A 'nano-robot' built entirely from DNA to explore cell processes

Constructing a tiny robot from DNA and using it to study cell processes invisible to the naked eye... You would be forgiven for thinking it is science fiction, but it is in fact the subject of serious research by scientists from Inserm, CNRS and Université de Montpellier at the Structural Biology Center in Montpellier[1]. This highly innovative "nano-robot" should enable closer study of the mechanical forces applied at microscopic levels, which are crucial for many biological and pathological processes. It is described in a new study published in Nature Communications.

Our cells are subject to mechanical forces exerted on a microscopic scale, triggering biological signals essential to many cell processes involved in the normal functioning of our body or in the development of diseases.

For example, the feeling of touch is partly conditional on the application of mechanical forces on specific cell receptors (the discovery of which was this year rewarded by the Nobel Prize in Physiology or Medicine). In addition to touch, these receptors that are sensitive to mechanical forces (known as mechanoreceptors) enable the regulation of other key biological processes such as blood vessel constriction, pain perception, breathing or even the detection of sound waves in the ear, etc.

The dysfunction of this cellular mechanosensitivity is involved in many diseases -- for example, cancer: cancer cells migrate within the body by sounding and constantly adapting to the mechanical properties of their microenvironment. Such adaptation is only possible because specific forces are detected by mechanoreceptors that transmit the information to the cell cytoskeleton.

At present, our knowledge of these molecular mechanisms involved in cell mechanosensitivity is still very limited. Several technologies are already available to apply controlled forces and study these mechanisms, but they have a number of limitations. In particular, they are very costly and do not allow us to study several cell receptors at a time, which makes their use very time-consuming if we want to collect a lot of data.

DNA origami structures

In order to propose an alternative, the research team led by Inserm researcher Gaëtan Bellot at the Structural Biology Center (Inserm/CNRS/Université de Montpellier) decided to use the DNA origami method. This enables the self-assembly of 3D nanostructures in a pre-defined form using the DNA molecule as construction material. Over the last ten years, the technique has allowed major advances in the field of nanotechnology.

This enabled the researchers to design a "nano-robot" composed of three DNA origami structures. Of nanometric size, it is therefore compatible with the size of a human cell. It makes it possible for the first time to apply and control a force with a resolution of 1 piconewton, namely one trillionth of a Newton -- with 1 Newton corresponding to the force of a finger clicking on a pen. This is the first time that a human-made, self-assembled DNA-based object can apply force with this accuracy.

The team began by coupling the robot with a molecule that recognizes a mechanoreceptor. This made it possible to direct the robot to some of our cells and specifically apply forces to targeted mechanoreceptors localized on the surface of the cells in order to activate them.

Such a tool is very valuable for basic research, as it could be used to better understand the molecular mechanisms involved in cell mechanosensitivity and discover new cell receptors sensitive to mechanical forces. Thanks to the robot, the scientists will also be able to study more precisely at what moment, when applying force, key signaling pathways for many biological and pathological processes are activated at cell level.

"The design of a robot enabling the in vitro and in vivo application of piconewton forces meets a growing demand in the scientific community and represents a major technological advance. However, the biocompatibility of the robot can be considered both an advantage for in vivo applications but may also represent a weakness with sensitivity to enzymes that can degrade DNA. So our next step will be to study how we can modify the surface of the robot so that it is less sensitive to the action of enzymes. We will also try to find other modes of activation of our robot using, for example, a magnetic field," emphasizes Bellot.

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Improving image sensors for machine vision

Image sensors measure light intensity, but angle, spectrum, and other aspects of light must also be extracted to significantly advance machine vision.

In Applied Physics Letters, published by AIP Publishing, researchers at the University of Wisconsin-Madison, Washington University in St. Louis, and OmniVision Technologies highlight the latest nanostructured components integrated on image sensor chips that are most likely to make the biggest impact in multimodal imaging.

The developments could enable autonomous vehicles to see around corners instead of just a straight line, biomedical imaging to detect abnormalities at different tissue depths, and telescopes to see through interstellar dust.

"Image sensors will gradually undergo a transition to become the ideal artificial eyes of machines," co-author Yurui Qu, from the University of Wisconsin-Madison, said. "An evolution leveraging the remarkable achievement of existing imaging sensors is likely to generate more immediate impacts."

Image sensors, which converts light into electrical signals, are composed of millions of pixels on a single chip. The challenge is how to combine and miniaturize multifunctional components as part of the sensor.

In their own work, the researchers detailed a promising approach to detect multiple-band spectra by fabricating an on-chip spectrometer. They deposited photonic crystal filters made up of silicondirectly on top of the pixels to create complex interactions between incident light and the sensor.

The pixels beneath the films record the distribution of light energy, from which light spectral information can be inferred. The device -- less than a hundredth of a square inch in size -- is programmable to meet various dynamic ranges, resolution levels, and almost any spectral regime from visible to infrared.

The researchers built a component that detects angular information to measure depth and construct 3D shapes at subcellular scales. Their work was inspired by directional hearing sensors found in animals, like geckos, whose heads are too small to determine where sound is coming from in the same way humans and other animals can. Instead, they use coupled eardrums to measure the direction of sound within a size that is orders of magnitude smaller than the corresponding acoustic wavelength.

Similarly, pairs of silicon nanowires were constructed as resonators to support optical resonance. The optical energy stored in two resonators is sensitive to the incident angle. The wire closest to the light sends the strongest current. By comparing the strongest and weakest currents from both wires, the angle of the incoming light waves can be determined.

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Taking your time makes a difference

Neanderthals are the closest relatives to modern humans. Comparisons with them can therefore provide fascinating insights into what makes present-day humans unique, for example regarding the development of the brain. The neocortex, the largest part of the outer layer of the brain, is unique to mammals and crucial for many cognitive capacities. It expanded dramatically during human evolution in species ancestral to both Neanderthals and modern humans, resulting that both Neanderthals and modern humans having brains of similar sizes. However, almost nothing is known about how modern human and Neanderthal brains may have differed in terms of their development and function.

Researchers from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden and the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) in Leipzig have now discovered that neural stem cells -- the cells from which neurons in the developing neocortex derive -- spend more time preparing their chromosomes for division in modern humans than in Neanderthals. This results in fewer errors when chromosomes are distributed to the daughter cells in modern humans than in Neanderthals or chimpanzees, and could have consequences for how the brain develops and functions. This study shows cellular differences in the development of the brain between modern humans and Neanderthals.

After the ancestors of modern humans split from those of Neanderthals and Denisovans, their Asian relatives, about one hundred amino acids, the building blocks of proteins in cells and tissues, changed in modern humans and spread to almost all modern humans. The biological significance of these changes is largely unknown. However, six of those amino acid changes occurred in three proteins that play key roles in the distribution of chromosomes, the carriers of genetic information, to the two daughter cells during cell division.

The effects of the modern human variants on brain development

To investigate the significance of these six changes for neocortex development, the scientists first introduced the modern human variants in mice. Mice are identical to Neanderthals at those six amino acid positions, so these changes made them a model for the developing modern human brain. Felipe Mora-Bermúdez, the lead author of the study, describes the discovery: "We found that three modern human amino acids in two of the proteins cause a longer metaphase, a phase where chromosomes are prepared for cell division, and this results in fewer errors when the chromosomes are distributed to the daughter cells of the neural stem cells, just like in modern humans." To check if the Neanderthal set of amino acids have the opposite effect, the researchers then introduced the ancestral amino acids in human brain organoids -- miniature organ-like structures that can be grown from human stem cells in cell culture dishes in the lab and that mimic aspects of early human brain development. "In this case, metaphase became shorter and we found more chromosome distribution errors." According to Mora-Bermúdez, this shows that those three modern human amino acid changes in the proteins known as KIF18a and KNL1 are responsible for the fewer chromosome distribution mistakes seen in modern humans as compared to Neanderthal models and chimpanzees. He adds that "having mistakes in the number of chromosomes is usually not a good idea for cells, as can be seen in disorders like trisomies and cancer."

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Researchers 3D print sensors for satellites

MIT scientists have created the first completely digitally manufactured plasma sensors for orbiting spacecraft. These plasma sensors, also known as retarding potential analyzers (RPAs), are used by satellites to determine the chemical composition and ion energy distribution of the atmosphere.

The 3D-printed and laser-cut hardware performed as well as state-of-the-art semiconductor plasma sensors that are manufactured in a cleanroom, which makes them expensive and requires weeks of intricate fabrication. By contrast, the 3D-printed sensors can be produced for tens of dollars in a matter of days.

Due to their low cost and speedy production, the sensors are ideal for CubeSats. These inexpensive, low-power, and lightweight satellites are often used for communication and environmental monitoring in Earth's upper atmosphere.

The researchers developed RPAs using a glass-ceramic material that is more durable than traditional sensor materials like silicon and thin-film coatings. By using the glass-ceramic in a fabrication process that was developed for 3D printing with plastics, there were able to create sensors with complex shapes that can withstand the wide temperature swings a spacecraft would encounter in lower Earth orbit.

"Additive manufacturing can make a big difference in the future of space hardware. Some people think that when you 3D-print something, you have to concede less performance. But we've shown that is not always the case. Sometimes there is nothing to trade off," says Luis Fernando Velásquez-García, a principal scientist in MIT's Microsystems Technology Laboratories (MTL) and senior author of a paper presenting the plasma sensors.

Joining Velásquez-García on the paper are lead author and MTL postdoc Javier Izquierdo-Reyes; graduate student Zoey Bigelow; and postdoc Nicholas K. Lubinsky. The research is published in Additive Manufacturing.

Versatile sensors

An RPA was first used in a space mission in 1959. The sensors detect the energy in ions, or charged particles, that are floating in plasma, which is a superheated mix of molecules present in the Earth's upper atmosphere. Aboard an orbiting spacecraft like a CubeSat, the versatile instruments measure energy and conduct chemical analyses that can help scientists predict the weather or monitor climate change.

The sensors contain a series of electrically charged meshes dotted with tiny holes. As plasma passes through the holes, electrons and other particles are stripped away until only ions remain. These ions create an electric current that the sensor measures and analyzes.

Key to the success of an RPA is the housing structure that aligns the meshes. It must be electrically insulating while also able to withstand sudden, drastic swings in temperature. The researchers used a printable, glass-ceramic material that displays these properties, known as Vitrolite.

Pioneered in the early 20th century, Vitrolite was often used in colorful tiles that became a common sight in art deco buildings.

The durable material can also withstand temperatures as high as 800 degrees Celsius without breaking down, whereas polymers used in semiconductor RPAs start to melt at 400 degrees Celsius.

"When you make this sensor in the cleanroom, you don't have the same degree of freedom to define materials and structures and how they interact together. What made this possible is the latest developments in additive manufacturing," Velásquez-García says.

Rethinking fabrication

The 3D printing process for ceramics typically involves ceramic powder that is hit with a laser to fuse it into shapes, but this process often leaves the material coarse and creates weak points due to the high heat from the lasers.

Instead, the MIT researchers used vat polymerization, a process introduced decades ago for additive manufacturing with polymers or resins. With vat polymerization, a 3D structure is built one layer at a time by submerging it repeatedly into a vat of liquid material, in this case Vitrolite. Ultraviolet light is used to cure the material after each layer is added, and then the platform is submerged in the vat again. Each layer is only 100 microns thick (roughly the diameter of a human hair), enabling the creation of smooth, pore-free, complex ceramic shapes.

In digital manufacturing, objects described in a design file can be very intricate. This precision allowed the researchers to create laser-cut meshes with unique shapes so the holes lined up perfectly when they were set inside the RPA housing. This enables more ions to pass through, which leads to higher-resolution measurements.

Because the sensors were cheap to produce and could be fabricated so quickly, the team prototyped four unique designs.

While one design was especially effective at capturing and measuring a wide range of plasmas, like those a satellite would encounter in orbit, another was well-suited for sensing extremely dense and cold plasmas, which are typically only measurable using ultraprecise semiconductor devices.

This high precision could enable 3D-printed sensors for applications in fusion energy research or supersonic flight. The rapid prototyping process could even spur more innovation in satellite and spacecraft design, Velásquez-García adds.

"If you want to innovate, you need to be able to fail and afford the risk. Additive manufacturing is a very different way to make space hardware. I can make space hardware and if it fails, it doesn't matter because I can make a new version very quickly and inexpensively, and really iterate on the design. It is an ideal sandbox for researchers," he says.

While Velásquez-García is pleased with these sensors, in the future he wants to enhance the fabrication process. Reducing the thickness of layers or pixel size in glass-ceramic vat polymerization could create complex hardware that is even more precise. Moreover, fully additively manufacturing the sensors would make them compatible with in-space manufacturing. He also wants to explore the use of artificial intelligence to optimize sensor design for specific use cases, such as greatly reducing their mass while ensuring they remain structurally sound.

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Octopus lures from the Mariana Islands found to be oldest in the world

An archaeological study has determined that cowrie-shell artifacts found throughout the Mariana Islands were lures used for hunting octopuses and that the devices, similar versions of which have been found on islands across the Pacific, are the oldest known artifacts of their kind in the world.

The study used carbon dating of archaeological layers to confirm that lures found on the Northern Mariana Islands of Tinian and Saipan were from about 1500 B.C., or 3,500 years ago.

"That's back to the time when people were first living in the Mariana Islands. So we think these could be the oldest octopus lures in the entire Pacific region and, in fact, the oldest in the world," said Michael T. Carson, an archaeologist with the Micronesian Area Research Center at the University of Guam.

The study, titled "Let's catch octopus for dinner: Ancient inventions of octopus lures in the Mariana Islands of the remote tropical Pacific," is published in World Archaeology, a peer-reviewed academic journal. Carson, who holds a doctorate in anthropology, is the lead author of the study, assisted by Hsiao-chun Hung from The Australian National University in Canberra, Australia.

The fishing devices were made with cowrie shells, a type of sea snail and a favorite food of octopuses, that were connected by a fiber cord to a stone sinker and a hook.

They have been found in seven sites in the Mariana Islands. The oldest lures were excavated in 2011 from Sanhalom near the House of Taga in Tinian and in 2016 from Unai Bapot in Saipan. Other locations include Achugao in Saipan, Unai Chulu in Tinian, and Mochom at Mangilao Golf Course, Tarague Beach, and Ritidian Beach Cave in Guam.

Known artifacts, unknown purpose -- until now

"The artifacts have been known -- we knew about them. It just took a long time considering the possibilities, the different hypotheses, of what they could be," Carson said. "The conventional idea -- what we were told long ago from the Bishop Museum [in Honolulu] -- was that these must be for scraping breadfruit or other plants, like maybe taro. [But] they don't look like that."

The shells didn't have the serrated edge of other known food-scraping tools. With their holes and grooves where the fiber cord would have been attached as well as the stone sinker components, they appeared a closer match to octopus lures found in Tonga from about 3,000 years ago, or 1100 B.C.

"We're confident they are the pieces of octopus lures, and we're confident they date back to 1500 B.C.," Carson said.

An invention of the ancient CHamorus?

Carson said the question now becomes: Did the ancient CHamoru people invent this adaptation to their environment during the time when they first lived in the islands?"

That's a possibility, he said, the other being that they brought the tradition with them from their former homeland; however, no artifacts of this kind have yet been discovered in the potential homelands of the first Marianas settlers.

If the CHamoru people did invent the first octopus lures, it provides new insight into their ingenuity and ability to problem solve -- having to create novel and specialized ways to live in a new environment and take advantage of an available food source.

"It tells us that […] this kind of food resource was important enough for them that they invented something very particular to trap these foods," Carson said. "We can't say that it contributed to a massive percentage of their diet -- it probably did not -- but it was important enough that it became what we would call a 'tradition' in archaeology."

The next question to look at, Carson said, is whether there are similar objects anywhere else from an older time.

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Chores, exercise, and social visits linked to lower risk of dementia

Physical and mental activities, such as household chores, exercise, and visiting with family and friends, may help lower the risk of dementia, according to a new study published in the July 27, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study looked at the effects of these activities, as well as mental activities and use of electronic devices in people both with and without higher genetic risk for dementia.

"Many studies have identified potential risk factors for dementia, but we wanted to know more about a wide variety of lifestyle habits and their potential role in the prevention of dementia," said study author Huan Song, MD, PhD, of Sichuan University in Chengdu, China. "Our study found that exercise, household chores, and social visits were linked to a reduced risk of various types of dementia."

The study involved 501,376 people from a UK database without dementia with an average age of 56.

Participants filled out questionnaires at the beginning of the study, including one on physical activities. They were asked how often they participated in activities such as climbing a flight of stairs, walking, and participating in strenuous sports. They were also asked about household chores, job-related activities, and what kind of transportation they used, including walking or biking to work.

Participants completed another questionnaire on mental activities. They were asked about their education level, whether they attend adult education classes, how often they visit with friends and family, visit pubs or social clubs or religious groups, and how often they use electronic devices such as playing computer games, watching TV, and talking on the phone.

Additionally, participants reported whether they had any immediate family members with dementia. This helped researchers determine if they had a genetic risk for Alzheimer's disease. Study participants were followed an average of 11 years. At the end of the study, 5,185 people had developed dementia.

After adjusting for multiple factors such as age, income, and smoking, researchers found that most physical and mental activities studied showed links to the risk of dementia. Importantly, the findings remain after considering the high correlations and interactions of these activities. People who were highly engaged in activity patterns including frequent exercises, household chores, and daily visits of family and friends had 35%, 21%, and 15% lower risk of dementia, respectively, compared to people who were the least engaged in these activity patterns.

Researchers also looked at dementia incidence rates by identified activity patterns. The rate in people who exercised frequently was 0.45 cases for every 1,000 person-years compared to 1.59 for people who rarely exercised. Person-years take into account the number of people in a study as well as the amount of time spent in the study. Those who frequently did household chores had a rate of 0.86 cases for every 1,000 person-years compared to 1.02 for people who rarely did household chores. People who visited family daily had a rate of 0.62 cases for every 1,000 person-years compared to 0.8 cases for those who only visited friends and family once every few months.

"Our study has found that by engaging more frequently in healthy physical and mental activities people may reduce their risk of dementia," Song said. "More research is needed to confirm our findings. However, our results are encouraging that making these simple lifestyle changes may be beneficial."

The researchers found that all participants benefited from the protective effect of physical and mental activities, whether or not they had a family history of dementia.

A limitation of the study was that people reported their own physical and mental activity, so they may not have remembered and reported these activities correctly.

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Some types of stress could be good for brain functioning

It may feel like an anvil hanging over your head, but that looming deadline stressing you out at work may actually be beneficial for your brain, according to new research from the Youth Development Institute at the University of Georgia.

Published in Psychiatry Research, the study found that low to moderate levels of stress can help individuals develop resilience and reduce the risk of developing mental health disorders, like depression and antisocial behaviors. Low to moderate stress can also help individuals to cope with future stressful encounters.

"If you're in an environment where you have some level of stress, you may develop coping mechanisms that will allow you to become a more efficient and effective worker and organize yourself in a way that will help you perform," said Assaf Oshri, lead author of the study and an associate professor in the College of Family and Consumer Sciences.

The stress that comes from studying for an exam, preparing for a big meeting at work or pulling longer hours to close the deal can all potentially lead to personal growth. Being rejected by a publisher, for example, may lead a writer to rethink their style. And being fired could prompt someone to reconsider their strengths and whether they should stay in their field or branch out to something new.

But the line between the right amount of stress and too much stress is a thin one.

"It's like when you keep doing something hard and get a little callous on your skin," continued Oshri, who also directs the UGA Youth Development Institute. "You trigger your skin to adapt to this pressure you are applying to it. But if you do too much, you're going to cut your skin."

Good stress can act as a vaccine against the effect of future adversity

The researchers relied on data from the Human Connectome Project, a national project funded by the National Institutes of Health that aims to provide insight into how the human brain functions. For the present study, the researchers analyzed the project's data from more than 1,200 young adults who reported their perceived stress levels using a questionnaire commonly used in research to measure how uncontrollable and stressful people find their lives.

Participants answered questions about how frequently they experienced certain thoughts or feelings, such as "in the last month, how often have you been upset because of something that happened unexpectedly?" and "in the last month, how often have you found that you could not cope with all the things that you had to do?"

Their neurocognitive abilities were then assessed using tests that measured attention and ability to suppress automatic responses to visual stimuli; cognitive flexibility, or ability to switch between tasks; picture sequence memory, which involves remembering an increasingly long series of objects; working memory and processing speed.

The researchers compared those findings with the participants' answers from multiple measures of anxious feelings, attention problems and aggression, among other behavioral and emotional problems.

The analysis found that low to moderate levels of stress were psychologically beneficial, potentially acting as a kind of inoculation against developing mental health symptoms.

"Most of us have some adverse experiences that actually make us stronger," Oshri said. "There are specific experiences that can help you evolve or develop skills that will prepare you for the future."

But the ability to tolerate stress and adversity varies greatly according to the individual.

Things like age, genetic predispositions and having a supportive community to fall back on in times of need all play a part in how well individuals handle challenges. While a little stress can be good for cognition, Oshri warns that continued levels of high stress can be incredibly damaging, both physically and mentally.

"At a certain point, stress becomes toxic," he said. "Chronic stress, like the stress that comes from living in abject poverty or being abused, can have very bad health and psychological consequences. It affects everything from your immune system, to emotional regulation, to brain functioning. Not all stress is good stress."

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Scientists discover new 'origins of life' chemical reactions

Four billion years ago, the Earth looked very different than it does today, devoid of life and covered by a vast ocean. Over the course of millions of years, in that primordial soup, life emerged. Researchers have long theorized how molecules came together to spark this transition. Now, scientists at Scripps Research have discovered a new set of chemical reactions that use cyanide, ammonia and carbon dioxide -- all thought to be common on the early earth -- to generate amino acids and nucleic acids, the building blocks of proteins and DNA.

"We've come up with a new paradigm to explain this shift from prebiotic to biotic chemistry," says Ramanarayanan Krishnamurthy, PhD, an associate professor of chemistry at Scripps Research, and lead author of the new paper, published July 28, 2022 in the journal Nature Chemistry. "We think the kind of reactions we've described are probably what could have happened on early earth."

In addition to giving researchers insight into the chemistry of the early earth, the newly discovered chemical reactions are also useful in certain manufacturing processes, such as the generation of custom labeled biomolecules from inexpensive starting materials.

Earlier this year, Krishnamurthy's group showed how cyanide can enable the chemical reactions that turn prebiotic molecules and water into basic organic compounds required for life. Unlike previously proposed reactions, this one worked at room temperature and in a wide pH range. The researchers wondered whether, under the same conditions, there was a way to generate amino acids, more complex molecules that compose proteins in all known living cells.

In cells today, amino acids are generated from precursors called α-keto acids using both nitrogen and specialized proteins called enzymes. Researchers have found evidence that α-keto acids likely existed early in Earth's history. However, many have hypothesized that before the advent of cellular life, amino acids must have been generated from completely different precursors, aldehydes, rather than α-keto acids, since enzymes to carry out the conversion did not yet exist. But that idea has led to debate about how and when the switch occurred from aldehydes to α-keto acids as the key ingredient for making amino acids.

After their success using cyanide to drive other chemical reactions, Krishnamurthy and his colleagues suspected that cyanide, even without enzymes, might also help turn α-keto acids into amino acids. Because they knew nitrogen would be required in some form, they added ammonia -- a form of nitrogen that would have been present on the early earth. Then, through trial and error, they discovered a third key ingredient: carbon dioxide. With this mixture, they quickly started seeing amino acids form.

"We were expecting it to be quite difficult to figure this out, and it turned out to be even simpler than we had imagined," says Krishnamurthy. "If you mix only the keto acid, cyanide and ammonia, it just sits there. As soon as you add carbon dioxide, even trace amounts, the reaction picks up speed."

Because the new reaction is relatively similar to what occurs today inside cells -- except for being driven by cyanide instead of a protein -- it seems more likely to be the source of early life, rather than drastically different reactions, the researchers say. The research also helps bring together two sides of a long-standing debate about the importance of carbon dioxide to early life, concluding that carbon dioxide was key, but only in combination with other molecules.

In the process of studying their chemical soup, Krishnamurthy's group discovered that a byproduct of the same reaction is orotate, a precursor to nucleotides that make up DNA and RNA. This suggests that the same primordial soup, under the right conditions, could have given rise to a large number of the molecules that are required for the key elements of life.

"What we want to do next is continue probing what kind of chemistry can emerge from this mixture," says Krishnamurthy. "Can amino acids start forming small proteins? Could one of those proteins come back and begin to act as an enzyme to make more of these amino acids?"

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Exploring factors that may underlie how domestic cats can live in groups

A new analysis explores relationships between domestic cats' hormone levels, gut microbiomes, and social behaviors, shedding light on how these solitary animals live in high densities. Hikari Koyasu of Azabu University in Kanagawa, Japan, and colleagues present these findings in the open-access journal PLOS ONE on July 27, 2022.

Most feline species display solitary and territorial behavior, but domestic cats often live in high densities, raising the question of what strategies cats use to establish cohabitating groups. Social behaviors of cats can be influenced by hormones and the mix of different microbe species living in their guts -- known as the gut microbiome. Studying these factors could help illuminate the group dynamics of cohabitating cats.

In that vein, Koyasu and colleagues conducted a two-week-long study of three different groups of five cats living together in a shelter. They used video cameras to observe the cats' behavior, measured hormone levels in their urine, and collected feces to evaluate the mix of microbial species in the cats' microbiomes.

Statistical analysis of the data revealed that cats with high levels of the hormones cortisol and testosterone had less contact with other cats, and those with high testosterone were more likely to try to escape. Meanwhile, cats with low cortisol and testosterone were more tolerant in their interactions with other cats. The researchers also found greater similarity of gut microbiomes between cats who had more frequent contact with each other, and they found links between the gut microbiome, social behavior, and cortisol levels.

Meanwhile, contrary to the researchers' expectations from research on animals that typically live in groups, cats with high levels of the hormone oxytocin did not display bonding behaviors described as "socially affiliative." This suggests that oxytocin might function differently for typically solitary animals living in groups than for animals that typically live in groups.

The researchers outline possible directions for future research to further deepen understanding of cohabitating cat dynamics, such as a follow-up study that observes cats for several months, rather than just two weeks, and investigations to tease out causal relationships between hormones and social behaviors.

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Sprint then stop? Brain is wired for the math to make it happen

Your new apartment is just a couple of blocks down the street from the bus stop but today you are late and you see the bus roll past you. You break into a full sprint. Your goal is to get to the bus as fast as possible and then to stop exactly in front of the doors (which are never in exactly the same place along the curb) to enter before they close. To stop quickly and precisely enough, a new MIT study in mice finds, the mammalian brain is niftily wired to implement principles of calculus.

One might think that coming to a screeching halt at a target after a flat out run would be as simple as a reflex, but catching a bus or running right up to a visually indicated landmark to earn a water reward (as the mice did), is a learned, visually guided, goal-directed feat. In such tasks, which are a major interest in the lab of senior author Mriganka Sur, Newton Professor of Neuroscience in The Picower Institute for Learning and Memory at MIT, the crucial decision to switch from one behavior (running) to another (stopping) comes from the brain's cortex, where the brain integrates the learned rules of life with sensory information to guide plans and actions.

"The goal is where the cortex comes in," said Sur, a faculty member of MIT's Department of Brain and Cognitive Sciences. "Where am I supposed to stop to achieve this goal of getting on the bus."

And that's also where it gets complicated. The mathematical models of the behavior that postdoc and study lead author Elie Adam developed predicted that a "stop" signal going directly from the M2 region of the cortex to regions in the brainstem, which actually control the legs, would be processed too slowly.

"You have M2 that is sending a stop signal, but when you model it and go through the mathematics, you find that this signal, by itself, would not be fast enough to make the animal stop in time," said Adam, whose work appears in the journal Cell Reports.

So how does the brain speed up the process? What Adam, Sur and co-author Taylor Johns found was that M2 sends the signal to an intermediary region called the subthalamic nucleus (STN), which then sends out two signals down two separate paths that re-converge in the brainstem. Why? Because the difference made by those two signals, one inhibitory and one excitatory, arriving one right after the other turns the problem from one of integration, which is a relatively slow adding up of inputs, to differentiation, which is a direct recognition of change. The shift in calculus implements the stop signal much more quickly.

Adam's model employing systems and control theory from engineering -- accurately -- predicted the speed needed for a proper stop and that differentiation would be necessary to achieve it, but it took a series of anatomical investigations and experimental manipulations to confirm the model's predictions.

First, Adam confirmed that indeed M2 was producing a surge in neural activity only when the mice needed to achieve their trained goal of stopping at the landmark. He also showed it was sending the resulting signals to the STN. Other stops for other reasons did not employ that pathway. Moreover, artificially activating the M2-STN pathway compelled the mice to stop and artificially inhibiting it caused mice overrun the landmark somewhat more often.

The STN certainly then needed to signal the brainstem -- specifically the pedunculopontine nucleus (PPN) in the mesenecephalic locomotor region. But when the scientists looked at neural activity starting in the M2 and then quickly resulting in the PPN, they saw that different types of cells in the PPN responded with different timing. Particularly, before the stop, excitatory cells were active and their activity reflected the speed of the animal during stops. Then, looking at the STN, they saw two kinds of surges of activity around stops -- one slightly slower than the other -- that were conveyed either directly to PPN through excitation or indirectly via the substantia nigra pars reticulata (SNr) through inhibition. The net result of the interplay of these signals in the PPN was an inhibition sharpened by excitation. That sudden change could be quickly found by differentiation to implement stopping.

"An inhibitory surge followed by excitation can create a sharp [change of] signal," Sur said.

The study dovetails with other recent papers. Working with Picower Institute investigator Emery N. Brown, Adam recently produced a new model of how deep brain stimulation in the STN quickly corrects motor problems that result from Parkinson's disease. And last year members of Sur's lab, including Adam, published a study showing how the cortex overrides the brain's more deeply ingrained reflexes in visually guided motor tasks. Together such studies contribute to understanding how the cortex can consciously control instinctually wired motor behaviors but also how important deeper regions, such as the STN, are to quickly implementing goal-directed behavior. A recent review from the lab expounds on this.

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