Fast-tracking drug development for neurodegenerative disorders

The three-dimensional structure of the SARM1 protein determined by cryo-electron microscopy. Credit: Jeff Nanson.

A Griffith University-led research team has discovered how a therapeutic target common among debilitating neurodegenerative disorders is activated, which could help accelerate drug development.

In a study published in the journal Neuron, the researchers from Griffith University’s Institute for Glycomics, the University of Queensland and Washington University, analyzed the structure and function of a protein called SARM1, which is involved in the destruction of nerve fibers. They found that the protein is a sensor that responds to the levels of specific molecules derived from metabolism.

“SARM1 is a potential therapeutic target for many neurodegenerative diseases,”‘ said lead author and Institute for Glycomics researcher, Dr. Thomas Ve.

“When nerve fibers are damaged, whether by injury, disease or as a side effect of certain drugs, SARM1 is called into action which sets off a series of events in the cell that trigger them to self-destruct.

“This destruction likely plays an important role in multiple neurodegenerative conditions, including peripheral neuropathy, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury and glaucoma.”

Dr. Ve and joint first author on the paper, Dr. Yun Shi used NMR spectroscopy, a biophysical tool to analyze interactions between proteins and small molecules, to demonstrate that two important metabolites in nerve cells compete for binding to the SARM1 protein, and the ratio of these two metabolites determines whether SARM1 becomes activated.

Dr. Ve and collaborators also used structural biology tools—Cryo-electron Microscopy and X-ray Crystallography—to determine three-dimensional structures of the SARM1 protein which enabled them to pinpoint exactly where these two metabolites bind to SARM1 and how they regulate SARM1 activation.

Dr. Ve, also an Australian Research Council Future Fellow and NHMRC Investigator, said the new structural information about SARM1 had the potential to accelerate the development of drugs that target neurodegenerative diseases.

“We are very excited by these findings as they greatly advance our understanding of how SARM1 is activated,” he said.

“It provides clues as to how one might block activation of this protein using structure-guided approaches to prevent nerve fiber loss in neurodegenerative diseases.”

Professor Mark von Itzstein AO, Director of the Institute for Glycomics, welcomed this important breakthrough. “New strategies towards solving neurodegenerative diseases have become increasingly important due to the enormous impact on the quality of life of those that suffer with these conditions.”

More information: Matthew D. Figley et al. SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration, Neuron (2021). DOI: 10.1016/j.neuron.2021.02.009

https://medicalxpress.com/news/2021-03-fast-tracking-drug-neurodegenerative-disorders.html

Renaissance-era letter sealed for centuries just virtually unfolded and read for the first time

Computer-generated unfolding animation of sealed letter DB-1538. (Image credit: Courtesy of the Unlocking History Research Group archive)
A seventeenth-century trunk that was bequeathed to the Dutch postal museum in the Hague contained thousands of letters that were sent from all over Europe and were never delivered. (Image credit: Courtesy of the Unlocking History Research Group archive)

“Virtual unfolding” enabled researchers to read the contents of sealed letterpackets from 17th-century Europe without physically opening them. (Image credit: Courtesy of the Unlocking History Research Group archive)

By Mindy Weisberger

More than 600 years ago, someone intricately folded, sealed and posted a letter that was never delivered. Now, scientists have digitally “unfolded” this and other similarly locked letters found in a 17th-century trunk in The Hague, using X-rays

For centuries prior to the invention of sealed envelopes, sensitive correspondence was protected from prying eyes through complex folding techniques called “letterlocking,” which transformed a letter into its own secure envelope. However, locked letters that survive to the present are fragile and can be opened physically only by slicing them to pieces. 

The new X-ray method offers researchers a non-invasive alternative, maintaining a letterpacket’s original folded shape. For the first time, scientists applied this method to “locked” letters from the Renaissance period, kept in a trunk that had been in the collection of the Dutch postal museum in The Hague, The Netherlands, since 1926. 

The trunk’s contents include more than 3,100 undelivered letters, of which 577 were unopened and letterlocked. Known as the Brienne Collection, the letters were written in Dutch, English, French, Italian, Latin and Spanish. For unknown reasons, once the missives reached The Hague they were never delivered to their intended recipients, and were instead kept by a postmaster named Simon de Brienne, Live Science previously reported

Locked letters used different mechanisms to stay securely closed, including folds and rolls; slits and holes; tucks and adhesives; and a variety of cleverly constructed locks, according to a study published online March 2 in the journal Nature Communications.

To penetrate the layers of folded paper, the study authors used an X‐ray microtomography scanner engineered in the dental research labs at Queen Mary University of London (QMU). Researchers designed the scanner to be exceptionally sensitive so that it could map the mineral content of teeth, “which is invaluable in dental research,” study co-author Graham Davis, a QMU professor of 3D X-ray imaging, said in a statement

“But this high sensitivity has also made it possible to resolve certain types of ink in paper and parchment,” Davis added.

“The rest of the team were then able to take our scan images and turn them into letters they could open virtually and read for the first time in over 300 years,” study co-author David Mills, an X-ray microtomography facilities manager at QMU, said in the statement.

From the scans, the team built 3D digital reconstructions of the letters, and then created a computational algorithm that deciphered the sophisticated folding techniques, crease by crease, opening the letters virtually “while preserving letterlocking evidence,” according to the study. 

The scientists digitally opened four letters using this groundbreaking method, deciphering the contents of one letter, DB-1627. Penned on July 31, 1697, it was written by a man named Jacques Sennacques to his cousin Pierre Le Pers, who lived in The Hague. Sennacques, a legal professional in Lille, France, requested an official death certificate for a relative named Daniel Le Pers, “perhaps due to a question of inheritance,” the scientists wrote.

“His request issued, Sennacques then spends the rest of the letter asking for news of the family and commending his cousin to the graces of God,” the authors wrote. “We do not know exactly why Le Pers did not receive Sennacques’ letter, but given the itinerancy of merchants, it is likely that Le Pers had moved on.” Tens of thousands of such sealed documents can now be unfolded and read virtually, the researchers reported.

“This algorithm takes us right into the heart of a locked letter,” the research team said in the statement. “Using virtual unfolding to read an intimate story that has never seen the light of day — and never even reached its recipient — is truly extraordinary.”

NYC woman discovers empty apartment behind bathroom mirror

By Wilson Wong

A woman in New York City went viral on TikTok Wednesday after posting a video series documenting her journey to discover a secret unoccupied apartment behind her bathroom mirror.

In the first video of her four-part saga, Samantha Hartsoe said she was trying to find the source of cold air that was blowing into her Manhattan apartment. When she discovered that the air was coming from behind her bathroom mirror, Hartsoe said she removed it from the wall.

What Hartsoe said she found was a large square-shaped hole in the wall that peered into a dark room — a scene that watchers compared to the Oscar-winning film, “Parasite” and the 1992 horror film “Candyman,” where a murderous spirit appears after victims repeatedly call his name into the mirror.

Hartsoe ultimately decided to venture into the other side of her bathroom.

“Curiosity killed the cat, curiosity is going to kill me,” Hartsoe told NBC New York. “I can’t not know what’s on the other side of my bathroom.”

The videos showed Hartsoe, clad in a face mask, headlight, and hammer, twisting her body into the hole, much to the dismay of her roommates.

“My roommates definitely thought I was going to be dead,” she said. “Every corner I would walk normal and then be like [moving her head] to check.”

On the other side of the hole was an entire apartment that appeared to be unfinished and unoccupied, the video showed. Bags of trash and an uninstalled toilet littered the floors.

After investigating both floors of the apartment, Hartsoe locked the front door to the empty apartment and returned back to her apartment through the hole in her bathroom.

“When I came back [my roommates] were excited,” she said.

More than nine million viewers have watched Hartsoe’s mysterious journey on TikTok as of Friday afternoon.

Hartsoe added she has not contacted her landlord yet, but has contacted the maintenance department to fix the hole behind her mirror.

https://www.nbcnews.com/news/us-news/nyc-woman-discovers-empty-apartment-behind-bathroom-mirror-n1259738

Green tea supplements modulate facial development of children with Down syndrome

The observational study suggests that the green tea supplements only affect facial development when they are administered in the early stages of life.

A new study led by Belgian and Spanish researchers published in Scientific Reports adds evidence about the potential benefits of green tea extracts in Down syndrome. The researchers observed that the intake of green tea extracts can reduce facial dysmorphology in children with Down syndrome when taken during the first three years of life. Additional experimental research in mice confirmed the positive effects at low doses. However, they also found that high doses of the extract can disrupt facial and bone development. More research is needed to fully understand the effects of green tea extracts and therefore they should always be taken under medical supervision.

Down syndrome is caused by the presence of a third copy of chromosome 21, leading to an overexpression of the genes in this region and resulting in a number of physical and intellectual disabilities. One of the genes, DYRK1A, contributes to altering brain and bone development in people with Down syndrome. The green tea compound EGCG (epigallocatechin-3-gallate) is known to inhibit DYRK1A activity, although it also has other mechanisms of action. Previous research has shown the potential of EGCG to improve cognition in young adults with Down syndrome.

In a new study, researchers analyzed the effect of green tea supplements on facial development in Down syndrome. In the experimental part of the study, the EGCG supplements were tested in mice at different dosages. In a second part of the research, they did an observational study on children with and without Down syndrome. This work, led by the Centre for Genomic Regulation (CRG), European Molecular Biology Laboratory (EMBL) and University of Barcelona in Spain and KU Leuven in Belgium, is an international effort involving researchers from University of Central Florida, La Salle—University Ramon Llull, and IMIM—Hospital del Mar Medical Research Institute.

For the mouse study, carried out at KU Leuven, the researchers started the treatment before birth, while the pups were developing in the wombs of their mothers, by adding either a low or a high dose of green tea extracts to their drinking water. “The low dose treatment had a positive effect on mice that are a model of Down syndrome,” Professor Greetje Vande Velde (KU Leuven) comments, co-lead author of the study. “Sixty percent of them showed a facial shape similar to the control group.”

“The high dose treatment, however, generated very mixed results, and even disrupted normal facial development in some cases, causing additional dysmorphology. This occurred in all mice, in the model of Down syndrome as well as in the control group.”

Age-dependent effects

The observational study was set up in Spain and also included participants from North America. 287 children between 0 and 18 years participated, including children with Down syndrome who did (n = 13) or didn’t (n = 63) receive EGCG supplementation. The treated group were all self-medicated and didn’t follow a prescribed protocol.

“All participants were photographed from various angles to create a 3-D model of their faces,” explains Neus Martínez-Abadías, professor at the University of Barcelona and co-lead author of the study. “We use 21 facial landmarks, and the distances between them, to compare the faces of the participants. In the youngest group between 0 and 3 years, we observed that 57 percent of the linear distances are significantly different when you compare the faces of children with Down syndrome that never received the treatment to those of children that do not have Down syndrome. For babies and toddlers who did receive EGCG treatment, this difference was much smaller, only 25 percent. After green tea supplementation, the facial dysmorphology decreases and the children with or without Down syndrome look more alike.”

“We didn’t identify a similar effect in the adolescent group. Even when treated with green tea extracts, children with Down syndrome still show a difference of more than 50 percent compared to the control group. These findings suggest that the green tea supplements only affect facial development when they are administered in the early stages of life when the face and skull are rapidly growing.”

Further research required

“Despite the potential benefits we observed, we must handle these findings with caution considering they are preliminary and based on an observational study,” Professor Vande Velde warns. “Much more research is necessary to evaluate the effects of EGCG-containing supplements, the appropriate dose and their therapeutic potential in general. We also need to take into the account possible effects on other organs and systems, not just on the development of the face. This requires first more basic research in the lab with mice, and then clinical studies with more participants and controlled use of these supplements.”

“Our findings suggest that effects of EGCG strongly depend on the dose.” Professor Martínez-Abadías concludes. “EGCG products are commercially available and they are used regularly as a general health-promoting compounds. However, it’s important to follow the European Food Safety Authority recommendations regarding the maximal intake and to always consult a physician before taking the supplements. Our research shows potential beneficial effects of facial development at low doses, but at very high doses they can produce unpredictable effects in mice. More research is needed in humans to determine the optimal dose at each age that maximizes the potential benefits.”

More information: John M. Starbuck et al, Green tea extracts containing epigallocatechin-3-gallate modulate facial development in Down syndrome, Scientific Reports (2021). DOI: 10.1038/s41598-021-83757-1

https://medicalxpress.com/news/2021-03-green-tea-supplements-modulate-facial.html

Discovery of three deep-sea sharks that glow in the dark

Researchers believe sharks probably glow for camouflage to protect from attack from beneath.

Scientists studying sharks off New Zealand have discovered that three deep-sea species glow in the dark – including one that is now the largest-known luminous vertebrate.

Bioluminescence – the production of visible light through a chemical reaction by living organisms – is a widespread phenomenon among marine life but this is the first time it has been documented and analysed in the kitefin shark, the blackbelly lanternshark, and the southern lanternshark.

The sharks were collected during a fish survey of the Chatham Rise off the east coast of New Zealand in January 2020.

The kitefin, which can grow to 180cm, is now the largest-known luminous vertebrate: what researchers referred to as a “giant luminous shark”.

The researchers, from the Université Catholique de Louvain in Belgium and the National Institute of Water and Atmospheric Research in New Zealand, said the findings had repercussions for our understanding of life in the deep sea; one of the least-studied ecosystems on the planet.

The sharks all live in what is known as the mesopelagic or “twilight” zone of the ocean, between 200 and 1,000 metres deep, beyond which sunlight does not penetrate. Seen from below, the sharks appear backlit against the bright surface of the water, leaving them exposed to potential predators without any place to hide.

Researchers suggest these three species’ glowing underbellies may help camouflage them from any threats that might strike from beneath.

In the case of the kitefin shark, which has few or no predators, it is possible that the slow-moving species uses its natural glow to illuminate the ocean floor while it searches for food, or to disguise itself while approaching its prey.

Further study would be needed to confirm either hypothesis, the researchers wrote in a paper published in the Frontiers in Marine Science journal, as well as to understand just how the species’ bioluminescence functioned – and possible implications for prey-predation relationships.

“Considering the vastness of the deep sea and the occurrence of luminous organisms in this zone, it is now more and more obvious that producing light at depth must play an important role structuring the biggest ecosystem on our planet,” the researchers wrote.

Jérôme Mallefet, lead researcher from the Marine Biology Laboratory of the Université Catholique de Louvain in Belgium, said: “The luminous pattern of the Kitefin shark was unknown and we are still very surprised by the glow on the dorsal fin. Why? For which purpose?”

The size of the territories inhabited by the sharks makes this kind of study very difficult, he said. “The two other Etmopterus sharks were also not documented, so it is the first time.”

Mallefet hopes to be back out at sea soon to continue the work, and look for more luminous species.

https://www.theguardian.com/environment/2021/mar/02/giant-luminous-shark-researchers-discover-that-three-deep-sea-sharks-glow-in-the-dark

Custom diets are essential to mental health, new research shows

Customized diets and lifestyle changes could be key to optimizing mental health, according to new research including faculty at Binghamton University, State University of New York.

“There is increasing evidence that diet plays a major role in improving mental health, but everyone is talking about a healthy diet,” said Begdache, an assistant professor of health and wellness studies at Binghamton University and co-author of a new paper in Nutrients.

“We need to consider a spectrum of dietary and lifestyle changes based on different age groups and gender,” she said. “There is not one healthy diet that will work for everyone. There is not one fix.”

Begdache, who is also a registered dietitian, believes that mental health therapies need to consider the differences in degree of brain maturity between young (18-29 years old) and mature (30 years or older) adults, as well as the brain morphology among men and women.

She and her research team conducted an online survey to examine food intake, dietary practices, exercise and other lifestyle factors in these four subpopulations. Over a five-year period (2014-19), more than 2,600 participants completed the questionnaire after responding to social media posts advertising the survey. The team collected data at different timepoints and seasons and found important dietary and lifestyle contributors to mental distress—defined as anxiety and depression—in each of the groups.

Key findings of this study:

  • Significant dietary and lifestyle approaches to improve mental well-being among young women include daily breakfast consumption, moderate-to-high exercise frequency, low caffeine intake and abstinence from fast food.
  • Dietary and lifestyle approaches to improve mental well-being among mature women include daily exercise and breakfast consumption, as well as high intake of fruits with limited caffeine ingestion.
  • To improve mental well-being of young men, dietary and lifestyle approaches include frequent exercise, moderate dairy consumption, high meat intake, as well as low consumption of caffeine and abstinence from fast food.
  • Dietary approaches to improve mental well-being among mature men include moderate intake of nuts.

Begdache and her team split the respondents into two age groups because human brain development continues into the late 20s. For young adults of both genders, quality of diet appears to have an impact on the developing brain.

“Young adults are still forming new connections between brain cells as well as building structures; therefore, they need more energy and nutrients to do that,” Begdache said.

As a result, young adults who consume a poor-quality diet and experience nutritional deficiencies may suffer from a higher degree of mental distress.

Age is also the reason high caffeine consumption was associated with mental distress in both young men and young women.

“Caffeine is metabolized by the same enzyme that metabolizes the sex hormones testosterone and estrogen, and young adults have high levels of these hormones,” Begdache said. “When young men and women consume high levels of caffeine, it stays in their system for a long time and keeps stimulating the nervous system, which increases stress and eventually leads to anxiety.”

The team also split respondents based on biological sex, since brain morphology and connectivity differ between men and women. Put simply, the male brain is “wired” to enable perception and coordination, whereas the female brain is built to support analysis and intuition. Begdache and her team believe these differences may influence nutritional needs.

“I have found it in my multiple studies so far, that men are less likely to be affected by diet than women are,” said Begdache. “As long as they eat a slightly healthy diet they will have good mental well-being. It’s only when they consume mostly fast food that we start seeing mental distress.

“Women, on the other hand, really need to be consuming a whole spectrum of healthy food and doing exercise in order to have positive mental well-being,” she added. “These two things are important for mental well-being in women across age groups.”

According to Begdache, current recommendations for food intake are all based on physical health; there are no recommendations for mental health. She hopes that will change—and that her work will play a role in making those changes.

“I hope to see more people doing research in this area and publishing on the customization of diet based on age and gender,” she said. “I hope that one day, institutions and governments will create dietary recommendations for brain health.”

https://medicalxpress.com/news/2021-03-custom-diets-essential-mental-health.html

More information: Lina Begdache et al, Diet, Exercise, Lifestyle, and Mental Distress among Young and Mature Men and Women: A Repeated Cross-Sectional Study, Nutrients (2020). DOI: 10.3390/nu13010024

Researchers identify brain ion channel as new approach to treating depression

JAMES MURROUGH, MD, PHD, DIRECTOR OF THE DEPRESSION AND ANXIETY CENTER FOR DISCOVERY AND TREATMENT AT THE ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI 

Researchers from the Icahn School of Medicine at Mount Sinai have identified a drug that works against depression by a completely different mechanism than existing treatments.

Their study showed that ezogabine (also known as retigabine), a drug that opens KCNQ2/3 type of potassium channels in the brain, is associated with significant improvements in depressive symptoms and anhedonia in patients with depression. Anhedonia is the reduced ability to experience pleasure or lack of reactivity to pleasurable stimuli; it is a core symptom of depression and associated with worse outcomes, poor response to antidepressant medication, and increased risk of suicide.

Ezogabine was approved by the U.S. Food and Drug Administration in 2011 as an anticonvulsant for epilepsy treatment but had not been previously studied in depression. The research results, published March 3 in the American Journal of Psychiatry, provide initial evidence in humans for the KCNQ2/3 channel as a new target for novel drug discovery for depression and anhedonia.

“Our study is the first randomized, placebo-controlled trial to show that a drug affecting this type of ion channel in the brain can improve depression and anhedonia in patients. Targeting this channel represents a completely different mechanism of action than any currently available antidepressant treatment,” says James Murrough, MD, PhD, Associate Professor of Psychiatry, and Neuroscience, Director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai, and senior author of the paper.

The new drug target, the KCNQ2/3 channel, is a member of a large family of ion channels referred to as the KCNQ (or Kv7) family that act as important controllers of brain cell excitability and function in the central nervous system. These channels affect brain cell function by controlling the flow of the electrical charge across the cell membrane in the form of potassium (K+) ions. Researchers at Mount Sinai, including study co-author Ming-Hu Han, PhD, Professor of Pharmacological Sciences, and Neuroscience, had previously conducted a series of studies in mice showing that changes in the KCNQ2/3 potassium channel play an important role in determining if the animals show depression and anhedonic-like behavior following chronic stress in an experimental model of depression. In particular, mice that appear to be resistant to developing depression in the face of stress show an increase in KCNQ2/3 channels in the brain.

“We viewed enhanced functioning of the KCNQ channel as a potential molecular mechanism of resilience to stress and depression,” said Dr. Han, who also discovered that if he gave a drug that could increase the activity of this channel, such as ezogabine, to mice that had become depressed in the stress model, the mice no longer showed the depression and anhedonic behaviors; in other words, the drug acted as an antidepressant.

The current study was a two-site, double-blind, randomized, placebo-controlled proof of concept clinical trial designed as a preliminary test of the hypothesis that increasing KCNQ2/3 channel activity in the brain is a viable new approach for the treatment of depression. Forty-five adult patients diagnosed with a depressive disorder were assigned to a five-week treatment period with daily dosing of either ezogabine or matching placebo. All participants underwent clinical evaluations and functional magnetic resonance imaging (fMRI) during a reward task at baseline and at the end of the treatment period. Compared to patients treated with placebo, those treated with ezogabine showed a significant and large reduction in several key measures of depression severity, anhedonia, and overall illness severity. For example, significant improvements following treatment with ezogabine compared to placebo was observed using the Montgomery-Asberg Depression Rating Scale (MADRS), the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), the Snaith-Hamilton Pleasure Scale (SHAPS), and the Temporal Experience of Pleasure Scale (TEPS)-Anticipatory Subscale. The ezogabine group showed also a trend towards an increase in response to reward anticipation in the brain compared to placebo although this effect did not reach statistical significance.

“The fundamental insight by Dr. Han’s group that a drug that essentially mimicked a mechanism of stress resilience in the brain could represent a whole new approach to the treatment of depression was very exciting to us,” said Dr. Murrough.

In collaboration with Dr. Han, Dr. Murrough carried out a series of studies in patients with depression to begin to test if the observations in mice could be translated to humans. An initial open-label (no placebo) study in patients with depression led by Dr. Murrough provided initial evidence that ezogabine could improve symptoms of depression and anhedonia in a manner that was associated with changes in brain function.

“I think it’s fair to say that most of us on the study team were quite surprised at the large size of the beneficial effect of ezogabine on clinical symptoms across multiple measures related to depression. We are greatly encouraged by these findings and the hope they offer for the prospect of developing novel, effective treatments for depression and related disorders. New treatments are urgently needed given that more than one-third of people suffering from depression are inadequately treated with currently approved therapeutics.”

Individualized brain cell grafts reverse Parkinson’s symptoms in monkeys

Grafting neurons grown from monkeys’ own cells into their brains relieved the debilitating movement and depression symptoms associated with Parkinson’s disease, researchers at the University of Wisconsin-Madison reported this week.

In a study published in the journal Nature Medicine, the UW team describes its success with neurons made from induced pluripotent stem cells from the monkeys’ own bodies. This approach avoided complications with the primates’ immune systems and takes an important step toward a treatment for millions of human Parkinson’s patients.

“This result in primates is extremely powerful, particularly for translating our discoveries to the clinic,” says UW-Madison neuroscientist Su-Chun Zhang, whose Waisman Center lab grew the brain cells.

Parkinson’s disease damages neurons in the brain that produce dopamine, a brain chemical that transmits signals between nerve cells. The disrupted signals make it progressively harder to coordinate muscles for even simple movements and cause rigidity, slowness and tremors that are the disease’s hallmark symptoms. Patients—especially those in earlier stages of Parkinson’s—are typically treated with drugs like L-DOPA to increase dopamine production.

“Those drugs work well for many patients, but the effect doesn’t last,” says Marina Emborg, a Parkinson’s researcher at UW-Madison’s Wisconsin National Primate Research Center. “Eventually, as the disease progresses and their motor symptoms get worse, they are back to not having enough dopamine, and side effects of the drugs appear.”

Scientists have tried with some success to treat later-stage Parkinson’s in patients by implanting cells from fetal tissue, but research and outcomes were limited by the availability of useful cells and interference from patients’ immune systems. Zhang’s lab has spent years learning how to dial donor cells from a patient back into a stem cell state, in which they have the power to grow into nearly any kind of cell in the body, and then redirect that development to create neurons.

“The idea is very simple,” Zhang says. “When you have stem cells, you can generate the right type of target cells in a consistent manner. And when they come from the individual you want to graft them into, the body recognizes and welcomes them as their own.”

The application was less simple. More than a decade in the works, the new study began in earnest with a dozen rhesus monkeys several years ago. A neurotoxin was administered—a common practice for inducing Parkinson’s-like damage for research—and Emborg’s lab evaluated the monkeys monthly to assess the progression of symptoms.

“We evaluated through observation and clinical tests how the animals walk, how they grab pieces of food, how they interact with people—and also with PET imaging we measured dopamine production,” Emborg says. (PET is positron emission tomography, a type of medical imaging.) “We wanted symptoms that resemble a mature stage of the disease.”

Guided by real-time MRI that can be used during procedures and was developed at UW-Madison by biomedical engineer Walter Block during the course of the Parkinson’s study, the researchers injected millions of dopamine-producing neurons and supporting cells into each monkey’s brain in an area called the striatum, which is depleted of dopamine as a consequence of the ravaging effects of Parkinson’s in neurons.

Half the monkeys received a graft made from their own induced pluripotent stem cells (called an autologous transplant). Half received cells from other monkeys (an allogenic transplant). And that made all the difference.

Within six months, the monkeys that got grafts of their own cells were making significant improvements. Within a year, their dopamine levels had doubled and tripled.

“The autologous animals started to move more,” Emborg says. “Where before they needed to grab the cage to stand up, they started moving much more fluidly and grabbing food much faster and easier.”

The monkeys who received allogenic cells showed no such lasting boost in dopamine or improvement in muscle strength or control, and the physical differences in the brains were stark. The axons—the extensions of nerve cells that reach out to carry electrical impulses to other cells—of the autologous grafts were long and intermingled with the surrounding tissue.

“They could grow freely and extend far out within the striatum,” says Yunlong Tao, a scientist in Zhang’s lab and first author of the study. “In the allogenic monkeys, where the grafts are treated as foreign cells by the immune system, they are attacked to stop the spread of the axons.”

The missing connections leave the allogenic graft walled off from the rest of the brain, denying them opportunities to renew contacts with systems beyond muscle management.

“Although Parkinson’s is typically classified as a movement disorder, anxiety and depression are typical, too,” Emborg says. “In the autologous animals, we saw extension of axons from the graft into areas that have to do with what’s called the emotional brain.”

Symptoms that resemble depression and anxiety—pacing, disinterest in others and even in favorite treats—abated after the autologous grafts grew in. The allogenic monkeys’ symptoms remained unchanged or worsened.

The results are promising enough that Zhang hopes to begin work on applications for human patients soon. In particular, Zhang says, the work Tao did in the new study to help measure the relationship between symptom improvement, graft size and resulting dopamine production gives the researchers a predictive tool for developing effective human grafts.

More information: Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys, Nature Medicine (2021). DOI: 10.1038/s41591-021-01257-1 , dx.doi.org/10.1038/s41591-021-01257-1

https://medicalxpress.com/news/2021-03-individualized-brain-cell-grafts-reverse.html

A new theory for how memories are stored in the brain

Research from the University of Kent has led to the development of the MeshCODE theory, a revolutionary new theory for understanding brain and memory function. This discovery may be the beginning of a new understanding of brain function and in treating brain diseases such as Alzheimer’s.

In a paper published by Frontiers in Molecular Neuroscience, Dr. Ben Goult from Kent’s School of Biosciences describes how his new theory views the brain as an organic supercomputer running a complex binary code with neuronal cells working as a mechanical computer. He explains how a vast network of information-storing memory molecules operating as switches is built into each and every synapse of the brain, representing a complex binary code. This identifies a physical location for data storage in the brain and suggests memories are written in the shape of molecules in the synaptic scaffolds.

The theory is based on the discovery of protein molecules, known as talin, containing ‘switch-like’ domains that change shape in response to pressures in mechanical force by the cell. These switches have two stable states, 0 and 1, and this pattern of binary information stored in each molecule is dependent on previous input, similar to the Save History function in a computer. The information stored in this binary format can be updated by small changes in force generated by the cell’s cytoskeleton.

In the brain, electrochemical signaling between trillions of neurons occurs between synapses, each of which contains a scaffold of the talin molecules. Once assumed to be structural, this research suggests that the meshwork of talin proteins actually represent an array of binary switches with the potential to store information and encode memory.

This mechanical coding would run continuously in every neuron and extend into all cells, ultimately amounting to a machine code coordinating the entire organism. From birth, the life experiences and environmental conditions of an animal could be written into this code, creating a constantly updated, mathematical representation of its unique life.

Dr. Goult, a reader in biochemistry, said: “This research shows that in many ways the brain resembles the early mechanical computers of Charles Babbage and his Analytical Engine. Here, the cytoskeleton serves as the levers and gears that coordinate the computation in the cell in response to chemical and electrical signaling. Like those early computation models, this discovery may be the beginning of a new understanding of brain function and in treating brain diseases.”

More information: Benjamin T. Goult, The Mechanical Basis of Memory – the MeshCODE Theory, Frontiers in Molecular Neuroscience (2021). DOI: 10.3389/fnmol.2021.592951

Social media use driven by search for reward, akin to animals seeking food, new study shows

Our use of social media, specifically our efforts to maximize “likes,” follows a pattern of “reward learning,” concludes a new study by an international team of scientists.

Our use of social media, specifically our efforts to maximize “likes,” follows a pattern of “reward learning,” concludes a new study by an international team of scientists. Its findings, which appear in the journal Nature Communications, reveal parallels with the behavior of animals, such as rats, in seeking food rewards.

“These results establish that social media engagement follows basic, cross-species principles of reward learning,” explains David Amodio, a professor at New York University and the University of Amsterdam and one of the paper’s authors. “These findings may help us understand why social media comes to dominate daily life for many people and provide clues, borrowed from research on reward learning and addiction, to how troubling online engagement may be addressed.”

In 2020, more than four billion people spent several hours per day, on average, on platforms such as Instagram, Facebook, Twitter, and other more specialized forums. This widespread social media engagement has been likened by many to an addiction, in which people are driven to pursue positive online social feedback, such as “likes,” over direct social interaction and even basic needs like eating and drinking.

While social media usage has been studied extensively, what actually drives people to engage, sometimes obsessively, with others on social media is less clear.

To examine these motivations, the Nature Communications study, which also included scientists from Boston University, the University of Zurich, and Sweden’s Karolinska Institute, directly tested, for the first time, whether social media use can be explained by the way our minds process and learn from rewards.

To do so, the authors analyzed more than one million social media posts from over 4,000 users on Instagram and other sites. They found that people space their posts in a way that maximizes how many “likes” they receive on average: they post more frequently in response to a high rate of likes and less frequently when they receive fewer likes.

The researchers then used computational models to reveal that this pattern conforms closely to known mechanisms of reward learning, a long-established psychological concept that posits behavior may be driven and reinforced by rewards.

More specifically, their analysis suggested that social media engagement is driven by similar principles that lead non-human animals, such as rats, to maximize their food rewards in a Skinner Box—a commonly used experimental tool in which animal subjects, placed in a compartment, access food by taking certain actions (e.g., pressing a particular lever).

The researchers then corroborated these results with an online experiment, in which human participants could post funny images with phrases, or “memes,” and receive likes as feedback on an Instagram-like platform. Consistent with the study’s quantitative analysis, the results showed that people posted more often when they received more likes—on average.

“Our findings can help lead to a better understanding of why social media dominates so many people’s daily lives and can also provide leads for ways of tackling excessive online behavior,” says the University of Amsterdam’s Björn Lindström, the paper’s lead author.

More information: Andreas Olsson et al. The neural and computational systems of social learning, Nature Reviews Neuroscience (2020). DOI: 10.1038/s41583-020-0276-4Journal information:Nature Communications Nature Reviews Neuroscience

https://medicalxpress.com/news/2021-02-social-media-driven-reward-akin.html