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Mice with hallucination-like behaviors reveal insight into psychotic illness: Study in mice and people offers new approach to investigating mental illnesses

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Mice with hallucination-like behaviors reveal insight into psychotic illness: Study in mice and people offers new approach to investigating mental illnesses

The humble lab mouse has provided invaluable clues to understanding diseases ranging from cancer to diabetes to COVID-19. But when it comes to psychiatric conditions, the lab mouse has been sidelined, its rodent mind considered too different from that of humans to provide much insight into mental illness.

A new study, however, shows there are important links between human and mouse minds in how they function — and malfunction. Researchers at Washington University School of Medicine in St. Louis devised a rigorous approach to study how hallucinations are produced in the brain, providing a promising entry point to the development of much-needed new therapies for schizophrenia.

The study, published April 2 in the journal Science, lays out a way to probe the biological roots of a defining symptom of psychosis: hallucinations. The researchers trained people and mice to complete a computer-based task that induced them to hear imaginary sounds. By analyzing performance of the task, the researchers were able to objectively measure hallucination-like events in people and mice. This innovative approach allowed them to study the neural circuits underlying hallucinations, opening up mental symptoms to the kind of scientific studies that have been so fruitful for diseases of other parts of the body.

“It’s so easy to accept the argument that psychosis is a fundamentally human thing and say, ‘Forget about mice’,” said senior author Adam Kepecs, PhD, a professor of neuroscience and of psychiatry, and a BJC Investigator at the School of Medicine. “But right now, we’re failing people with serious psychiatric conditions. The prognosis for psychotic patients has not substantially improved over the past decades, and that’s because we don’t really understand the neurobiology of the disease. Animal models have driven advances in every other field of biomedicine. We’re not going to make progress in treating psychiatric illnesses until we have a good way to model them in animals.”

Psychosis occurs when a person loses touch with reality. During a psychotic episode, people may acquire false beliefs (delusions) or confidently believe that they are seeing or hearing things that are not occurring (hallucinations). A psychotic episode can be a sign of a serious mental illness such as schizophrenia or bipolar disorder, but people without mental illness also can experience symptoms such as hallucinations.

To study how hallucinations occur, Kepecs — with first author Katharina Schmack, MD, PhD, of Cold Spring Harbor Laboratory, and colleagues — set up a computer game that could be completed by both people and mice. The researchers played a particular sound, and subjects indicated that they’d heard it by clicking a button (people) or poking their noses into a port (mice). The task was made challenging by obscuring the sound with background noise. People in the study rated how confident they felt that they’d accurately identified a real sound by moving a slider on a scale; mice indicated their confidence by how long they waited for a reward. When a subject confidently reported that he or she had heard a sound that was not actually played, the researchers labeled that a hallucination-like event.


While simple in design, the task appeared to tap into the brain circuits underlying hallucinations. People with more hallucination-like events during the experiment also were more likely to experience spontaneous hallucinations — as measured by questionnaires designed to evaluate psychiatric symptoms in the general population — even though no participants were diagnosed with a psychiatric condition.

People’s beliefs and expectations can prime them to experience hallucinations. Expecting to hear a certain word makes it more likely that people actually report that they have heard it, even when it wasn’t spoken. In fact, previous studies have shown that people who are prone to hallucinations are particularly susceptible to this kind of priming.

“Human speech is very difficult to comprehend in a noisy environment,” Kepecs said. “We are always balancing our prior knowledge of human speech against what we’re hearing in the moment to understand spoken language. You can easily imagine that this system can get imbalanced, and all of a sudden you’re hearing things.”

To test whether mice also can be primed the same way, Kepecs and colleagues manipulated the mice’s expectations by adjusting how frequently the sound was played. When the sound was played frequently, the mice were even more likely to confidently but wrongly report that they’d heard it — similar to people.

To better connect mouse and human experience, the researchers also used a drug that induces hallucinations. Ketamine can induce distortions in perceptions of sight and sound and can trigger psychotic episodes in healthy people. Mice that were given ketamine before performing the task also reported more hallucination-like events.

Having established these crucial similarities between mice and people, the researchers then investigated the biological roots of hallucinations. By studying mice, they could make use of an arsenal of technologies for monitoring and controlling brain circuits to figure out what happens during hallucination-like events.

The brain chemical dopamine has long been known to play a role in hallucinations. People experiencing hallucinations can be treated with antipsychotic medications that block dopamine. But how dopamine changes brain circuits to produce hallucinations has remained unknown.

When studying mice, the researchers observed that elevations in dopamine levels preceded hallucination-like events and that artificially boosting dopamine levels induced more hallucination-like events. These behavioral effects could be blocked by administering the antipsychotic drug haloperidol, which blocks dopamine.

“There seems to be a neural circuit in the brain that balances prior beliefs and evidence, and the higher the baseline level of dopamine, the more you rely on your prior beliefs,” Kepecs said. “We think that hallucinations occur when this neural circuit gets unbalanced, and antipsychotics rebalance it. Our computer game probably engages this same circuit, so hallucination-like events reflect this circuit imbalance. We are very excited about this computational approach to study hallucinations across species that enables us to finally probe the neurobiological roots of this mysterious experience.”

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Mechanism found to determine which memories last

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Mice with hallucination-like behaviors reveal insight into psychotic illness: Study in mice and people offers new approach to investigating mental illnesses


Neuroscientists have established in recent decades the idea that some of each day’s experiences are converted by the brain into permanent memories during sleep the same night. Now, a new study proposes a mechanism that determines which memories are tagged as important enough to linger in the brain until sleep makes them permanent.

Led by researchers from NYU Grossman School of Medicine, the study revolves around brain cells called neurons that “fire” — or bring about swings in the balance of their positive and negative charges — to transmit electrical signals that encode memories. Large groups of neurons in a brain region called the hippocampus fire together in rhythmic cycles, creating sequences of signals within milliseconds of each other that can encode complex information.

Called “sharp wave-ripples,” these “shouts” to the rest of the brain represent the near-simultaneous firing of 15 percent of hippocampal neurons, and are named for the shape they take when their activity is captured by electrodes and recorded on a graph.

While past studies had linked ripples with memory formation during sleep, the new study, published online in the journal Science on March 28, found that daytime events followed immediately by five to 20 sharp wave-ripples are replayed more during sleep and so consolidated into permanent memories. Events followed by very few or no sharp wave-ripples failed to form lasting memories.

“Our study finds that sharp wave-ripples are the physiological mechanism used by the brain to ‘decide’ what to keep and what to discard,” said senior study author György Buzsáki, MD, PhD, the Biggs Professor of Neuroscience in the Department of Neuroscience and Physiology at NYU Langone Health.

Walk and Pause

The new study is based on a known pattern: mammals including humans experience the world for a few moments, then pause, then experience a little more, then pause again. After we pay attention to something, say the study authors, brain computation often switches into an “idle” re-assessment mode. Such momentary pauses occur throughout the day, but the longest idling periods occur during sleep.

Buzsaki and colleagues had previously established that no sharp wave-ripples occur as we actively explore sensory information or move, but only during the idle pauses before or after. The current study found that sharp wave-ripples represent the natural tagging mechanism during such pauses after waking experiences, with the tagged neuronal patterns reactivated during post-task sleep.

Importantly, sharp wave-ripples are known to be made up the firing of hippocampal “place cells” in a specific order that encodes every room we enter, and each arm of a maze entered by a mouse. For memories that are remembered, those same cells fire at high speed, as we sleep, “playing back the recorded event thousands times per night.” The process strengthens the connections between the cells involved.

For the current study, successive maze runs by study mice were tracked via electrodes by populations of hippocampal cells that constantly changed over time despite recording very similar experiences. This revealed for the first time the maze runs during which ripples occurred during waking pauses, and then were replayed during sleep.

Sharp wave-ripples were typically recorded when a mouse paused to enjoy a sugary treat after each maze run. The consumption of the reward, say the authors, prepared the brain to switch from an exploratory to an idle pattern so that sharp wave-ripples could occur.

Using dual-sided silicon probes, the research team was able to record up to 500 neurons simultaneously in the hippocampus of animals during maze runs. This in turn created a challenge because data becomes exceedingly complex the more neurons are independently recorded. To gain an intuitive understanding of the data, visualize neuronal activity, and form hypotheses, the team successfully reduced the number of dimensions in the data, in some ways like converting a three-dimensional image into a flat one, and without losing the data’s integrity.

“We worked to take the external world out of the equation, and looked at the mechanisms by which the mammalian brain innately and subconsciously tags some memories to become permanent,” said first author Wannan (Winnie) Yang, PhD, a graduate student in Buzsáki’s lab. “Why such a system evolved is still a mystery, but future research may reveal devices or therapies that can adjust sharp wave-ripples to improve memory, or even lessen recall of traumatic events.”

Along with Drs. Buzsáki and Yang, study authors from the Neuroscience Institute at NYU Langone Health were Roman Huszár and Thomas Hainmueller. Kirill Kiselev of the Center for Neural Science at New York University was also an author, as was Chen Sun of Mila, the Quebec Artificial Intelligence Institute, in Montréal. The work was supported by National Institute of Health grants R01MH122391 and U19NS107616.



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Long-period oscillations control the Sun’s differential rotation

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Mice with hallucination-like behaviors reveal insight into psychotic illness: Study in mice and people offers new approach to investigating mental illnesses


The Sun’s differential rotation pattern has puzzled scientists for decades: while the poles rotate with a period of approximately 34 days, mid-latitudes rotate faster and the equatorial region requires only approximately 24 days for a full rotation. In addition, in past years advances in helioseismology, i.e. probing the solar interior with the help of solar acoustic waves, have established that this rotational profile is nearly constant throughout the entire convection zone. This layer of the Sun stretches from a depth of approximately 200,000 kilometers to the visible solar surface and is home to violent upheavals of hot plasma which play a crucial role in driving solar magnetism and activity.

While theoreticaThe interior of the Sun does not rotate at the same rate at all latitudes. The physical origin of this differential rotation is not fully understood. A team of scientists at the Max Planck Institute for Solar System Research (MPS) in Germany has made a ground-breaking discovery. As the team reports today in the journal Science Advances, the long-period solar oscillations discovered by MPS scientists in 2021 play a crucial role in controlling the Sun’s rotational pattern. The long-period oscillations are analogous to the baroclinically unstable waves in Earth’s atmosphere that shape the weather. In the Sun, these oscillations carry heat from the slightly hotter poles to the slightly cooler equator. To obtain their new results, the scientists interpreted observations from NASA’s Solar Dynamics Observatory using cutting-edge numerical simulations of the solar interior. They found that the difference in temperature between the poles and the equator is about seven degrees.

l models have long postulated a slight temperature difference between solar poles and equator to maintain the Sun’s rotational pattern, it has proven notoriously difficult to measure. After all, observations have to “look through” the background of the Sun’s deep interior which measures up to million degrees in temperature. However, as the researchers from MPS show, it is now possible to determine the temperature difference from the observations of the long-period oscillations of the Sun.

In their analysis of observational data obtained by the Helioseismic and Magnetic Imager (HMI) onboard NASA’s Solar Dynamics Observatory from 2017 to 2021, the scientists turned to global solar oscillations with long periods that can be discerned as swirling motions at the solar surface. Scientists from MPS reported their discovery of these inertial oscillations three years ago. Among these observed modes, the high-latitude modes with velocities of up to 70 km per hour, proved to be especially influential.

To study the nonlinear nature of these high-latitude oscillations, a set of three-dimensional numerical simulations was conducted. In their simulations, the high-latitude oscillations carry heat from the solar poles to the equator, which limits the temperature difference between the Sun’s poles and the equator to less than seven degrees. “This very small temperature difference between the poles and the equator controls the angular momentum balance in the Sun and thus is an important feedback mechanism for the Sun’s global dynamics” says MPS Director Prof. Dr. Laurent Gizon.

In their simulations, the researchers for the first time described the crucial processes in a fully three-dimensional model. Former endeavors had been limited to two-dimensional approaches that assumed the symmetry about the Sun’s rotation axis. “Matching the nonlinear simulations to the observations allowed us to understand the physics of the long-period oscillations and their role in controlling the Sun’s differential rotation,” says MPS postdoc and the lead author of the study, Dr. Yuto Bekki.

The solar high-latitude oscillations are driven by a temperature gradient in a similar way to extratropical cyclones on the Earth. The physics is similar, though the details are different: “In the Sun, the solar pole is about seven degrees hotter than equator and this is enough to drive flows of about 70 kilometers per hour over a large fraction of the Sun. The process is somewhat similar to the driving of cyclones,” says MPS scientist Dr. Robert Cameron.

Probing the physics of the Sun’s deep interior is difficult. This study is important as it shows that the long-period oscillations of the Sun are not only useful probes of the solar interior, but that they play an active role in the way the Sun works. Future work, which will be carried out in the context of the ERC Synergy Grant WHOLESUN and the DFG Collaborative Research Center 1456 Mathematics of Experiments, will be aimed at better understanding the role of these oscillations and their diagnostic potential.



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Artificial reef designed by MIT engineers could protect marine life, reduce storm damage

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Mice with hallucination-like behaviors reveal insight into psychotic illness: Study in mice and people offers new approach to investigating mental illnesses


The beautiful, gnarled, nooked-and-crannied reefs that surround tropical islands serve as a marine refuge and natural buffer against stormy seas. But as the effects of climate change bleach and break down coral reefs around the world, and extreme weather events become more common, coastal communities are left increasingly vulnerable to frequent flooding and erosion.

An MIT team is now hoping to fortify coastlines with “architected” reefs — sustainable, offshore structures engineered to mimic the wave-buffering effects of natural reefs while also providing pockets for fish and other marine life.

The team’s reef design centers on a cylindrical structure surrounded by four rudder-like slats. The engineers found that when this structure stands up against a wave, it efficiently breaks the wave into turbulent jets that ultimately dissipate most of the wave’s total energy. The team has calculated that the new design could reduce as much wave energy as existing artificial reefs, using 10 times less material.

The researchers plan to fabricate each cylindrical structure from sustainable cement, which they would mold in a pattern of “voxels” that could be automatically assembled, and would provide pockets for fish to explore and other marine life to settle in. The cylinders could be connected to form a long, semipermeable wall, which the engineers could erect along a coastline, about half a mile from shore. Based on the team’s initial experiments with lab-scale prototypes, the architected reef could reduce the energy of incoming waves by more than 95 percent.

“This would be like a long wave-breaker,” says Michael Triantafyllou, the Henry L. and Grace Doherty Professor in Ocean Science and Engineering in the Department of Mechanical Engineering. “If waves are 6 meters high coming toward this reef structure, they would be ultimately less than a meter high on the other side. So, this kills the impact of the waves, which could prevent erosion and flooding.”

Details of the architected reef design are reported today in a study appearing in the open-access journal PNAS Nexus. Triantafyllou’s MIT co-authors are Edvard Ronglan SM ’23; graduate students Alfonso Parra Rubio, Jose del Auila Ferrandis, and Erik Strand; research scientists Patricia Maria Stathatou and Carolina Bastidas; and Professor Neil Gershenfeld, director of the Center for Bits and Atoms; along with Alexis Oliveira Da Silva at the Polytechnic Institute of Paris, Dixia Fan of Westlake University, and Jeffrey Gair Jr. of Scinetics, Inc.

Leveraging turbulence

Some regions have already erected artificial reefs to protect their coastlines from encroaching storms. These structures are typically sunken ships, retired oil and gas platforms, and even assembled configurations of concrete, metal, tires, and stones. However, there’s variability in the types of artificial reefs that are currently in place, and no standard for engineering such structures. What’s more, the designs that are deployed tend to have a low wave dissipation per unit volume of material used. That is, it takes a huge amount of material to break enough wave energy to adequately protect coastal communities.

The MIT team instead looked for ways to engineer an artificial reef that would efficiently dissipate wave energy with less material, while also providing a refuge for fish living along any vulnerable coast.

“Remember, natural coral reefs are only found in tropical waters,” says Triantafyllou, who is director of the MIT Sea Grant. “We cannot have these reefs, for instance, in Massachusetts. But architected reefs don’t depend on temperature, so they can be placed in any water, to protect more coastal areas.”

The new effort is the result of a collaboration between researchers in MIT Sea Grant, who developed the reef structure’s hydrodynamic design, and researchers at the Center for Bits and Atoms (CBA), who worked to make the structure modular and easy to fabricate on location. The team’s architected reef design grew out of two seemingly unrelated problems. CBA researchers were developing ultralight cellular structures for the aerospace industry, while Sea Grant researchers were assessing the performance of blowout preventers in offshore oil structures — cylindrical valves that are used to seal off oil and gas wells and prevent them from leaking.

The team’s tests showed that the structure’s cylindrical arrangement generated a high amount of drag. In other words, the structure appeared to be especially efficient in dissipating high-force flows of oil and gas. They wondered: Could the same arrangement dissipate another type of flow, in ocean waves?

The researchers began to play with the general structure in simulations of water flow, tweaking its dimensions and adding certain elements to see whether and how waves changed as they crashed against each simulated design. This iterative process ultimately landed on an optimized geometry: a vertical cylinder flanked by four long slats, each attached to the cylinder in a way that leaves space for water to flow through the resulting structure. They found this setup essentially breaks up any incoming wave energy, causing parts of the wave-induced flow to spiral to the sides rather than crashing ahead.

“We’re leveraging this turbulence and these powerful jets to ultimately dissipate wave energy,” Ferrandis says.

Standing up to storms

Once the researchers identified an optimal wave-dissipating structure, they fabricated a laboratory-scale version of an architected reef made from a series of the cylindrical structures, which they 3D-printed from plastic. Each test cylinder measured about 1 foot wide and 4 feet tall. They assembled a number of cylinders, each spaced about a foot apart, to form a fence-like structure, which they then lowered into a wave tank at MIT. They then generated waves of various heights and measured them before and after passing through the architected reef.

“We saw the waves reduce substantially, as the reef destroyed their energy,” Triantafyllou says.

The team has also looked into making the structures more porous, and friendly to fish. They found that, rather than making each structure from a solid slab of plastic, they could use a more affordable and sustainable type of cement.

“We’ve worked with biologists to test the cement we intend to use, and it’s benign to fish, and ready to go,” he adds.

They identified an ideal pattern of “voxels,” or microstructures, that cement could be molded into, in order to fabricate the reefs while creating pockets in which fish could live. This voxel geometry resembles individual egg cartons, stacked end to end, and appears to not affect the structure’s overall wave-dissipating power.

“These voxels still maintain a big drag while allowing fish to move inside,” Ferrandis says.

The team is currently fabricating cement voxel structures and assembling them into a lab-scale architected reef, which they will test under various wave conditions. They envision that the voxel design could be modular, and scalable to any desired size, and easy to transport and install in various offshore locations. “Now we’re simulating actual sea patterns, and testing how these models will perform when we eventually have to deploy them,” says Anjali Sinha, a graduate student at MIT who recently joined the group.

Going forward, the team hopes to work with beach towns in Massachusetts to test the structures on a pilot scale.

“These test structures would not be small,” Triantafyllou emphasizes. “They would be about a mile long, and about 5 meters tall, and would cost something like 6 million dollars per mile. So it’s not cheap. But it could prevent billions of dollars in storm damage. And with climate change, protecting the coasts will become a big issue.”

This work was funded, in part, by the U.S. Defense Advanced Research Projects Agency.



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