Scientists identify new brain circuit in mice that controls body's inflammatory reactions

The brain can direct the immune system to an unexpected degree, capable of detecting, ramping up and tamping down inflammation, shows a new study in mice from researchers at Columbia's Zuckerman Institute.

"The brain is the center of our thoughts, emotions, memories and feelings," said Hao Jin, PhD, a co-first author of the study published online today in Nature. "Thanks to great advances in circuit tracking and single-cell technology, we now know the brain does far more than that. It is monitoring the function of every system in the body."

Future research could identify drugs that can target this newfound brain circuit to help treat a vast range of disorders and diseases in which the immune system goes haywire.

"This new discovery could provide an exciting therapeutic venue to control inflammation and immunity," said Charles S. Zuker, PhD, the study's senior author, a principal investigator at Columbia's Zuckerman Institute and a Howard Hughes Medical Institute investigator.

Recent work from the Zuker lab and other groups is revealing the importance of the body-brain axis, a vital pathway that conveys data between the organs and the brain. For example, Dr. Zuker and his colleagues discovered that sugar and fat entering the gut use the body-brain axis to drive the craving and strong appetite for sugary and fatty foods.

"We found all these ways in which the body is informing the brain about the body's current state," said co-first author Mengtong Li, PhD, a postdoctoral researcher in the Zuker lab. "We wanted to understand how much farther the brain's knowledge and control of the body's biology went."

The scientists looked for connections the brain might have with inflammation and innate immunity, the defense system shared by all animals and the most ancient component of the immune system. Whereas the adaptive immune system remembers previous encounters with intruders to help it resist them if they invade again, the innate immune system attacks anything with common traits of germs. The relative simplicity of innate immunity lets it respond to new insults more quickly than adaptive immunity.

Prior studies in humans revealed that electrically stimulating the vagus nerve -- a bundle of thousands of nerve fibers linking the brain and the body's internal organs -- could reduce the response linked to a specific inflammatory molecule. However, much remained unknown about the nature of this body-brain system: for instance, the generality of the brain's modulation of immunity and the inflammatory response, the selective lines of communication between the body and the brain, the logic of the underlying neural circuit, and the identity of the vagal and brain components that monitor and regulate inflammation.

The Zuker lab turned to a bacterial compound that sets off innate immune responses. The scientists found that giving this molecule to mice activated the caudal nucleus of the solitary tract, or cNST, which is tucked inside the brainstem. The cNST plays a major role in the body-brain axis and is the primary target of the vagus nerve.

The scientists showed that chemically suppressing the cNST resulted in an out-of-control inflammatory response to the immune insult: levels of pro-inflammatory molecules released by the immune system were more than three times higher than usual, and levels of anti-inflammatory immune compounds were roughly three times lower than normal. In contrast, artificially activating the cNST reduced pro-inflammatory molecule levels by nearly 70 percent and increased anti-inflammatory chemical levels almost tenfold.

"Similar to a thermostat, this newfound brain circuit helps increase or decrease inflammatory responses to keep the body responding in a healthy manner," said Dr. Jin, who started this study as a postdoctoral researcher in Dr. Zuker's lab. Dr. Jin is now a tenure track investigator at the National Institute of Allergy and Infectious Diseases. "In retrospect, it makes sense to have a master arbiter controlling this vital response."

Previous vagus nerve stimulation research in humans suggests the findings go beyond mice. The new research may also be in line with thousands of years of thought on the potential importance of the mind on the body.

"A lot of psychosomatic effects could actually be linked to brain circuits telling your body something," Dr. Jin noted.

The scientists identified the specific groups of neurons in the vagus nerve and in the cNST that help detect and control pro- and anti-inflammatory activity. "This opens up a new window into how the brain monitors and modulates body physiology," said Dr. Zuker, a professor of biochemistry, molecular biophysics and neuroscience at Columbia's Vagelos College of Physicians and Surgeons.

Discovering ways to control this newfound brain circuit may lead to novel therapies for common auto-immune diseases such as rheumatoid arthritis, type I diabetes, multiple sclerosis, neurodegenerative diseases, lupus, inflammatory bowel disease and Crohn's disease, as well as conditions such as long COVID syndrome, immune rejection of transplanted organs, and the potentially deadly outbursts known as cytokine storms that COVID infections can trigger.

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Illusion helps demystify the way vision works

For the first time, research shows that a certain kind of visual illusion, neon color spreading, works on mice. The study is also the first to combine the use of two investigative techniques called electrophysiology and optogenetics to study this illusion. Results from experiments on mice settle a long-standing debate in neuroscience about which levels of neurons within the brain are responsible for the perception of brightness.

We're all familiar with optical illusions; some are novelties, while some are all around us. Even as you look at the screen in front you, you are being fooled into thinking that you're seeing the color white. What you're really seeing is lots of red, green and blue elements packed so tightly together it gives the impression of being white. Another example is a fast rotating wheel or propeller, which can briefly look like it's reversing direction while it's accelerating to full speed. In any case, it might be surprising to know that optical illusions are not just fun to look at but can also be a useful tool to learn more about eyes, nerves, minds and brains.

Associate Professor Masataka Watanabe from the Department of Systems Innovation at the University of Tokyo is on a mission to understand more about the nature of consciousness. It's a vast subject area so naturally there are many ways to explore it, and amongst other things, he uses optical illusions. His most recent research looked at whether a certain kind of illusion that works on humans would also work on mice. And it turns out, it does. But why is this significant?

"Knowing this kind of illusion, called a neon-color-spreading illusion, works on mice as well as humans, is useful for neuroscientists like myself, as it means that mice can serve as useful test subjects for cases where humans cannot," said Watanabe. "To really understand what goes on inside the brain during perceptual experiences, we need to use certain methods that we cannot use on people. These include electrophysiology, the recording of neural activity with electrodes, and optogenetics, where light pulses enable or disable firing of specific neurons in a living brain."

Watanabe's experiment was the first of its kind to make use of both electrophysiology and optogenetics at the same time in animal test subjects exposed to the neon-color-spreading illusion, which allowed his team to see precisely what structures within the brain are responsible for processing the illusion.

"After a visual stimulus lands on the eye, it's carried to the brain by nerves and is then received by a series of layers of neurons called V1, V2 and so on, where V1 is the first and most basic layer, and V2 and above are considered higher layers," said Watanabe. "There is a long-standing debate in neuroscience about the role higher levels play in the perception of brightness and it was not an easy thing to study. Our experiment on mice has shown us that neurons in V1 responded not just to the illusion, but also to a nonillusory version of the same kind of pattern shown. But only when the illusory version was shown to the mice did neurons in V2 also play a crucial role: that of modulating the activity of neurons in V1, thus proving that V2 neurons do in fact play a role in the perception of brightness."

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The fountain of youth is ... a T cell?

The fountain of youth has eluded explorers for ages. It turns out the magic anti-aging elixir might have been inside us all along.

Cold Spring Harbor Laboratory (CSHL) Assistant Professor Corina Amor Vegas and colleagues have discovered that T cells can be reprogrammed to fight aging, so to speak.

Given the right set of genetic modifications, these white blood cells can attack another group of cells known as senescent cells.

These cells are thought to be responsible for many of the diseases we grapple with later in life.

Senescent cells are those that stop replicating. As we age, they build up in our bodies, resulting in harmful inflammation.

While several drugs currently exist that can eliminate these cells, many must be taken repeatedly over time.

As an alternative, Amor Vegas and colleagues turned to a "living" drug called CAR (chimeric antigen receptor) T cells.

They discovered CAR T cells could be manipulated to eliminate senescent cells in mice.

As a result, the mice ended up living healthier lives. They had lower body weight, improved metabolism and glucose tolerance, and increased physical activity.

All benefits came without any tissue damage or toxicity.

"If we give it to aged mice, they rejuvenate. If we give it to young mice, they age slower. No other therapy right now can do this, " says Amor Vegas.

Perhaps the greatest power of CAR T cells is their longevity.

The team found that just one dose at a young age can have lifelong effects.

That single treatment can protect against conditions that commonly occur later in life, like obesity and diabetes.

"T cells have the ability to develop memory and persist in your body for really long periods, which is very different from a chemical drug, " explains Amor Vegas.

"With CAR T cells, you have the potential of getting this one treatment, and then that's it. For chronic pathologies, that's a huge advantage. Think about patients who need treatment multiple times per day versus you get an infusion, and then you're good to go for multiple years."

CAR T cells have been used to treat a variety of blood cancers, receiving FDA approval for this purpose in 2017.

But Amor Vegas is one of the first scientists to show that CAR T cells' medical potential goes even further than cancer.

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Amnesia caused by head injury reversed in early mouse study

A mouse study designed to shed light on memory loss in people who experience repeated head impacts, such as athletes, suggests the condition could potentially be reversed. The research in mice finds that amnesia and poor memory following head injury is due to inadequate reactivation of neurons involved in forming memories.

The study, conducted by researchers at Georgetown University Medical Center in collaboration with Trinity College Dublin, Ireland, is reported January 16, 2024, in the Journal of Neuroscience.

Importantly for diagnostic and treatment purposes, the researchers found that the memory loss attributed to head injury was not a permanent pathological event driven by a neurodegenerative disease.

Indeed, the researchers could reverse the amnesia to allow the mice to recall the lost memory, potentially allowing cognitive impairment caused by head impact to be clinically reversed.

The Georgetown investigators had previously found that the brain adapts to repeated head impacts by changing the way the synapses in the brain operate.

This can cause trouble in forming new memories and remembering existing memories.

In their new study, investigators were able to trigger mice to remember memories that had been forgotten due to head impacts.

"Our research gives us hope that we can design treatments to return the head-impact brain to its normal condition and recover cognitive function in humans that have poor memory caused by repeated head impacts," says the study's senior investigator, Mark Burns, PhD, a professor and Vice-Chair in Georgetown's Department of Neuroscience and director of the Laboratory for Brain Injury and Dementia.

In the new study, the scientists gave two groups of mice a new memory by training them in a test they had never seen before.

One group was exposed to a high frequency of mild head impacts for one week (similar to contact sport exposure in people) and one group were controls that didn't receive the impacts.

The impacted mice were unable to recall the new memory a week later.

"Most research in this area has been in human brains with chronic traumatic encephalopathy (CTE), which is a degenerative brain disease found in people with a history of repetitive head impact," said Burns.

"By contrast, our goal was to understand how the brain changes in response to the low-level head impacts that many young football players regularly experience."

Researchers have found that, on average, college football players receive 21 head impacts per week with defensive ends receiving 41 head impacts per week.

The number of head impacts to mice in this study were designed to mimic a week of exposure for a college football player, and each single head impact by itself was extraordinarily mild.

Using genetically modified mice allowed the researchers to see the neurons involved in learning new memories, and they found that these memory neurons (the "memory engram") were equally present in both the control mice and the experimental mice.

To understand the physiology underlying these memory changes, the study's first author, Daniel P. Chapman, Ph.D., said, "We are good at associating memories with places, and that's because being in a place, or seeing a photo of a place, causes a reactivation of our memory engrams. This is why we examined the engram neurons to look for the specific signature of an activated neuron. When the mice see the room where they first learned the memory, the control mice are able to activate their memory engram, but the head impact mice were not. This is what was causing the amnesia."

The researchers were able to reverse the amnesia to allow the mice to remember the lost memory using lasers to activate the engram cells.

"We used an invasive technique to reverse memory loss in our mice, and unfortunately this is not translatable to humans," Burns adds.

"We are currently studying a number of non-invasive techniques to try to communicate to the brain that it is no longer in danger, and to open a window of plasticity that can reset the brain to its former state."

Read more at Science Daily

What happens in the brain while daydreaming?

You are sitting quietly, and suddenly your brain tunes out the world and wanders to something else entirely -- perhaps a recent experience, or an old memory. You just had a daydream.

Yet despite the ubiquity of this experience, what is happening in the brain while daydreaming is a question that has largely eluded neuroscientists.

Now, a study in mice, published Dec. 13 in Nature, has brought a team led by researchers at Harvard Medical School one step closer to figuring it out.

The researchers tracked the activity of neurons in the visual cortex of the brains of mice while the animals remained in a quiet waking state. They found that occasionally these neurons fired in a pattern similar to one that occurred when a mouse looked at an actual image, suggesting that the mouse was thinking -- or daydreaming -- about the image. Moreover, the patterns of activity during a mouse's first few daydreams of the day predicted how the brain's response to the image would change over time.

The research provides tantalizing, if preliminary, evidence that daydreams can shape the brain's future response to what it sees. This causal relationship needs to be confirmed in further research, the team cautioned, but the results offer an intriguing clue that daydreams during quiet waking may play a role in brain plasticity -- the brain's ability to remodel itself in response to new experiences.

"We wanted to know how this daydreaming process occurred on a neurobiological level, and whether these moments of quiet reflection could be important for learning and memory," said lead author Nghia Nguyen, a PhD student in neurobiology in the Blavatnik Institute at HMS.

An overlooked brain region

Scientists have spent considerable time studying how neurons replay past events to form memories and map the physical environment in the hippocampus, a seahorse-shaped brain region that plays a key role in memory and spatial navigation.

By contrast, there has been little research on the replay of neurons in other brain regions, including the visual cortex. Such efforts would provide valuable insights about how visual memories are formed.

"My lab became interested in whether we could record from enough neurons in the visual cortex to understand what exactly the mouse is remembering -- and then connect that information to brain plasticity," said senior author Mark Andermann, professor of medicine at Beth Israel Deaconess Medical Center, and professor of neurobiology at HMS.

In the new study, the researchers repeatedly showed mice one of two images, each consisting of a different checkerboard pattern of gray and dappled black and white squares. Between images, the mice spent a minute looking at a gray screen. The team simultaneously recorded activity from around 7,000 neurons in the visual cortex.

The researchers found that when a mouse looked at an image, the neurons fired in a specific pattern, and the patterns were different enough to discern image one from image two. More important, when a mouse looked at the gray screen between images, the neurons sometimes fired in a similar, but not identical, pattern, as when the mouse looked at the image, a sign that it was daydreaming about the image. These daydreams occurred only when mice were relaxed, characterized by calm behavior and small pupils.

Unsurprisingly, mice daydreamed more about the most recent image -- and they had more daydreams at the beginning of the day than at the end, when they had already seen each image dozens of times.

But what the researchers found next was completely unexpected.

Throughout the day, and across days, the activity patterns seen when the mice looked at the images changed -- what neuroscientists call "representational drift." Yet this drift wasn't random. Over time, the patterns associated with the images became even more different from each other, until each involved an almost entirely separate set of neurons. Notably, the pattern seen during a mouse's first few daydreams about an image predicted what the pattern would become when the mouse looked at the image later.

"There's drift in how the brain responds to the same image over time, and these early daydreams can predict where the drift is going," Andermann said.

Finally, the researchers found that the visual cortex daydreams occurred at the same time as replay activity occurred in the hippocampus, suggesting that the two brain regions were communicating during these daydreams.

To sit, perchance to daydream

Based on the results of the study, the researchers suspect that these daydreams may be actively involved in brain plasticity.

"When you see two different images many times, it becomes important to discriminate between them. Our findings suggest that daydreaming may guide this process by steering the neural patterns associated with the two images away from each other," Nguyen said, while noting that this relationship needs to be confirmed.

Nguyen added that learning to differentiate between the images should help the mouse respond to each image with more specificity in the future.

These observations align with a growing body of evidence in rodents and humans that entering a state of quiet wakefulness after an experience can improve learning and memory.

Next, the researchers plan to use their imaging tools to visualize the connections between individual neurons in the visual cortex and to examine how these connections change when the brain "sees" an image.

"We were chasing this 99 percent of unexplored brain activity and discovered that there's so much richness in the visual cortex that nobody knew anything about," Andermann said.

Whether daydreams in people involve similar activity patterns in the visual cortex is an open question, and the answer will require additional experiments. However, there is preliminary evidence that an analogous process occurs in humans when they recall visual imagery.

Randy Buckner, the Sosland Family Professor of Psychology and of Neuroscience at Harvard University, has shown that brain activity in the visual cortex increases when people are asked to recall an image in detail. Other studies have recorded flurries of electrical activity in the visual cortex and the hippocampus during such recall.

For the researchers, the results of their study and others suggest that it may be important to make space for moments of quiet waking that lead to daydreams. For a mouse, this may mean taking a pause from looking at a series of images and, for a human, this could mean taking a break from scrolling on a smartphone.

"We feel pretty confident that if you never give yourself any awake downtime, you're not going to have as many of these daydream events, which may be important for brain plasticity," Andermann said.

Read more at Science Daily

First mice engineered to survive COVID-19 like young, healthy humans

Researchers have genetically engineered the first mice that get a human-like form of COVID-19, according to a study published online November 1in Nature.

Led by researchers from NYU Grossman School of Medicine, the new work created lab mice with human genetic material for ACE2 -- a protein snagged by the pandemic virus so it can attach to human cells as part of the infection. The mice with this genetic change developed symptoms similar to young humans infected with the virus causing COVID-19, instead of dying upon infection as had occurred with prior mouse models.

"That these mice survive creates the first animal model that mimics the form of COVID-19 seen in most people -- down to the immune system cells activated and comparable symptoms," said senior study author Jef Boeke, the Sol and Judith Bergstein Director of the Institute for Systems Genetics at NYU Langone Health. "This has been a major missing piece in efforts to develop new drugs against this virus."

"Given that mice have been the lead genetic model for decades," added Boeke, "there are thousands of existing mouse lines that can now be crossbred with our humanized ACE2 mice to study how the body reacts differently to the virus in patients with diabetes or obesity, or as people age."

Problem of Large DNA

The new study revolves around a new method to edit DNA, the 3 billion "letters" of the genetic code that serve as instructions for building our cells and bodies.

While famous techniques like CRISPR enable the editing of DNA editing just one or a few letters at a time, some challenges require changes throughout genes that can be up to 2 million letters long. In such cases, it may be more efficient to build DNA from scratch, with far-flung changes made in large swaths of code pre-assembled and then swapped into a cell in place of its natural counterpart. Because human genes are so complex, Boeke's lab first developed its "genome writing" approach in yeast, one-celled fungi that share many features with human cells but that are simpler and easier to study.

More recently, Boeke's team adapted their yeast techniques to the mammalian genetic code, which is made up of not just of genes that encode proteins, but also of many switches that turn on different genes at different levels in different cell types. By studying this poorly understood "dark matter" that regulates genes, the research team was able to design living mice with cells that had more human-like levels of ACE gene activity for the first time. The study authors used yeast cells to assemble DNA sequences of up to 200,000 letters in a single step, and then delivered these "naked" DNAs into mouse embryonic stem cells using their new delivery method, mSwAP-In.

Overcoming the size limits of past methods, mSwAP-In delivered a humanized mouse model of COVID-19 pathology by "overwriting" 72 kilobases (kb) of mouse Ace2 code with 180 kb of the human ACE2 gene and its regulatory DNA.

To accomplish this cross-species swap, the study method cut into a key spot in the DNA code around the natural gene, swapped in a synthetic counterpart in steps, and with each addition, added a quality control mechanism so that only cells with the synthetic gene survived. The research team then worked with Sang Yong Kim at NYU's Rodent Genome Engineering Lab using a stem cell technique called "tetraploid complementation" to create a living mouse whose cells included the overwritten genes.

In addition, the researchers had previously designed a synthetic version of the gene Trp53, the mouse version of the human gene TP53, and swapped it into mouse cells. The protein encoded by this gene coordinates the cell's response to damaged DNA, and can even instruct cells containing it to die to prevent the build-up of cancerous cells. When this "guardian of the genome" itself becomes faulty, it is a major contributor to human cancers.

Whereas the ACE2 experiments had swapped in an unchanged version of a human gene, the synthetic, swapped-in Trp53 gene had been designed to no longer include a combination of molecular code letters -- cytosine (C) next to guanine (G) -- known to be vulnerable to random, cancer-causing changes. The researchers overwrote key CG "hotspots" with code containing a different DNA letter in adenine (A).

"The AG switch left the gene's function intact, but lessened its vulnerability to mutation, with the swap predicted to lead to a 10-to-50 fold lower mutation rate," said first author Weimin Zhang, PhD, a post-doctoral scholar in Boeke's lab. "Our goal is to demonstrate in a living test animal that this swap leads to fewer mutations and fewer resulting tumors, and those experiments are being planned."

Read more at Science Daily

Mummified mice discovered atop sky-high Andean volcanoes

They were the summits of 20,000-foot volcanoes. Amid the driest desert on Earth. Where temperatures never breached freezing, where less than half of sea-level oxygen quenched lungs, where gale-force winds scoured the hardscrabble rocks littering the peaks.

So when archaeologists first reported stumbling across a few mouse cadavers during expeditions to several Andean peaks in the 1970s and '80s, they figured, naturally, that the rodents must have hitched a ride with the Incas who once pilgrimaged a thousand-plus miles to what they considered sacred sites.

Those apexes served as altars for Capacocha, the ritual sacrifice of children to several Incan gods. Maybe, the thinking went, the mice had scurried into firewood or other supplies hauled up the slopes by the Incas. Or they were among the animal sacrifices that sometimes accompanied the human.

"You can't fault the archaeologists for thinking this way, because what other explanation is there?" said Jay Storz, a Willa Cather Professor of biological sciences at the University of Nebraska-Lincoln. "Nothing could be living up there, so they had to have been brought there."

But Storz would inadvertently cast doubt on the hypothesis in early 2020. Alongside friend and fellow mountaineer Mario Pérez Mamani, he captured a live specimen of leaf-eared mouse atop the 22,000-foot peak of Llullaillaco (zhoo-zhuh-ZHEYE'-koh), a volcano straddling the Chile-Argentina border. No mammal had ever been found living at such extreme altitude.

Alongside the capture of more live specimens, Storz and his colleagues have now reported the discovery of 13 leaf-eared mouse cadavers across the summits of three neighboring volcanoes -- Salín, Púlar and Copiapó -- that each stretch nearly 4 miles above sea level.

"These are basically freeze-dried, mummified mice," Storz said.

Analyzing the baker's dozen of mummies has only reinforced the team's conviction that the seemingly modest mice ascended the volcanoes without Incan assistance. By measuring concentrations of carbon-14, an atom that decays at a known rate, the team determined that the eight mummies atop Salín and one on Copiapó died no more than a few decades ago, likely after 1955. The four mummies on Púlar perished, at most, 350 years ago -- a full century after the last of the Incan empire fell to Spanish invaders.

"It now seems more and more clear," Storz said, "that the mice got there of their own accord."

The mummified state of the mice also helped preserve their DNA, allowing Storz's collaborators from the University of Montana to compare genetic variation among leaf-eared mice collected in the lowlands, midlands and highlands of Atacama Desert. Analyzing that variation across members of a species can help trace the evolutionary history of populations separated by distance, barriers or, in this case, altitude.

Storz and his colleagues wondered whether the genomes of the skyscraping, mummified mice might represent a distinct subpopulation of the leaf-eared rodent -- one with a colonization history different from that of their lower-dwelling peers.

"Our genomic data indicate no: that the mice from the summits, and those from the flanks or the base of the volcanoes in the surrounding desert terrain, are all one big happy family," Storz said, citing it as more evidence that the mummies were not hitchhikers but mountaineers.

In fact, the team found that two pairs of the leaf-eared mummies on Salín were closely related, possibly siblings or parents and offspring. And it noted another telltale: the equal ratio of males to females among the mummies. Combined with the recent discovery of other live specimens and mouse burrows in the heights of the Puna de Atacama, or Atacama Plateau, Storz said it seems that the leaf-eared mouse is not just touring the volcanic summits, but somehow living on them.

"It's exactly what you'd expect," he said, "if you were to capture a set of mice from some localized area in an environment that's habitable."

Which is bewildering, Storz said, given that the Puna de Atacama ranks among the most inhospitable locales on the planet -- one so arid, cold and oxygen-poor that NASA has visited the Atacama to practice searching for life on Mars.

"Even at the base of the volcanoes, the mice are living in an extreme, Martian environment," he said. "And then, on the summits of the volcanoes, it's even more so. It feels like outer space.

"It just boggles the mind that any kind of animal, let alone a warm-blooded mammal, could be surviving and functioning in that environment. When you experience it all firsthand, it even further impresses upon you: How in God's name is anything living up there?"

It's one of a few questions that the researchers are continuing to pursue. Members of Storz's lab and colleagues in Santiago, Chile, have since established colonies of leaf-eared mice collected from various altitudes. By acclimating each group to conditions that simulate the Puna de Atacama at 20,000 feet, the researchers hope to pinpoint whatever physiological adaptations are helping the rodents cope.

Even more fundamental is the question of what would drive the mice to such heights in the first place. Like most small rodents, the leaf-eared mouse -- which grows to about 2 ounces -- spends a fair amount of its time, energy and attention avoiding predators. And even in the Puna de Atacama, those predators are numerous: foxes, mountain lions, smaller cats, birds of prey.

Could the dangers imposed by the Atacama summits -- the near-absence of water, the seeming lack of food, the threat of freezing to death -- really be worth the promise of escaping predation all together?

"Certainly, if you're hunkering down on top of a 6,000-meter volcano, you're at least safe from that," Storz said. "You just have other things to worry about.

Read more at Science Daily

Jellyfish, with no central brain, shown to learn from past experience

Even without a central brain, jellyfish can learn from past experiences like humans, mice, and flies, scientists report for the first time on September 22 in the journal Current Biology. They trained Caribbean box jellyfish (Tripedalia cystophora) to learn to spot and dodge obstacles. The study challenges previous notions that advanced learning requires a centralized brain and sheds light on the evolutionary roots of learning and memory.

No bigger than a fingernail, these seemingly simple jellies have a complex visual system with 24 eyes embedded in their bell-like body. Living in mangrove swamps, the animal uses its vision to steer through murky waters and swerve around underwater tree roots to snare prey. Scientists demonstrated that the jellies could acquire the ability to avoid obstacles through associative learning, a process through which organisms form mental connections between sensory stimulations and behaviors.

"Learning is the pinnacle performance for nervous systems," says first author Jan Bielecki of Kiel University, Germany. To successfully teach jellyfish a new trick, he says "it's best to leverage its natural behaviors, something that makes sense to the animal, so it reaches its full potential."

The team dressed a round tank with gray and white stripes to simulate the jellyfish's natural habitat, with gray stripes mimicking mangrove roots that would appear distant. They observed the jellyfish in the tank for 7.5 minutes. Initially, the jelly swam close to these seemingly far stripes and bumped into them frequently. But by the end of the experiment, the jelly increased its average distance to the wall by about 50%, quadrupled the number of successful pivots to avoid collision and cut its contact with the wall by half. The findings suggest that jellyfish can learn from experience through visual and mechanical stimuli.

"If you want to understand complex structures, it's always good to start as simple as you can," says senior author Anders Garm of the University of Copenhagen, Denmark. "Looking at these relatively simple nervous systems in jellyfish, we have a much higher chance of understanding all the details and how it comes together to perform behaviors."

The researchers then sought to identify the underlying process of jellyfish's associative learning by isolating the animal's visual sensory centers called rhopalia. Each of these structures houses six eyes and generates pacemaker signals that govern the jellyfish's pulsing motion, which spikes in frequency when the animal swerves from obstacles.

The team showed the stationary rhopalium moving gray bars to mimic the animal's approach to objects. The structure did not respond to light gray bars, interpreting them as distant. However, after the researchers trained the rhopalium with weak electric stimulation when the bars approach, it started generating obstacle-dodging signals in response to the light gray bars. These electric stimulations mimicked the mechanical stimuli of a collision. The findings further showed that combining visual and mechanical stimuli is required for associative learning in jellyfish and that the rhopalium serves as a learning center.

Next, the team plans to dive deeper into the cellular interactions of jellyfish nervous systems to tease apart memory formation. They also plan to further understand how the mechanical sensor in the bell works to paint a complete picture of the animal's associative learning.

Read more at Science Daily

Scientists regenerate neurons that restore walking in mice after paralysis from spinal cord injury

In a new study in mice, a team of researchers from UCLA, the Swiss Federal Institute of Technology, and Harvard University have uncovered a crucial component for restoring functional activity after spinal cord injury. The neuroscientists have shown that re-growing specific neurons back to their natural target regions led to recovery, while random regrowth was not effective.

In a 2018 study published in Nature, the team identified a treatment approach that triggers axons -- the tiny fibers that link nerve cells and enable them to communicate -- to regrow after spinal cord injury in rodents. But even as that approach successfully led to the regeneration of axons across severe spinal cord lesions, achieving functional recovery remained a significant challenge.

For the new study, published this week in Science, the team aimed to determine whether directing the regeneration of axons from specific neuronal subpopulations to their natural target regions could lead to meaningful functional restoration after spinal cord injury in mice. They first used advanced genetic analysis to identify nerve cell groups that enable walking improvement after a partial spinal cord injury.

The researchers then found that merely regenerating axons from these nerve cells across the spinal cord lesion without specific guidance had no impact on functional recovery. However, when the strategy was refined to include using chemical signals to attract and guide the regeneration of these axons to their natural target region in the lumbar spinal cord, significant improvements in walking ability were observed in a mouse model of complete spinal cord injury.

"Our study provides crucial insights into the intricacies of axon regeneration and requirements for functional recovery after spinal cord injuries," said Michael Sofroniew, MD, PhD, professor of neurobiology at the David Geffen School of Medicine at UCLA and a senior author of the new study. "It highlights the necessity of not only regenerating axons across lesions but also of actively guiding them to reach their natural target regions to achieve meaningful neurological restoration."

The authors say understanding that re-establishing the projections of specific neuronal subpopulations to their natural target regions holds significant promise for the development of therapies aimed at restoring neurological functions in larger animals and humans. However, the researchers also acknowledge the complexity of promoting regeneration over longer distances in non-rodents, necessitating strategies with intricate spatial and temporal features. Still, they conclude that applying the principles laid out in their work "will unlock the framework to achieve meaningful repair of the injured spinal cord and may expedite repair after other forms of central nervous system injury and disease."

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Longevity gene from naked mole rats extends lifespan of mice

In a groundbreaking endeavor, researchers at the University of Rochester have successfully transferred a longevity gene from naked mole rats to mice, resulting in improved health and an extension of the mouse's lifespan.

Naked mole rats, known for their long lifespans and exceptional resistance to age-related diseases, have long captured the attention of the scientific community. By introducing a specific gene responsible for enhanced cellular repair and protection into mice, the Rochester researchers have opened exciting possibilities for unlocking the secrets of aging and extending human lifespan.

"Our study provides a proof of principle that unique longevity mechanisms that evolved in long-lived mammalian species can be exported to improve the lifespans of other mammals," says Vera Gorbunova, the Doris Johns Cherry Professor of biology and medicine at Rochester. Gorbunova, along with Andrei Seluanov, a professor of biology, and their colleagues, report in a study published in Nature that they successfully transferred a gene responsible for making high molecular weight hyaluronic acid (HMW-HA) from a naked mole rat to mice. This led to improved health and an approximate 4.4 percent increase in median lifespan for the mice.

A unique mechanism for cancer resistance

Naked mole rats are mouse-sized rodents that have exceptional longevity for rodents of their size; they can live up to 41 years, nearly ten times as long as similar-size rodents. Unlike many other species, naked mole rats do not often contract diseases -- including neurodegeneration, cardiovascular disease, arthritis, and cancer -- as they age. Gorbunova and Seluanov have devoted decades of research to understanding the unique mechanisms that naked mole rats use to protect themselves against aging and diseases.

The researchers previously discovered that HMW-HA is one mechanism responsible for naked mole rats' unusual resistance to cancer. Compared to mice and humans, naked mole rats have about ten times more HMW-HA in their bodies. When the researchers removed HMW-HA from naked mole rat cells, the cells were more likely to form tumors.

Gorbunova, Seluanov, and their colleagues wanted to see if the positive effects of HMW-HA could also be reproduced in other animals.

Transferring a gene that produces HMW-HA

The team genetically modified a mouse model to produce the naked mole rat version of the hyaluronan synthase 2 gene, which is the gene responsible for making a protein that produces HMW-HA. While all mammals have the hyaluronan synthase 2 gene, the naked mole rat version seems to be enhanced to drive stronger gene expression.

The researchers found that the mice that had the naked mole rat version of the gene had better protection against both spontaneous tumors and chemically induced skin cancer. The mice also had improved overall health and lived longer compared to regular mice. As the mice with the naked mole rat version of the gene aged, they had less inflammation in different parts of their bodies -- inflammation being a hallmark of aging -- and maintained a healthier gut.

While more research is needed on exactly why HMW-HA has such beneficial effects, the researchers believe it is due to HMW-HA's ability to directly regulate the immune system.

A fountain of youth for humans?

The findings open new possibilities for exploring how HMW-HA could also be used to improve lifespan and reduce inflammation-related diseases in humans.

"It took us 10 years from the discovery of HMW-HA in the naked mole rat to showing that HMW-HA improves health in mice," Gorbunova says. "Our next goal is to transfer this benefit to humans."

They believe they can accomplish this through two routes: either by slowing down degradation of HMW-HA or by enhancing HMW-HA synthesis.

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How tasty is the food?

To know when it's time for a meal -- and when to stop eating again -- is important to survive and to stay healthy, for humans and animals alike. Researchers at the Max Planck Institute for Biological Intelligence investigated how the brain regulates feeding behavior in mice. The team found that the hormone ghrelin activates specialized nerve cells in a brain region known as the amygdala. Here, the interaction between ghrelin and the specialized neurons promotes food consumption and conveys hunger and the pleasant and rewarding feelings associated with eating.

Hunger is a powerful sensation with important biological underpinnings. It signals the body to look for food, which is a crucial behavior to prevent starvation and ensure survival. When we're hungry, we crave for food -- and when we finally get to eat, our body rewards us with pleasant feelings and a general state of happiness.

A network of brain circuits and signaling pathways orchestrates the eating behavior of humans and animals and elicits the associated sensations. One of the central players in this network is the hormone ghrelin. It is released by stomach cells when humans and animals are hungry or fasting, and promotes feeding behavior.

The department of Rüdiger Klein at the Max Planck Institute for Biological Intelligence studies the brain networks that underly feeding behavior in mice. To this end, the researchers conducted a thorough analysis of the different cell types in a brain region known as the central amygdala. "Previously, the amygdala had mostly been studied in the context of feelings like fear and reward, while the regulation of feeding was thought to happen in different parts of the brain, such as the hypothalamus," says Christian Peters, a postdoctoral researcher in the department.

Nine cell clusters

Peters and his colleagues analyzed individual cells in the central amygdala, studying messenger RNA molecules -- the cell's working copies of their genes. The analysis revealed that the cells are organized into nine different cell clusters. Some of these clusters promote appetite while others inhibit it, and they adjust their production of messenger RNAs when the mice are fed or fasting.

"We now have a much better understanding of the diversity of cell types and the physiological processes that promote feeding in the central amygdala," says Rüdiger Klein. "Our research uncovers for the first time that the 'hunger hormone' ghrelin also acts on cells in the central amygdala." There, it activates a small subset of cell clusters, collectively marked by the presence of the protein Htr2a, to increase feeding.

Multiple functions for ghrelin

The scientists found that the Htr2a neurons became active after an overnight fast or when stimulated by the hormone ghrelin. The cells also responded when the researchers presented food to the mice. "We think that ghrelin performs multiple functions," explains Christian Peters. "When mice are hungry, ghrelin activates the appetitive brain regions to predispose the animals for eating. In addition, the hormone enhances the activity in brain circuits, such as the amygdala, that confer rewards, which is likely an incentive to eat additional food." This way, ghrelin increases the palatability of food in proportion to how satiated the mice currently are.

After a fasting diet, when the animals were very hungry the activity of Htr2a neurons was not needed to start feeding, presumably because the tastiness of food is less important under these conditions. "Other brain circuits, for example the hypothalamus, which regulate the body's metabolism, take over and signal the mice that it's important to eat in order to survive," says Christian Peters.

Feeling hungry or satiated has profound impacts on physical but also on emotional wellbeing, as probably everyone knows by the pleasures associated with eating tasty food. "The neuronal networks that convey these feelings are obviously linked to those that control eating, yet it is not fully understood how exactly they influence each other," says Rüdiger Klein.

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Move over, armadillos: There's a new bone-plated mammal in town

Mammals are a bit odd when it comes to bones. Rather than the bony plates and scales of crocodiles, turtles, lizards, dinosaurs and fish, mammals long ago traded in their ancestral suit of armor for a layer of insulating hair.

Armadillos, with their protective and flexible shell of imbricated bone, are considered the only living exception. But a new study, published in the journal iScience, unexpectedly shows that African spiny mice produce the same structures beneath the skin of their tails, which until now had gone largely undetected.

The discovery was made during routine CT scanning of museum specimens for the openVertebrate program, an initiative to provide 3D models of vertebrate organisms for researchers, educators and artists.

"I was scanning a mouse specimen from the Yale Peabody Museum, and the tails looked abnormally dark," said co-author Edward Stanley, director of the Florida Museum of Natural History's digital imaging laboratory.

He initially assumed the discoloration was caused by an imperfection introduced during the specimen's preservation. But when he analyzed the X-Rays several days later, Stanley observed an unmistakable feature he was intimately familiar with.

"My entire PhD was focused on osteoderm development in lizards. Once the specimen scans had been processed, the tail was very clearly covered in osteoderms."

Spiny mice osteoderms have been observed at least once before and were noted by German biologist Jochen Niethammer, who compared their architecture to medieval stonework in an article published in 1975. Niethammer correctly interpreted the plates as being a type of bone but never followed up on his initial observations, and the group was largely overlooked for several decades -- until scientists discovered another, seemingly unrelated peculiarity of spiny mice.

A study from 2012 demonstrated spiny mice can completely regenerate injured tissue without scarring, an ability common in reptiles and invertebrates but previously unknown in mammals. Their skin is also particularly fragile, tearing at roughly one-fourth the amount of force required to injure the skin of a common mouse. But spiny mice can heal twice as fast as their relatives.

Researchers hoping to find a model for human tissue regeneration have begun mapping the genetic pathways that give spiny mice their extraordinary powers of healing. One such researcher, Malcolm Maden, just so happened to have a lab in the building across from Stanley's office.

"Spiny mice can regenerate skin, muscle, nerves, spinal cord and perhaps even cardiac tissue, so we maintain a colony of these rare creatures for research," said Maden, a biology professor at the University of Florida and lead author on the study.

Maden and his colleagues analyzed the development of spiny mice osteoderms, confirming they were in fact similar to those of armadillos but had most likely evolved independently. Osteoderms are also distinct from the scales of pangolins or the quills of hedgehogs and porcupines, which are composed of keratin, the same tissue that makes up hair, skin and nails.

There are four genera of spiny mice, which all belong to the subfamily Deomyinae. However, aside from similarities in their DNA and potentially the shape of their teeth, scientists have been unable to find a single feature shared among species of this group that distinguishes them from other rodents.

Stanley, suspecting their differences might only be skin deep, scanned additional museum specimens from all four genera. In each, he found spiny mice tails were covered in the same sheath of bone. The closest relatives of Deomyinae -- gerbils -- lacked osteoderms, meaning the trait had likely evolved just once, in the ancestor of erstwhile disparate spiny mice.

The ubiquity of osteoderms in the group indicate they serve an important protective function. Just what that function might be wasn't immediately apparent, however, due to yet another peculiar attribute of spiny mice: Their tails are uncharacteristically detachable. Tail loss is so common in some spiny mouse species that nearly half the individuals of a given population have been shown to lack them in the wild.

"This was a real head-scratcher," Stanley said. "Spiny mice are famously able to deglove their tails, meaning the outer layer of skin comes off, leaving behind the muscle and bone. Individuals will often chew off the remainder of the tail when this happens."

Despite their powers of regeneration, tail shedding is a trick that spiny mice can only perform once. Unlike some lizards, they can't regrow their tails, and not every part of the tail separates easily.

To find out why rodents that seem ambivalent about keeping their tails would go through the trouble of covering them in armor, the authors turned to a group of similarly odd fish-tale geckos from Madagascar. Most geckos lack osteoderms, but as their name implies, fish-tale geckos are covered in thin, overlapping plates, and just like spiny mice, they have incredibly fragile skin that sheds at the slightest provocation.

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Gel-like, radioactive tumor implant obliterates pancreatic cancer in mice

Biomedical engineers at Duke University have demonstrated the most effective treatment for pancreatic cancer ever recorded in mouse models. While most mouse trials consider simply halting growth a success, the new treatment completely eliminated tumors in 80% of mice across several model types, including those considered the most difficult to treat.

The approach combines traditional chemotherapy drugs with a new method for irradiating the tumor. Rather than delivering radiation from an external beam that travels through healthy tissue, the treatment implants radioactive iodine-131 directly into the tumor within a gel-like depot that protects healthy tissue and is absorbed by the body after the radiation fades away.

The results appear online October 19 in the journal Nature Biomedical Engineering.

"We did a deep dive through over 1100 treatments across preclinical models and never found results where the tumors shrank away and disappeared like ours did," said Jeff Schaal, who conducted the research during his PhD in the laboratory of Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke. "When the rest of the literature is saying that what we're seeing doesn't happen, that's when we knew we had something extremely interesting."

Despite accounting for only 3.2% of all cancer cases, pancreatic cancer is the third leading cause of cancer-related death. It is a very difficult to treat because its tumors tend to develop aggressive genetic mutations that make it resistant to many drugs, and it is typically diagnosed very late, when it has already spread to other sites in the body.

The current leading treatment combines chemotherapy, which keeps cells in a stage of reproduction vulnerable to radiation for longer periods of time, with a beam of radiation targeted at the tumor. This approach, however, is ineffective unless a certain threshold of radiation reaches the tumor. And despite recent advances in shaping and targeting radiation beams, that threshold is very difficult to reach without risking severe side effects.

Another method researchers have tried involves implanting a radioactive sample encased in titanium directly within the tumor. But because titanium blocks all radiation other than gamma rays, which travel far outside the tumor, it can only remain within the body for a short period of time before damage to surrounding tissue begins to defeat the purpose.

"There's just no good way to treat pancreatic cancer right now," said Schaal, who is now director of research at Cereius, Inc., a Durham, North Carolina biotechnology startup working to commercialize a targeted radionuclide therapy through a different technology scheme.

To skirt these issues, Schaal decided to try a similar implantation method using a substance made of elastin-like polypeptides (ELPs), which are synthetic chains of amino acids bonded together to form a gel-like substance with tailored properties. Because ELPs are a focus of the Chilkoti lab, he was able to work with colleagues to design a delivery system well suited for the task.

The ELPs exist in a liquid state at room temperature but form a stable gel-like substance within the warmer human body. When injected into a tumor along with a radioactive element, the ELPs form a small depot encasing radioactive atoms. In this case, the researchers decided to use iodine-131, a radioactive isotope of iodine, because doctors have used it widely in medical treatments for decades and its biological effects are well understood.

The ELP depot encases the iodine-131 and prevents it from leaking out into the body. The iodine-131 emits beta radiation, which penetrates the biogel and deposits almost all its energy into the tumor without reaching the surrounding tissue. Over time, the ELP depot degrades into its constituent amino acids and is absorbed by the body -- but not before the iodine-131 has decayed into a harmless form of xenon.

"The beta radiation also improves the stability of the ELP biogel," Schaal said. "That helps the depot last longer and only break down after the radiation is spent."

In the new paper, Schaal and his collaborators in the Chilkoti laboratory tested the new treatment in concert with paclitaxel, a commonly used chemotherapy drug, to treat various mouse models of pancreatic cancer. They chose pancreatic cancer because of its infamy for being difficult to treat, hoping to show that their radioactive tumor implant creates synergistic effects with chemotherapy that relatively short-lived radiation beam therapy does not.

The researchers tested their approach on mice with cancers just under their skin created by several different mutations known to occur in pancreatic cancer. They also tested it on mice that had tumors within the pancreas, which is much more difficult to treat.

Overall, the tests saw a 100% response rate across all models, with the tumors being completely eliminated in three-quarters of the models about 80% of the time. The tests also revealed no immediately obvious side effects beyond what is caused by chemotherapy alone.

"We think the constant radiation allows the drugs to interact with its effects more strongly than external beam therapy allows," Schaal said. "That makes us think that this approach might actually work better than external beam therapy for many other cancers, too."

The approach, however, is still in its early preclinical stages and will not be available for human use anytime soon. The researchers say their next step is large animal trials, where they will need to show that the technique can be accurately done with the existing clinical tools and endoscopy techniques that doctors are already trained on. If successful, they look toward a Phase 1 clinical trial in humans.

"My lab has been working on developing new cancer treatments for close to 20 years, and this work is perhaps the most exciting we have done in terms of its potential impact, as late-stage pancreatic cancer is impossible to treat and is invariably fatal," Chilkoti said. "Pancreatic cancer patients deserve better treatment options than are currently available, and I am deeply committed to taking this all the way into the clinic."

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Clusters of genes help mice live longer

Researchers from the National Institute on Aging (NIA)-funded Interventions Testing Program recently reported the discovery of multiple candidate genes that influence longevity. The three Interventions Testing Program sites -- The University of Texas Health Science Center at San Antonio, The University of Michigan at Ann Arbor and The Jackson Laboratory at Bar Harbor, Maine -- collaborated on the study with the labs of Robert W. Williams, PhD, of the University of Tennessee Health Science Center at Memphis and Johan Auwerx, MD, PhD, of the École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland.

"Some candidate genes impacted female life span while others affected the male life span," said Randy Strong, PhD, of the Sam and Ann Barshop Institute for Longevity and Aging Studies at UT Health San Antonio. "One cluster of genes increased longevity of both sexes. In a rarity for these types of studies, the findings were made in a population of mice with genetic diversity comparable to human populations."

The high-impact journal Science published the findings Sept. 30. Strong directs the Interventions Testing Program site at the Barshop Institute, which first attracted National Institute on Aging (NIA) grant funding for the Interventions Testing Program in 2003 and is in its 19th year of the NIA funding.

Genetic smorgasbord

"The study models what happens in people," said research coauthor James Nelson, PhD, of the Barshop Institute. "Unlike mice in many other studies, mice in this newly reported research are not all the same. Each has different genetic variants, resulting in slightly different proteins that do slightly different things, which together can impact aging."

Even subtle differences can lead to different health outcomes as we age. Slight variations in the hemoglobin gene, for example, can cause the hemoglobin protein in red blood cells to be less effective at binding to oxygen and transferring it from the lungs to the body's tissues, Nelson noted. Anemia is one effect.

Female longevity

The discovery of genetic loci that influence longevity only in females is interesting and important, Strong said. Genetic loci are clusters of between 10 and 100 genes.

"Females and males differ in almost every aspect of aging you can explore," Strong said. "They each must be studied, both to understand aging in the two sexes and to develop effective treatments. If we offer the same drug therapies to females that we offer to males, and females' aging is caused by different genes, we are not going to be as effective in our treatments."

Confirmation in roundworms

The next steps are scrutinizing these candidate genes to find ones that are responsible for increased longevity. In the final part of the Science article, the team reported doing this. The researchers tested candidate genes in roundworms, which are often used in aging research because of their short life span. "A number of the candidate genes did affect longevity in the worms," Nelson said.

That doesn't prove that those same genes in humans are going to affect human life span, the researchers said. But it's another part of the case for continuing to study the genetic basis of longevity.

Powerful study design

As envisioned when the Interventions Testing Program began, having three sites where studies are conducted ensures statistical power and rigor and reproducibility of findings, Strong said.

The study is unique in that it is based on a large sample size of animals numbering several thousand, the authors said. "It is among the largest number of mice of any study that has attempted to identify genes that influence life span," Nelson said.

Barshop Institute excellence

The Interventions Testing Program is one of several NIA-funded centers at the Sam and Ann Barshop Institute. Among them, the Nathan Shock Center of Excellence in the Basic Biology of Aging provides core services to enhance research of the fundamental biological questions of aging. The Claude D. Pepper Older Americans Independence Center, named for the late U.S. representative, is a center of excellence aimed at increasing scientific knowledge to develop better ways of maintaining or restoring independence in senior adults. The Barshop Institute is the only institute or university in the nation to have these three centers.

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Gene mutation linked to learning deficits in 'Clueless' mice

A single mutation in a gene, Kcnc3, which encodes a potassium channel in neurons, causes learning deficits in mice, UT Southwestern researchers report in a new study in PNAS. The novel mutation decreases the activity of neurons in the hippocampus, the area of the brain important for learning and memory, and highlights a new role for potassium channels.

"Learning and memory are very complex at the genetic level. Unbiased searches for genes underlying learning and memory have not been successfully conducted in mice before," said Joseph Takahashi, Ph.D., Professor and Chair of Neuroscience at UT Southwestern and a Howard Hughes Medical Institute Investigator.

The discovery of the Kcnc3 mutation came out of an extraordinary effort by Dr. Takahashi and colleagues to conduct a large-scale mutagenesis screen in mice. Using a highly potent mutagen called ENU, the researchers induced random mutations in the mouse genome. The progeny of ENU-treated mice were then screened for neural and behavioral traits that could be mapped to specific genes to identify the causal mutation. This approach to unbiased gene discovery is called forward genetics.

From the mutagenesis screen, Dr. Takahashi and his team isolated a mutant mouse with spatial learning defects, which they named Clueless. In fear-conditioning tests, the mutants exhibited reduced freezing (a natural fear response in mice) as well as defects in long-term and short-term memory. The defects in Clueless mice mapped to a mutation in the Kcnc3 gene, which encodes a subunit of a special type of potassium channel called a voltage-gated potassium channel.

This is the first study to implicate Kcnc3 in learning, explained Dr. Takahashi, an investigator in UTSW's Peter O'Donnell Jr. Brain Institute. The full Kcnc3 knockout mouse model shows only mild gait issues with no defects in learning and memory, which could be due to developmental compensation or functional redundancy with other voltage-gated potassium channel subunits. Future research will help to answer some of these outstanding questions.

Dr. Takahashi said the findings underscore the power of applying forward genetics to gene discovery and could lead to potential new targets for therapy in learning and memory as well as other disease areas.

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How sound reduces pain in mice

An international team of scientists has identified the neural mechanisms through which sound blunts pain in mice. The findings, which could inform development of safer methods to treat pain, were published in Science. The study was led by researchers at the National Institute of Dental and Craniofacial Research (NIDCR); the University of Science and Technology of China, Hefei; and Anhui Medical University, Hefei, China. NIDCR is part of the National Institutes of Health.

"We need more effective methods of managing acute and chronic pain, and that starts with gaining a better understanding of the basic neural processes that regulate pain," said NIDCR Director Rena D'Souza, D.D.S., Ph.D. "By uncovering the circuitry that mediates the pain-reducing effects of sound in mice, this study adds critical knowledge that could ultimately inform new approaches for pain therapy."

Dating back to 1960, studies in humans have shown that music and other kinds of sound can help alleviate acute and chronic pain, including pain from dental and medical surgery, labor and delivery, and cancer. However, how the brain produces this pain reduction, or analgesia, was less clear.

"Human brain imaging studies have implicated certain areas of the brain in music-induced analgesia, but these are only associations," said co-senior author Yuanyuan (Kevin) Liu, Ph.D., a Stadtman tenure-track investigator at NIDCR. "In animals, we can more fully explore and manipulate the circuitry to identify the neural substrates involved."

The researchers first exposed mice with inflamed paws to three types of sound: a pleasant piece of classical music, an unpleasant rearrangement of the same piece, and white noise. Surprisingly, all three types of sound, when played at a low intensity relative to background noise (about the level of a whisper) reduced pain sensitivity in the mice. Higher intensities of the same sounds had no effect on animals' pain responses.

"We were really surprised that the intensity of sound, and not the category or perceived pleasantness of sound would matter," Liu said.

To explore the brain circuitry underlying this effect, the researchers used non-infectious viruses coupled with fluorescent proteins to trace connections between brain regions. They identified a route from the auditory cortex, which receives and processes information about sound, to the thalamus, which acts as a relay station for sensory signals, including pain, from the body. In freely moving mice, low-intensity white noise reduced the activity of neurons at the receiving end of the pathway in the thalamus.

In the absence of sound, suppressing the pathway with light- and small molecule-based techniques mimicked the pain-blunting effects of low-intensity noise, while turning on the pathway restored animals' sensitivity to pain.

Liu said it is unclear if similar brain processes are involved in humans, or whether other aspects of sound, such as its perceived harmony or pleasantness, are important for human pain relief.

"We don't know if human music means anything to rodents, but it has many different meanings to humans -- you have a lot of emotional components," he said.

The results could give scientists a starting point for studies to determine whether the animal findings apply to humans, and ultimately could inform development of safer alternatives to opioids for treating pain.

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Molecule boosts fat burning

Normally, fat cells store energy. In brown fat cells, however, energy is dissipated as heat -- brown fat thus serves as a biological heater. Most mammals therefore have this mechanism. In humans it keeps newborns warm, in human adults, brown fat activation positively correlates with cardio-metabolic health.

"Nowadays, however, we're toasty warm even in winter," explains Prof. Dr. Alexander Pfeifer from the Institute of Pharmacology and Toxicology at the University of Bonn. "So our body's own furnaces are hardly needed anymore." At the same time, we are eating an increasingly energy-dense diet and are also moving far less than our ancestors. These three factors are poison for brown fat cells: They gradually cease to function and eventually even die. On the other hand, the number of severely overweight people worldwide continues to increase. "Research groups around the world are therefore looking for substances that stimulate brown fat and thus increase fat burning," says Pfeifer.

Dying fat cells boost energy combustion of their neighbors

Together with a group of colleagues, the team at the University of Bonn has now identified a key molecule named inosine that is capable of burning fat. "It is known that dying cells release a mix of messenger molecules that influence the function of their neighbors," explains Dr. Birte Niemann from Pfeifer's research group. Together with her colleague Dr. Saskia Haufs-Brusberg, she planned and conducted the central experiments of the study. "We wanted to know if this mechanism also exists in brown fat."

The researchers therefore studied brown fat cells subjected to severe stress, so that the cells were virtually dying. "We found that they secrete the purine inosine in large quantities," Niemann says. More interesting, however, was how intact brown fat cells responded to the molecular call for help: They were activated by inosine (or simply by dying cells in their vicinity). Inosine thus fanned the furnace inside them. White fat cells also converted to their brown siblings. Mice fed a high-energy diet and treated with inosine at the same time remained leaner compared to control animals and were protected from diabetes.

The inosine transporter seems to play an important role in this context: This protein in the cell membrane transports inosine into the cell, thus lowering the extracellular concentration. Therefore, inosine can no longer exert its combustion-promoting effect.

Drug inhibits the inosine transporter

"There is a drug that was actually developed for coagulation disorders, but also inhibits the inosine transporter," says Pfeifer, who is also a member of the Transdisciplinary Research Areas "Life and Health" and "Sustainable Futures" at the University of Bonn. "We gave this drug to mice, and as a result they burned more energy." Humans also have an inosine transporter. In two to four percent of all people, it is less active due to a genetic variation. "Our colleagues at the University of Leipzig have genetically analyzed 900 individuals," Pfeifer explains. "Those subjects with the less active transporter were significantly leaner on average."

These results suggest that inosine also regulates thermogenesis in human brown fat cells. Substances that interfere with the activity of the transporter could therefore potentially be suitable for the treatment of obesity. The drug already approved for coagulation disorders could serve as a starting point. "However, further studies in humans are needed to clarify the pharmacological potential of this mechanism," Pfeifer says. Neither does he believe that a pill alone will be the solution to the world's rampant obesity pandemic. "But the available therapies are not effective enough at the moment," he stresses. "We therefore desperately need medications to normalize energy balance in obese patients."

The key role played by the body's own heating system is also demonstrated by a major new joined research consortium: The German Research Foundation (DFG) recently approved a Transregional Collaborative Research Center in which the Universities of Bonn, Hamburg and Munich conduct targeted research on brown adipose tissue.

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A gene could prevent Parkinson's disease

Parkinson's disease is a neurodegenerative disorder characterized by the destruction of a specific population of neurons: the dopaminergic neurons. The degeneration of these neurons prevents the transmission of signals controlling specific muscle movements and leads to tremors, involuntary muscle contractions or balance problems characteristic of this pathology. A team from the University of Geneva (UNIGE) has investigated the destruction of these dopaminergic neurons using the fruit fly as study model. The scientists identified a key protein in flies, and also in mice, which plays a protective role against this disease and could be a new therapeutic target. This work can be read in the journal Nature Communications.

Apart from rare forms involving a single gene, most Parkinson's cases result from an interaction between multiple genetic and environmental risk factors. However, a common element in the onset of the disease is a dysfunction of mitochondria in dopaminergic neurons. These small factories within cells are responsible for energy production, but also for activating the cell's self-destruct mechanisms when damaged.

The laboratory of Emi Nagoshi, Professor in the Department of Genetics and Evolution at the UNIGE Faculty of Science, uses the fruit fly, or Drosophila, to study the mechanisms of dopaminergic neuron degeneration. Her group is particularly interested in the Fer2 gene, whose human homolog encodes a protein that controls the expression of many other genes and whose mutation might lead to Parkinson's disease via mechanisms that are not yet well understood.

In a previous study, this scientific team demonstrated that a mutation in the Fer2 gene causes Parkinson's-like deficiencies in flies, including a delay in the initiation of movement. They had also observed defects in the shape of the mitochondria of dopaminergic neurons, similar to those observed in Parkinson's patients.

Protecting neurons

Since the absence of Fer2 causes Parkinson's disease-like conditions, the researchers tested whether -- on the contrary -- an increase in the amount of Fer2 in the cells could have a protective effect. When flies are exposed to free radicals, their cells undergo oxidative stress which leads to the degradation of dopaminergic neurons. However, the scientists were able to observe that oxidative stress no longer has any deleterious effect on the flies if they overproduce Fer2, confirming the hypothesis of its protective role.

"We have also identified the genes regulated by Fer2 and these are mainly involved in mitochondrial functions. This key protein therefore seems to play a crucial role against the degeneration of dopaminergic neurons in flies by controlling not only the structure of mitochondria but also their functions," explains Federico Miozzo, researcher in the Department of Genetics and Evolution and first author of the study.

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Tweaked genes borrowed from bacteria excite heart cells in live mice

Biomedical engineers at Duke University have demonstrated a gene therapy that helps heart muscle cells electrically activate in live mice. The first demonstration of its kind, the approach features engineered bacterial genes that code for sodium ion channels and could lead to therapies to treat a wide variety of electrical heart diseases and disorders.

The results appeared online February 2 in the journal Nature Communications.

"We were able to improve how well heart muscle cells can initiate and spread electrical activity, which is hard to accomplish with drugs or other tools," said Nenad Bursac, professor of biomedical engineering at Duke. "The method we used to deliver genes in heart muscle cells of mice has been previously shown to persist for a long time, which means it could effectively help hearts that struggle to beat as regularly as they should."

Sodium-ion channels are proteins in the outer membranes of electrically excitable cells, such as heart or brain cells, that transmit electrical charges into the cell. In the heart, these channels tell muscle cells when to contract and pass the instruction along so that the organ pumps blood as a cohesive unit. Damaged heart cells, however, whether from disease or trauma, often lose all or part of their ability to transmit these signals and join the effort.

One approach researchers can take to restoring this functionality is gene therapy. By delivering the genes responsible for creating sodium channel proteins, the technique can produce more ion channels in the diseased cells to help boost their activity.

In mammals, sodium channel genes are unfortunately too large to fit within the viruses currently used in modern gene therapies in humans. To skirt this issue, Bursac and his laboratory instead turned to smaller genes that code for similar sodium ion channels in bacteria. While these bacterial genes are different than their human counterparts, evolution has conserved many similarities in the channel design since multi-cellular organisms diverged from bacteria hundreds of millions of years ago.

Several years ago, Hung Nguyen, a former doctoral student in Bursac's laboratory who now works for Fujifilm Diosynth Biotechnologies, mutated these bacterial genes so that the channels they encode could become active in human cells. In the new work, current doctoral student Tianyu Wu further optimized the content of the genes and combined them with a "promoter" that exclusively restricts channel production to heart muscle cells. The researchers then tested their approach by delivering a virus loaded with the bacterial gene into veins of a mouse to spread throughout the body.

"We worked to find where the sodium ion channels were actually formed, and, as we hoped, we found that they only went into the working muscle cells of the heart within the atria and ventricles," Wu said. "We also found that they did not end up in the heart cells that originate the heartbeat, which we also wanted to avoid."

This gene therapy approach only delivers extra genes within a cell; it does not attempt to cut out, replace or rewrite the existing DNA in any way. Scientists believe these types of delivered genes make proteins while floating freely within the cell, making use of the existing biochemical machinery. Previous research with this viral gene delivery approach suggests the transplanted genes should remain active for many years.

As a proof of concept, tests on cells in a laboratory setting suggest that the treatment improves electrical excitability enough to prevent human abnormalities like arrhythmias. Within live mice, the results demonstrate that the sodium ion channels are active in the hearts, showing trends toward improved excitability. However, further tests are needed to measure how much of an improvement is made on the whole-heart level, and whether it is enough to rescue electrical function in damaged or diseased heart tissue to be used as a viable treatment.

Moving forward, the researchers have already identified different bacterial sodium channel genes that work better in preliminary benchtop studies. The team is also working with the laboratories of Craig Henriquez, professor of biomedical engineering at Duke, and Andrew Landstrom, director of the Duke Pediatric Research Scholars Program, to test the ability of these genes to restore heart functionality in mouse models that mimic human heart diseases.

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Newly identified hormone may be a critical driver of type 1 and type 2 diabetes

A newly discovered hormone named fabkin helps regulate metabolism and may play an important role in the development of both type 1 and type 2 diabetes, according to research led by the Sabri Ülker Center for Metabolic Research at Harvard T.H. Chan School of Public Health.

The study showed blood levels of fabkin were abnormally high in mice and human patients with either type 1 or type 2 diabetes. The researchers found that blocking the activity of fabkin prevented the development of both forms of diabetes in the animals. Fabkin likely plays a similar role in humans and the hormone complex could be a promising therapeutic target, according to the researchers.

"For many decades, we have been searching for the signal that communicates the status of energy reserves in adipocytes to generate appropriate endocrine responses, such as the insulin production from pancreatic beta cells," said senior author Gökhan S. Hotamisligil, director of the Sabri Ülker Center. "We now have identified fabkin as a novel hormone that controls this critical function through a very unusual molecular mechanism."

The findings will be published online in Nature on December 8, 2021.

Many hormones are involved in the regulation of metabolism, such as insulin and leptin. Fabkin is different from traditional hormones in that it is not a single molecule with a single defined receptor. Instead, fabkin is composed of a functional protein complex consisting of multiple proteins, including fatty acid binding protein 4 (FABP4), adenosine kinase (ADK) and nucleoside diphosphate kinase (NDPK). Through a series of experiments, the researchers determined that fabkin regulates energy signals outside of cells. These signals then act through a family of receptors to control target cell function. In the case of diabetes, fabkin controls the function of beta cells in the pancreas that are responsible for insulin production.

More than a decade ago, Hotamisligil and colleagues discovered that a protein known as FABP4 is secreted from fat cells during lipolysis, the process in which lipids stored within fat cells are broken down, typically in response to starvation. Numerous studies have since shown correlations between circulating FABP4 and metabolic diseases including obesity, diabetes, cardiovascular disease, and cancer. However, the mechanism of action was unknown.

In the new study, the researchers showed that when FABP4 is secreted from fat cells and enters the blood stream, it binds with the enzymes NDPK and ADK to form the protein complex now identified as fabkin. In this protein complex, FABP4 modifies the activity of NDPK and ADK to regulate levels of molecules known as ATP and ADP, which are the essential units of energy in biology. The researchers discovered that surface receptors on nearby cells sense the changing ratio of ATP to ADP, triggering the cells to respond to the changing energy status. As such, fabkin is able to regulate the function of these target cells.

The authors showed that the insulin-producing beta cells of the pancreas are a target of fabkin and that the hormone is a driving force behind the development of diabetes. When the researchers used an antibody to neutralize fabkin in mice, the animals did not develop diabetes. When the antibody was given to obese, diabetic mice, they reverted to a healthy state.

"The discovery of fabkin required us to take a step back and reconsider our fundamental understanding of how hormones work." said lead author Kacey Prentice, research associate in the Sabri Ülker Center and Department of Molecular Metabolism. "I am extremely excited to find a new hormone, but even more so about seeing the long-term implications of this discovery."

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