NS/ Progress in decoding genetics of insomnia
Neuroscience biweekly vol. 76, 4th January — 18th January
TL;DR
- A National Institutes of Health-funded effort involving researchers from Texas A&M University, the Perelman School of Medicine at the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) has used human genomics to identify a new genetic pathway involved in regulating sleep from fruit flies to humans — a novel insight that could pave the way for new treatments for insomnia and other sleep-related disorders.
- The neocortex is the largest and most complex part of the brain and has long been considered the ultimate storage site for long-term memories. But how are traces of past events and experiences laid down there? Researchers have discovered that a little-studied area of the brain, the “zone of uncertainty” or “zona incerta,” communicates with the neocortex in unconventional ways to rapidly control memory formation. Their work provides the first functional analysis of how long-range inhibition shapes information processing in the neocortex. The signals identified in this study are likely critical not only for memory but also for a number of additional brain functions, such as attention. The results have just been published in the journal Neuron.
- Negative emotions, anxiety, and depression are thought to promote the onset of neurodegenerative diseases and dementia. But what is their impact on the brain and can their deleterious effects be limited? Neuroscientists have observed the activation of the brains of young and older adults when confronted with the psychological suffering of others. The neuronal connections of older adults show significant emotional inertia: negative emotions modify them excessively and over a long period of time, particularly in the posterior cingulate cortex and the amygdala, two brain regions strongly involved in the management of emotions and autobiographical memory. These results indicate that better management of these emotions — through meditation for example — could help limit neurodegeneration.
- Researchers have created an artificial organic neuron that closely mimics the characteristics of biological nerve cells. This artificial neuron can stimulate natural nerves, making it a promising technology for various medical treatments in the future.
- A team that has used two-photon imaging technology to show the creation and elimination of synapses between neurons in the brains of live mice.
- The brain performs various cognitive and behavioral functions in everyday life, flexibly transitioning to various states to carry out these functions. Scientists view the brain as a system that performs these numerous functions by controlling its states. To better understand the properties of this control in the brain, scientists look for ways to estimate the difficulty of control, or control cost, when the brain transitions from one state to another. So a team of researchers undertook a study to quantify such control costs in the brain and was successful in building a framework that evaluates these costs.
- Researchers have created the first highly mature neurons from human induced pluripotent stem cells (iPSCs), a feat that opens new opportunities for medical research and potential transplantation therapies for neurodegenerative diseases and traumatic injuries.
- New research has found a better education has a strong genetic correlation and a protective causal association with several gut disorders.
- Cats always land on their feet, but what makes them so agile? Their unique sense of balance has more in common with humans than it may appear. Researchers at the Georgia Institute of Technology are studying cat locomotion to better understand how the spinal cord works to help humans with partial spinal cord damage walk and maintain balance.
- And more!
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The latest news and research
Variant-to-gene mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as a regulator of sleep
by Palermo J, Chesi A, Zimmerman A, et al. in Science Advances.
A National Institutes of Health-funded effort involving researchers from Texas A&M University, the Perelman School of Medicine at the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) has used human genomics to identify a new genetic pathway involved in regulating sleep from fruit flies to humans — a novel insight that could pave the way for new treatments for insomnia and other sleep-related disorders.
Texas A&M geneticist and evolutionary biologist Alex Keene collaborated with Penn’s Allan Pack and Philip Gehrman and CHOP’s Struan Grant on the groundbreaking research, which is published in Science Advances.
“There have been enormous amounts of effort to use human genomic studies to find sleep genes,” Keene said. “Some studies have hundreds of thousands of individuals. But validation and testing in animal models is critical to understanding function. We have achieved this here, largely because we each bring a different area of expertise that allowed for this collaboration’s ultimate effectiveness.”
Keene says the most exciting thing about the team’s work is that they developed a pipeline starting not with a model organism, but with actual human genomics data.
“There is an abundance of human genome-wide association studies (GWAS) that identify genetic variants associated with sleep in humans,” Keene said. “However, validating them has been an enormous challenge. Our team used a genomics approach called variant-to-gene mapping to predict the genes impacted by each genetic variant. Then we screened the effect of these genes in fruit flies.
“Our studies found that mutations in the gene Pig-Q, which is required for the biosynthesis of a modifier of protein function, increased sleep. We then tested this in a vertebrate model, zebrafish, and found a similar effect. Therefore, in humans, flies and zebrafish, Pig-Q is associated with sleep regulation.”
Keene says the team’s next step is to study the role of a common protein modification, GPI-anchor biosynthesis, on sleep regulation. In addition, he notes that the human-to-fruit flies-to-zebrafish pipeline the team developed will allow them to functionally assess not only sleep genes but also other traits commonly studied using human GWAS, including neurodegeneration, aging and memory.
“Understanding how genes regulate sleep and the role of this pathway in sleep regulation can help unlock future findings on sleep and sleep disorders, such as insomnia,” said Gehrman, an associate professor of clinical psychology in psychiatry at Penn and a clinical psychologist with the Penn Chronobiology and Sleep Institute. “Moving forward, we will continue to use and study this system to identify more genes regulating sleep, which could point in the direction of new treatments for sleep disorders.”
Keene’s research within his Center for Biological Clocks Research-affiliated laboratory lies at the intersection of evolution and neuroscience, with a primary focus on understanding the neural mechanisms and evolutionary underpinnings of sleep, memory formation and other behavioral functions in fly and fish models. Specifically, he studies fruit flies (Drosophila melanogaster) and Mexican cavefish that have lost both their eyesight and ability to sleep with the goal of identifying the genetic basis of behavioral choices that factor into human disease, including obesity, diabetes and heart disease.
Inhibitory top-down projections from zona incerta mediate neocortical memory
by Anna Schroeder, M. Belén Pardi, Joram Keijser, Tamas Dalmay, Ayelén I. Groisman, Erin M. Schuman, Henning Sprekeler, Johannes J. Letzkus in Neuron
The neocortex is the largest and most complex part of the brain and has long been considered the ultimate storage site for long-term memories. But how are traces of past events and experiences laid down there? Researchers at the University of Freiburg Medical School led by Prof. Dr. Johannes Letzkus and the Max Planck Institute for Brain Research have discovered that a little-studied area of the brain, the “zone of uncertainty” or “zona incerta,” communicates with the neocortex in unconventional ways to rapidly control memory formation. Their work provides the first functional analysis of how long-range inhibition shapes information processing in the neocortex. The signals identified in this study are likely critical not only for memory, but also for a number of additional brain functions, such as attention. The results have just been published in the journal Neuron.
Memory is one of the most fundamental functions of the brain, enabling people to learn from experience and remember the past. Moreover, a mechanistic understanding of memory has implications that can range from the treatment of memory and anxiety disorders to the development of artificial intelligence and efficient hardware and software design. To form memories, the brain must make connections between sensory “bottom-up” signals from the environment and internally generated “top-down” signals that convey information about past experiences and current goals. These top-down signals are a central focus of current research.
In recent years, researchers have begun to identify a number of such top-down projection systems, all of which share a number of common features: They signal through synaptic excitation, the standard way of sending information between cortical regions, and they also exhibit a common regime for memory encoding. A stimulus with learned relevance elicits a stronger response in these systems, suggesting that this positive potentiation is one piece of the puzzle that is the memory trace.
In contrast to these systems, long-range inhibitory pathways are much sparser and less numerous, but mounting evidence suggests that they can still have surprisingly robust effects on network function and behavior,” says Prof. Dr. Johannes Letzkus, Professor at the University of Freiburg and former Research Group Leader at the Max Planck Institute for Brain. “We set out to determine whether such inputs might be present in neocortex, and if so, how they might uniquely contribute to memory.”
Dr. Anna Schroeder, first author of the study and postdoctoral researcher in the Letzkus lab, decided to focus on a predominantly inhibitory subthalamic nucleus, the zona incerta, to address this question. While the function of this brain region remains as mysterious as its name suggests, her preliminary findings indicated that the zona incerta sends inhibitory projections which selectively innervate regions of neocortex known to be important for learning. In her efforts to study plasticity in this system across all stages of learning, she implemented an innovative approach that allowed her to track the responses of individual zona incerta synapses in neocortex before, during and after a learning paradigm.
“The results were striking,” recalls Schroeder. “While about half of the synapses developed stronger positive responses during learning, the other half did exactly the opposite. In effect, what we observed was thus a complete redistribution of inhibition within the system due to learning.”
This suggests that zona incerta synapses encode previous experience in a unique, bidirectional fashion. This was especially clear when the scientists compared the magnitude of the plasticity with the strength of the acquired memory. They found a positive correlation, which shows that zona incerta projections encode the learned relevance of sensory stimuli.
In separate experiments, Schroeder discovered that silencing these projections during the learning phase impairs the memory trace later on, indicating that the bidirectional plasticity occurring in these projections is required for learning. She also found that these inhibitory projections preferentially form functional connections with other inhibitory neurons in neocortex, in effect forming a long-range disinhibitory circuit.
“This connectivity implies that an activation of the zona incerta should result in a net excitation of neocortical circuits,” says Schroeder. “However, combining this with the redistribution of inhibition that we see with learning shows that this pathway likely has even richer computational consequences for neocortical processing.”
The scientists were particularly intrigued by the population of zona incerta synapses that showed negative potentiation, as this type of plasticity has never been observed before in the top-down excitatory pathways that were previously studied. They felt that computational approaches might provide valuable insights into how these unique responses develop. Further analyses in collaboration with the laboratory of Prof. Dr. Henning Sprekeler and his team at the Technical University of Berlin revealed that, remarkably, these negative responses are the main driver in the changes in stimulus representation that occur during learning itself.
Moreover, the zona incerta is among the very few regions standardly targeted for deep brain stimulation in human Parkinson’s patients, opening up an intriguing possibility for translational work in the future.
“Ultimately, this study will hopefully also inspire other researchers to keep exploring the role of long-range inhibition in regulating neocortical function, both from the zona incerta and from additional, yet to be identified sources,” says Letzkus.
Exposure to negative socio-emotional events induces sustained alteration of resting-state brain networks in older adults
by Sebastian Baez-Lugo, Yacila I. Deza-Araujo, Christel Maradan, Fabienne Collette, Antoine Lutz, Natalie L. Marchant, Gaël Chételat, Patrik Vuilleumier, Olga Klimecki, Eider Arenaza-Urquijo, Claire André, Maelle Botton, Pauline Cantou, Gaëlle Chételat, Anne Chocat, Vincent De la Sayette, Marion Delarue, Stéphanie Egret, Eglantine Ferrand Devouge, Eric Frison, Julie Gonneaud, Marc Heidmann, Elizabeth Kuhn, Brigitte Landeau, Gwendoline Le Du, Valérie Lefranc, Florence Mezenge, Inès Moulinet, Valentin Ourry, Géraldine Poisnel, Anne Quillard, Géraldine Rauchs, Stéphane Rehel, Clémence Tomadesso, Edelweiss Touron, Caitlin Ware, Miranka Wirth in Nature Aging
Negative emotions, anxiety and depression are thought to promote the onset of neurodegenerative diseases and dementia. But what is their impact on the brain and can their deleterious effects be limited? Neuroscientists at the University of Geneva (UNIGE) observed the activation of the brains of young and older adults when confronted with the psychological suffering of others. The neuronal connections of older adults show significant emotional inertia: negative emotions modify them excessively and over a long period of time, particularly in the posterior cingulate cortex and the amygdala, two brain regions strongly involved in the management of emotions and autobiographical memory. These results, to be published in Nature Aging, indicate that better management of these emotions — through meditation for example — could help limit neurodegeneration.
For the past 20 years, neuroscientists have been looking at how the brain reacts to emotions.
‘’We are beginning to understand what happens at the moment of perception of an emotional stimulus,’’ explains Dr Olga Klimecki, a researcher at the UNIGE’s Swiss Centre for Affective Sciences and at the Deutsches Zentrum für Neurodegenerative Erkrankungen, who is last author of this study carried out as part of a European research project co-directed by the UNIGE. ‘’However, what happens afterwards remains a mystery. How does the brain switch from one emotion to another? How does it return to its initial state? Does emotional variability change with age? What are the consequences for the brain of mismanagement of emotions?’’
Previous studies in psychology have shown that an ability to change emotions quickly is beneficial for mental health. Conversely, people who are unable to regulate their emotions and remain in the same emotional state for a long time are at higher risks of depression.
‘’Our aim was to determine what cerebral trace remains after the viewing of emotional scenes, in order to evaluate the brain’s reaction, and, above all, its recovery mechanisms. We focused on the older adults, in order to identify possible differences between normal and pathological ageing,’’ says Patrik Vuilleumier, professor in the Department of Basic Neurosciences at the Faculty of Medicine and at the Swiss Centre for Affective Sciences at the UNIGE, who co-directed this work.
The scientists showed volunteers short television clips showing people in a state of emotional suffering — during a natural disaster or distress situation for example — as well as videos with neutral emotional content, in order to observe their brain activity using functional MRI. First, the team compared a group of 27 people over 65 years of age with a group of 29 people aged around 25 years. The same experiment was then repeated with 127 older adults.
‘’Older people generally show a different pattern of brain activity and connectivity from younger people,’’ says Sebastian Baez Lugo, a researcher in Patrik Vuilleumier’s laboratory and the first author of this work. ‘’This is particularly noticeable in the level of activation of the default mode network, a brain network that is highly activated in resting state. Its activity is frequently disrupted by depression or anxiety, suggesting that it is involved in the regulation of emotions. In the older adults, part of this network, the posterior cingulate cortex, which processes autobiographical memory, shows an increase in its connections with the amygdala, which processes important emotional stimuli. These connections are stronger in subjects with high anxiety scores, with rumination, or with negative thoughts.’’
However, older people tend to regulate their emotions better than younger people, and focus more easily on positive details, even during a negative event. But changes in connectivity between the posterior cingulate cortex and the amygdala could indicate a deviation from the normal ageing phenomenon, accentuated in people who show more anxiety, rumination and negative emotions. The posterior cingulate cortex is one of the regions most affected by dementia, suggesting that the presence of these symptoms could increase the risk of neurodegenerative disease.
‘’Is it poor emotional regulation and anxiety that increases the risk of dementia or the other way around? We still don’t know,’’ says Sebastian Baez Lugo. ‘’Our hypothesis is that more anxious people would have no or less capacity for emotional distancing. The mechanism of emotional inertia in the context of ageing would then be explained by the fact that the brain of these people remains ‘frozen’ in a negative state by relating the suffering of others to their own emotional memories.”
Could it be possible to prevent dementia by acting on the mechanism of emotional inertia? The research team is currently conducting an 18-month interventional study to evaluate the effects of foreign language learning on the one hand, and meditation practice on the other.
‘’In order to further refine our results, we will also compare the effects of two types of meditation: mindfulness, which consists of anchoring oneself in the present in order to concentrate on one’s own feelings, and what is known as ‘compassionate’ meditation, which aims to actively increase positive emotions towards others,’’ the authors add.
Ion-tunable antiambipolarity in mixed ion–electron conducting polymers enables biorealistic organic electrochemical neurons
by Padinhare Cholakkal Harikesh, Chi-Yuan Yang, Han-Yan Wu, Silan Zhang, Mary J. Donahue, April S. Caravaca, Jun-Da Huang, Peder S. Olofsson, Magnus Berggren, Deyu Tu, Simone Fabiano in Nature Materials
Researchers at Linköping University (LiU), Sweden, have created an artificial organic neuron that closely mimics the characteristics of biological nerve cells. This artificial neuron can stimulate natural nerves, making it a promising technology for various medical treatments in the future.
Work to develop increasingly functional artificial nerve cells continues at the Laboratory for Organic Electronics, LOE. In 2022, a team of scientists led by associate professor Simone Fabiano demonstrated how an artificial organic neuron could be integrated into a living carnivorous plant to control the opening and closing of its maw. This synthetic nerve cell met 2 of the 20 characteristics that differentiate it from a biological nerve cell.
In their latest study, published in the journal Nature Materials, the same researchers at LiU have developed a new artificial nerve cell called “conductance-based organic electrochemical neuron” or c-OECN, which closely mimics 15 out of the 20 neural features that characterise biological nerve cells, making its functioning much more similar to natural nerve cells.
“One of the key challenges in creating artificial neurons that effectively mimic real biological neurons is the ability to incorporate ion modulation. Traditional artificial neurons made of silicon can emulate many neural features but cannot communicate through ions. In contrast, c-OECNs use ions to demonstrate several key features of real biological neurons,” says Simone Fabiano, principal investigator of the Organic Nanoelectronics group at LOE.
In 2018, this research group at Linköping University was one of the first to develop organic electrochemical transistors based on n-type conducting polymers, which are materials that can conduct negative charges. This made it possible to build printable complementary organic electrochemical circuits. Since then, the group has been working to optimize these transistors so that they can be printed in a printing press on a thin plastic foil. As a result, it is now possible to print thousands of transistors on a flexible substrate and use them to develop artificial nerve cells.
In the newly developed artificial neuron, ions are used to control the flow of electronic current through an n-type conducting polymer, leading to spikes in the device’s voltage. This process is similar to that which occurs in biological nerve cells. The unique material in the artificial nerve cell also allows the current to be increased and decreased in an almost perfect bell-shaped curve that resembles the activation and inactivation of sodium ion channels found in biology.
“Several other polymers show this behaviour, but only rigid polymers are resilient to disorder, enabling stable device operation,” says Simone Fabiano.
In experiments carried out in collaboration with Karolinska Institute (KI), the new c-OECN neurons were connected to the vagus nerve of mice. The results show that the artificial neuron could stimulate the mice’s nerves, causing a 4.5% change in their heart rate. The fact that the artificial neuron can stimulate the vagus nerve itself could, in the long run, pave the way for essential applications in various forms of medical treatment. In general, organic semiconductors have the advantage of being biocompatible, soft, and malleable, while the vagus nerve plays a key role, for example, in the body’s immune system and metabolism.
The next step for the researchers will be to reduce the energy consumption of the artificial neurons, which is still much higher than that of human nerve cells. Much work remains to be done to replicate nature artificially.
“There is much we still don’t fully understand about the human brain and nerve cells. In fact, we don’t know how the nerve cell makes use of many of these 15 demonstrated features. Mimicking the nerve cells can enable us to understand the brain better and build circuits capable of performing intelligent tasks. We’ve got a long road ahead, but this study is a good start,” says Padinhare Cholakkal Harikesh, postdoc and main author of the scientific paper.
Hippocampal engram networks for fear memory recruit new synapses and modify pre-existing synapses in vivo
by Chaery Lee, Byung Hun Lee, Hyunsu Jung, Chiwoo Lee, Yongmin Sung, Hyopil Kim, Jooyoung Kim, Jae Youn Shim, Ji-il Kim, Dong Il Choi, Hye Yoon Park, Bong-Kiun Kaang in Current Biology
A University of Minnesota Twin Cities researcher is part of an international team that has used imaging technology to show, for the first time, the creation and elimination of synapses between neurons in the brains of live mice.
The research provides insight into what happens when memories are created and forgotten and could help scientists better understand and treat conditions like post-traumatic stress disorder (PTSD).
“Researchers have been wondering what happens to the synapses that form after we have a fearful experience,” said Hye Yoon Park, co-lead author of the study and an associate professor in the University of Minnesota Department of Electrical and Computer Engineering. “Previously, researchers were able to detect these synapses in mice only after they sacrificed the mouse, which made it difficult to track those synapses over time. But now, we’ve made it possible to image the synapses in a live mouse brain over several days, so we can better understand what happens to them long-term. It’s the first time this has been done in a live mouse brain, so that’s pretty exciting news in this field.”
This study builds upon Park’s previous research, which leveraged her lab’s expertise in imaging to visualize nerve cells, or neurons, and mRNA molecules associated with memory in the brains of live mice.
Now, the researchers have added more detail by imaging the synapses, or connections, between the neurons. On average, each neuron in the brain has around 7,000 synaptic connections with other neurons, which allow the cells to pass signals to each other and drive cognitive functions like learning and memory.
The University of Minnesota team collaborated with researchers at Seoul National University in Korea who developed a technology called eGRASP to detect synapses in the brain. Combined with Park’s imaging techniques, the researchers were able to see the dynamics of synapses in a live mouse brain both while it was remembering a fearful experience and while it was experiencing “memory extinction,” or fear memory suppression.
“There are two different hypotheses about this in the neuroscience field,” Park explained. “When memory extinction happens, some people believed the synapses that develop during fear conditioning may disappear, also called the ‘unlearning’ of pre-acquired memories. Others thought that they were still there, but maybe another set of synapses formed to show that the mouse has now learned the environment is safe again, which is referred to as ‘new learning’ about the contingency.”
The researchers’ data supported the unlearning hypothesis. They found that some of the new synapses formed during a fearful experience were eliminated over the course of the memory extinction process. These findings could help scientists better understand brain activity in patients with conditions like post-traumatic stress disorder (PTSD).
Optimal Control Costs of Brain State Transitions in Linear Stochastic Systems
by Shunsuke Kamiya, Genji Kawakita, Shuntaro Sasai, Jun Kitazono, Masafumi Oizumi inThe Journal of Neuroscience
The brain performs various cognitive and behavioral functions in everyday life, flexibly transitioning to various states to carry out these functions. Scientists view the brain as a system that performs these numerous functions by controlling its states. To better understand the properties of this control in the brain, scientists look for ways to estimate the difficulty of control, or control cost, when the brain transitions from one state to another. So a team of researchers undertook a study to quantify such control costs in the brain, and was successful in building a framework that evaluates these costs.
Controlling transitions to some states incurs greater “costs” than controlling transitions to others. With the development of a framework for quantifying transition costs, scientists will have a way to evaluate the difficulty of the shifts between various brain states. Possibly, they might also have a quantifiable measure for explaining cognitive loads, sleep-wake differences, habituation of cognitive tasks and psychiatric disorders.
The team worked to build a novel framework to quantify control cost that takes account of stochasticity, or the randomness, of neural activity. This stochasticity has been ignored in previous studies. The current control paradigm in neuroscience uses a deterministic framework that is unable to consider stochasticity. But it is well known that the neural dynamics are stochastic and the noise is ubiquitous throughout the whole brain.
“In this work, we addressed the issue of stochasticity and first proposed a novel theoretical framework that quantifies the control cost taking account of the stochastic fluctuations of the neural dynamics,” said Shunsuke Kamiya, a doctoral student in the Graduate School of Arts and Sciences at the University of Tokyo.
In their study, the researchers established the analytical expression of the stochastic control cost, which enabled them to compute the cost in high-dimensional neural data. By the analytical expression, they discovered that the optimal control cost can be decomposed into the costs to control the mean and covariance.
“This decomposition enables us to investigate how various brain areas differently contribute to controlling the transitions from one brain state to another,” said Kamiya.
The researchers also identified the significant brain regions for the optimal control of cognitive tasks in human whole-brain imaging data. They examined the significant brain regions in the optimal control of transitions from the resting state to seven cognitive task states, using human whole-brain imaging data from 352 healthy adults. They found that, with these different transitions, the lower visual areas commonly played a significant role in controlling the means, while the posterior cingulate cortex commonly played a significant role in controlling the covariances. The posterior cingulate cortex is the upper part of the limbic lobe, the region of the brain that plays an important role in memory and emotional behaviors.
In this study, the team only considered the optimal control cost where brain state transitions are controlled in an optimal manner, with minimization of stochastic control cost. However, in real neural systems, it is not likely that state transitions are controlled in an optimal manner.
“An intriguing future direction will be to compare the optimally controlled dynamics and the actual dynamics using neural data during tasks,” said Masafumi Oizumi, associate professor in the Graduate School of Arts and Sciences at the University of Tokyo.
Looking ahead to future research, Oizumi explains that the ultimate goal of his lab is to understand the connection between brain dynamics and human behaviors, cognitions and consciousness.
“For example, we suspect that the decrease of controllability in the brain dynamics may be related to mental fatigue or the loss of consciousness. We expect that control theoretical perspective will provide a new insight to this goal,” said Oizumi.
Artificial extracellular matrix scaffolds of mobile molecules enhance maturation of human stem cell-derived neurons
by Zaida Álvarez, J. Alberto Ortega, Kohei Sato, Ivan R. Sasselli, Alexandra N. Kolberg-Edelbrock, Ruomeng Qiu, Kelly A. Marshall, Thao Phuong Nguyen, Cara S. Smith, Katharina A. Quinlan, Vasileios Papakis, Zois Syrgiannis, Nicholas A. Sather, Chiara Musumeci, Elisabeth Engel, Samuel I. Stupp, Evangelos Kiskinis in Cell Stem Cell
Northwestern University-led researchers have created the first highly mature neurons from human induced pluripotent stem cells (iPSCs), a feat that opens new opportunities for medical research and potential transplantation therapies for neurodegenerative diseases and traumatic injuries.
Although previous researchers have differentiated stem cells to become neurons, those neurons were functionally immature — resembling neurons from embryonic or early postnatal stages. The limited maturation obtained with current stem cell culture techniques diminish their potential for neurodegeneration studies.
To create the mature neurons, the team used “dancing molecules,” a breakthrough technique introduced last year by Northwestern professor Samuel I. Stupp. The team first differentiated human iPSCs into motor and cortical neurons and then placed them onto coatings of synthetic nanofibers containing the rapidly moving dancing molecules.
Not only were the enriched neurons more mature, but they also demonstrated enhanced signaling capabilities and greater branching ability, which is required for neurons to make synaptic contact with one another. And, unlike typical stem cell-derived neurons which tend to clump together, these neurons did not aggregate, making them less challenging to maintain.
With further development, the researchers believe these mature neurons could be transplanted into patients as a promising therapy for spinal cord injuries as well as neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease or multiple sclerosis.
The mature neurons also present new opportunities for studying neurodegenerative diseases like ALS and other age-related illnesses in culture dish-based in vitromodels. By advancing the age of neurons in cellular cultures, researchers could improve experiments to better understand late-onset diseases.
“This is the first time we have been able to trigger advanced functional maturation of human iPSC-derived neurons by plating them on a synthetic matrix,” said Northwestern’s Evangelos Kiskinis, co-corresponding author of the study. “It’s important because there are many applications that require researchers to use purified populations of neurons. Most stem cell-based labs use mouse or rat neurons co-cultured with human stem cell-derived neurons. But that does not allow scientists to investigate what happens in human neurons because you end up working with a mixture of mouse and human cells.”
“When you have an iPSC that you manage to turn into a neuron, it’s going to be a young neuron,” said Stupp, co-corresponding author of the study. “But, in order for it to be useful in a therapeutic sense, you need a mature neuron. Otherwise, it is like asking a baby to carry out a function that requires an adult human being. We have confirmed that neurons coated with our nanofibers achieve more maturity than other methods, and mature neurons are better able to establish the synaptic connections that are fundamental to neuronal function.”
Kiskinis is an assistant professor of neurology and neuroscience at Northwestern University Feinberg School of Medicine, a New York Stem Cell Foundation-Robertson Investigator and a core faculty member of the Les Turner ALS Center. Stupp is the Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern, where he is founding director of the Simpson Querrey Institute for BioNanotechnology (SQI) and its affiliated research center, the Center for Regenerative Nanomedicine. Stupp has appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences and Feinberg School of Medicine.
To develop the mature neurons, the researchers used nanofibers composed of “dancing molecules,” a material that Stupp’s lab developed as a potential treatment for acute spinal cord injuries. In previous research published in the journal Science, Stupp discovered how to tune the motion of molecules, so they can find and properly engage with constantly moving cellular receptors. By mimicking the motion of biological molecules, the synthetic materials can communicate with cells.
A key innovation of Stupp’s research was discovering how to control the collective motion of more than 100,000 molecules within the nanofibers. Because cellular receptors in the human body can move at swift rates — sometimes at timescales of milliseconds — they become difficult-to-hit moving targets.
“Imagine dividing a second into 1,000 time periods,” Stupp said. “That’s how fast receptors could move. These timescales are so fast that they are difficult to grasp.”
In the new study, Stupp and Kiskinis found that nanofibers tuned to contain molecules with the most motion led to the most enhanced neurons. In other words, neurons cultured on more dynamic coatings — essentially scaffolds composed of many nanofibers — were also the neurons that became the most mature, least likely to aggregate and had more intense signaling capabilities.
“The reason we think this works is because the receptors move very fast on the cell membrane and the signaling molecules of our scaffolds also move very fast,” Stupp said. “They are more likely to be synchronized. If two dancers are not in sync, then the pairing doesn’t work. The receptors become activated by the signals through very specific spatial encounters. It also is possible that our fast-moving molecules enhance receptor movement, which in turn helps cluster them to benefit signaling.”
Stupp and Kiskinis believe their mature neurons will give insights into aging-related illnesses and become better candidates for testing various drug therapies in cellular cultures. Using the dancing molecules, the researchers were able to advance human neurons to much older ages than previously possible, enabling scientists to study the onset of neurodegenerative diseases.
As part of the research, Kiskinis and his team took skin cells from a patient with ALS and converted them into patient-specific iPSCs. Then, they differentiated those stem cells into motor neurons, which is the cell type afflicted in this neurodegenerative disease. Finally, the researchers cultured neurons on the novel synthetic coating materials to further develop ALS signatures. Not only did this give Kiskinis a new window into ALS, these “ALS neurons” also could be used to test potential therapies.
“For the first time, we have been able to see adult-onset neurological protein aggregation in the stem cell-derived ALS patient motor neurons. This represents a breakthrough for us,” Kiskinis said. “It’s unclear how the aggregation triggers the disease. It’s what we are hoping to find out for the first time.”
Further down the road, iPSC-derived mature, enhanced neurons also could be transplanted into patients with spinal cord injuries or neurodegenerative diseases. For example, physicians could take skin cells from a patient with ALS or Parkinson’s disease, convert them into iPSCs and then culture those cells on the coating to create healthy, highly functional neurons.
Transplanting healthy neurons into a patient could replace damaged or lost neurons, potentially restoring lost cognition or sensations. And, because the initial cells came from the patient, the new, iPSC-derived neurons would genetically match the patient, eliminating the possibility of rejection.
“Cell replacement therapy can be very challenging for a disease like ALS, as transplanted motor neurons in the spinal cord will need to project their long axons to the appropriate muscle sites in the periphery but could be more straightforward for Parkinson’s disease,” Kiskinis said. “Either way this technology will be transformative.”
“It is possible to take cells from a patient, transform them into stem cells and then differentiate them into different types of cells,” Stupp said. “But the yield for those cells tends to be low, and achieving proper maturation is a big issue. We could integrate our coating into large-scale manufacturing of patient-derived neurons for cell transplantation therapies without immune rejection.”
Relationship of Cognition and Alzheimer’s Disease with Gastrointestinal Tract Disorders: A Large-Scale Genetic Overlap and Mendelian Randomisation Analysis
by Emmanuel O. Adewuyi, Eleanor K. O’Brien, Tenielle Porter, Simon M. Laws in International Journal of Molecular Sciences
We’ve long known education is important for many aspects of life, but now a new benefit has been discovered: it can look after your gut health.
Landmark Edith Cowan University (ECU) research has found a better education has a strong genetic correlation and a protective causal association with several gut disorders.
A previous study from ECU’s Centre for Precision Health (CPH) discovered a genetic link between gut health and Alzheimer’s Disease (AD) but couldn’t conclude whether one caused the other.
This study breaks new ground by finding that a higher level of education protects against gut disorders.
CPH Director and study supervisor Professor Simon Laws said these findings build upon the centre’s previous work to provide further evidence of the strong links between the brain and gut, known as the gut-brain axis.
“Gut disorders and Alzheimer’s may not only share a common genetic predisposition but may be similarly influenced by genetic variations underpinning educational attainment,” Professor Laws said.
This large-scale study examined the genetic information of more than 766,000 individuals, with an emphasis on AD, cognitive traits and gut disorders, including peptic ulcer disease (PUD), gastritis-duodenitis, gastroesophageal reflux disease (GERD), irritable bowel syndrome, diverticulosis and inflammatory bowel disease (IBD).
It found higher levels of education and cognitive functioning reduced the risk of gut disorders.
Lead researcher Dr Emmanuel Adewuyi said the findings have significant implications. “The results support education as a possible avenue for reducing the risk of gut disorders by, for example, encouraging higher educational attainment or a possible increase in the length of schooling,” he said. “Hence, policy efforts aimed at increasing educational attainment or cognitive training may contribute to a higher level of intelligence, which could lead to better health outcomes including a reduced risk of gut disorders.”
ECU’s study further revealed the gut may also influence the brain.
GERD showed evidence of causing a decline in cognitive function across a number of cognitive traits assessed in the study, such as intelligence, cognitive performance, educational attainment and educational qualification.
Although this is the first study to report this finding, the results support recent research reporting an increased incidence of dementia and GERD, which Dr Adewuyi said could help with earlier diagnoses and potential treatments.
“GERD may be a risk factor for cognitive impairment, so it’s important for health workers to look for signs or symptoms of cognitive dysfunction in patients presenting with the gut disorder,” he said. “This could lead to earlier detection of cognitive decline and therefore earlier interventions aimed at reducing the rate of cognitive decline. “More studies are needed to investigate whether treatment for, cure or remission of GERD can contribute to a reduced risk of cognitive decline.”
Interestingly, higher levels of education and cognitive function protecting against gut disorders was true of all the disorders examined in the study — but largely with the exception of inflammatory bowel disease.
Further analysis reveals different effects of IBD on cognitive traits and AD at different genomic locations, indicating its relationship depend on effects at specific locations across the genome.
This new understanding may explain the lack of significant genetic correlation of IBD with cognitive traits and AD, and the inconsistency reported in previous observational studies.
Dr Adewuyi said this finding was also important, as it brings a new insight into the relationship of IBD with cognitive traits (and AD), which may shape the direction of future studies.
“For example, some risk genes for AD may be protective against IBD, and vice versa,” he said.
Sensory Perturbations from Hindlimb Cutaneous Afferents Generate Coordinated Functional Responses in All Four Limbs during Locomotion in Intact Cats.
by Merlet AN, Jéhannin P, Mari S, et al. in eNeuro
Cats always land on their feet, but what makes them so agile? Their unique sense of balance has more in common with humans than it may appear. Researchers at the Georgia Institute of Technology are studying cat locomotion to better understand how the spinal cord works to help humans with partial spinal cord damage walk and maintain balance.
Using a mix of experimental studies and computational models, the researchers show that somatosensory feedback, or neural signals from specialized sensors throughout a cat’s body, help inform the spinal cord about the ongoing movement and coordinate the four limbs to keep cats from falling when they encounter obstacles. Research suggests that with those motion-related sensory signals the animal can walk even if the connection between the spinal cord and the brain is partially fractured.
Understanding the mechanisms of this type of balance control is particularly relevant to older people who often have balance issues and can injure themselves in falls. Eventually, the researchers hope this could bring new understanding to somatosensory feedback’s role in balance control. It could also lead to progress in spinal cord injury treatment because the research suggests activation of somatosensory neurons can improve spinal neural networks’ function below the site of spinal cord damage.
“We have been interested in the mechanisms that make it possible to reactivate injured networks in the spinal cord,” said School of Biological Sciences Professor Boris Prilutsky. “We know from previous studies that somatosensory feedback from moving legs helps activate spinal networks that control locomotion, enabling stable movement.”
Although genetically modified mouse models have recently become dominant in neural control of locomotion research, the cat model offers an important advantage. When they move, mice remain crouched, meaning they are less likely to have balance problems even if somatosensory feedback fails. Humans and cats, on the other hand, cannot maintain balance or even move if they lose sensory information about limb motion. This suggests that larger species, like cats and humans, might have a different organization of spinal neural network controlling locomotion compared to rodents.
Georgia Tech partnered with researchers at the University of Sherbrooke in Canada and Drexel University in Philadelphia to better understand how signals from sensory neurons coordinate movements of the four legs. The Sherbrooke lab trained cats to walk on a treadmill at a pace consistent with human gait and then used electrodes to stimulate their sensory nerve.
The researchers focused on the sensory nerve that transmits touch sensation from the top of the foot to the spinal cord. By electrically stimulating this nerve, researchers mimicked hitting an obstacle and saw how the cats stumbled and corrected their movement in response. Stimulations were applied in four periods of the walking cycle: mid-stance, stance-to-swing transition, mid-swing, and swing-to-stance transition. From this, they learned that mid-swing and the stance-to-swing transition were the most significant periods because the stimulation increased activity in muscles that flex the knee and hip joints, joint flexion and toe height, step length, and step duration of the stimulated limb.
“In order to maintain balance, the animal must coordinate movement of the other three limbs, otherwise it would fall,” Prilutsky said. “We found that stimulation of this nerve during the swing phase increases the duration of the stance phase of the other limbs and improves stability.”
In effect, when the cat stumbles during the swing phase, the sensation triggers spinal reflexes that ensure the three other limbs stay on the ground and keep the cat upright and balanced, while the swing limb steps over the obstacle.
With these Canadian lab experiments, the researchers at Georgia Tech and Drexel University are using observations to develop a computational model of the cat’s musculoskeletal and spinal neural control systems. The data gathered are used to compute somatosensory signals related to length, velocity, and produced force of muscles, as well as pressure on the skin in all limbs. This information forms motion sensations in the animal’s spinal cord and contributes to interlimb coordination by the spinal neuronal networks.
“To help treat any disease, we need to understand how the intact system works,” Prilutsky said. “That was one reason why this study was performed, so we could understand how the spinal networks coordinate limb movements and develop a realistic computational model of spinal control of locomotion. This will help us know better how the spinal cord controls locomotion.”
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