NS/ Transparent brain implant captures deep neural activity from the surface
Neuroscience biweekly vol. 101, 3rd January — 17th January
TL;DR
- Researchers at the University of California San Diego have developed a neural implant that provides information about activity deep inside the brain while sitting on its surface. The implant is made up of a thin, transparent, and flexible polymer strip that is packed with a dense array of graphene electrodes. The technology, tested in transgenic mice, brings the researchers a step closer to building a minimally invasive brain-computer interface (BCI) that provides high-resolution data about deep neural activity by using recordings from the brain surface. The work was published in Nature Nanotechnology.
- New research from the Netherlands Institute for Neuroscience shows that chandelier cells, a specific type of brain cell, become active during unexpected situations. ‘Researchers have been wondering about the functionality of these cells for a long time’.
- Researchers have created the world’s largest ancient human gene bank by analyzing the bones and teeth of almost 5,000 humans who lived across Western Europe and Asia up to 34,000 years ago. By sequencing ancient human DNA and comparing it to modern-day samples, the international team of experts mapped the historical spread of genes — and diseases — over time as populations migrated. They found: The startling origins of neurodegenerative diseases including multiple sclerosis; why northern Europeans today are taller than people from southern Europe; and how major migration around 5,000 years ago introduced risk genes into the population in north-western Europe — leaving a legacy of higher rates of MS today.
- Research reveals that adults with PTSD have a 2% smaller cerebellum than people without the disorder. The finding expands understanding of the cerebellum’s role in the brain beyond balance and movement to include emotion and cognition and also suggests that targeting the cerebellum may improve current treatments for PTSD, such as deep brain stimulation.
- Scientists have discovered that the estrogen receptor (ER), expressed in the lateral septum of the limbic system, plays a crucial role in suppressing anxiety-like behavior exhibited by male mice in social situations. They also discovered that the distribution and expression region of ER differs from that of ER.
- Love is blind, the saying goes, and thanks to a new study we are now a step closer to understanding why. Researchers have measured how a part of the brain is responsible for putting our loved one on a pedestal in that first flush of romance.
- Restricting calories is known to improve health and increase lifespan, but much of how it does so remains a mystery, especially regarding how it protects the brain. Buck scientists have uncovered a role for a gene called OXR1 that is necessary for the lifespan extension seen with dietary restriction and is essential for healthy brain aging.
- Researchers have found a gene that links deafness to cell death in the inner ear in humans — creating new opportunities for averting hearing loss.
- By investigating a molecule in the brain tied to cellular communication, scientists uncover important information about the proteins that do — and do not — influence alcohol-drinking behavior.
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The latest news and research
High-density transparent graphene arrays for predicting cellular calcium activity at depth from surface potential recordings
by Ramezani M, Kim JH, Liu X, et al. in Nature Nanotechnol
Researchers at the University of California San Diego have developed a neural implant that provides information about activity deep inside the brain while sitting on its surface. The implant is made up of a thin, transparent and flexible polymer strip that is packed with a dense array of graphene electrodes. The technology, tested in transgenic mice, brings the researchers a step closer to building a minimally invasive brain-computer interface (BCI) that provides high-resolution data about deep neural activity by using recordings from the brain surface.
“We are expanding the spatial reach of neural recordings with this technology,” said study senior author Duygu Kuzum, a professor in the Department of Electrical and Computer Engineering at the UC San Diego Jacobs School of Engineering. “Even though our implant resides on the brain’s surface, its design goes beyond the limits of physical sensing in that it can infer neural activity from deeper layers.”
This work overcomes the limitations of current neural implant technologies. Existing surface arrays, for example, are minimally invasive, but they lack the ability to capture information beyond the brain’s outer layers. In contrast, electrode arrays with thin needles that penetrate the brain are capable of probing deeper layers, but they often lead to inflammation and scarring, compromising signal quality over time.
The new neural implant developed at UC San Diego offers the best of both worlds.
The implant is a thin, transparent and flexible polymer strip that conforms to the brain’s surface. The strip is embedded with a high-density array of tiny, circular graphene electrodes, each measuring 20 micrometers in diameter. Each electrode is connected by a micrometers-thin graphene wire to a circuit board.
In tests on transgenic mice, the implant enabled the researchers to capture high-resolution information about two types of neural activity–electrical activity and calcium activity–at the same time. When placed on the surface of the brain, the implant recorded electrical signals from neurons in the outer layers. At the same time, the researchers used a two-photon microscope to shine laser light through the implant to image calcium spikes from neurons located as deep as 250 micrometers below the surface. The researchers found a correlation between surface electrical signals and calcium spikes in deeper layers. This correlation enabled the researchers to use surface electrical signals to train neural networks to predict calcium activity — not only for large populations of neurons, but also individual neurons — at various depths.
“The neural network model is trained to learn the relationship between the surface electrical recordings and the calcium ion activity of the neurons at depth,” said Kuzum. “Once it learns that relationship, we can use the model to predict the depth activity from the surface.”
An advantage of being able to predict calcium activity from electrical signals is that it overcomes the limitations of imaging experiments. When imaging calcium spikes, the subject’s head must be fixed under a microscope. Also, these experiments can only last for an hour or two at a time.
“Since electrical recordings do not have these limitations, our technology makes it possible to conduct longer duration experiments in which the subject is free to move around and perform complex behavioral tasks,” said study co-first author Mehrdad Ramezani, an electrical and computer engineering Ph.D. student in Kuzum’s lab. “This can provide a more comprehensive understanding of neural activity in dynamic, real-world scenarios.”
The technology owes its success to several innovative design features: transparency and high electrode density combined with machine learning methods.
“This new generation of transparent graphene electrodes embedded at high density enables us to sample neural activity with higher spatial resolution,” said Kuzum. “As a result, the quality of signals improves significantly. What makes this technology even more remarkable is the integration of machine learning methods, which make it possible to predict deep neural activity from surface signals.”
This study was a collaborative effort among multiple research groups at UC San Diego. The team, led by Kuzum, one of the world leaders in developing multimodal neural interfaces, includes nanoengineering professor Ertugrul Cubukcu, who specializes in advanced micro- and nanofabrication techniques for graphene materials; electrical and computer engineering professor Vikash Gilja, whose lab integrates domain-specific knowledge from the fields of basic neuroscience, signal processing, and machine learning to decode neural signals; and neurobiology and neurosciences professor Takaki Komiyama (UC San Diego School of Biological Sciences and School of Medicine), whose lab focuses on investigating neural circuit mechanisms that underlie flexible behaviors.
Transparency is one of the key features of this neural implant. Traditional implants use opaque metal materials for their electrodes and wires, which block the view of neurons beneath the electrodes during imaging experiments. In contrast, an implant made using graphene is transparent, which provides a completely clear field of view for a microscope during imaging experiments.
“Seamless integration of recording electrical signals and optical imaging of the neural activity at the same time is only possible with this technology,” said Kuzum. “Being able to conduct both experiments at the same time gives us more relevant data because we can see how the imaging experiments are time-coupled to the electrical recordings.
To make the implant completely transparent, the researchers used super thin, long graphene wires instead of traditional metal wires to connect the electrodes to the circuit board. However, fabricating a single layer of graphene as a thin, long wire is challenging because any defect will render the wire nonfunctional, explained Ramezani.
“There may be a gap in the graphene wire that prevents the electrical signal from flowing through, so you basically end up with a broken wire.”
The researchers addressed this issue using a clever technique. Instead of fabricating the wires as a single layer of graphene, they fabricated them as a double layer doped with nitric acid in the middle.
“By having two layers of graphene on top of one another, there’s a good chance that defects in one layer will be masked by the other layer, ensuring the creation of fully functional, thin and long graphene wires with improved conductivity,” said Ramezani.
According to the researchers, this study demonstrates the most densely packed transparent electrode array on a surface-sitting neural implant to date. Achieving high density required fabricating extremely small graphene electrodes. This presented a considerable challenge, as shrinking graphene electrodes in size increases their impedance — this hinders the flow of electrical current needed for recording neural activity. To overcome this obstacle, the researchers used a microfabrication technique developed by Kuzum’s lab that involves depositing platinum nanoparticles onto the graphene electrodes. This approach significantly improved electron flow through the electrodes while keeping them tiny and transparent.
The team will next focus on testing the technology in different animal models, with the ultimate goal of human translation in the future.
Kuzum’s research group is also dedicated to using technology to advance fundamental neuroscience research. In that spirit, they are sharing the technology with labs across the U.S. and Europe, contributing to diverse studies ranging from understanding how vascular activity is coupled to electrical activity in the brain to investigating how place cells in the brain are so efficient at creating spatial memory. To make this technology more widely available, Kuzum’s team has applied for a National Institutes of Health (NIH) grant to fund efforts in scaling up production and facilitating its adoption by researchers worldwide.
“This technology can be used for so many different fundamental neuroscience investigations, and we are eager to do our part to accelerate progress in better understanding the human brain,” said Kuzum.
Experience shapes chandelier cell function and structure in the visual cortex
by Koen Seignette, Nora Jamann, Paolo Papale, Huub Terra, Ralph O Porneso, Leander de Kraker, Chris van der Togt, Maaike van der Aa, Paul Neering, Emma Ruimschotel, Pieter R Roelfsema, Jorrit S Montijn, Matthew W Self, Maarten HP Kole, Christiaan N Levelt in eLife
New research from the Netherlands Institute for Neuroscience shows that chandelier cells, a specific type of brain cell, become active during unexpected situations. “Researchers have been wondering about the functionality of these cells for a long time.”
You’re cycling to work through the city and suddenly you see a new building somewhere. On the first day that is very surprising. On day 2 this diminishes somewhat, and after a week you no longer notice it at all. The same thing happens the other way around: when a building that was always there suddenly disappeared, you are also surprised.
But how does your brain signal unexpected changes and which cells are involved?
To learn more about this phenomenon, Koen Seignette from Christiaan Levelt’s lab joined forces with his colleagues from the Kole lab and Roelfsema lab. Together, they investigated a special type of brain cell found in small numbers in the cortex: the chandelier cell. In contrast to other inhibitory brain cells, they only inhibit one spot of other cells, but there is remarkably little known about why and when.
Koen Seignette:
‘We already knew quite a lot about the function of most types of inhibitory brain cells, but chandelier cells were a mystery. This is because they are not clearly marked genetically, and so could not be properly examined. We have now obtained a mouse model in which the chandelier cells are fluorescently labeled. This allows us to image them live and determine when they are active. That offers new opportunities.’
‘As a first step, we looked at what chandelier cells in the visual cortex respond to. What happens to these cells when the mouse starts running or when we present visual stimuli? In one of the experiments we had the mice walk in a virtual tunnel. When the mouse ran, the tunnel moved, and when it stopped, so did the tunnel. Using this setup, we could create an unexpected situation by stopping the tunnel while the mouse was still running. It was during these events that the chandelier cells started firing like crazy.’
Christiaan Levelt:
‘We see that the type of stimulus does not actually matter that much, what matters is that it is unexpected and surprising. We also noticed that habituation and change occurs, comparable to the aforementioned example of the new building. At first the cells react strongly, but after repeated exposure the activity becomes weaker. This shows that the cells are able to adapt, which is a concept known as plasticity. This plasticity also occurs at a structural anatomical level: we can literally see changes in the synapses chandelier cells form on other brain cells.’
‘What makes this study important is that this is the first really comprehensive study of chandelier cells in the visual cortex. We have not only determined what they respond to, but also which brain cells they form connections with, and what their influence is on other brain cells. This has never been looked at in such detail before. Understanding the role of these inhibitory neurons in the cortex is crucial for many processes, including learning from unexpected circumstances. We all know that you remember things better when it really surprises you. If the prediction is incorrect, that’s where you can find the information. You need plasticity to update your insights, and these cells could play a role in that.’
Chandelier cells, named for their resemblance to a chandelier, are inhibitory brain cells that focus on the starting point (axon initial segment) of electrical signals in the pyramidal cells, the most common cells in the cortex. It was thought that chandelier cells could exert strong control over pyramidal cells by blocking the action potential. Surprisingly, the current research shows that this effect is actually very weak, which contradicts previously drawn conclusions.
Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations
by William Barrie, Yaoling Yang, Evan K. Irving-Pease, Kathrine E. Attfield, Gabriele Scorrano, Lise Torp Jensen, Angelos P. Armen, Evangelos Antonios Dimopoulos, Aaron Stern, Alba Refoyo-Martinez, Alice Pearson, Abigail Ramsøe, Charleen Gaunitz, Fabrice Demeter, Marie Louise S. Jørkov, Stig Bermann Møller, Bente Springborg, Lutz Klassen, Inger Marie Hyldgård, Niels Wickmann, Lasse Vinner, Thorfinn Sand Korneliussen, Morten E. Allentoft, Martin Sikora, Kristian Kristiansen, Santiago Rodriguez, Rasmus Nielsen, Astrid K. N. Iversen, Daniel J. Lawson, Lars Fugger, Eske Willerslev in Nature
Researchers have created the world’s largest ancient human gene bank by analysing the bones and teeth of almost 5,000 humans who lived across western Europe and Asia up to 34,000 years ago.
By sequencing ancient human DNA and comparing it to modern-day samples, the international team of experts mapped the historical spread of genes — and diseases — over time as populations migrated.
The ‘astounding’ results have been revealed in four trailblazing research papers published in the same issue of Nature and provide new biological understanding of debilitating disorders.
The extraordinary study involved a large international team led by Professor Eske Willerslev at the Universities of Cambridge and Copenhagen, Professor Thomas Werge at the University of Copenhagen, and Professor Rasmus Nielsen at University of California, Berkeley and involved contributions from 175 researchers from around the globe.
The scientists found:
- The startling origins of neurodegenerative diseases including multiple sclerosis
- Why northern Europeans today are taller than people from southern Europe
- How major migration around 5,000 years ago introduced risk genes into the population in north-western Europe — leaving a legacy of higher rates of MS today
- Carrying the MS gene was an advantage at the time as it protected ancient farmers from catching infectious diseases from their sheep and cattle
- Genes known to increase the risk of diseases such as Alzheimer’s and type 2 diabetes were traced back to hunter gatherers
- Future analysis is hoped to reveal more about the genetic markers of autism, ADHD, schizophrenia, bipolar disorder, and depression
Northern Europe has the highest prevalence of multiple sclerosis in the world. A new study has found the genes that significantly increase a person’s risk of developing multiple sclerosis (MS) were introduced into north-western Europe around 5,000 years ago by sheep and cattle herders migrating from the east.
By analyzing the DNA of ancient human bones and teeth, found at documented locations across Eurasia, researchers traced the geographical spread of MS from its origins on the Pontic Steppe (a region spanning parts of what are now Ukraine, South-West Russia and the West Kazakhstan Region).
They found that the genetic variants associated with a risk of developing MS ‘travelled’ with the Yamnaya people — livestock herders who migrated over the Pontic Steppe into North-Western Europe.
These genetic variants provided a survival advantage to the Yamnaya people, most likely by protecting them from catching infections from their sheep and cattle. But they also increased the risk of developing MS.
“It must have been a distinct advantage for the Yamnaya people to carry the MS risk genes, even after arriving in Europe, despite the fact that these genes undeniably increased their risk of developing MS,” said Professor Eske Willerslev, jointly at the Universities of Cambridge and Copenhagen and a Fellow of St John’s College, an expert in analysis of ancient DNA and Director of the project.
He added:
“These results change our view of the causes of multiple sclerosis and have implications for the way it is treated.”
The age of specimens ranges from the Mesolithic and Neolithic through the Bronze Age, Iron Age and Viking period into the Middle Ages. The oldest genome in the data set is from an individual who lived approximately 34,000 years ago.
The findings provide an explanation for the ‘North-South Gradient’, in which there are around twice as many modern-day cases of MS in northern Europe than southern Europe, which has long been a mystery to researchers.
From a genetic perspective, the Yamnaya people are thought to be the ancestors of the present-day inhabitants of much of North-Western Europe. Their genetic influence on today’s population of southern Europe is much weaker.
Previous studies have identified 233 genetic variants that increase the risk of developing MS. These variants, also affected by environmental and lifestyle factors, increase disease risk by around 30 percent. The new research found that this modern-day genetic risk profile for MS is also present in bones and teeth that are thousands of years old.
“These results astounded us all. They provide a huge leap forward in our understanding of the evolution of MS and other autoimmune diseases. Showing how the lifestyles of our ancestors impacted modern disease risk just highlights how much we are the recipients of ancient immune systems in a modern world,” said Dr William Barrie, a postdoc in the University of Cambridge’s Department of Zoology and co-author of the paper.
Multiple sclerosis is a neurodegenerative disease in which the body’s immune system mistakenly attacks the ‘insulation’ surrounding the nerve fibres of the brain and spinal cord. This causes symptom flares known as relapses as well as longer-term degeneration, known as progression.
Professor Lars Fugger, a co-author of the MS study professor and consultant physician at John Radcliffe Hospital, University of Oxford, said: “This means we can now understand and seek to treat MS for what it actually is: the result of a genetic adaptation to certain environmental conditions that occurred back in our prehistory.”
Professor Astrid Iversen, another co-author based at the University of Oxford, said:
“We now lead very different lives to those of our ancestors in terms of hygiene, diet, and medical treatment options and this combined with our evolutionary history means we may be more susceptible to certain diseases than our ancestors were, including autoimmune diseases such as MS.”
The new findings were made possible by the analysis of data held in a unique gene bank of ancient DNA, created by the researchers over the past five years with funding from the Lundbeck Foundation.
This is the first gene bank of its kind in the world and already it has enabled fascinating new insights in areas from ancient human migrations, to genetically-determined risk profiles for the development of brain disorders.
By analyzing the bones and teeth of almost 5,000 ancient humans, held in museum collections across Europe and Western Asia, the researchers generated DNA profiles ranging across the Mesolithic and Neolithic through the Bronze Age, Iron Age and Viking period into the Middle Ages. They compared the ancient DNA data to modern DNA from 400,000 people living in Britain, held in the UK Biobank.
“Creating a gene bank of ancient DNA from Eurasia’s past human inhabitants was a colossal project, involving collaboration with museums across the region,” said Willerslev.
He added:
“We’ve demonstrated that our gene bank works as a precision tool that can give us new insights into human diseases, when combined with analyses of present-day human DNA data and inputs from several other research fields. That in itself is amazing, and there’s no doubt it has many applications beyond MS research.”
The team now plans to investigate other neurological conditions including Parkinson’s and Alzheimer’s diseases and psychiatric disorders including ADHD and schizophrenia.
They have received requests from disease researchers across the world for access to the ancient DNA profiles, and eventually aim to make the gene bank open access.
Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup
by Ashley A. Huggins, C. Lexi Baird, Melvin Briggs, Sarah Laskowitz, Ahmed Hussain, Samar Fouda, Courtney Haswell, Delin Sun, Lauren E. Salminen, Neda Jahanshad, Sophia I. Thomopoulos, Dick J. Veltman, Jessie L. Frijling, Miranda Olff, Mirjam van Zuiden, Saskia B. J. Koch, Laura Nawjin, et al. in Molecular Psychiatry
Adults with posttraumatic stress disorder (PTSD) have smaller cerebellums, according to new research from a Duke-led brain imaging study.
The cerebellum, a part of the brain well known for helping to coordinate movement and balance, can influence emotion and memory, which are impacted by PTSD. What isn’t known yet is whether a smaller cerebellum predisposes a person to PTSD or PTSD shrinks the brain region.
“The differences were largely within the posterior lobe, where a lot of the more cognitive functions attributed to the cerebellum seem to localize, as well as the vermis, which is linked to a lot of emotional processing functions,” said Ashley Huggins, Ph.D., the lead author of the report who helped carry out the work as a postdoctoral researcher at Duke in the lab of psychiatrist Raj Morey, M.D.
Huggins, now an assistant professor of psychology at the University of Arizona, hopes these results encourage others to consider the cerebellum as an important medical target for those with PTSD.
“If we know what areas are implicated, then we can start to focus interventions like brain stimulation on the cerebellum and potentially improve treatment outcomes,” Huggins said.
The findings, published in the journal Molecular Psychiatry, have prompted Huggins and her lab to start looking for what comes first: a smaller cerebellum that might make people more susceptible to PTSD, or trauma-induced PTSD that leads to cerebellum shrinkage.
PTSD is a mental health disorder brought about by experiencing or witnessing a traumatic event, such as a car accident, sexual abuse, or military combat.
Though most people who endure a traumatic experience are spared from the disorder, about 6% of adults develop PTSD, which is often marked by increased fear and reliving the traumatizing event.
Researchers have found several brain regions involved in PTSD, including the almond-shaped amygdala that regulates fear, and the hippocampus, a critical hub for processing memories and routing them throughout the brain.
The cerebellum (Latin for “little brain”), by contrast, has received less attention for its role in PTSD. A grapefruit-sized lump of cells that look like it was clumsily tacked underneath the back of the brain as an afterthought, the cerebellum is best known for its role in coordinating balance and choreographing complex movements, like walking or dancing. But there is much more to it than that.
“It’s a really complex area,” Huggins said. “If you look at how densely populated with neurons it is relative to the rest of the brain, it’s not that surprising that it does a lot more than balance and movement.”
Dense may be an understatement. The cerebellum makes up just 10% of the brain’s total volume but packs in more than half of the brain’s 86 billion nerve cells.
Researchers have recently observed changes to the size of the tightly-packed cerebellum in PTSD. Most of that research, however, is limited by either a small dataset (fewer than 100 participants), broad anatomical boundaries, or a sole focus on certain patient populations, such as veterans or sexual assault victims with PTSD.
To overcome those limitations, Duke’s Dr. Morey, along with over 40 other research groups that are part of a larger data-sharing initiative, pooled together their brain imaging scans to study PTSD as broadly and universally as possible.
The group ended up with images from 4,215 adult MRI scans, about a third of whom had been diagnosed with PTSD.
“I spent a lot of time looking at cerebellums,” Huggins said.
Even with automated software to analyze the thousands of brain scans, Huggins manually spot-checked every image to make sure the boundaries drawn around the cerebellum and its many subregions were accurate.
The result of this thorough methodology was a fairly simple and consistent finding: PTSD patients had cerebellums about 2% smaller. When Huggins zoomed in to specific areas within the cerebellum that influence emotion and memory, she found similar cerebellar reductions in people with PTSD. Huggins also discovered that the worse PTSD was for a person, the smaller their cerebellum was.
“Focusing purely on a yes-or-no categorical diagnosis doesn’t always give us the clearest picture,” Huggins said. “When we looked at PTSD severity, people who had more severe forms of the disorder had an even smaller cerebellar volume.”
The results are an important first step at looking at how and where PTSD affects the brain.
There are more than 600,000 combinations of symptoms that can lead to a PTSD diagnosis, Huggins explained. Figuring out if different PTSD symptom combinations have different impacts on the brain will also be important to keep in mind.
For now, though, Huggins hopes this work helps others recognize the cerebellum as an important driver of complex behavior and processes beyond gait and balance, as well as a potential target for new and current treatments for people with PTSD.
“While there are good treatments that work for people with PTSD, we know they don’t work for everyone,” Huggins said. “If we can better understand what’s going on in the brain, then we can try to incorporate that information to come up with more effective treatments that are longer lasting and work for more people.”
Estrogen Receptor β in the Lateral Septum Mediates Estrogen Regulation of Social Anxiety-like Behavior in Male Mice
by Kansuke Hasunuma, Tomoaki Murakawa, Satoshi Takenawa, Koshiro Mitsui, Tetsu Hatsukano, Kazuhiro Sano, Mariko Nakata, Sonoko Ogawa in Neuroscience
Researchers from the University of Tsukuba have discovered that estrogen receptor (ER) β, expressed in the lateral septum of the limbic system, plays a crucial role in suppressing anxiety-like behavior exhibited by male mice in social situations. They also discovered that the distribution and expression region of ERβ differs from that of ERα.
Estradiol (E2), a sex steroid hormone, plays an essential role in social behavior, including regulating social anxiety, which is anxiety experienced when unknown individuals are encountered.
In males, testosterone secreted by the testes is converted to E2 in the brain, and the E2 binds to two types of estrogen receptors (ERs), ERα and ERβ, to regulate social behavior.
However, its neuroendocrine basis has not been understood. In this study, the role of ERα and ERβ expressed in the lateral septum (LS), which regulates social anxiety, was investigated using male mice.
The researchers first investigated the expression of ERα and ERβ in LS using genetically modified male mice.
ERβ-expressing cells in the mice were labeled with red fluorescent protein, which revealed that the distributions of ERα and ERβ are different.
Furthermore, the researchers investigated the knockdown effects of ERα or ERβ gene expression in the LS of male mice during situations of social and nonsocial anxiety.
The results show that social anxiety increases with the inhibition of ERβ expression. Additionally, ERα- and ERβ-positive cells in the LS projected into different regions of the hypothalamus.
Thus, the researchers concluded that ERα- and ERβ-expressing cells in LS are distinct cell populations with different localizations and neuronal projections, and the ERβ population plays a crucial role in neural circuitry that regulates anxiety-like behavior in social situations.
Romantic Love and Behavioral Activation System Sensitivity to a Loved One
by Adam Bode, Phillip S. Kavanagh in Behavioral Sciences
Love is blind, the saying goes, and thanks to a world-first Australian study, we are now a step closer to understanding why.
It is well known that romantic love changes the brain, releasing the so-called love hormone oxytocin, responsible for the euphoria we feel when falling in love.
Now, researchers from the ANU, University of Canberra and University of South Australia have measured how a part of the brain is responsible for putting our loved one on a pedestal in that first flush of romance.
In the world’s first study investigating the link between the human brain’s behavioral activation system (BAS) and romantic love, researchers surveyed 1556 young adults who identified as being “in love.”
The survey questions focused on the emotional reaction to their partner, their behavior around them, and the focus they placed on their loved one above all else. It turns out that when we are in love, our brain reacts differently. It makes the object of our affections the centre of our lives.
ANU lead researcher and PhD student Adam Bode says the study — recently published in the journal Behavioural Sciences — sheds light on the mechanisms that cause romantic love.
“We actually know very little about the evolution of romantic love,” Bode says. “It is thought that romantic love first emerged some five million years ago after we split from our ancestors, the great apes. We know the ancient Greeks philosophized about it a lot, recognising it both as an amazing as well as traumatic experience. The oldest poem ever to be recovered was in fact a love poem dated to around 2000 BC.”
University of Canberra academic and UniSA Adjunct Associate Professor, Dr Phil Kavanagh, says the study shows that romantic love is linked to changes in behaviour as well as emotion.
“We know the role that oxytocin plays in romantic love, because we get waves of it circulating throughout our nervous system and blood stream when we interact with loved ones,” Dr Kavanagh says. “The way that loved ones take on special importance, however, is due to oxytocin combining with dopamine, a chemical that our brain releases during romantic love. Essentially, love activates pathways in the brain associated with positive feelings.”
The next stage of the research involves investigating the differences between men and women in their approach to love, and a worldwide survey identifying four different types of romantic lovers.
OXR1 maintains the retromer to delay brain aging under dietary restriction
by Kenneth A. Wilson, Sudipta Bar, Eric B. Dammer, Enrique M. Carrera, Brian A. Hodge, Tyler A. U. Hilsabeck, Joanna Bons, George W. Brownridge, Jennifer N. Beck, Jacob Rose, Melia Granath-Panelo, Christopher S. Nelson, Grace Qi, Akos A. Gerencser, Jianfeng Lan, Alexandra Afenjar, Geetanjali Chawla, Rachel B. Brem, Philippe M. Campeau, Hugo J. Bellen, Birgit Schilling, Nicholas T. Seyfried, Lisa M. Ellerby, Pankaj Kapahi in Nature Communications
Restricting calories is known to improve health and increase lifespan, but much of how it does so remains a mystery, especially in regard to how it protects the brain. Buck scientists have uncovered a role for a gene called OXR1 that is necessary for the lifespan extension seen with dietary restriction and is essential for healthy brain aging.
“When people restrict the amount of food that they eat, they typically think it might affect their digestive tract or fat buildup, but not necessarily about how it affects the brain,” said Kenneth Wilson, Ph.D., Buck postdoc and first author of the study, published online in Nature Communications. “As it turns out, this is a gene that is important in the brain.”
The team additionally demonstrated a detailed cellular mechanism of how dietary restriction can delay aging and slow the progression of neurodegenerative diseases.
The work, done in fruit flies and human cells, also identifies potential therapeutic targets to slow aging and age-related neurodegenerative diseases.
“We found a neuron-specific response that mediates the neuroprotection of dietary restriction,” said Buck Professor Pankaj Kapahi , Ph.D., co-senior author of the study. “Strategies such as intermittent fasting or caloric restriction, which limit nutrients, may enhance levels of this gene to mediate its protective effects.”
“The gene is an important brain resilience factor protecting against aging and neurological diseases,” said Buck Professor Lisa Ellerby, Ph.D., co-senior author of the study.
Members of the team have previously shown mechanisms that improve lifespan and healthspan with dietary restriction, but there is so much variability in response to reduced calories across individuals and different tissues that it is clear there are many yet-to-be-discovered processes in play.
This project was started to understand why different people respond to diets in different ways. The team began by scanning about 200 strains of flies with different genetic backgrounds. The flies were raised with two different diets, either with a normal diet or with dietary restriction, which was only 10% of normal nutrition. Researchers identified five genes which had specific variants that significantly affected longevity under dietary restriction. Of those, two had counterparts in human genetics.
The team chose one gene to explore thoroughly, called “mustard” (mtd) in fruit flies and “Oxidation Resistance 1” (OXR1) in humans and mice. The gene protects cells from oxidative damage, but the mechanism for how this gene functions was unclear. The loss of OXR1 in humans results in severe neurological defects and premature death. In mice, extra OXR1 improves survival in a model of amyotrophic lateral sclerosis (ALS). To figure out how a gene that is active in neurons affects overall lifespan, the team did a series of in-depth tests. They found that OXR1 affects a complex called the retromer, which is a set of proteins necessary for recycling cellular proteins and lipids.
“The retromer is an important mechanism in neurons because it determines the fate of all proteins that are brought into the cell,” said Wilson.
Retromer dysfunction has been associated with age-related neurodegenerative diseases that are protected by dietary restriction, specifically Alzheimer’s and Parkinson’s diseases.
Overall, their results told the story of how dietary restriction slows brain aging by the action of mtd/OXR1 in maintaining the retromer.
“This work shows that the retromer pathway, which is involved in reusing cellular proteins, has a key role in protecting neurons when nutrients are limited,” said Kapahi.
The team found that mtd/OXR1 preserves retromer function and is necessary for neuronal function, healthy brain aging, and lifespan extension seen with dietary restriction.
“Diet is influencing this gene. By eating less, you are actually enhancing this mechanism of proteins being sorted properly in your cells, because your cells are enhancing the expression of OXR1,” said Wilson.
The team also found that boosting mtd in flies caused them to live longer, leading researchers to speculate that in humans excess expression of OXR1 might help extend lifespan.
“Our next step is to identify specific compounds that increase the levels of OXR1 during aging to delay brain aging,” said Ellerby. “Hopefully from this we can get more of an idea of why our brains degenerate in the first place,” said Wilson. “Diet impacts all the processes in your body,” he said. “I think this work supports efforts to follow a healthy diet, because what you eat is going to affect more than you know.”
TMTC4 is a hair cell–specific human deafness gene
by Jiang Li, Byung Yoon Choi, Yasmin Eltawil, Noura Ismail Mohamad, Yesai Park, Ian R. Matthews, Jin Hee Han, Bong Jik Kim, Elliott H. Sherr, Dylan K. Chan in JCI Insight
Researchers have found a gene that links deafness to cell death in the inner ear in humans — creating new opportunities for averting hearing loss.
A person’s hearing can be damaged by loud noise, aging and even certain medications, with little recourse beyond a hearing aid or cochlear implant.
But now, UCSF scientists have achieved a breakthrough in understanding what is happening in the inner ear during hearing loss, laying the groundwork for preventing deafness.
The research links animal studies on hearing loss with a rare type of inherited deafness in humans. In both cases, mutations to the TMTC4 gene trigger a molecular domino effect known as the unfolded protein response (UPR), leading to the death of hair cells in the inner ear.
Intriguingly, hearing loss from loud noise exposure or drugs such as cisplatin, a common form of chemotherapy, also stems from activation of the UPR in hair cells, suggesting that the UPR may underly several different forms of deafness.
There are several drugs that block the UPR — and stop hearing loss — in laboratory animals. The new findings make a stronger case for testing these drugs in people who are at risk of losing their hearing, according to the researchers.
“Millions of American adults lose their hearing due to noise exposure or aging each year, but it’s been a mystery what was going wrong,” said Dylan Chan, MD, PhD, co-senior author on the paper and director of the Children’s Communication Center (CCC) in the UCSF Department of Otolaryngology. “We now have solid evidence that TMTC4 is a human deafness gene and that the UPR is a genuine target for preventing deafness.”
In 2014, Elliott Sherr, MD, PhD, director of the UCSF Brain Development Research Program and co-senior author of the paper, noticed that several of his young patients with brain malformations all had mutations to TMTC4. But laboratory studies of this gene soon presented a conundrum.
“We expected mice with TMTC4 mutations to have severe brain defects early on, like those pediatric patients, yet to our surprise, they seemed normal at first,” Sherr said. “But as those animals grew, we saw that they didn’t startle in response to loud noise. They had gone deaf after they had matured.”
Sherr partnered with Chan, an expert on the inner ear, to look into what was happening to the mice, which looked like an accelerated version of age-related hearing loss in humans. They showed that mutations to TMTC4 primed hair cells in the ear to self-destruct, and loud noise did the same thing. In both cases, hair cells were flooded with excess calcium, throwing off the balance of other cellular signals, including the UPR.
But they found there was a way to stop this. ISRIB, a drug developed at UCSF to block the UPR’s self-destruct mechanism in traumatic brain injury, prevented animals who were exposed to noise from going deaf.
In 2020, scientists from South Korea, led by Bong Jik Kim, MD, PhD, connected Chan and Sherr’s 2018 findings with genetic mutations they found in two siblings who were losing their hearing in their mid-20s. The mutations were in TMTC4 and matched what Chan and Sherr had seen in animals, although they were distinct from those in Sherr’s pediatric neurology patients.
“It’s rare to so quickly connect mouse studies with humans,” Sherr said. “Thanks to our Korean collaborators, we could more easily prove the relevance of our work for the many people who go deaf over time.”
Kim, an otolaryngologist at the Chungnam National University College of Medicine (Korea), facilitated the shipping of cells from those patients to UCSF. Sherr and Chan tested those cells for UPR activity and found that, indeed, this flavor of TMTC4 mutation turned on the destructive UPR pathway in a human context.
When Chan and Sherr mutated TMTC4 only in hair cells in mice, the mice went deaf. When they mutated TMTC4 in cells from individuals in the Korean family who hadn’t gone deaf, and in laboratory human cell lines, the UPR drove the cells to self-destruct. TMTC4 was more than a deafness gene in mice — it was a deafness gene in humans, too.
Understanding TMTC4 mutations gives researchers a new way of studying progressive deafness, since it is critical for maintaining the health of the adult inner ear. The mutations mimic damage from noise, aging or drugs like cisplatin.
The researchers envision a future where people who must take cisplatin, or who have to be exposed to loud noises for their jobs, take a drug that dampens the UPR and keeps hair cells from withering away, preserving their hearing.
The science also suggests that the UPR could be targeted in other contexts where nerve cells become overwhelmed and die, including diseases long thought to be incurable, like Alzheimer’s or Lou Gehrig’s disease.
“If there’s any way that we can get in the way of the hair cells dying, that’s how we’re going to be able to prevent hearing loss,” Chan said.
Ethanol’s interaction with BK channel α subunit residue K361 does not mediate behavioral responses to alcohol in mice
by Agbonlahor Okhuarobo, Max Kreifeldt, Pauravi J. Gandhi, Catherine Lopez, Briana Martinez, Kiera Fleck, Michal Bajo, Pushpita Bhattacharyya, Alex M. Dopico, Marisa Roberto, Amanda J. Roberts, Gregg E. Homanics, Candice Contet in Molecular Psychiatry,
Ethanol — the compound found in alcoholic beverages — interferes with the normal functioning of a long list of biological molecules, but how each of these interactions contributes to the behavioral effects of alcohol is not fully understood. A guiding, but elusive, goal of researchers is to identify the protein (or proteins) to which ethanol binds that makes some people vulnerable to excessive drinking. Solving this question would point the way to effective therapies for alcohol use disorder, which affects more than 10% of the U.S. adult population and is responsible for a myriad of health and societal issues.
Previous studies identified one such molecule, a protein widely expressed in the brain, called the BK channel.
Ethanol can directly interact with a component of BK channels, known as the α subunit, to facilitate their opening.
However, scientists at Scripps Research found that this interaction may not drive behaviors related to alcohol abuse as much as previously thought.
Their study, appearing in the journal Molecular Psychiatry demonstrates that preventing ethanol from interacting with the BK α subunit does not reduce or increase the motivation to consume alcohol in mice.
The relationship between the BK α subunit and ethanol had previously been explored in vitro, ex vivo and in live invertebrates.
Previous studies suggested that the BK α subunit was involved in an animal’s response to alcohol exposure, but there was a gap in understanding its role in mammals, particularly for the control of alcohol drinking.
“Knowing what a molecule does from in vitro experiments really doesn’t tell you much about what the behavioral consequences of that action might be,” says senior author Candice Contet, PhD, associate professor in the Department of Molecular Medicine at Scripps Research.
“Things get complicated in vivo, because there are many layers of modulation that may occur in a cell-type specific manner. Moreover, the initial effect often changes with repeated or prolonged exposure to alcohol. We thus sought to determine whether the ability of ethanol to alter BK channel activity was in any way influencing the motivation to drink alcohol.”
Tackling this question didn’t lend itself well to conventional pharmacological testing: blocking BK channels with a drug causes tremors, which then interfere with drinking behavior.
However, Contet’s collaborator Alex Dopico, MD, PhD, of the University of Tennessee, had identified a residue in the mouse BK α subunit that is required for ethanol to activate BK channels but is dispensable for normal BK channel activity, as shown in frog eggs.
In the new study, Contet and her colleagues leveraged this discovery to unlock the significance of ethanol’s interaction with BK channels for alcohol drinking in mice.
Accordingly, the team tested mice that had a mutation in this particular BK α subunit residue.
First, they found that the mutation prevented alcohol from altering the firing properties of neurons in the medial habenula, a brain region with high levels of BK channels, thereby demonstrating that it also confers resistance to ethanol in mouse brain cells, not just in frog eggs.
At the behavioral level, the mice harboring the mutation did not display any anomalies when compared to control littermates.
Notably, they exhibited the standard signs of intoxication upon alcohol injection, such as loss of balance and hypothermia, and they consumed the same amount of alcohol when tested under various conditions of moderate or excessive drinking.
“The lack of effect of the mutation was surprising, especially in light of our previous results showing that other BK channel subunits, β1 and β4, influence alcohol intake escalation in the same model of alcohol dependence,” says Contet. “However, these negative results, which were replicated in multiple cohorts and both sexes, are just as important as positive ones, because they encourage the field to study other targets rather than focusing on the wrong culprit.”
While the study does not point to a critical role of the BK α subunit in the motivation to drink alcohol or several physiological responses related to ethanol intoxication and withdrawal, the group will continue to explore whether the molecular target plays a role in other aspects of alcohol use disorder.
“Ethanol is highly pleiotropic. Beyond its reinforcing effects, it alters the functioning of multiple organs and cell types,” Contet says. “It is likely that ethanol’s interaction with BK channels contribute to some of these effects, but we’ve only explored the tip of the iceberg so far; the next challenge will be to find the right experimental readout.”
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