NS/ Researchers 3D-print functional human brain tissue
Neuroscience biweekly vol. 103, 31st January — 14th February
TL;DR
- It’s an achievement with important implications for scientists studying the brain and working on treatments for a broad range of neurological and neurodevelopmental disorders, such as Alzheimer’s and Parkinson’s disease.
- In a recent study of the brain’s waste drainage system, researchers discovered a direct connection between the brain and its tough protective covering, the dura mater. These links may allow waste fluid to leave the brain while also exposing the brain to immune cells and other signals coming from the dura. This challenges the conventional wisdom which has suggested that the brain is cut off from its surroundings by a series of protective barriers, keeping it safe from dangerous chemicals and toxins lurking in the environment.
- Scientists have found the strongest evidence yet that our brains can compensate for age-related deterioration by recruiting other areas to help with brain function and maintain cognitive performance.
- The world’s largest brain study of childhood trauma has revealed how it affects development and rewires vital pathways. The study uncovered a disruption in neural networks involved in self-focus and problem-solving. This means under-18s who experienced abuse may struggle with emotions, empathy, and understanding of their bodies.
- Scientists have found soundwaves from low-intensity focused ultrasound aimed at a place deep in the brain called the insula can reduce both the perception of pain and other effects of pain, such as heart rate changes.
- By using advanced brain recording techniques, a new study demonstrates how neurons in the human brain work together to allow people to think about what words they want to say and then produce them aloud through speech.
- Researchers have unveiled unprecedentedly detailed images of brain cancer tissue through the use of a new microscopy technology called decrowding expansion pathology (dExPath).
- People with polycystic ovary syndrome may be more likely to have memory and thinking problems in middle age, according to new research. The study does not prove that polycystic ovary syndrome causes cognitive decline. It only shows an association.
- New research has uncovered a way to ‘hack’ neurons’ internal clocks to speed up their development. The approach promises to accelerate research into neurological disease.
- Axon damage is an early sign of neurodegenerative diseases like, ALS, and Alzheimer’s, Huntington’s and Parkinson’s. Researchers found that nicotinamide nucleotide adenylyl transferase 2, or NMNAT2, can play an important role in keeping axons healthy and functional as people age.
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3D bioprinting of human neural tissues with functional connectivity
by Yuanwei Yan, Xueyan Li, Yu Gao, Sakthikumar Mathivanan, Linghai Kong, Yunlong Tao, Yi Dong, Xiang Li, Anita Bhattacharyya, Xinyu Zhao, Su-Chun Zhang in Cell Stem Cell
University of Wisconsin-Madison scientists have developed the first 3D-printed brain tissue that can grow and function like typical brain tissue.
It’s an achievement with important implications for scientists studying the brain and working on treatments for a broad range of neurological and neurodevelopmental disorders, such as Alzheimer’s and Parkinson’s disease.
“This could be a hugely powerful model to help us understand how brain cells and parts of the brain communicate in humans,” says Su-Chun Zhang, professor of neuroscience and neurology at UW-Madison’s Waisman Center. “It could change the way we look at stem cell biology, neuroscience, and the pathogenesis of many neurological and psychiatric disorders.”
Printing methods have limited the success of previous attempts to print brain tissue, according to Zhang and Yuanwei Yan, a scientist in Zhang’s lab.
The group behind the new 3D-printing process described their method today in the journal Cell Stem Cell. Instead of using the traditional 3D-printing approach, stacking layers vertically, the researchers went horizontally. They situated brain cells, neurons grown from induced pluripotent stem cells, in a softer “bio-ink” gel than previous attempts had employed.
“The tissue still has enough structure to hold together but it is soft enough to allow the neurons to grow into each other and start talking to each other,” Zhang says.
The cells are laid next to each other like pencils laid next to each other on a tabletop.
“Our tissue stays relatively thin and this makes it easy for the neurons to get enough oxygen and enough nutrients from the growth media,” Yan says.
The results speak for themselves — which is to say, the cells can speak to each other. The printed cells reach through the medium to form connections inside each printed layer as well as across layers, forming networks comparable to human brains.
The neurons communicate, send signals, interact with each other through neurotransmitters, and even form proper networks with support cells that were added to the printed tissue.
“We printed the cerebral cortex and the striatum and what we found was quite striking,” Zhang says. “Even when we printed different cells belonging to different parts of the brain, they were still able to talk to each other in a very special and specific way.”
The printing technique offers precision — control over the types and arrangement of cells — not found in brain organoids, miniature organs used to study brains.
The organoids grow with less organization and control.
“Our lab is very special in that we are able to produce pretty much any type of neurons at any time. Then we can piece them together at almost any time and in whatever way we like,” Zhang says. “Because we can print the tissue by design, we can have a defined system to look at how our human brain network operates. We can look very specifically at how the nerve cells talk to each other under certain conditions because we can print exactly what we want.”
That specificity provides flexibility. The printed brain tissue could be used to study signaling between cells in Down syndrome, interactions between healthy tissue and neighboring tissue affected by Alzheimer’s, testing new drug candidates, or even watching the brain grow.
“In the past, we have often looked at one thing at a time, which means we often miss some critical components. Our brain operates in networks. We want to print brain tissue this way because cells do not operate by themselves. They talk to each other. This is how our brain works and it has to be studied all together like this to truly understand it,” Zhang says. “Our brain tissue could be used to study almost every major aspect of what many people at the Waisman Center are working on. It can be used to look at the molecular mechanisms underlying brain development, human development, developmental disabilities, neurodegenerative disorders, and more.”
The new printing technique should also be accessible to many labs.
It does not require special bio-printing equipment or culturing methods to keep the tissue healthy, and can be studied in depth with microscopes, standard imaging techniques and electrodes already common in the field.
The researchers would like to explore the potential of specialization, though, further improving their bio-ink and refining their equipment to allow for specific orientations of cells within their printed tissue.
“Right now, our printer is a benchtop commercialized one,” Yan says. “We can make some specialized improvements to help us print specific types of brain tissue on-demand.”
Identification of direct connections between the dura and the brain
by Leon C. D. Smyth, Di Xu, Serhat V. Okar, Taitea Dykstra, Justin Rustenhoven, Zachary Papadopoulos, Kesshni Bhasiin, Min Woo Kim, Antoine Drieu, Tornike Mamuladze, Susan Blackburn, Xingxing Gu, María I. Gaitán, Govind Nair, Steffen E. Storck, Siling Du, Michael A. White, Peter Bayguinov, Igor Smirnov, Krikor Dikranian, Daniel S. Reich, Jonathan Kipnis in Nature
In a recent study of the brain’s waste drainage system, researchers from Washington University in St. Louis, collaborating with investigators at the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institute of Health (NIH), discovered a direct connection between the brain and its tough protective covering, the dura mater. These links may allow waste fluid to leave the brain while also exposing the brain to immune cells and other signals coming from the dura. This challenges the conventional wisdom which has suggested that the brain is cut off from its surroundings by a series of protective barriers, keeping it safe from dangerous chemicals and toxins lurking in the environment.
“Waste fluid moves from the brain into the body much like how sewage leaves our homes,” said NINDS’s Daniel S. Reich, M.D., Ph.D. “In this study, we asked the question of what happens once the ‘drain pipes’ leave the ‘house’ — in this case, the brain — and connect up with the city sewer system within the body.” Reich’s group worked jointly with the lab of Jonathan Kipnis, Ph.D., a professor at Washington University in St. Louis.
Reich’s lab used high-resolution magnetic resonance imaging (MRI) to observe the connection between the brain and the body’s lymphatic systems in humans. Meanwhile, Kipnis’s group was independently using live-cell and other microscopic brain imaging techniques to study these systems in mice.
Using MRI, the researchers scanned the brains of a group of healthy volunteers who had received injections of gadobutrol, a magnetic dye used to visualize disruptions in the blood-brain barrier or other kinds of blood vessel damage.
Large veins are known to pass through the arachnoid barrier carrying blood away from the brain, and these were observed on the MRI scans.
As the scan progressed, a ring of dye appeared around those large veins that slowly spread out over time, suggesting that fluid could make its way through the space around those large veins where they pass through the arachnoid barrier on their way into the dura.
Kipnis’s lab was making similar observations in mice. His group injected mice with light-emitting molecules. Like with the MRI experiments, fluid containing these light-emitting molecules was seen to slip through the arachnoid barrier where blood vessels passed through.
Together, the labs found a “cuff” of cells that surround blood vessels as they pass through the arachnoid space.
These areas, which they called arachnoid cuff exit (ACE) points, appear to act as areas where fluid, molecules, and even some cells can pass from the brain into the dura and vice versa, without allowing complete mixing of the two fluids.
In some disorders like Alzheimer’s disease, impaired waste clearance can cause disease-causing proteins to build up. Continuing the sewer analogy, Kipnis explained the possible connection to ACE points:
“If your sink is clogged, you can remove water from the sink or fix the faucet, but ultimately you need to fix the drain,” he said. “In the brain, clogs at ACE points may prevent waste from leaving. If we can find a way to clean these clogs, its possible we can protect the brain.”
One implication of ACE points is that they are areas where the immune system can be exposed to and react to changes occurring in the brain.
When mice in Dr. Kipnis’s lab were induced to have a disorder where the immune system attacks the myelin in their brain and spinal cord, immune cells could be seen around ACE points and even between the blood vessel wall and the cuff cells; this led over time to a breakdown of the ACE point itself.
When the ability of immune cells to interact directly with ACE points was blocked, the severity of infection was reduced.
“The immune system uses molecules to communicate that cross from the brain into the dura mater,” said Kipnis. “This crossing needs to be tightly regulated, otherwise detrimental effects on brain function can occur.”
Reich and his team also observed an interesting connection between the participant’s age and the leakiness of ACE points.
In older participants, more dye leaked into the surrounding fluid and space around the blood vessels.
“This might point to a slow breakdown of the ACE points over the course of aging,” said Reich, “and this could be consequential in that the brain and immune system can now interact in ways that they’re not supposed to.”
The connection to aging and the disruption of a barrier separating the brain and immune system fits with what has been observed in aging mice and in autoimmune disorders like multiple sclerosis.
Neural Evidence of Functional Compensation for Fluid Intelligence in Healthy Ageing
by Ethan Knights, Richard N. Henson, Alexa M. Morcom, Daniel J. Mitchell, Kamen A. Tsvetanov in eLife
Scientists have found the strongest evidence yet that our brains can compensate for age-related deterioration by recruiting other areas to help with brain function and maintain cognitive performance.
As we age, our brain gradually atrophies, losing nerve cells and connections and this can lead to a decline in brain function. It’s not fully understood why some people appear to maintain better brain function than others, and how we can protect ourselves from cognitive decline.
A widely accepted notion is that some people’s brains can compensate for the deterioration in brain tissue by recruiting other areas of the brain to help perform tasks. While brain imaging studies have shown that the brain does recruit other areas, until now it has not been clear whether this makes any difference to performance on a task, or whether it provides any additional information about how to perform that task.
In a study published in the journal eLife, a team led by scientists at the University of Cambridge in collaboration with the University of Sussex has shown that when the brain recruits other areas, it improves performance specifically in the brains of older people.
Study lead Dr Kamen Tsvetanov, an Alzheimer’s Society Dementia Research Leader Fellow in the Department of Clinical Neurosciences, University of Cambridge, said: “Our ability to solve abstract problems is a sign of so-called ‘fluid intelligence’, but as we get older, this ability begins to show significant decline. Some people manage to maintain this ability better than others. We wanted to ask why that was the case — are they able to recruit other areas of the brain to overcome changes in the brain that would otherwise be detrimental?”
Brain imaging studies have shown that fluid intelligence tasks engage the ‘multiple demand network’ (MDN), a brain network involving regions both at the front and rear of the brain, but its activity decreases with age. To see whether the brain compensated for this decrease in activity, the Cambridge team looked at imaging data from 223 adults between 19 and 87 years of age who had been recruited by the Cambridge Centre for Ageing & Neuroscience (Cam-CAN).
The volunteers were asked to identify the odd-one-out in a series of puzzles of varying difficulty while lying in a functional magnetic resonance imaging (fMRI) scanner, so that the researchers could look at patterns of brain activity by measuring changes in blood flow.
As anticipated, in general, the ability to solve problems decreased with age. The MDN was particularly active, as were regions of the brain involved in processing visual information.
When the team analyzed the images further using machine-learning, they found two areas of the brain that showed greater activity in the brains of older people and also correlated with better performance on the task. These areas were the cuneus, at the rear of the brain, and a region in the frontal cortex. But of the two, only activity in the cuneus region was related to the performance of the task more strongly in the older than younger volunteers and contained extra information about the task beyond the MDN.
Although it is not clear exactly why the cuneus should be recruited for this task, the researchers point out that this brain region is usually good at helping us stay focused on what we see. Older adults often have a harder time briefly remembering information that they have just seen, like the complex puzzle pieces used in the task. The increased activity in the cuneus might reflect a change in how often older adults look at these pieces, as a strategy to make up for their poorer visual memory.
Dr Ethan Knights from the Medical Research Council Cognition and Brain Sciences Unit at Cambridge said: “Now that we’ve seen this compensation happening, we can start to ask questions about why it happens for some older people, but not others, and in some tasks, but not others. Is there something special about these people — their education or lifestyle, for example — and if so, is there a way we can intervene to help others see similar benefits?”
Dr Alexa Morcom from the University of Sussex’s School of Psychology and Sussex Neuroscience Research Center said:
“This new finding also hints that compensation in later life does not rely on the multiple demand network as previously assumed, but recruits areas whose function is preserved in aging.”
An FMRI Meta-Analysis of Childhood Trauma
by Rebecca Ireton, Anna Hughes, Megan Klabunde in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
The world’s largest brain study of childhood trauma has revealed how it affects development and rewires vital pathways.
The University of Essex study — led by the Department of Psychology’s Dr Megan Klabunde — uncovered a disruption in neural networks involved in self-focus and problem-solving.
This means under-18s who experienced abuse will likely struggle with emotions, empathy, and understanding of their bodies. Difficulties in school caused by memory, hard mental tasks and decision-making may also emerge.
Dr Klabunde’s cutting-edge research used AI to re-examine hundreds of brain scans and identify patterns. It is hoped the research will help hone new treatments for children who have endured mistreatment.
PRISMA flowchart illustrating study identification, exclusion, and inclusion in the meta-analysis. Included searches of databases and registers only.
This could mean therapists focus on techniques that rewire these centers and rebuild their sense of self.
Dr Klabunde said: “Currently, science-based treatments for childhood trauma primarily focus on addressing the fearful thoughts and avoidance of trauma triggers. This is a very important part of trauma treatment. However, our study has revealed that we are only treating one part of the problem. Even when children who have experienced trauma are not thinking about their traumatic experiences, their brains are struggling to process the sensations within their bodies. This influences how one thinks and feels about one’s ‘internal world’ and this also influences one’s ability to empathize and form relationships.”
Dr Klabunde reviewed 14 studies involving more than 580 children for the research published in Biological Psychiatry Cognitive Neuroscience and Neuroimaging.
The paper re-examined functional magnetic resonance imaging (fMRI) scans. This procedure highlights blood flow in different centres, showing neurological activity.
The study discovered a marked difference in traumatized children’s default mode (DMN) and central executive networks (CEN) — two large scale brain systems. The DMN and the posterior insula are involved in how people sense their body, their sense of self and their internal reflections. New studies are finding the DMN plays an important role in most mental health problems — and may be influenced by experiencing childhood trauma. The CEN is also more active than in healthy children, which means that children with trauma histories tend to ruminate and relive terrible experiences when triggered.
Dr Klabunde hopes this study will be a springboard to find out more about how trauma affects developing minds.
She said: “Our brain findings indicate that childhood trauma treatments appear to be missing an important piece of the puzzle.
“In addition to preventing avoidance of scary situations and addressing one’s thoughts, trauma therapies in children should also address how trauma’s impacts on one’s body, sense of self, emotional/empathetic processing, and relationships. “This is important to do so since untreated symptoms will likely contribute to other health and mental health problems throughout the lifespan.”
Noninvasive neuromodulation of subregions of the human insula differentially affect pain processing and heart-rate variability: a within-subjects pseudo-randomized trial
by Wynn Legon, Andrew Strohman, Alexander In, Brighton Payne in Pain
You feel pain, so you pop a couple of ibuprofen or acetaminophen. If the pain is severe or chronic, you might be prescribed something stronger — an opioid painkiller that can be addictive under some circumstances.
But what if you could ease pain by non-invasively manipulating a spot inside your brain where the pain is registered?
A new study by Wynn Legon, assistant professor at the Fralin Biomedical Research Institute at VTC, and his team points to that possibility.
The study found sound waves from low-intensity focused ultrasound aimed at a place deep in the brain called the insula can reduce both the perception of pain and other effects of pain, such as heart rate changes.
“This is a proof-of-principle study,” Legon said. “Can we get the focused ultrasound energy to that part of the brain, and does it do anything? Does it change the body’s reaction to a painful stimulus to reduce your perception of pain?”
Focused ultrasound uses the same technology used to view a baby in the womb, but it delivers a narrow band of sound waves to a tiny point.
At high intensity, ultrasound can ablate tissue. At low-intensity, it can cause gentler, transient biological effects, such as altering nerve cell electrical activity Neuroscientists have long studied how non-surgical techniques, such as transcranial magnetic stimulation, might be used to treat depression and other issues.
Legon’s study, however, is the first to target the insula and show that focused ultrasound can reach deep into the brain to ease pain.
The study involved 23 healthy human participants. Heat was applied to the backs of their hands to induce pain. At the same time, they wore a device that delivered focused ultrasound waves to a spot in their brain guided by magnetic resonance imaging (MRI). Participants rated their pain perception in each application on a scale of zero to nine.
Researchers also monitored each participant’s heart rate and heart rate variability — the irregularity of the time between heart beats — as a means to discern how ultrasound of the brain also affects the body’s reaction to a painful stimulus. Participants reported an average reduction in pain of three-fourths of a point.
“That might seem like a small amount, but once you get to a full point, it verges on being clinically meaningful,” said Legon, also an assistant professor in the School of Neuroscience in Virginia Tech’s College of Science.
“It could make a significant difference in quality of life, or being able to manage chronic pain with over-the-counter medicines instead of prescription opioids.”
The study also found the ultrasound application reduced physical responses to the stress of pain — heart rate and heart rate variability, which are associated with better overall health.
“Your heart is not a metronome. The time between your heart beats is irregular, and that’s a good thing,” Legon said. “Increasing the body’s ability to deal with and respond to pain may be an important means of reducing disease burden.”
The effect of focused ultrasound on those factors suggests a future direction for the Legon lab’s research — to explore the heart-brain axis, or how the heart and brain influence each other, and whether pain can be mitigated by reducing its cardiovascular stress effects.
Single-neuronal elements of speech production in humans
by Arjun R. Khanna, William Muñoz, Young Joon Kim, Yoav Kfir, Angelique C. Paulk, Mohsen Jamali, Jing Cai, Martina L. Mustroph, Irene Caprara, Richard Hardstone, Mackenna Mejdell, Domokos Meszéna, Abigail Zuckerman, Jeffrey Schweitzer, Sydney Cash, Ziv M. Williams in Nature
By using advanced brain recording techniques, a new study led by researchers from Massachusetts General Hospital (MGH) demonstrates how neurons in the human brain work together to allow people to think about what words they want to say and then produce them aloud through speech.
Together, these findings provide a detailed map of how speech sounds such as consonants and vowels are represented in the brain well before they are even spoken and how they are strung together during language production.
The work, which is published in Nature, reveals insights into the brain’s neurons that enable language production, and which could lead to improvements in the understanding and treatment of speech and language disorders.
“Although speaking usually seems easy, our brains perform many complex cognitive steps in the production of natural speech — including coming up with the words we want to say, planning the articulatory movements and producing our intended vocalizations,” says senior author Ziv Williams, MD, an associate professor in Neurosurgery at MGH and Harvard Medical School. “Our brains perform these feats surprisingly fast — about three words per second in natural speech — with remarkably few errors. Yet how we precisely achieve this feat has remained a mystery.”
When they used a cutting-edge technology called Neuropixels probes to record the activities of single neurons in the prefrontal cortex, a frontal region of the human brain, Williams and his colleagues identified cells that are involved in language production and that may underlie the ability to speak.
They also found that there are separate groups of neurons in the brain dedicated to speaking and listening.
“The use of Neuropixels probes in humans was first pioneered at MGH. These probes are remarkable — they are smaller than the width of a human hair, yet they also have hundreds of channels that are capable of simultaneously recording the activity of dozens or even hundreds of individual neurons,” says Williams who had worked to develop these recording techniques with Sydney Cash, MD, PhD, a professor in Neurology at MGH and Harvard Medical School, who also helped lead the study.
“Use of these probes can therefore offer unprecedented new insights into how neurons in humans collectively act and how they work together to produce complex human behaviors such as language.”
The study showed how neurons in the brain represent some of the most basic elements involved in constructing spoken words — from simple speech sounds called phonemes to their assembly into more complex strings such as syllables.
For example, the consonant “da,” which is produced by touching the tongue to the hard palate behind the teeth, is needed to produce the word dog. By recording individual neurons, the researchers found that certain neurons become active before this phoneme is spoken out loud.
Other neurons reflected more complex aspects of word construction such as the specific assembly of phonemes into syllables. With their technology, the investigators showed that it’s possible to reliably determine the speech sounds that individuals will say before they articulate them. In other words, scientists can predict what combination of consonants and vowels will be produced before the words are actually spoken. This capability could be leveraged to build artificial prosthetics or brain-machine interfaces capable of producing synthetic speech, which could benefit a range of patients.
“Disruptions in the speech and language networks are observed in a wide variety of neurological disorders — including stroke, traumatic brain injury, tumors, neurodegenerative disorders, neurodevelopmental disorders, and more,” says Arjun Khanna who is a co-author on the study. “Our hope is that a better understanding of the basic neural circuitry that enables speech and language will pave the way for the development of treatments for these disorders.”
The researchers hope to expand on their work by studying more complex language processes that will allow them to investigate questions related to how people choose the words that they intend to say and how the brain assembles words into sentences that convey an individual’s thoughts and feelings to others.
Improved immunostaining of nanostructures and cells in human brain specimens through expansion-mediated protein decrowding
by Pablo A. Valdes, Chih-Chieh (Jay) Yu, Jenna Aronson, Debarati Ghosh, Yongxin Zhao, Bobae An, Joshua D. Bernstock, Deepak Bhere, Michelle M. Felicella, Mariano S. Viapiano, Khalid Shah, E. Antonio Chiocca, Edward S. Boyden in Science Translational Medicine
Researchers from Brigham and Women’s Hospital, a founding member of Mass General Brigham, and the Massachusetts Institute of Technology (MIT) have unveiled unprecedentedly detailed images of brain cancer tissue through the use of a new microscopy technology called decrowding expansion pathology (dExPath).Their findings, published in Science Translational Medicine, provide novel insights into brain cancer development, with potential implications for advancing the diagnosis and treatment of aggressive neurological diseases.
“In the past, we have relied on expensive, super-resolution microscopes that only very well-funded labs could afford, required specialized training to use, and are often impractical for high-throughput analyses of brain tissues at the molecular level,” said Pablo Valdes, MD, PhD, a neurosurgery resident alumnus at the Brigham and lead author of the study.
“This technology brings reliable, super-resolution imaging to the clinic, enabling scientists to study neurological diseases at a never-before-achieved nanoscale level on conventional clinical samples with conventional microscopes.”
Researchers previously relied on costly, super-high-resolution microscopes to image nanoscale structures in cells and brain tissue, and, even with the most advanced technology, they often struggled to effectively capture these structures at the nanoscale level.
Ed Boyden, PhD, the Y. Eva Tan Professor in Neurotechnology at MIT and co-senior author on this study, began addressing this problem by labeling tissues, and then chemically modifying them to enable uniform physical expansion of tissues. However, this expansion technology was far from perfect. Relying on enzymes known as proteases to break up tissue, scientists found that this chemical treatment with enzymes destroyed proteins before they could analyze them, leaving behind only a skeleton of the original structure, retaining only the labels.
Working together, Boyden and E. Antonio Chiocca, MD, PhD, Neurosurgery Chair at Brigham and Women’s Hospital and co-senior author on this study, mentored Valdes during his training as a neurosurgeon-scientist, to develop novel chemistries with dExPath to address the limitations of the original expansion technology.
Their new technology chemically modifies tissues by embedding them in a gel and ‘softening’ the tissues with a special chemical treatment that separates protein structures without destroying them and allows tissues to expand. This provided exciting findings to the MIT and Brigham researchers, who routinely use commercially available antibodies to bind to and illuminate biomarkers in a sample. Antibodies, however, are large and many times cannot easily penetrate cell structures to reach their target. Now, by pulling proteins apart with dExPath, these same antibodies used for staining can penetrate spaces to bind proteins in tissue that could not be accessed before expansion, highlighting nanometer-sized structures or even cell populations that were previously hidden.
“The human brain has several stop guards in place to protect itself from pathogens and environmental toxins. But these elements make studying brain activity challenging. It can be a bit like driving a car through mud and ditches. We cannot access certain cell structures in the brain because of barriers that stand in the way,” said E. Antonio Chiocca, MD, PhD, chair of the Department of Neurosurgery at the Brigham. “That is just is one of the reasons that this new technology could be so practice changing. If we can take more detailed and accurate images of brain tissue, we can identify more biomarkers and be better equipped to diagnose and treat aggressive brain diseases.”
To validate the effectiveness of dExPath, Boyden and Chiocca’s team applied the technology to healthy human brain tissue, high and low-grade brain cancer tissues, and brain tissues affected by neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. Investigators stained tissue for brain and disease-specific biomarkers and captured images before and after expanding samples with dExPath.
The results revealed uniform and consistent expansion of the tissue without distortion, enabling accurate analysis of protein structures. Additionally, dExPath effectively eliminated fluorescent signals in brain tissue called lipofuscin, which makes imaging of subcellular structures in brain tissues very difficult, further enhancing image quality. Further, dExPath provided stronger fluorescent signals for improved labeling as well as simultaneous labeling of up to 16 biomarkers in the same tissue specimen. Notably, dExPath imaging revealed that tumors previously classified as “low-grade” contained more aggressive features and cell populations, suggesting the tumor could become far more dangerous than anticipated.
While promising, dExPath requires validation on larger sample sizes before it can contribute to the diagnosis of neurological conditions such as brain cancer. Valdes underscores that, although still in its early stages, his team aspires for this technology to eventually serve as a diagnostic tool, ultimately enhancing patient outcomes.
“We hope that with this technology, we can better understand at the nanoscale levels the intricate workings of brain tumors and their interactions with the nervous system without depending on exorbitantly expensive lab equipment,” said Valdes who is now an assistant professor of neurosurgery and Jennie Sealy Distinguished Chair in Neuroscience at the University of Texas Medical Branch. “The accessibility of dExPath will bring enable super-resolution imaging to understand biological processing at the nanometer level in human tissue in neuro-oncology and in neurological disease such as Alzheimer’s and Parkinson’s, and one day, could even improve diagnostic strategies and patient outcomes.”
Associations of Polycystic Ovary Syndrome With Indicators of Brain Health at Midlife in the CARDIA Cohort
by Heather G. Huddleston, Eleni G. Jaswa, Kaitlin B. Casaletto, John Neuhaus, Catherine Kim, Melissa Wellons, Lenore J. Launer, Kristine Yaffe in Neurology
People with polycystic ovary syndrome may be more likely to have memory and thinking problems in middle age, according to new research published in Neurology, the medical journal of the American Academy of Neurology. The study does not prove that polycystic ovary syndrome causes cognitive decline. It only shows an association.
Polycystic ovary syndrome is a hormonal disorder that is defined by irregular menstruation and elevated levels of a hormone called androgen. Other symptoms may include excess hair growth, acne, infertility and poor metabolic health.
“Polycystic ovary syndrome is a common reproductive disorder that impacts up to 10% of women,” said study author Heather G. Huddleston, MD, of the University of California, San Francisco.
“While it has been linked to metabolic diseases like obesity and diabetes that can lead to heart problems, less is known about how this condition affects brain health. Our results suggest that people with this condition have lower memory and thinking skills and subtle brain changes at midlife. This could impact a person on many levels, including quality of life, career success and financial security.”
The study involved 907 female participants who were 18 to 30 years old at the start of the study. They were followed for 30 years, at which time they completed tests to measure memory, verbal abilities, processing speed and attention. At the time of testing, 66 participants had polycystic ovary syndrome.
In a test measuring attention, participants looked at a list of words in different colors and were asked to state the color of the ink rather than read the actual word. For example, the word “blue” could be displayed in red, so the correct response would be red.
Researchers found for this test, people with polycystic ovary syndrome had an average score that was approximately 11% lower compared to people without the condition.
After adjusting for age, race and education, researchers found that people with polycystic ovary syndrome had lower scores on three of the five tests that were given, specifically in areas of memory, attention and verbal abilities, when compared to those without this condition.
At years 25 and 30 of the study, a smaller group of 291 participants had brain scans. Of those, 25 had polycystic ovary syndrome. With the scans, researchers looked at the integrity of the white matter pathways in the brain by looking at movement of water molecules in the brain tissue.
Researchers found that people with polycystic ovary syndrome had lower white matter integrity, which may indicate early evidence of brain aging.
“Additional research is needed to confirm these findings and to determine how this change occurs, including looking at changes that people can make to reduce their chances of thinking and memory problems,” Huddleston said. “Making changes like incorporating more cardiovascular exercise and improving mental health may serve to also improve brain aging for this population.”
A limitation of the study was that polycystic ovary syndrome diagnosis was not made by a doctor but was based on androgen levels and self-reported symptoms, so participants may not have remembered all the information accurately.
An epigenetic barrier sets the timing of human neuronal maturation
by Gabriele Ciceri, Arianna Baggiolini, Hyein S. Cho, Meghana Kshirsagar, Silvia Benito-Kwiecinski, Ryan M. Walsh, Kelly A. Aromolaran, Alberto J. Gonzalez-Hernandez, Hermany Munguba, So Yeon Koo, Nan Xu, Kaylin J. Sevilla, Peter A. Goldstein, Joshua Levitz, Christina S. Leslie, Richard P. Koche, Lorenz Studer in Nature
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Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons
by Emiliano Hergenreder, Andrew P. Minotti, Yana Zorina, Polina Oberst, Zeping Zhao, Hermany Munguba, Elizabeth L. Calder, Arianna Baggiolini, Ryan M. Walsh, Conor Liston, Joshua Levitz, Ralph Garippa, Shuibing Chen, Gabriele Ciceri, Lorenz Studer in Nature Biotechnology
The neurons that make up our brains and nervous systems mature slowly over many months. And while this may be beneficial from an evolutionary standpoint, the slow pace makes growing cells to study neurodegenerative and neurodevelopmental diseases — like Parkinson’s disease, Alzheimer’s disease, and autism — in the laboratory quite challenging.
Currently, nerve cells derived from human pluripotent stem cells take months to reach an adultlike state in the lab — a timeline that mirrors the slow pace of human brain development. (“Pluripotent stem cells” have the potential to develop into many other kinds of cells.)
New research led by Memorial Sloan Kettering Cancer Center (MSK), however, has uncovered a way to “hack” the cells’ internal clocks to speed up the process. And the work is shedding new light on how cells’ developmental timetables are regulated.
“This slow pace of nerve cell development has been linked to humans’ unique and complex cognitive abilities,” says Lorenz Studer, MD, Director of MSK’s Center for Stem Cell Biology and the senior author of two recent studies. “Previous research has suggested the presence of a ‘clock’ within cells that sets the pace of our neurons’ development, but its biological nature had largely remained unknown — until now.”
Researchers, led by study first author Gabriele Ciceri, PhD, identified an epigenetic “barrier” in the stem cells that give rise to neural cells. (“Epigenetic changes” do not alter the DNA code.) This barrier acts as a brake on the development process and determines the rate at which the cells mature. By inhibiting the barrier, the scientists were able to speed up the neurons’ development.
“While studying brain development in mice, I was struck by how neurons progress through a series of steps in a very precise schedule,” says Dr. Ciceri, a senior research scientist in the Studer Lab at MSK’s Sloan Kettering Institute. “But this schedule creates a big practical challenge when working with human neurons — what takes hours and days in the mouse requires weeks and months in human cells.”
Furthermore, the team showed that this rate-setting epigenetic barrier is built into neural stem cells well before they differentiate into different types of neurons. They also found higher levels of the barrier in human neurons compared with mouse neurons, which may help explain differences in the pace of cell maturation in different species.
That such discoveries were made at a cancer center isn’t as surprising as it might seem at first blush. The Studer Lab has long focused on harnessing advances in stem cell biology to develop new therapies for degenerative diseases and cancer — both of which are strongly associated with aging.
Moreover, MSK has long been a leader in “basic science” research — that is, science that seeks to build a fundamental understanding of human biology.
About half of the National Institutes of Health (NIH) budget goes to funding basic science research. The vast majority of drugs approved by the Food and Drug Administration in recent years involved publicly funded basic research, according to the NIH.
“All of the major advances in cancer treatment in recent years — immune checkpoint inhibitor therapy, CAR T cell therapy, cancer vaccines — they’re all rooted in basic research,” says Joan Massagué, PhD, Director of the Sloan Kettering Institute and MSK’s Chief Scientific Officer. “Sometimes it can take years for the medical relevance of a particular discovery to become clear.”
A second study, led by Studer Lab graduate students Emiliano Hergenreder and Andrew Minotti and published in Nature Biotechnology, identified a combination of four chemicals that together can promote neuronal maturation. Dubbed GENtoniK, the chemical cocktail both represses epigenetic factors that inhibit cell maturation and stimulates factors that promote it.
Along with helping to bring neurons to an adultlike state faster in the lab, the approach holds promise for other cell types, the researchers note.
Not only was GENtoniK shown to speed the maturation of cortical neurons (involved in cognitive functions) and spinal motor neurons (involved in movement), but the chemicals were also able to accelerate the development of several other types of cells derived from stem cells, including melanocytes (pigment cells) and pancreatic beta cells (endocrine cells).
“The generation of human neurons in a dish from stem cells provides a unique inroad into the study of brain health and disease,” the journal editors note in a research briefing that accompanied the study. “A major obstacle in the field arises from the fact that human neurons require many months to mature during development, making it difficult to recapitulate the process in vitro. The authors provide a valuable research tool by developing a simple drug cocktail that speeds up the maturation timeframe.”
The findings could be particularly helpful in modeling disorders like autism that involve problems with synaptic connectivity, Dr. Studer says.
Still, he notes, additional research is needed to develop models of neurodegenerative disorders that don’t occur until very late in life, such as Parkinson’s disease, which has long been a focus of Studer’s research.
“Typically, a person is 60 to 70 years old when the disease begins. No baby gets Parkinson’s,” he says. “So, for those diseases, we need to be able to put the cells not just into an adult state but into an aged-like state. That’s something we’re continuing to work on.”
NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport
by Sen Yang, Zhen-Xian Niou, Andrea Enriquez, Jacob LaMar, Jui-Yen Huang, Karen Ling, Paymaan Jafar-Nejad, Jonathan Gilley, Michael P. Coleman, Jason M. Tennessen, Vidhya Rangaraju, Hui-Chen Lu in Molecular Neurodegeneration
Indiana University researchers in the College of Arts and Sciences in Bloomington have identified a missing link that can help protect the brain from aging.
Hui-Chen Lu, professor and director of the Linda and Jack Gill Center for Biomolecular Science at IU, alongside graduate students Sen Yang and Zhen Xian Niou, found that nicotinamide nucleotide adenylyl transferase 2, or NMNAT2, provides energy to axons independent of the mitochondria.
It does this by propelling glycolysis, a process in which glucose is broken down to produce energy. This gives axons enough energy to carry out nerve impulses to the brain and other parts of the body, keeping them healthy and functional.
The enzyme can play a critical role in fending off neurodegenerative diseases like ALS, Alzheimer’s, Huntington’s and Parkinson’s as people age. The study can be found in Molecular Neurodegeneration.
Axons are long, thin fibers that connect nerve cells and allow them to communicate with each other. Axons are typically one micrometer in diameter — several times thinner than a human hair — making them vulnerable and easily damaged by inflammation, trauma, reduced blood flow to the brain and infection.
Often, axon damage is the first sign of neurodegenerative disease, but their protection can delay neurodegeneration.
Axons quickly convey information throughout the entire body, a process of traveling long distances within an extremely short time scale that requires significant amounts of energy. However, the mitochondria, widely known as the cellular powerhouse, are in relatively sparse density in axons.
NMNAT2 is a vital provider of nicotinamide adenine dinucleotide for the brain. NAD has been studied intensively for its regenerative properties and is sometimes referred to as the “fountain of youth.”
“This new finding showcases the importance of neuron-intrinsic glycolysis in supporting axonal transport, essential for the establishment and maintenance of neuronal circuitry,” Lu said. “With this information, the next step could be designing drugs to target NMNAT2 to boost its expression or activity in pre-symptomatic stages of neurodegeneration.”
Lu’s laboratory has studied NMNAT2 extensively, publishing research in 2017 which found that caffeine, along with 23 other compounds, can increase the body’s production of NMNAT2. In 2016, Lu published a study that found those with higher levels of NMNAT2 had greater resistance to cognitive decline as they aged.
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