NS/ How long-lasting memories form in the brain
Neuroscience biweekly vol. 83, 12th April — 26th April
TL;DR
- Helping your mother make pancakes when you were three…riding your bike without training wheels…your first romantic kiss: How do we retain vivid memories of long-ago events? As described in a paper published in Neuron, researchers at Albert Einstein College of Medicine have found the explanation.
- A new study has found that older persons with mild cognitive impairment (MCI), a common type of memory loss, were 30% more likely to regain normal cognition if they had taken in positive beliefs about aging from their culture, compared to those who had taken in negative beliefs. Researchers also found that these positive beliefs also enabled participants to recover their cognition up to two years earlier than those with negative age beliefs. This cognitive recovery advantage was found regardless of baseline MCI severity.
- A preclinical study using stem cells to produce progenitor photoreceptor cells — light-detecting cells found in the eye — and then transplanting these into experimental models of damaged retinas has resulted in significant vision recovery. This finding, by scientists at Duke-NUS Medical School, the Singapore Eye Research Institute and the Karolinska Institute in Sweden, marks a first step towards potentially restoring vision in eye diseases characterized by photoreceptor loss.
- Researchers have developed a model that detects workplace stress just by how people type and move their computer mouse. This might enable employees to prevent chronic stress early on.
- New research shows that poor air quality could be causing cognitive problems in babies and toddlers. A new study reveals an association between poor air quality in India and impaired cognition in infants under two. Without action, the negative impact on children’s long-term brain development could have consequences for life.
- Problems with the brain’s ability to ‘prune’ itself of unnecessary connections may underlie a wide range of mental health disorders that begin during adolescence, according to research. The findings may help explain why people are often affected by more than one mental health disorder, and may in the future help identify those at greatest risk.
- Researchers at Ruhr University Bochum, Germany, have successfully implemented a special form of classical conditioning. They showed on a group of 75 people that effects of transcranial magnetic stimulation (TMS) can be triggered solely by listening to a tone.
- Multiple sclerosis (MS) is an autoimmune disease that destroys the protective myelin covering around nerves. Every five minutes, someone is diagnosed with the disease around the world, adding to about 2.8 million individuals that currently have to live with it. Now researchers have developed a cell therapy that leverages myeloid cells, the very type of immune cells that cause MS-triggering nerve inflammation in patients. By attaching ‘backpacks’ loaded with anti-inflammatory drugs to the cells, and infusing them into a mouse model of MS, they were able to partially reverse paralysis and restore movement.
- Researchers from the University of Michigan have found that an extra copy of a gene in Down syndrome patients causes improper development of neurons in mice.
- A protein called FNIP1 is the critical link between a cell sensing low energy levels and eliminating and replacing damaged mitochondria. The finding will help scientists understand healthy aging, cancerous tumors, neurodegenerative diseases, and beyond.
- And more!
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The latest news and research
Maintenance of a short-lived protein required for long-term memory involves cycles of transcription and local translation
by Sulagna Das, Pablo J. Lituma, Pablo E. Castillo, Robert H. Singer in Neuron
Helping your mother make pancakes when you were three…riding your bike without training wheels…your first romantic kiss: How do we retain vivid memories of long-ago events? As described in a paper published in Neuron, researchers at Albert Einstein College of Medicine have found the explanation.
“The ability to learn new information and store it for long periods is one of the brain’s most remarkable features,” said Robert H. Singer, Ph.D., a co-corresponding author of the paper. “We’ve made a startling discovery in mice regarding the molecular basis for making those long-term memories.” Dr. Singer is professor of cell biology and in the Dominick P. Purpura Department of Neuroscience, chair emeritus of anatomy & structural biology, and director of the Program in RNA Biology at Einstein.
Some aspects of the cellular basis of memory were already known. They’re made by neurons (nerve cells) and stored in a brain region called the hippocampus. They form when repeated neural stimulation strengthens synapses — the connections between nerve cells. Proteins are needed to stabilize the long-lasting synaptic connections required for long-term memories. The blueprints for those proteins are molecules of messenger RNA (mRNA) that, in turn, are transcribed (copied) from memory-associated genes.
“The paradox is that it takes a long time — several hours — to form a lasting memory, yet the mRNAs and proteins associated with making proteins disappear in less than an hour,” said Sulagna Das, Ph.D., first and co-corresponding author of the paper and research assistant professor of cell biology at Einstein. “How could that be?”
To answer that question, the research team developed a mouse model in which they fluorescently tagged all the molecules of mRNA that flow from Arc, a gene critically important for converting our activities and other experiences into long-term memories. The researchers stimulated synapses in neurons from the mouse hippocampus and then — using high-resolution imaging techniques they developed — observed the results in individual nerve cells in real time.
To their amazement, they observed that a single stimulus to the neuron triggered numerous cycles in which the memory-coding gene Arc produced mRNA molecules that were then translated into synapse-strengthening Arc proteins.
“We saw that some of the protein molecules made from that initial synaptic stimulus go back to Arc and reactivate it, initiating another cycle of mRNA formation and protein production followed by several others,” said Dr. Singer.
“With each cycle, we saw more and more protein accumulating to form ‘hot spots’ at the synapse, which are where memories are cemented into place. We’d discovered a previously unknown feedback loop that explained how short-lived mRNAs and proteins can create long-lived memories,” said Dr. Das.
Consider what’s involved in memorizing a poem, suggested Dr. Singer:
“To make a lasting memory requires that you read the poem repeatedly and each reading can be thought of as an intermittent stimulus that adds memory-building protein to the synapse.”
Dr. Das noted that faulty expression of the Arc gene has been implicated in memory difficulties in humans and is linked to neurological disorders including autism spectrum disorder and Alzheimer’s disease.
“What we learn about Arc’s response to nerve-cell stimulation can provide insights into the causes of these health problems,” she noted.
Role of Positive Age Beliefs in Recovery From Mild Cognitive Impairment Among Older Persons
by Becca R. Levy, Martin D. Slade in JAMA Network Open
A Yale School of Public Health study has found that older persons with mild cognitive impairment (MCI), a common type of memory loss, were 30% more likely to regain normal cognition if they had taken in positive beliefs about aging from their culture, compared to those who had taken in negative beliefs.
Researchers also found that these positive beliefs also enabled participants to recover their cognition up to two years earlier than those with negative age beliefs. This cognitive recovery advantage was found regardless of baseline MCI severity.
“Most people assume there is no recovery from MCI, but in fact half of those who have it do recover. Little is known about why some recover while others don’t. That’s why we looked at positive age beliefs, to see if they would help provide an answer,” said Becca Levy, professor of public health and of psychology and lead author of the study.
Levy predicted that positive age beliefs could play an important role in cognitive recovery because her previous experimental studies with older persons found that positive age beliefs reduced the stress caused by cognitive challenges, increased self-confidence about cognition, and improved cognitive performance.
The new study is the first to find evidence that a culture-based factor — positive age beliefs — contributes to MCI recovery. The study appeared in JAMA Network Open. Martin Slade, a biostatistician and lecturer in internal medicine at Yale, is co-author of the study.
Older persons in the positive age-belief group who started the study with normal cognition were less likely to develop MCI over the next 12 years than those in the negative age-belief group, regardless of their baseline age and physical health.
The National Institute on Aging funded this study. It had 1,716 participants aged 65 and above who were drawn from the Health and Retirement Study, a national longitudinal study.
“Our previous research has demonstrated that age beliefs can be modified; therefore, age-belief interventions at the individual and societal levels could increase the number of people who experience cognitive recovery,” Levy said.
Photoreceptor laminin drives differentiation of human pluripotent stem cells to photoreceptor progenitors that partially restore retina function
by Hwee Goon Tay, Helder Andre, Vicki Chrysostomou, Swarnaseetha Adusumalli, Jing Guo, Xiaoyuan Ren, Wei Sheng Tan, Jia En Tor, Aida Moreno-Moral, Flavia Plastino, Hammurabi Bartuma, Zuhua Cai, Sai Bo Bo Tun, Veluchamy Amutha Barathi, Gavin Tan Siew Wei, Gianluca Grenci, Li Yen Chong, Arne Holmgren, Anders Kvanta, Crowston Jonathan Guy, Enrico Petretto, Karl Tryggvason in Molecular Therapy
A preclinical study using stem cells to produce progenitor photoreceptor cells — light-detecting cells found in the eye — and then transplanting these into experimental models of damaged retinas has resulted in significant vision recovery. This finding, by scientists at Duke-NUS Medical School, the Singapore Eye Research Institute and the Karolinska Institute in Sweden, marks a first step towards potentially restoring vision in eye diseases characterised by photoreceptor loss.
“Our laboratory has developed a novel method that enables the production of photoreceptor progenitor cells resembling those in human embryos,” said Assistant Professor Tay Hwee Goon, first author of the study from Duke-NUS’ Centre for Vision Research. “Transplantation of these cells into experimental models has yielded partial restoration of the retinal function.”
The degeneration of photoreceptors in the eye is a significant cause of declining vision that can eventually lead to blindness and for which there is currently no effective treatment. Photoreceptor degeneration occurs in a variety of inherited retinal diseases, such as retinitis pigmentosa — a rare eye disease that breaks down cells in the retina over time and eventually causes vision loss — and age-related macular degeneration, a leading cause of vision impairment worldwide.
Asst Prof Tay and her team developed a procedure to grow human embryonic stem cells in the presence of purified laminin proteins that are involved in normal development of human retinas. In the presence of the laminins, stem cells could be directed to differentiate into photoreceptor progenitor cells responsible for converting light into signals that are sent to the brain.
When these cells were transplanted into damaged retinas, the preclinical models showed significant recovery of vision. A diagnostic test called electroretinogram also identified significant recovery in the retinas via electrical activity in the retina in response to a light stimulus. The transplanted cells established connections with surrounding retinal cells and nerves in the inner retina. They also survived and functioned for many weeks after transplantation.
Moving forward, the team hopes to refine their method to make it simpler and achieve more consistent results than earlier attempts to explore stem cell therapy for photoreceptor cell replacement.
“It is exciting to find these results, which suggest a promising route towards using stem cells to treat those forms of visual deterioration and blindness caused by the loss of photoreceptors,” said Dr Helder Andre, Head of Molecular and Cellular Research from Karolinska Institute’s Department of Clinical Neuroscience and a senior author of the study.
Associate Professor Enrico Petretto, Director of the Centre for Computational Biology at Duke-NUS and the study’s bioinformatics analysis lead, added:
“Our method may also be useful for understanding the molecular and cellular pathways that drive the progression of macular degeneration, perhaps leading to the development of other therapeutic approaches.”
The next challenge for the researchers is to explore the efficacy of their method in models of photoreceptor degeneration that more closely match the human condition.
“If we get promising results in our future studies, we hope to move to clinical trials in patients,” said Professor Karl Tryggvason, from Duke-NUS’ Cardiovascular and Metabolic Disorders Programme, and the corresponding author of the study. “That would be an important step towards for being able to reverse damage of the retina and restore vision.”
The protocol underlying the procedure developed by Asst Prof Tay has since been licensed to Swedish biotech start-up Alder Therapeutics.
An interpretable machine learning approach to multimodal stress detection in a simulated office environment
by Mara Naegelin, Raphael P. Weibel, Jasmine I. Kerr, Victor R. Schinazi, Roberto La Marca, Florian von Wangenheim, Christoph Hoelscher, Andrea Ferrario in Journal of Biomedical Informatics
In Switzerland, one in three employees suffers from workplace stress. Those affected often don’t realise that their physical and mental resources are dwindling until it’s too late. This makes it all the more important to identify work-related stress as early as possible where it arises: in the workplace.
Researchers at ETH Zurich are now taking a crucial step in this direction. Using new data and machine learning, they have developed a model that can tell how stressed we are just from the way we type and use our mouse.
And there’s more: “How we type on our keyboard and move our mouse seems to be a better predictor of how stressed we feel in an office environment than our heart rate,” explains study author Mara Nägelin, a mathematician who conducts research at the Chair of Technology Marketing and the Mobiliar Lab for Analytics at ETH Zurich. Applied correctly, these findings could be used in future to prevent increased stress in the workplace early on.
The ETH researchers proved in an experiment that stressed people type and move their mouse differently from relaxed people.
“People who are stressed move the mouse pointer more often and less precisely and cover longer distances on the screen. Relaxed people, on the other hand, take shorter, more direct routes to reach their destination and take more time doing so,” Nägelin says.
What’s more, people who feel stressed in the office make more mistakes when typing. They write in fits and starts with many brief pauses. Relaxed people take fewer but longer pauses when typing on a keyboard.
The connection between stress and our typing and mouse behaviour can be explained with what is known as neuromotor noise theory:
“Increased levels of stress negatively impact our brain’s ability to process information. This also affects our motor skills,” explains psychologist Jasmine Kerr, who researches with Nägelin and is a coauthor of the study.
To develop their stress model, the ETH researchers observed 90 study participants in the lab performing office tasks that were as close to reality as possible, such as planning appointments or recording and analysing data. They recorded the participants’ mouse and keyboard behaviour as well as their heart rates. In addition, the researchers asked the participants several times during the experiment how stressed they felt.
While some participants were allowed to work undisturbed, others also had to take part in a job interview. Half of this group were also repeatedly interrupted with chat messages. In contrast to earlier studies by other scientists, where the control group often did not have to solve any tasks at all and could relax, in the ETH researchers’ experiment, all participants had to perform the office tasks.
“We were surprised that typing and mouse behaviour was a better predictor of how stressed subjects felt better than heart rate,” Nägelin says. She explains that this is because the heart rates of the participants in the two groups did not differ as much as in other studies. One possible reason is that the control group was also given activities to perform, which is more in line with workplace reality.
The researchers are currently testing their model with data from Swiss employees who have agreed to have their mouse and keyboard behaviour as well as their heart data recorded directly at their workplace using an app. The same app also regularly asks the employees about their subjective stress levels. Results should be available by the end of the year.
However, workplace stress detection also raises some thorny issues: “The only way people will accept and use our technology is if we can guarantee that we will anonymize and protect their data. We want to help workers to identify stress early, not create a monitoring tool for companies,” Kerr says.
In another study involving employees and ethicists, the researchers are investigating which features an app needs to have to meet these requirements and ensure responsible handling of sensitive data.
Poor air quality is associated with impaired visual cognition in the first two years of life: A longitudinal investigation
by John P Spencer, Samuel H Forbes, Sophie Naylor, Vinay P Singh, Kiara Jackson, Sean Deoni, Madhuri Tiwari, Aarti Kumar in eLife
Poor air quality could be causing cognitive deficits in babies and toddlers, according to new research from the University of East Anglia.
A new study published today reveals an association between poor air quality in India and impaired cognition in infants under two.
Without action, the negative impact on children’s long-term brain development could have consequences for life.
Lead researcher Prof John Spencer, from UEA’s School of Psychology, said: “Prior work has shown that poor air quality is linked to cognitive deficits in children, as well as to emotional and behavioural problems, which can have a severe impact on families.
“Very small particulate fragments in the air are a major concern as they can move from the respiratory tract into the brain. Until now, studies had failed to show a link between poor air quality and cognitive problems in babies, when brain growth is at its peak and the brain may be particularly sensitive to toxins. Our study is the first to show this association. We worked with families in rural India to see how in-home air quality affects infants’ cognition.”
The team collaborated with the Community Empowerment Lab in Lucknow, India — a global health research and innovation organization that works with rural communities to engage in science collaboratively.
They worked with families from a range of socio-economic backgrounds in Shivgarh, a rural community in Uttar Pradesh — one of the states in India that has been most strongly impacted by poor air quality.
They assessed the visual working memory and visual processing speed of 215 infants using a specially-designed cognition task from October 2017 to June 2019.
On one display, the tots were shown flashing coloured squares that were always the same after each ‘blink’. On a second display, one coloured square changed after each blink.
Prof Spencer said: “This task capitalises on infant’s tendency to look away from something that’s visually familiar and towards something new. We were interested in whether infants could detect the changing side and how well they did as we made the task harder by including more squares on each display.”
The team used air quality monitors in the children’s homes to measure emission levels and air quality. They also took into account and controlled for family socio-economic status.
“This research shows for the first time that there is an association between poor air quality and impaired visual cognition in the first two years of life, when brain growth is at its peak,” said Prof Spencer.
“Such impacts could carry forward across years, negatively impacting long-term development. Reversely, our research indicates that global efforts to improve air quality could have benefits to infants’ emerging cognitive abilities. This, in turn, could have a cascade of positive impacts because improved cognition can lead to improved economic productivity in the long term and reduce the burden on healthcare and mental health systems.
One key factor the team measured was the cooking fuel commonly used at home.
“We found that air quality was poorer in homes that used solid cooking materials like cow dung cake,” he added. “Therefore, efforts to reduce cooking emissions in homes should be a key target for intervention.”
Consistent with this aim and with the goal of improving maternal and child health, the Government of India has launched a national-level flagship program called the “Ujjwala Yojana” — a scheme that brings LPG fuel to women below the poverty line across the entire country.
This research was led by the University of East Anglia in collaboration with Durham University, the Community Empowerment Lab in Lucknow (India) and Brown University (US).
‘Poor air quality is associated with impaired visual cognition in the first two years of life: a longitudinal investigation’ is published in the journal eLife.
A shared neural basis underlying psychiatric comorbidity
by Chao Xie, Shitong Xiang, Chun Shen, Xuerui Peng, Jujiao Kang, Yuzhu Li, Wei Cheng, Shiqi He, Tobias Banaschewski, Gareth J. Barker, Arun L. W. Bokde, Uli Bromberg, Christian Büchel, Sylvane Desrivières, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Barbara J. Sahakian, Trevor W. Robbins, Gunter Schumann, Tianye Jia, Jianfeng Feng in Nature Medicine
Problems with the brain’s ability to ‘prune’ itself of unnecessary connections may underlie a wide range of mental health disorders that begin during adolescence, according to research published.
The findings, from an international collaboration, led by researchers in the UK, China and Germany, may help explain why people are often affected by more than one mental health disorder, and may in future help identify those at greatest risk.
One in seven adolescents (aged 10–19 years old) worldwide experiences mental health disorders, according to the World Health Organization (WHO). Depression, anxiety and behavioural disorders, such as attention deficit hyperactivity disorder (ADHD), are among the leading causes of illness and disability among young people, and adolescents will commonly have more than one mental health disorder.
Many mental health problems emerge during adolescence. Among these are disorders such as depression and anxiety, which manifest as ‘internalising’ symptoms, including low mood and worrying. Other conditions such as attention deficit hyperactivity disorder (ADHD) manifest as ‘externalising’ symptoms, such as impulsive behaviour.
Professor Barbara Sahakian from the Department of Psychiatry at the University of Cambridge said: “Young people often experience multiple mental health disorders, beginning in adolescence and continuing — and often transforming — into adult life. This suggests that there’s a common brain mechanism that could explain the onset of these mental health disorders during this critical time of brain development.”
In a study published in Nature Medicine, the researchers say they have identified a characteristic pattern of brain activity among these adolescents, which they have termed the ‘neuropsychopathological factor’, or NP factor for short.
The team examined data from 1,750 adolescents, aged 14 years, from the IMAGEN cohort, a European research project examining how biological, psychological, and environmental factors during adolescence may influence brain development and mental health. In particular, they examined imaging data from brain scans taken while participants took part in cognitive tasks, looking for patterns of brain connectivity — in other words, how different regions of the brain communicate with each other.
Adolescents who experienced mental health problems — regardless of whether their disorder was one of internalising or externalising symptoms, or whether they experienced multiple disorders — showed similar patterns of brain activity. These patterns — the NP factor — were largely apparent in the frontal lobes, the area at the front of the brain responsible for executive function which, among other functions, controls flexible thinking, self-control and emotional behaviour.
The researchers confirmed their findings by replicating them in 1,799 participants from the ABCD Study in the USA, a long-term study of brain development and child health, and by studying patients who had received psychiatric diagnoses.
When the team looked at genetic data from the IMAGEN cohort, they found that the NP factor was strongest in individuals who carried a particular variant of the gene IGSF11 that has been previously associated with multiple mental health disorders. This gene is known to play an important role in synaptic pruning, a process whereby unnecessary brain connections — synapses — are discarded. Problems with pruning may particularly affect the frontal lobes, since these regions are the last brain areas to complete development in adolescents and young adults.
Dr Tianye Jia from the Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China and the Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK said: “As we grow up, our brains make more and more connections. This is a normal part of our development. But too many connections risk making the brain inefficient. Synaptic pruning helps ensure that brain activity doesn’t get drowned out in ‘white noise’.
“Our research suggests that when this important pruning process is disrupted, it affects how brain regions talk to each other. As this impact is seen most in the frontal lobes, this then has implications for mental health.”
The researchers say that the discovery of the NP factor could help identify those young people at greatest risk of compounding mental health problems.
Professor Jianfeng Feng from Fudan University in Shanghai, China, and the University of Warwick, UK, said: “We know that many mental health disorders begin in adolescence and that individuals who develop one disorder are at increased risk of developing other disorders, too. By examining brain activity and looking for this NP factor, we might be able to detect those at greatest risk sooner, offering us more opportunity to intervene and reduce this risk.”
Classical conditioning of faciliatory paired-pulse TMS
by Stefan P. Ewers, Timo M. Dreier, Siham Al-Bas, Peter Schwenkreis, Burkhard Pleger in Scientific Reports
Researchers at Ruhr University Bochum, Germany, have successfully implemented a special form of classical conditioning. They showed on a group of 75 people that effects of transcranial magnetic stimulation (TMS) can be triggered solely by listening to a tone. Professor Burkhard Pleger from the Neurology Department at Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil describes the results together with the medical doctoral students Stefan Ewers and Timo Dreier and other colleagues in the journal Scientific Reports.
To perform TMS, a magnetic coil is placed externally over a specific part of the brain. The strong magnetic field stimulates the underlying nerve cells to become active. If a certain area of the motor cortex is stimulated in this way, the index finger or thumb, for example, will move. For their research, the Bochum-based team used the so-called paired-pulse transcranial magnetic stimulation (TMS). This involved two TMS stimuli spaced twelve milliseconds apart, which leads to a stronger contraction of a muscle than a single TMS. In the conditioning phase, the researchers always combined this paired-pulse TMS with a tone that the participants heard via headphones while the TMS was applied.
In the test phase, the participants were no longer exposed to double TMS, but only to a single TMS pulse — paired either with the conditioned tone or with a tone that the participants hadn’t heard before. At the same time, the researchers once again measured the intensity of the muscle contraction on the thumb: it was significantly stronger when the participants listened to the conditioned tone, as opposed to the tone that they hadn’t heard during conditioning.
“Our basic research proves that traditional conditioning works not only with conscious behaviour patterns,” concludes Burkhard Pleger. “Brain activity can also be conditioned when manipulated through external brain stimulation.” This is interesting, because TMS can also be used as a therapeutic approach, for example to improve the mobility of people with Parkinson’s disease or to treat depression. “Generally, the effects of TMS are only temporary. They disappear if the stimulation is not continued. If these effects could be maintained by conditioned tones, therapy could become much more straightforward,” as Pleger describes one possible benefit of the research.
A backpack-based myeloid cell therapy for multiple sclerosis
by Neha Kapate, Michael Dunne, Ninad Kumbhojkar, Supriya Prakash, Lily Li-Wen Wang, Amanda Graveline, Kyung Soo Park, Vineeth Chandran Suja, Juhee Goyal, John R. Clegg, Samir Mitragotri in Proceedings of the National Academy of Sciences
Multiple sclerosis (MS) is a devastating autoimmune disease that destroys the protective myelin covering around nerves, disrupting communication between the brain and body, and causing patients’ ability to move and function to progressively decline. The MS atlas reported in 2020 that someone is diagnosed with MS every five minutes around the world, adding to about 2.8 million individuals that currently have to live with the disease. Alarmingly, since 2013, the world-wide prevalence of MS has risen by 30%.
A key driver of MS is the sudden inflammation of nerves caused by so-called myeloid cells of the “innate” immune system in vulnerable regions of the brain and spinal cord, which together form the central nervous system (CNS). These “acute inflammatory lesions” then attract other myeloid cells, as well as self-reactive T and B cells that belong to the immune system’s second arm, known as the “adaptive immune system” and directly attack the myelin covering. While no cure is available for MS, existing disease-modifying therapies in the form of small molecule and protein drugs either directly target the self-reactive immune cells or broadly dampen inflammation. However, many of those therapies cause severe side effects in different parts of the body, including the immune system itself, and thus carry significant health risks.
Now, a research team at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) has developed a cell therapy as a strong alternative to existing small molecule and protein therapies that leverages myeloid cells, the very type of immune cells that cause the MS-triggering nerve inflammation in patients.
To transform potentially inflammatory myeloid cells into therapeutic cells, they isolated and cultured monocytes (a type of myeloid cell) from the bone marrow of donor mice and stably attached tiny microparticles, termed “backpacks,” to the cells’ surfaces. These backpacks are loaded with anti-inflammatory molecules that direct the carrier cells’ differentiation into anti-inflammatory cells in vivo. When infused back into a mouse model of MS, the backpack-laden monocytes were able to affect MS-specific immune responses, and partially reverse hind limb paralysis and improve motor functions.
“Current MS therapies do not specifically target myeloid cells. These are very plastic cells that can toggle between different states and are thus hard to control. Our biomaterial-based backpack approach is a highly effective way to keep them locked into their anti-inflammatory state,” said senior author Samir Mitragotri, Ph.D., who is a Core Faculty member at the Wyss Institute. “In many ways simpler than other cell therapies, myeloid cells can be easily obtained from patients’ peripheral blood, modified with backpacks in a short culture step, and reinfused back into the original donor, where they find their way to inflammatory lesions and affect the MS-specific immune response not only locally, but more broadly.”
Many cell therapies, such as the famed CAR-T cell therapies, require the mobilization of immune cells from specific tissue compartments in the body with drugs, genetic modification, and then amplification over weeks outside of the body. Myeloid cells can be directly retrieved using established methods and modified with backpacks within hours, making the therapy more easily translatable. In addition, some myeloid cell types possess the ability to traverse the blood-brain barrier, which makes them particularly suitable for treating CNS diseases.
Mitragotri’s group had previously found that when they attached small disc-shaped backpacks to cells of the myeloid lineage, they remained stably exposed on the cells’ surface, whereas many other cells would readily internalize and inactivate them. Adding certain molecules to the backpacks allowed the team sustained control over the cells’ behavior. They made use of this finding in a tumor-fighting cell therapy consisting of backpack-laden macrophages, which is a specific type of myeloid cell. In their new study, they focused on monocytes, which also belong to the myeloid differentiation lineage and are a precursor to macrophages. Monocytes can effectively infiltrate the brain and then differentiate into macrophages, which are one of the predominant inflammatory cell types in active MS lesions.
“Because of their ability to invade the CNS, infiltrate inflammatory lesions, and differentiate into macrophages, a backpack strategy allowing control over monocyte differentiation made extreme sense,” said first author Neha Kapate, a graduate student working with Mitragotri. “We decided on backpacks that contained interleukin-4 [IL-4] and dexamethasone, two molecules that we later found to provide a synergistic anti-inflammatory effect.”
The team fabricated their micrometer-size backpacks via a process known as serial “spin coating,” in which thin films made up of a PLGA polymer and other biocompatible substances, and containing the anti-inflammatory molecules are layered on top of each other like layers of an onion. As a final step, the outer surface of the backpack was furnished with an antibody fragment to allow it to stick to monocytes.
To test the backpack-laden monocytes for their therapeutic efficacy, the researchers isolated monocytes from healthy donor mice and, in a short cell culture step, attached the backpacks to them. They then infused the modified cells into a mouse model of MS, known among researchers as experimental autoimmune encephalomyelitis (EAE) model.
“When we infused backpack-carrying monocytes and, in parallel, unaltered control monocytes into EAE mice with ongoing nerve inflammation, backpack-carrying monocytes more effectively infiltrated into inflamed CNS lesions. They also reduced inflammation inside the lesions and shifted the local and systemic MS-associated immune response towards a therapeutic outcome,” said Kapate. “The resulting anti-inflammatory monocytes also elicited cross-talk effects with other immune cell populations, such as specific T helper cells that are linked to the self-directed adaptive auto-immune response.”
The disease symptoms in EAE mice treated with backpack-laden monocytes were significantly improved and, by the end of the study, the animals merely exhibited a limp tail, compared to complete a paralysis in the control animals’ hind limbs. The treatment also extended the animals’ survival — all mice receiving backpack-carrying monocytes survived to the end of the study, whereas a significant number of the control mice had died. Importantly, the magnitude of therapeutic benefit the team observed is on par with reported therapeutic treatments that had been tested in other studies using the same model. Since the EAE model mainly mimics the progressive form of MS and not the more prevalent “relapsing-remitting” form, with which the disease begins in about 85% of MS patients, and which at later stages can also become progressive, the team plans to also investigate their approach in models of relapsing-remitting MS. Being able to suppress inflammation early on could have enormous benefits for patients.
“The ability of this team to convert a potentially pathogenic type of immune cell into a therapeutic one for MS, which is extremely hard or impossible to treat, could open an entirely new path to treat patients with a variety of neurological diseases,” said Wyss Founding Director Donald Ingber, M.D., Ph.D
DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models
by Hao Liu, René N. Caballero-Florán, Ty Hergenreder, Tao Yang, Jacob M. Hull, Geng Pan, Ruonan Li, Macy W. Veling, Lori L. Isom, Kenneth Y. Kwan, Z. Josh Huang, Peter G. Fuerst, Paul M. Jenkins, Bing Ye in PLOS Biology
Researchers from the University of Michigan have found that an extra copy of a gene in Down syndrome patients causes improper development of neurons in mice.
The gene in question, called Down syndrome cell adhesion molecule, or DSCAM, is also implicated in other human neurological conditions, including autism spectrum disorders, bipolar disorder and intractable epilepsy.
The cause of Down syndrome is known to be an extra copy of chromosome 21, or trisomy 21. But because this chromosome contains more than 200 genes — including DSCAM — a major challenge in Down syndrome research and treatments is determining which gene or genes on the chromosome contribute to which specific symptoms of the syndrome.
“The ideal path for treatment would be to identify the gene that causes a medical condition, and then target this gene or other genes that it works with to treat that aspect of Down syndrome,” said Bing Ye, a neuroscientist at the U-M Life Sciences Institute and lead author of the study.
“But for Down syndrome, we can’t just sequence patient genomes to find such genes, because we’d find at least 200 different genes that are changed. We have to dig deeper to figure out which of those genes causes which problem.”
For this work, researchers turn to animal models of Down syndrome. By studying mice that have a third copy of the mouse equivalent of chromosome 21, Ye and his team have now demonstrated how an extra copy of DSCAM contributes to neuronal dysfunction.
Each neuron has two sets of branches that extend out from the cell center: dendrites, which receive signals from other nerve cells, and axons, which send signals to other neurons. Ye and colleagues previously determined that overabundance of the protein encoded by DSCAM can cause overgrowth of axons in fruit fly neurons.
Guided by their research in flies, the team has now found that a third copy of DSCAM in mice leads to increased axon growth and neuronal connections (called synapses) in the types of neurons that put the brakes on other neurons’ activities. These changes lead to greater inhibition of other neurons in the cerebral cortex — a part of the brain that is involved in sensation, cognition and behavior.
“It’s known that these inhibitory synapses are changed in Down syndrome mouse models, but the gene that underlies this change is unknown,” said Ye, who is also a professor of cell and developmental biology at the U-M Medical School. “We show here that the extra copy of DSCAMis the primary cause of the excessive inhibitory synapses in the cerebral cortex.”
The team demonstrated that in mice that had only two copies of DSCAM, but three copies of the other genes that are similar to human chromosome 21 genes, axon growth appeared normal.
“These results are striking because, although these mice have an extra copy of about a hundred genes, normalization of this single gene, DSCAM, rescues normal inhibitory synaptic function,” said Paul Jenkins, assistant professor of pharmacology and psychiatry at the Medical School and co-corresponding author of the study.
“This suggests that modulation of DSCAM expression levels could be a viable therapeutic strategy for repairing synaptic deficits seen in Down syndrome. In addition, given that alterations of DSCAM levels are associated with other brain disorders like autism spectrum disorder and bipolar disorder, these results shed insight into potential mechanisms underlying other human diseases.”
Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1
by Nazma Malik, Bibiana I. Ferreira, Pablo E. Hollstein, Stephanie D. Curtis, Elijah Trefts, Sammy Weiser Novak, Jingting Yu, Rebecca Gilson, Kristina Hellberg, Lingjing Fang, Arlo Sheridan, Nasun Hah, Gerald S. Shadel, Uri Manor, Reuben J. Shaw in Science
Scientists often act as detectives, piecing together clues that alone may seem meaningless but together crack the case. Professor Reuben Shaw has spent nearly two decades piecing together such clues to understand the cellular response to metabolic stress, which occurs when cellular energy levels dip. Whether energy levels fall because the cell’s powerhouses (mitochondria) are failing or due to a lack of necessary energy-making supplies, the response is the same: get rid of the damaged mitochondria and create new ones.
Now, in a study published in Science, Shaw and the team cracked the case on this process of removal and replacement. It turns out that a protein called FNIP1 is the critical link between a cell sensing low energy levels and eliminating and replacing damaged mitochondria.
“This is a final puzzle piece that connects decades of studies from labs all over the world. It solves one of the final mysteries about how the signal to make new mitochondria is tied to the original signal that energy levels are low,” says Shaw, senior author and director of Salk’s Cancer Center. “This discovery that FNIP1 is at the heart of the metabolic stress response will help us understand healthy aging, cancerous tumors, neurodegenerative diseases, and so much more. This is a fundamental cellular process that ties into many diseases and will be in textbooks for years to come.”
Nearly 15 years ago, Shaw’s lab discovered that an enzyme called AMPK was responsible for starting the removal process of damaged mitochondria. Later, the team showed that a part of this removal process is the cell breaking damaged mitochondria into hundreds of fragments, then sorting through those fragments to remove the damaged parts and repurpose the functional parts. But the question remained — how is the repair of damaged powerhouses connected to the signal to start making new powerhouses from scratch?
When mitochondria are damaged, or when sugar (glucose) or oxygen levels fall in the cell, energy levels quickly fall. After an energy decrease as small as 10 percent, AMPK is triggered. AMPK communicates with another protein, called TFEB, to instruct genes to make 1) lysosomes (cellular recycling centers) to remove damaged mitochondria, and 2) replacement mitochondria. But how AMPK and TFEB communicated was unclear.
When a new suspect, FNIP1, joined in on the metabolic stress mystery, the answer was finally within reach. FNIP1 is the most recently discovered protein of the AMPK, TFEB, FNIP1 trio. For years, researchers were only able to connect FNIP1 to AMPK, and thus thought it may be a throwaway clue or a red herring — instead, it was the clue that cracked the case.
“Many years ago, we suspected the FNIP1 protein might be important for AMPK-TFEB communication that led to mitochondria synthesis and replacement in the cell during metabolic stress, but we didn’t know how FNIP1 was involved,” says first author Nazma Malik, a postdoctoral fellow in Shaw’s lab. “If correct, this finding would finally link AMPK and TFEB, which would both enrich our understanding of metabolism and cellular communication and provide a novel target for therapeutics.”
To determine whether FNIP1 was the missing link between AMPK and TFEB, the researchers compared unaltered human kidney cells with two altered types of human kidney cells: one that lacked AMPK entirely, and another that lacked only the specific parts of FNIP1 that AMPK talks to. The team discovered that AMPK signals FNIP1, which then opens the gate to let TFEB into the nucleus of the cell. Without FNIP1 receiving the signal from AMPK, TFEB remains trapped outside the nucleus, and the entire process of breaking down and replacing damaged mitochondria is not possible. And without this robust response to metabolic stress, our bodies — along with the many plants and animals whose cells also rely on mitochondria — would not be able to function effectively.
“Watching this project evolve over the last 15 years has been a rewarding experience,” says Shaw, holder of the William R. Brody Chair. “I am proud of my dedicated, talented team, and I cannot wait to see how this monumental finding will influence future research — at Salk and beyond.”
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