Neuroscience

Neurochemicals Dopamine and Serotonin Have Unexpected Role in Perception – Technology Networks

In first-of-their-kind observations in the human brain, an international team of researchers has revealed two well-known neurochemicals -- dopamine and serotonin -- are at work at sub-second speeds to shape how people perceive the world and take action based on their perception.

The discovery shows researchers can continually and simultaneously measure the activity of both dopamine and serotonin -- whose receptor and uptake sites are therapeutic targets for disorders ranging from depression to Parkinson's disease -- in the human brain.

Furthermore, the neurochemicals appear to integrate people's perceptions of the world with their actions, indicating dopamine and serotonin have far more expansive roles in the human nervous system than previously known.

Known as neuromodulators, dopamine and serotonin have traditionally been linked to reward processing -- how good or how bad people perceive an outcome to be after taking an action.

The study online today in the journal Neuron opens the door to a deeper understanding of an expanded role for these systems and their roles in human health.

"An enormous number of people throughout the world are taking pharmaceutical compounds to perturb the dopamine and serotonin transmitter systems to change their behavior and mental health," said P. Read Montague, senior author of the study and a professor and director of the Center for Human Neuroscience Research and the Human Neuroimaging Laboratory at the Fralin Biomedical Research Institute at Virginia Tech Carilion. "For the first time, moment-to-moment activity in these systems has been measured and determined to be involved in perception and cognitive capacities. These neurotransmitters are simultaneously acting and integrating activity across vastly different time and space scales than anyone expected."

Better understanding of the underlying actions of dopamine and serotonin during perception and decision-making could deliver important insight into psychiatric and neurological disorders, the researchers said.

"Every choice that someone executes involves taking in information, interpreting that information, and making decisions about what they perceived," said Kenneth Kishida, a corresponding author of the study and an assistant professor of physiology and pharmacology, and neurosurgery, at Wake Forest School of Medicine. "There's a whole host of psychiatric conditions and neurological disorders where that process is altered in the patients, and dopamine and serotonin are prime suspects."

Lack of chemically specific methods to study neuromodulation in humans at fast time scales has impeded understanding of these systems, according to Montague, who is an honorary professor at the Wellcome Center for Human Neuroimaging at University College London and a professor of physics at the Virginia Tech College of Science.

But now, in first-ever measurements, scientists used an electrochemical method called "fast scan cyclic voltammetry," which employs a small carbon fiber microelectrode that has low voltages ramped across it for real-time detection of dopamine and serotonin activity.

In the study, researchers recorded fluctuations in dopamine and serotonin using specially designed electrodes in five patients undergoing deep brain stimulation electrode implantation surgery to treat essential tremor or Parkinson's disease. Patients were awake during surgery, playing a computer game designed to quantify aspects of thought and behavior while the measurements were taken.

On each round of the game, patients briefly viewed a cloud of dots and were asked to judge the direction they were moving. The method, designed by corresponding author Dan Bang, a Sir Henry Wellcome Postdoctoral Fellow, and Steve Fleming, a Sir Henry Dale/Royal Society Fellow, both at the Wellcome Center for Human Neuroimaging at University College London, helped indicate that dopamine and serotonin were involved in simple perceptual decisions, outside of the traditional context of rewards and losses.

"These neuromodulators play a much broader role in supporting human behavior and thought, and in particular they are involved in how we process the outside world," Bang said. "For example, if you move through a room and the lights are off, you move differently because you're uncertain about where objects are. Our work suggests these neuromodulators -- serotonin in particular-- are playing a role in signaling how uncertain we are about the outside environment."

Montague and Kishida, along with Terry Lohrenz, a research assistant professor, and Jason White, a senior research associate, now both at the Fralin Biomedical Research Institute, started working on a new statistical approach to identify dopamine and serotonin signals while still at the Baylor College of Medicine in Houston, Texas.

"Ken rose to the challenge of doing fast neurochemistry in human beings during active cognition," Montague said. "A lot of other good groups of scientists were not able to do it. Aside from the computation of enormous amounts of data, there are complicated issues to solve, including great, fundamental algorithmic tasks."

Until recently, only slow methodologies such as PET scanning could measure the impact of neurotransmitters, but they were nowhere near the frequency or volume of the second-to-second measurements of fast scan cyclic voltammetry.

The measurements in the new study were taken at the Wake Forest Baptist Medical Center, and involved neurosurgical teams led by Adrian W. Laxton and Stephen B. Tatter.

"The enthusiasm the neurosurgeons have for this research is derived from the same reasons that drove them to be doctors -- first and foremost, they want to do the best for their patients, and they have a real passion for understanding how the brain works to improve patient outcomes," said Kishida, who oversaw the data collection in the operating room during the surgeries. "Both are collaborative scientists along with Charles Branch, the chair of the neurosurgery department at Wake Forest, who has been an amazing advocate for this work."

Likewise, Montague said, "You can't do it without the surgeons being real, shoulder-to-shoulder partners, and certainly not without the people who let you make recordings from their brains while they are having electrodes implanted to alleviate the symptoms of a neurological disorder."

Montague had read a study in the Proceedings of the National Academy of Sciences that prompted him to approach colleagues Bang and Fleming at University College London to tailor a task for patients to perform during surgery that would reveal sub-second dopamine and serotonin signaling in real-time inference about the external world - separate from their often-reported roles in reward-related processes.

"I said I have this new method to measure dopamine and serotonin, but I need you to help with the task," Montague said. "They ended up in the study. The research really took a lot of hard work and an integrated a constellation of people to obtain these results."

The research was funded by grants to various researchers from the Wellcome Trust, the National Institutes of Health including the National Institute on Drug Abuse, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke.Reference: Bang D, Kishida KT, Lohrenz T, et al.Sub-second Dopamine and Serotonin Signaling in Human Striatum during Perceptual Decision-Making. Neuron. 2020.doi:10.1016/j.neuron.2020.09.015

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Neuroscience

Middlebury Welcomes 33 New Faculty – Middlebury College News and Events

MIDDLEBURY, Vt. Middlebury College welcomes 33 new faculty members this fall, including 13 in tenure-track positions. The new teachers and researchers participated in orientation sessions that were conducted weekly throughout August via Zoom. As a group, they represent 19 academic disciplines.

Middlebury is fortunate to be able to hire some of the best faculty emerging in their fields, said Sujata Moorti, vice president for academic affairs and dean of the faculty. They come from a wide array of institutions and offer expertise in research topics ranging from ethnic violence in India to pain processing in the spinal cord.

We are excited to welcome them to Middlebury, said Moorti.

The following will join Middlebury this fall as tenure-track faculty members, with the exception of Alexis Mychajliw, who will join in the spring.

Kathryn Crawford, assistant professor of environmental studies, comes to Middlebury from the Geisel School of Medicine at Dartmouth, where she was a postdoctoral research associate in epidemiology. Crawford earned her PhD in environmental health at Boston University, and an MS in natural resources and a BS in environmental science at the University of Vermont.

Jennifer Crodelle, assistant professor of mathematics, was most recently a postdoctoral research fellow at the Courant Institute of Mathematical Sciences at New York University. Crodelle earned her PhD in mathematics and her MS in applied mathematics at Rensselaer Polytechnic Institute, and her BS from Marist College. Her research interests include the dynamics of neuronal networks during development and mechanisms underlying pain processing in the spinal cord.

John Foley, assistant professor of computer science, earned his PhD and MS in computer science at the University of Massachusetts Amherst and his BS in computer engineering at the University of Massachusetts Lowell. Before teaching at Middlebury, he was a visiting assistant professor at Smith.

Raphaelle Gauvin-Coulombe, assistant professor of economics, earned her PhD and MA in economics at Queens University in Kingston, Ontario, and her BA in economics at the University of Ottawa in Ottawa, Ontario.

Kara Karpman, assistant professor of mathematics, earned her PhD and MS in applied mathematics at Cornell and her BS in mathematics at Duke University.

Niwaeli Kimambo, assistant professor of geography, was previously a GIS teaching fellow at Middlebury beginning in 2019. She earned her PhD and MS in geography from the University of WisconsinMadison. She also holds a BA in geologic sciences and history from Brown.

Alexis Mychajliw, assistant professor of biology and environmental studies, will join the faculty this spring. She is a postdoctoral research fellow at Hokkaido University in Japan. Mychajliw earned her PhD in biology at Stanford and her BS in biological sciences at Cornell. Her areas of interest include the study of genomes, bones, and sediments to determine how organisms responded to anthropogenic and climatic changes in the past.

Gregory Pask, assistant professor of biology, comes to Middlebury from Bucknell University, where he was an assistant professor of biology. He earned his PhD in biological sciences at Vanderbilt University and his BS in biochemistry at Muhlenberg College. His area of research includes the powerful sense of smell insects use to locate food, find mates, and communicate with others.

Olga Sanchez-Saltveit, assistant professor of theatre, earned her PhD in theatre arts from the University of Oregon, her MA in human and bicultural development from Pacific Oaks College, and her BA in theatre at Hunter College. Most recently she was a visiting assistant professor of theatre at Franklin and Marshall College. Virginia Thomas, assistant professor of psychology, arrived at Middlebury from Wilmington College, where she held the same position. She earned her PhD in developmental psychology with an emphasis on feminist studies at the University of California, Santa Cruz; MA in depth psychology at Sonoma State University; and BS in psychology at the University of Evansville.

Ajay Verghese, assistant professor of political science, served in the same role at the University of California, Riverside, prior to coming to Middlebury. He earned his PhD in political science at George Washington University and BA in political science and French at Temple University. His first book, The Colonial Origins of Ethnic Violence in India, was published in 2016 by Stanford University Press.

Zu Wei Zhai 07, assistant professor of neuroscience, joined the Middlebury faculty as a visiting assistant professor of psychology in 2017. He received his PhD in pharmaceutical sciences from the University of Pittsburgh and his BA in neuroscience from Middlebury.

Gyula Zsombok, assistant professor of French and Francophone studies, earned his PhD and MA in French linguistics at the University of Illinois Urbana-Champaign and his BA in French philology atEtvs Lornd Tudomnyegyetem in Budapest.

Middlebury is also pleased to welcome the following visiting faculty, professors of the practice, instructors, lecturers, and teaching assistants:

Visiting Assistant Professors

Cole Dovey 06, PhD, University of California, San Francisco, visiting assistant professor of chemistry and biochemistry

Alla Fil, PhD, Georgetown University, visiting assistant professor of Luso-Hispanic studies

Michael French, PhD, Northwestern University, visiting assistant professor of chemistry and biochemistry

Alena Giesche 11, PhD, University of Cambridge, UK, visiting assistant professor of geology

Robert Izsak, PhD, Cardiff University, visiting assistant professor of chemistry and biochemistry

Allison Jacobel, PhD, Columbia University, visiting assistant professor of geology

Joshua Nelson, PhD, Fordham University, visiting assistant professor of psychology

Shelly Pottorf, MArch, Rice University, visiting assistant professor of architecture

Roger Russi, PhD, University of North Carolina, visiting assistant professor of first-year seminar

Tessa Wegener, PhD, Georgetown University, visiting assistant professor of German

Roger White, MFA, Columbia University, visiting assistant professor of studio art

Visiting Instructors

Tina Donaldson, MA, University at AlbanyState University of New York, visiting instructor in psychology

Mon Zabala, BA, University of Puerto Rico, visiting instructor in Luso-Hispanic studies

Lecturers and Teaching PositionsCatherine Canavan, MA, Castleton State College, lecturer in education studies, will join the faculty in the spring.

Carolyn Dash, PhD, University of Illinois Urbana-Champaign, visiting assistant laboratory professor

Daniel Fram, PhD, Michigan State University, postdoctoral fellow in political science

Emily French 19, assistant in instruction, geography

James Gallagher, PhD, Princeton University, visiting assistant laboratory professor, chemistry and biochemistry

Emily Malcolm-White, MS, University of Victoria, lecturer in mathematics

Ori Tzuriel, BA, Bar-Ilan University, Israel, lecturer in modern Hebrew

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Neuroscience

The brilliant mind of Oliver Sacks – Ockham’s Razor – ABC News

Who was Oliver Sacks?

He's best known as the author of case histories on neurology among them the tale of the man who mistook his wife for a hat.

But how did he get the nickname Dr Squats? What was his relation to the Fern Society? And why did he remain celibate for more than 30 years?

Neuroscience PhD student Samuel Mills reflects and shares a few stories about the brilliant neurologist and author at Melbourne's Laborastory.

This program first aired on April 22, 2018.

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Neuroscience

Traveling Brain Waves Reveal Hard-To-See Objects – Technology Networks

Imagine that you're late for work and desperately searching for your car keys. You've looked all over the house but cannot seem to find them anywhere. All of a sudden you realize your keys have been sitting right in front of you the entire time. Why didn't you see them until now?

Now, a team of Salk Institute scientists led by Professor John Reynolds has uncovered details of the neural mechanisms underlying the perception of objects. They found that patterns of neural signals, called traveling brain waves, exist in the visual system of the awake brain and are organized to allow the brain to perceive objects that are faint or otherwise difficult to see. The findings were published inNatureon October 7, 2020.

"We've discovered that faint objects are much more likely to be seen if visualizing the object is timed with the traveling brain waves. The waves actually facilitate perceptual sensitivity, so there are moments in time when you can see things that you otherwise could not," says Reynolds, senior author of the paper and holder of the Fiona and Sanjay Jha Chair in Neuroscience. "It turns out that these traveling brain waves are an information-gathering process leading to the perception of an object."

Scientists have studied traveling brain waves during anesthesia but dismissed the waves as an artifact of the anesthesia. Reynolds' team, however, wondered if these waves exist in the visual part of the brain while awake and if they play a role in perception. They combined recordings in the visual cortex with cutting-edge computational techniques that enabled them to detect and track traveling brain waves.

"In order to understand the neural mechanisms of perception, we needed to develop new computational techniques to track neuronal activity in the visual cortex moment by moment," says co-first author Lyle Muller, BrainsCAN-funded assistant professor in the Department of Applied Mathematics and the Brain and Mind Institute at Western University in Ontario, Canada, and previously a postdoctoral fellow in the Sejnowski lab at Salk. "We then used these computational methods to uncover what change was occurring in the nervous system to suddenly allow for object recognition."

The scientists recorded the activity of the neurons from an area of the brain that contained a complete map of the visual world. They then tracked the trajectories of the traveling brain waves during a visual perception task. The scientists held an onscreen target at the threshold of visibility, so that observers could only detect the object 50 percent of the time, and recorded when the target was spotted. Since the target was not changing, the researchers reasoned that the observer's ability to perceive the object only half of the time had to be due to some change in the neural signals inside the brain.

They found that the brain's ability to recognize targets was directly related to when and where the traveling brain waves occurred in the visual system: when the traveling waves aligned with the stimulus, the observer could detect the target more easily. These traveling brain waves, which occurred several times per second, were similar to a stadium of sports fans successively standing up and raising their arms, then lowering them and sitting down again. It appears that the visual system is actively sensing the external environment, according to the team.

"There is a spontaneous level of activity in the brain that appears to be regulated by these traveling waves," says Salk Professor Terrence Sejnowski, an author of the paper and holder of the Francis Crick Chair. "We think the waves are the product of the activity that is propagating around the brain, driven by local neurons firing."

"We go about our everyday lives thinking that we are accurately seeing the world, but, in fact, our brains are filling in details that are difficult to see," says Zac Davis, co-first and corresponding author of the paper and a Salk postdoctoral fellow in the Reynolds lab. "Now, we have discovered how the brain weaves together hard-to-see information to perceive an object."

In the future, the scientists plan to examine whether these brain waves are coordinated across different brain regions devoted to vision. The researchers theorize that the brain waves could serve as a gate between the sensory processing and conscious perception that emerges from the brain as a whole.

Reference:Davis ZW, Muller L, Martinez-Trujillo J, Sejnowski T, Reynolds JH. Spontaneous travelling cortical waves gate perception in behaving primates. Nature. Published online October 7, 2020:1-5. doi:10.1038/s41586-020-2802-y

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Neuroscience

Instinct and Training Both Count When Responding to Infant Cries, Says Mouse Study – Technology Networks

Caregivers learn to decipher differences in newborn cries through a combination of hard-wired instincts and on-the-job experience, a new study in rodents shows.

Understanding the specific meaning of a baby's vocal expressions is critical in childcare for humans and other animals, experts say. However, every infant has its own unique set of cries, so the most successful parents must quickly learn to recognize subtle variations of distress and other kinds of calls.

Led by researchers at NYU Grossman School of Medicine, the study showed that female mice instinctively hurried to fetch crying infants, even if they'd never had pups of their own before. In addition, certain nerve cells in the auditory cortex, the part of the brain that processes sound, became active when the mice heard the wails.

The study, published online Oct. 7 inNature, also showed that experienced "babysitter" mice recognized more variations of cries that were calls for attention than mice with little caregiving experience. The latter group only responded to a narrow range of cries.

As the unexperienced animals spent more time living with a veteran caregiver, however, they were able to recognize a wider variety of cries and would quickly retrieve the babies.

"Our findings show that while some parenting skills are innate, there is a significant learning curve," says study lead author Jennifer Schiavo, a predoctoral fellow in the Skirball Institute of Biomolecular Medicine at NYU Langone Health. "For mother mice, and possibly for humans too, hard-earned experience matters."

The investigation also affirmed the role of the hormone oxytocin in learning parenting behavior. Extra amounts of the chemical, best known for its role in breastfeeding and parent-infant bonding, was previously shown by the team to improve recognition of barely audible pup distress calls. In the new study, when the researchers instead blocked oxytocin, experienced babysitters only retrieved crying pups as little as 40 percent of the time, compared with well over 80 percent when the hormone levels were left alone.

Similarly, without oxytocin, cells in the auditory cortex did not respond to a broader range of distress calls, even after the mice observed more experienced mothers parenting. According to Schiavo, this suggests that oxytocin helps rewire the brain and prepare it to learn new skills more easily.

For the study, the investigators measured the average number of syllables in the "come get me" cries of dozens of mouse pups to determine the standard version of the call. Then, the team sped up or slowed down recordings of the cries to create alterations that fell outside the typical range. These modified audio clips were dubbed over the pups' natural cries.

The study authors only compared expert and inexperienced caregivers, neither groups having had their own pups, in order to tease apart instinctive versus learned elements of parenting, without pregnancy complicating the matter.

They found that seasoned babysitters' brain cells became active in response to normal calls, and those mice accordingly retrieved the pups over 80 percent of the time. Meanwhile, the new babysitters' brain cells did not respond to normal calls, and these mice only picked up the pups about 33 percent of the time.

The study also showed that novices could learn to recognize altered calls over time, with pup retrieval rates as much as 75 percent. By comparison, experienced babysitters who heard the altered calls for the first time had a retrieval rate of just 14 percent.

"Our study provides new insight into how the brain learns new skills," says senior study author Robert Froemke, PhD, an associate professor in the Skirball Institute of Biomolecular Medicine at NYU Langone. "There is a built-in understanding that serves as a foundation for developing more complex behaviors in rodents."

He adds that next, the research team plans to investigate whether the inexperienced mice learn by passively observing mothers or if they are actively trained to respond to unusual calls. Froemke also serves as an associate professor in the departments of Otolaryngology-Head and Neck Surgery, and Neuroscience and Physiology at NYU Langone.

Reference: Schiavo JK, Valtcheva S, Bair-Marshall CJ, Song SC, Martin KA, Froemke RC. Innate and plastic mechanisms for maternal behaviour in auditory cortex. Nature. Published online October 7, 2020:1-6. doi:10.1038/s41586-020-2807-6

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Neuroscience

The Clever Combination of Neuroscience and Ancient Wisdom That Is Re-Writing the Rule Book on Success and Happiness – Press Release – Digital Journal

Passion and purpose coach Andrew Low teaches tools to create harmony between your conscious and unconscious mind so you can live your life on purpose.

Life can suck for us at times! We face stressors that take their toll on our wellbeing. Uncertainty in the world around us can trigger anxiety and even depression. We find ourselves disempowered and reacting to the world around us. We lash out, our relationships suffer. We suffer!

What can we learn from the ancient wisdom of ages past? Could the latest developments in neuroscience unlock secrets to personal transformation lost to the ages?

After toiling and struggling in a corporate job of more than 16-hour workdays, Low had been working nights and weekends when one day, he fell asleep behind the wheel and crashed his car. His accident made him realize that things had to change. He has been on a journey ever since, and now, his mission is to help you uncover your life's passion and purpose.

Low describes his pioneering approach to transformation:

"Combining ancient wisdom with the latest in neuroscience and coaching to help us let go of the past so we can live in the present with passion and purpose this is the secret to earning a great income from doing what we love. Many personal development gurus tell us what we need to do - let go, find our passions, live our purpose. But how do we do them? There are proven tools that create harmony between your conscious and unconscious minds that give you deep, cathartic and sustainable results."

Engaging with Low allows a client access to a collection of three courses that gives the formula for achieving the trifecta of success, love, and happiness. It is an immersive, practical, and experiential program that gives the whys, whats, and how-tos of the eight principles of success, love, and happiness.

According to Low, this approach empowers you to imagine the full experience of mental, emotional, and tangible breakthroughs to discover answers that are in line with your passion and purpose. If youve always dreamed of living a full, enriched, and joyful life, while earning income from doing what you love; this training can be a journey of transformation like nothing else youve ever experienced.

Low also trains individuals interested in becoming life coaches themselves. The key to serving others is first to work on yourself to heal your own past. This way, you become a shining example to others. Then, get certified in the processes to help others on a deep level, and learn and apply a blueprint to transition to full-time coaching.

For more information, visithttps://andrewlow.coach.

About Andrew Low Coaching and Training

Andrew Low is a transformation coach and trainer who focuses on helping others live their passion and purpose. Andrew is internationally certified as neuro-linguistic programming (NLP) trainer, Archetypal Coaching trainer for Passion and Purpose Coaching, Masculine and Feminine Coaching and Matrix Therapies Coaching. He holds a Diploma in Life Coaching. He has over 20 years experience in training, mentoring, and coaching in both private and public sectors and is known for his fun and effective workshop facilitation skills. He specializes in helping entrepreneurs, business professionals and everyday people discover their passions and purpose, earn a good income from it, while having fun and laughter on their journeys.

Media ContactCompany Name: Andrew Low Coaching and TrainingContact Person: Andrew Ee-Kuan LowEmail: Send EmailPhone: +61-413-885339Country: AustraliaWebsite: https://andrewlow.coach/

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The Clever Combination of Neuroscience and Ancient Wisdom That Is Re-Writing the Rule Book on Success and Happiness - Press Release - Digital Journal

Neuroscience

This Alzheimer’s-Linked Gene Disrupts a Key Cell Process – But Another Risk Gene Could Help – Technology Networks

In a new study, a team of scientists based at The Picower Institute for Learning and Memory at MIT and the Whitehead Institute for Biomedical Research reveals evidence showing that the most prominent Alzheimer's disease risk gene may disrupt a fundamental process in a key type of brain cell. Moreover, in a sign of how important it is to delve into the complex ways that genes intersect in disease, they found that increasing the expression of another Alzheimer's-associated gene in those cells could help alleviate the problem.

About 25 percent of people have the APOE4 variant of the APOE gene, which puts them at substantially greater risk for Alzheimer's disease than those with the more common APOE3 version. Scientists have been working for decades to understand why this is so. The new study in Cell Reports finds that in astrocytes, which are the most common non-neuron cell in the brain, the variant hampers the process of endocytosis, which is a major way that cells bring materials in from outside. That functional deficit could undermine several of the vital roles that astrocytes play in the brain, the researchers noted, including how they facilitate communication among neurons or maintain the blood-brain barrier, which stringently filters what circulates into or out of the brain.

"We have identified that APOE4 imposes an endocytosis deficiency in astrocytes," said Priyanka Narayan, a researcher at the National Institutes of Health who co-led the work while a postdoc in the labs of the late Susan Lindquist, member of the Whitehead Institute, and of Li-Huei Tsai, Picower Professor of Neuroscience and the study's corresponding author. "This effect could have a number of downstream consequences such as impaired communication with other cell types, poor clearance of extracellular material, or poor maintenance of metabolic homeostasis."

The research began in the lab of Lindquist, who was also a Professor of Biology at MIT. Lindquist and Tsai, were close collaborators. After Lindquist died, the research team completed the work in the Tsai lab at MIT. The study's co-lead author is Grzegorz Sienski of the Whitehead Institute.

As part of their work, the team also found that in APOE4-carrying astrocytes increasing expression of an Alzheimer's associated gene called PICALM reversed the endocytosis defects.

"Both APOE and PICALM are Alzheimer's risk genes," said Tsai, a founding director of MIT's Aging Brain Initiative. "It is really interesting that the two genes converge on endocytosis. This indicates that faulty endocytosis plays a key role in the etiology of Alzheimer's."

Reduction and rescue

For at least a decade, studies have suggested connections among Alzheimer's, APOE4 and errant endocytosis, but have not pinpointed specific mechanisms. The team sought them out--and also looked for ways to remediate the deficits--through a series of lab experiments in cultures of stem cell-derived human astrocytes and genetically engineered yeast. Tsai's team focused on astrocytes because they produce the most ApoE protein in the brain.

By comparing astrocytes that were identical except in whether they had the APOE4 or APOE3 variants, the researchers found several signs of disrupted endocytosis, specifically in the early stage of the process when key proteins were notably reduced in the APOE4 carrying cells. They were able to directly observe that the afflicted astrocytes were less capable of bringing in materials from the outside. When they knocked out the APOE gene they no longer saw a defect in early endocytosis, affirming that the problem related to having the APOE4 variant.

By engineering human APOE3 and APOE4 into yeast cells, Tsai's team was able to replicate clear signs of APOE4's early endocytic disruption. This is possible because the function is so fundamental to how cells work, it is similar, or "conserved," in yeast and people. Once they knew they could use yeast as a model, they could then set out to look for endocytosis proteins that, if manipulated, could rescue the observed defect. They found one: a yeast protein called Yap1802p. When they made the yeast cells express extra Yap1802p, early endocytosis proteins were produced at normal levels, endocytosis function operated better and APOE4 cells, which had failed to grow as healthfully as APOE3 cells did, exhibited better growth.

Importantly, the gene that encodes Yap1802p has a human counterpart: PICALM. Studies have shown PICALM to have a complex but significant role in affecting Alzheimer's disease risk.

With their promising results in yeast, the researcher team returned to their human astrocyte cultures. Overexpressing PICALM in APOE4 astrocytes repaired early endocytosis function, as measured by the increased intake of test proteins. But they also saw that overexpressing PICALM in APOE3 astrocytes caused an endocytosis defect, illustrating that the effects of PICALM varies markedly in astrocytes based on APOE variant.

Although, it is difficult to find drugs that specifically increase endocytosis, this study could help scientists and clinicians better understand patients' risk, Narayan said.

"In our study, we see that in the context of an APOE4 genotype, increasing PICALM can alleviate deficiencies in early endocytosis," she said. "Given that APOE4 carriers represent a significant proportion of AD patients, this functional interaction between APOE4 and PICALM could be relevant to assessing their level of disease risk. It also gives an example of how the genetic background of an individual can interact and potentially modulate the detrimental effects of the APOE4 genotype."

Moreover, the team's method of going back and forth between human cell cultures and yeast, provides a way of identifying how AD risk genes impact cellular biology, and how other genes can modulate these effects.

Reference: Narayan P, Sienski G, Bonner JM, et al.PICALM Rescues Endocytic Defects Caused by the Alzheimers Disease Risk Factor APOE4. Cell, 2020;33(1). doi:10.1016/j.celrep.2020.108224

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This Alzheimer's-Linked Gene Disrupts a Key Cell Process - But Another Risk Gene Could Help - Technology Networks

Genetics

Found: genes that sway the course of the coronavirus – Science Magazine

A study of some of the sickest COVID-19 patients, such as those placed on ventilators, has identified gene variants that put people at greater risk of severe disease.

By Jocelyn KaiserOct. 13, 2020 , 1:25 PM

Sciences COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

Its one of the pandemics puzzles: Most people infected by SARS-CoV-2 never feel sick, whereas others develop serious symptoms or even end up in an intensive care unit clinging to life. Age and preexisting conditions, such as obesity, account for much of the disparity. But geneticists have raced to see whether a persons DNA also explains why some get hit hard by the coronavirus, and they have uncovered tantalizing leads.

Now, a U.K. group studying more than 2200 COVID-19 patients has pinned down common gene variants that are linked to the most severe cases of the disease, and that point to existing drugs that could be repurposed to help. Its really exciting. Each one provides a potential target for treatment, says genetic epidemiologist Priya Duggal of Johns Hopkins University.

In a standard approach to finding genes that influence a condition, geneticists scan the DNA of large numbers of people for millions of marker sequences, looking for associations between specific markers and cases of the disease. In June, one such genomewide association study in The New England Journal of Medicine (NEJM) found two hits linked to respiratory failure in 1600 Italian and Spanish COVID-19 patients: a marker within the ABO gene, which determines a persons blood type, and a stretch of chromosome 3 that holds a half-dozen genes. Those two links have also emerged in other groups data, including some from the DNA testing company 23andMe.

The new study confirmed the chromosome 3 regions involvement. And because 74% of its patients were so sick that they needed invasive ventilation, it had the statistical strength to reveal other markers, elsewhere in the genome, linked to severe COVID-19. One find is a gene called IFNAR2 that codes for a cell receptor for interferon, a powerful molecular messenger that rallies the immune defenses when a virus invades a cell. A variant of IFNAR2 found in one in four Europeans raised the risk of severe COVID-19 by 30%. Baillie says the IFNAR2 hit is entirely complementary to a finding reported in Science last month: very rare mutations that disable IFNAR2 and seven other interferon genes may explain about 4% of severeCOVID-19 cases. Both studies raise hopes for ongoing trials of interferons as a COVID-19 treatment.

A more surprising hit from the U.K. study points to OAS genes, which code for proteins that activate an enzyme that breaks down viral RNA. A change in one of those genes might impair this activation, allowing the virus to flourish. The U.K. data suggest there is a variant as common and influential on COVID-19 as the interferon genetic risk factor.

Other genes identified by Baillies team could ramp up the inflammatory responses to lung damage triggered by SARS-CoV-2, reactions that can be lethal to some patients. One, DPP9, codes for an enzyme known to be involved in lung disease; another, TYK2, encodes a signaling protein involved in inflammation. Drugs that target those two genes proteins are already in useinhibitors of DPP9s enzyme for diabetes and baricitinib, which blocks TYK2s product, for arthritis. Baricitinib is in early clinical testing for COVID-19, and the new data could push it up the priority list, Baillie says.

The chromosome 3 region still stands out as the most powerful genetic actor: A single copy of the disease-associated variant more than doubles an infected persons odds of developing severe COVID-19. Evolutionary biologists reported last month in Nature that this suspicious region actually came from Neanderthals, through interbreeding with our species tens of thousands of years ago. It is now found in about 16% of Europeans and 50% of South Asians.

But the specific chromosome 3 gene or genes at play remain elusive. By analyzing gene activity data from normal lung tissue of people with and without the variant, the U.K. team homed in on CCR2, a gene that encodes a receptor for cytokine proteins that play a role in inflammation. But other data discussed at last weeks meeting point to SLC6Z20, which codes for a protein that interacts with the main cell receptor used by SARS-CoV-2 to enter cells. I dont think anyone at this point has a clear understanding of what are the underlying genes for the chromosome 3 link, says Andrea Ganna of the University of Helsinki, who co-leads the COVID-19 Host Genetics Initiative.

The U.K. genetics study did not confirm that the ABO variants affect the odds of severe disease. Some studies looking directly at blood type, not genetic markers, have reported that type O blood protects against COVID-19, whereas A blood makes a person more vulnerable. It may be that blood type influences whether a person gets infected, but not how sick they get, says Stanford University geneticist Manuel Rivas. In any case, O blood offers at best modest protection. There are a lot of people with O blood that have died of the disease. It doesnt really help you, says geneticist Andre Franke of the Christian-Albrecht University of Kiel, a coleader of the NEJM study.

Researchers expect to pin down more COVID-19 risk genesalready, after folding in the U.K. data plumbed by Baillies team, the COVID-19 Host Genetics Initiative has found another hit, a gene called FOXP4 implicated in lung cancer. And in a new medRxiv preprint posted last week, the company Ancestry.com reports that a gene previously connected to the effects of the flu may also boost COVID-19 susceptibility only in men, who are more likely to die of the disease than women.

Geneticists have had little luck so far identifying gene variants that explain why COVID-19 has hit Black people in the United States and United Kingdom particularly hard. The chromosome 3 variant is absent in most people of African ancestry. Researchers suspect that socioeconomic factors and preexisting conditions may better explain the increased risks. But several projects, including Baillies, are recruiting more people of non-European backgrounds to bolster their power to find COVID-19 gene links. And in an abstract for an online talk later this month at the American Society of Human Genetics annual meeting, the company Regeneron reports it has found a genome region that may raise the risk of severe disease mainly in people of African ancestry.

Even as more genetic risk factors are identified, their overall effect on infected people will be modest compared with other COVID-19 factors, Duggal says. But studies like the U.K. teams could help reveal the underlying biology of the disease and inspire better treatments. I dont think genetics will lead us out of this. I think genetics may give us new opportunities, Duggal says.

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Found: genes that sway the course of the coronavirus - Science Magazine

Genetics

Trumps Lifelong Obsession With His Superior DNA Is Being Put to the Test – New York Magazine

After returning to the White House from the hospital on October 5, Trump waved from the balcony. Photo: Win McNamee/Getty Images, Nicholas Kamm/AFP via Getty Images, Erin Scott/Reuters,

Last month, appearing at a rally in Minnesota, President Trump praised the superior genetic stock of his supporters in the state. You have good genes, you know that, right? Trump observed. You have good genes. A lot of its about the genes, isnt it, dont you believe? The racehorse theory. You think were so different? You have good genes in Minnesota.

The comment received some attention as fresh evidence of a decades-long streak of racism, which it certainly is. (There is obviously a reason the lineage of the heavily Nordic state drew his attention.) But Trumps observations on genetics are not only an expression of racism. It is also one of his deepest obsessions and the explanation for the bizarre passivity that has characterized his response to the coronavirus pandemic from the outset and that has led him to his likely political, if not corporeal, demise.

The classic American millionaire myth, from Carnegie to Warren Buffett, has an origin story, employing at least elements of truth, built on hard work. The hero rose at dawn and sweated and strove on his rise to greatness. And yet, despite having spent decades carefully polishing his place in the lineage of aspirational wealth, Trump has few well-known stories of pounding the pavement or poring over real-estate listings. Its instincts, not marketing studies, he wrote in The Art of the Deal, the original manifesto of his personality cult.

Instinct is something you are born with or not. In 1988, Oprah Winfrey asked Trump if all of the people reading Art of the Deal hoping to find some answer that will satisfy their own desire for success could take away inspiration and lessons. The American prosperity gospel has a hackneyed response to this question: Yes, with relentless effort and perhaps some luck, anybody can get rich in America. Even though he was peddling a book marketed to advance precisely such a fantasy, Trump could not bring himself to supply the familiar answer. You have to be born lucky in the sense that you have to have the right genes, he explained. You have to have a certain gene.

Trump brings up his belief in genes over and over. I have a certain gene, he told CNN in 2010. Im a gene believer. Hey, when you connect two racehorses, you usually end up with a fast horse. And I really was you know, I had a a good gene pool from the standpoint of that. Addressing a rally in Mississippi in 2016, he instructed the crowd, I have Ivy League education, smart guy, good genes. I have great genes and all that stuff, which Im a believer in. (In the annals of Mississippi politics, Trumps highlighting his Ivy League pedigree was probably more novel than his emphasis on genetic purity.)

The presidents idea of a fixed genetic elite and its necessary underclass counterpart would seem to undercut any moral basis for his own privilege. (The best moral case for letting rich people keep their money is that they worked hard to earn it. So if Trumps wealth is entirely the product of winning the genetic lottery, why not tax it away and redistribute the proceeds to his less fortunate inferiors?) It also stands in stark contrast to the American credo of progress.

What Hath God Wrought?, Daniel Walker Howes history of early-19th-century America, emphasizes a belief among the Founders, and especially the progressive Yankee faction, in improvement. This concept constituted both an individual and a collective responsibility, involving both the cultivation of personal faculties and the development of national resources. Just as people could and must develop their own talents through study and disciplined labor, they could enhance the potential of the country by building schoolhouses, canals, lighthouses, and universities.

It was a creed embraced by such disparate figures as John Quincy Adams, Abraham Lincoln, and Frederick Douglass. Their political rivals were southern planters who distrusted centralized government, which might threaten their immutable place atop the hierarchy. The planters defined success not as hard work but as liberation from hard work, the burden of which would fall on the people they had enslaved.

Trump has not necessarily absorbed antebellum southern thought. But he has internalized the idea of success as genetically coded and impervious to effort. The Trump success formula is 100 percent inspiration, zero percent perspiration. He has repeatedly cited his MIT-professor uncle as his own scientific credential. Trump said at the Centers for Disease Control and Prevention that he impressed his hosts with his innate grasp of public health: I really get it Every one of these doctors said, How do you know so much about this? Maybe I have a natural ability, he said, as if he were literally born understanding the workings of a virus that did not exist until 2019. NBC reported that Trump waved off the need to rigorously prepare for his debate on the grounds that debating isnt something you have to practice. His biographer Michael DAntonio once explained that Trump disdains exercise and gorges on burgers and junk food because he really believes in genetic gifts. He wants to assume that he can do something that others cant do simply because of who he is.

That is not an ideal mentality for the person youd want to be in charge of well, anything. But especially not a pandemic that requires careful study and flexibility of mind to follow a quickly mutating scientific understanding and the perseverance to encourage and adhere to disciplined hygienic rituals. Everything to him is about who you are, not what you do. Trump did not need to learn about the pandemic because he is smart. He did not need to protect himself from it because he is strong.

Trump not only lacks the patience for a laborious public-health regimen; the entire concept of it runs against his genetic fatalism. The very possibility a disease could fell blond bermensch Donald Trump almost surely never occurred to him. The president is neither a rationalist nor a religious believer. The closest proxy in his mind to a divine force is genes: invisible, all-powerful, mapping out our destinies. Were he capable of introspection, he might look upon his stricken body and dying presidency and question his false god.

*This article appears in the October 12, 2020, issue ofNew York Magazine. Subscribe Now!

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Trumps Lifelong Obsession With His Superior DNA Is Being Put to the Test - New York Magazine