

Scientists Discover the Mechanism for Peripheral Nerve Regeneration

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Weizmann Institute scientists have discovered hundreds of molecules that promote nerve regeneration in mice – and may even encourage growth in brain neurons

Top: Overexpression of genes from the B2-SINE family in retinal ganglion neurons led to accelerated growth after injury. Bottom: Ganglion cells after injury without B2-SINE overexpression. Credit: Weizmann Institute of Science

Unlike the brain and spinal cord, peripheral nerve cells, whose long extensions reach the skin and internal organs, are capable of regenerating after injury. This is why injuries to the central nervous system are considered irreversible, while damage to peripheral nerves can, in some cases, heal, even if it takes months or years. Despite decades of research, the mechanisms behind peripheral nerve regeneration remain only partially understood.

In a new study published in Cell, researchers from Prof Michael (Mike) Fainzilber’s lab at the Weizmann Institute of Science discovered that a family of hundreds of RNA molecules with no known physiological function is essential to nerve regeneration. Remarkably, the study showed that these molecules can stimulate growth not only in the peripheral nervous system of mice but also in their central nervous system. These findings could pave the way for new treatments for a variety of nerve injuries and neurodegenerative diseases.

For a peripheral nerve to regenerate, it must maintain communication between the neuron’s cell body and its long extension – the axon – which in humans can reach more than a meter in length. In a series of studies over the past two decades, Fainzilber’s lab has revealed key components of this communication: proteins that act like postal couriers, delivering instructions for the production of growth-controlling factors and other proteins, from the cell body to the axon. These molecular couriers also help assess the distance between the cell body and the axon tip, allowing the neuron to modulate its growth accordingly. Yet one central issue remained: What triggers the regenerative growth after injury, and why does this not happen in central nervous system cells?

“While the growth acceleration observed in our study is not yet sufficient to address clinical paralysis, it is definitely significant”

In the new study, Dr Indrek Koppel of Fainzilber’s lab, in collaboration with Dr Riki Kawaguchi of the University of California, Los Angeles (UCLA), examined a specific kind of gene expression in the peripheral nerves of mice following injury. The researchers were surprised to find that one day after damage, the neurons increased the expression of an entire family of short genetic sequences called B2-SINEs, whose role was previously unknown. These sequences do not encode any proteins, and because they are known for “jumping” around the genome, meaning that they can appear at the wrong place or time, they have a bad reputation. But the researchers found that after injury, the neurons began expressing many B2-SINE RNA transcripts, in parallel with other processes preparing the cell for regeneration and repair.

However, B2-SINE is an enormous family, comprising some 150 000 sequences scattered throughout the mouse genome. The initial analysis could not determine which of these were responsible for promoting growth. Dr. Eitan Erez Zahavi, also of Fainzilber’s lab, who led the new study alongside Koppel, used bioinformatics tools to identify 453 B2-SINE sequences that are highly expressed after injury, promoting nerve growth. Collaborating with international research teams, the scientists showed that this overexpression after injury is unique to peripheral nerve cells and does not occur in the central nervous system.

The periphery leads, the center follows

The researchers then tested whether B2-SINEs from peripheral nerve cells could also stimulate neuronal growth in the central nervous system. They induced retinal neurons in mice to overexpress RNA molecules of the B2-SINE type and observed faster regeneration after injury. A similar experiment in the mouse motor cortex – the brain region that controls muscle movement via long axons projecting to the spinal cord – showed that neurons expressing high levels of B2-SINE also regenerated faster than control neurons.

“There are still no effective treatments to accelerate nerve cell growth and regeneration,” Fainzilber notes. “While the growth acceleration observed in our study is not yet sufficient to address clinical paralysis, it is definitely significant. Of course, the path from basic research to clinical application is long, and we must make sure that enhancing growth mechanisms does not, for example, increase the risk of cancer.”

One final mystery remained: How do B2-SINE RNA molecules actually promote regeneration? With help from Prof Alma L. Burlingame’s group at the University of California, San Francisco, the researchers discovered that these RNAs promote a physical link between the molecular “couriers” carrying instructions for producing growth-associated proteins and the ribosomes that read these instructions and carry them out. This means that production of the critical factors takes place closer to the cell body rather than to the tip of the axon. The researchers believe that this signals to the neuron that it is “too small,” triggering a growth response.

“There are over a million sequences called Alu elements in the human genome, the human equivalent of B2-SINEs in mice,” says Fainzilber. “These molecules had been previously shown to bind to ribosomes and mail couriers, but why this happens was unknown. We’re now trying to determine whether Alu or other noncoding RNA elements are involved in nerve regeneration in humans.”

“Recovery from peripheral nerve injuries, or from systemic diseases like diabetes that affect these nerves, can be very slow,” he adds. “That’s why we’re now testing a therapy that might speed up regeneration by mimicking B2-SINE activity. This therapy involves small molecules that connect the couriers to ribosomes while keeping them close to the nerve cell body, promoting faster growth. We are conducting this research in collaboration with Weizmann’s Bina unit for early-stage research with applicative potential.”

Beyond promoting peripheral nerve regeneration, the new study also hints at an even broader prospect: regeneration in the central nervous system. “We are currently working with UCLA on a study showing that the mechanism we discovered plays a role in recovery from stroke in mouse models,” Fainzilber says. “Additionally, we’re collaborating with Tel Aviv University, Hebrew University and Sheba Medical Center to study its possible role in ALS, a progressive neurodegenerative disease. Neurodegenerative conditions affect many millions of people worldwide. While the road ahead is long, I truly hope we’ll one day be able to harness our newly discovered regeneration mechanism to treat them.”

Science Numbers

After injury, the axon of a peripheral nerve cell regrows at a rate of around 1 millimetre a day.

Source: Weizmann Institute of Science

Categories : Lab Tests and Imaging NeurologyTags :

Researchers Discover a Significant Problem in Brain Imaging, Identify Fix

On By ModernMedia
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In a new study, investigators from McLean Hospital (a member of Mass General Brigham), Harvard Medical School, and the National Institute on Drug Abuse Intramural Research Program (NIDA-IRP) discovered that the tendency of people’s arousal to wane over the course of brain scans has been distorting the brain connection maps produced by functional magnetic resonance imaging (fMRI).

The study is out now in Nature Human Behaviour.

The team found that as people’s arousal levels dwindle during an fMRI, such as if they become more relaxed and sleepy, changes in breathing and heart rates alter blood oxygen levels in the brain—which are then falsely detected on the scan as neuronal activity.

“You’re laying down in a snug scanner for quite some time, often with only a low-engagement button press task to attend to or nothing to do at all, as the scanner monotonously hums and vibrates around you,” said first author Cole Korponay, PhD, MPA, a research fellow at the McLean Hospital Imaging Center. “These arousal-dampening conditions create the illusion that people’s brain connection strengths continuously inflate throughout the scan.”

fMRI scans are commonly used to non-invasively map brain connectivity, but the technique relies on changes in brain blood oxygen to indirectly measure neuronal activity. It is therefore vulnerable to “noise” from other processes that can affect blood oxygen – such as changes in breathing and heart rates.

And because breathing and heart rate patterns are closely tied to arousal levels, changes in arousal can introduce significant noise into fMRI data. Problematically, the conditions of an fMRI scan tend to progressively lull people into lower arousal states.

In the present study, the research team identified a specific blood flow signal that seemed to track both the decline in subject arousal levels and the illusory inflation of functional brain connection strengths.

This non-neuronal, physiological noise signal, termed the “systemic low frequency oscillation” (sLFO) signal, grew over time during scanning, in a spatial and temporal pattern that closely followed the pattern of the connection strength increases.

The researchers then demonstrated that a method called RIPTiDe, developed by co-senior author Blaise Frederick, PhD, an associate biophysicist at the McLean Imaging Center, to remove the sLFO signal from fMRI data, was able to eliminate the illusory connection strength increases.

“By adopting this sLFO denoising procedure, future studies can mitigate the distortive effects of arousal changes during brain scans and enhance the validity and reliability of fMRI findings,” said Korponay.

This research was supported by the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute on Aging, all part of the National Institutes of Health.

Source: Mass General Brigham McLean Hospital