NS/ VR goggles for mice enhance behavioral research
Neuroscience biweekly vol. 100🎉, 6th December — 19th December
TL;DR
- Northwestern University researchers have developed new virtual reality (VR) goggles for mice. Besides just being cute, these miniature goggles provide more immersive experiences for mice living in laboratory settings. By more faithfully simulating natural environments, the researchers can more accurately and precisely study the neural circuitry that underlies behavior.
- ETH Zurich researchers have shown for the first time that microvehicles can be steered through blood vessels in the brains of mice using ultrasound. They hope that this will eventually lead to treatments capable of delivering drugs with pinpoint precision.
- Tracking rare cell types in the brain has proved equally elusive. Yet alterations in some of these cells may be associated with a variety of diseases, including Alzheimer’s. Being able to find and study them could potentially open up a new world of brain analysis and disease intervention. As described in a new paper in Nature Genetics, scientists have developed a low-cost, high-throughput technique for finding these secretive cells by scanning an entire mouse brain at once — a digital bucket that captured 1.5 million cells and can hold many more.
- Researchers from the GrapheneX-UTS Human-centric Artificial Intelligence Centre at the University of Technology Sydney (UTS) have developed a portable, non-invasive system that can decode silent thoughts and turn them into text. The technology could aid communication for people who are unable to speak due to illness or injury, including stroke or paralysis. It could also enable seamless communication between humans and machines, such as the operation of a bionic arm or robot.
- New research reveals that neurons in the preoptic hypothalamus — the region of the brain that regulates sleep and body temperature — are rhythmically activated during non-rapid eye movement sleep (NREM). Stress activates these brain cells out of turn, causing ‘microarousals,’ that interrupt sleep cycles and decrease the duration of sleep episodes, according to new research.
- Researchers have created a complete cell atlas of a whole mammalian brain. This atlas serves as a map for the mouse brain, describing the type, location, and molecular information of more than 32 million cells and providing information on connectivity between these cells.
- A new study provides us with a better understanding of how the brain responds to injuries. Researchers have discovered that a protein called Snail plays a key role in coordinating the response of brain cells after an injury.
- In mice and human cell cultures, MIT researchers showed that novel nanoparticles can deliver a potential therapy for inflammation in the brain, a prominent symptom of Alzheimer’s disease.
- In research conducted on mice, a team discovered brain mechanisms that go awry as a result of exposure to trauma in infancy and showed that these changes may be reversible if treated early.
- Practicing yoga nidra — a kind of mindfulness training — might improve sleep, cognition, learning, and memory, even in novices, according to a pilot study published in PLOS ONE. After a two-week intervention with a cohort of novice practitioners, the researchers found that the percentage of delta-waves in deep sleep increased and that all tested cognitive abilities improved.
Neuroscience market
The global neuroscience market size was valued at USD 28.4 billion in 2016 and it is expected to reach USD 38.9 billion by 2027.
The latest news and research
Generation of innervated cochlear organoid recapitulates early development of auditory unit
by Xia M, Ma J, Wu M, et al. in Stem Cell Rep
Northwestern University researchers have developed new virtual reality (VR) goggles for mice. Besides just being cute, these miniature goggles provide more immersive experiences for mice living in laboratory settings. By more faithfully simulating natural environments, the researchers can more accurately and precisely study the neural circuitry that underlies behavior.
Compared to current state-of-the-art systems, which simply surround mice with computer or projection screens, the new goggles provide a leap in advancement. In current systems, mice can still see the lab environment peeking out from behind the screens, and the screens’ flat nature cannot convey three-dimensional (3D) depth. Another disadvantage, researchers have been unable to easily mount screens above mice’s heads to simulate overhead threats, such as looming birds of prey.
The new VR goggles bypass all those issues. And, as VR grows in popularity, the goggles also could help researchers glean new insights into how the human brain adapts and reacts to repeated VR exposure — an area that is currently little understood. The research marks the first time researchers have used a VR system to simulate an overhead threat.
“For the past 15 years, we have been using VR systems for mice,” said Northwestern’s Daniel Dombeck, the study’s senior author. “So far, labs have been using big computer or projection screens to surround an animal. For humans, this is like watching a TV in your living room. You still see your couch and your walls. There are cues around you, telling you that you aren’t inside the scene. Now think about putting on VR goggles, like Oculus Rift, that take up your full vision. You don’t see anything but the projected scene, and a different scene is projected into each eye to create depth information. That’s been missing for mice.”
Dombeck is a professor of neurobiology at Northwestern’s Weinberg College of Arts and Sciences. His laboratory is a leader in developing VR-based systems and high-resolution, laser-based imaging systems for animal research.
Although researchers can observe animals in nature, it is incredibly difficult to image patterns of real-time brain activity while animals engage with the real world. To overcome this challenge, researchers have integrated VR into laboratory settings. In these experimental setups, an animal uses a treadmill to navigate scenes, such as a virtual maze, projected onto surrounding screens.
By keeping the mouse in place on the treadmill — rather than allowing it to run through a natural environment or physical maze — neurobiologists can use tools to view and map the brain as the mouse traverses a virtual space. Ultimately, this helps researchers grasp general principles of how activated neural circuits encode information during various behaviors.
“VR basically reproduces real environments,” Dombeck said. “We’ve had a lot of success with this VR system, but it’s possible the animals aren’t as immersed as they would be in a real environment. It takes a lot of training just to get the mice to pay attention to the screens and ignore the lab around them.”
With recent advances in hardware miniaturization, Dombeck and his team wondered if they could develop VR goggles to more faithfully replicate a real environment. Using custom-designed lenses and miniature organic light-emitting diode (OLED) displays, they created compact goggles.
Called Miniature Rodent Stereo Illumination VR (iMRSIV), the system comprises two lenses and two screens — one for each side of the head to separately illuminate each eye for 3D vision. This provides each eye with a 180-degree field-of-view that fully immerses the mouse and excludes the surrounding environment.
Unlike VR goggles for a human, the iMRSIV (pronounced “immersive”) system does not wrap around the mouse’s head. Instead, the goggles are attached to the experimental setup and closely perch directly in front of the mouse’s face. Because the mouse runs in place on a treadmill, the goggles still cover the mouse’s field of view.
“We designed and built a custom holder for the goggles,” said John Issa, a postdoctoral fellow in Dombeck’s laboratory and study co-first author. “The whole optical display — the screens and the lenses — go all the way around the mouse.”
By mapping the mice’s brains, Dombeck and his team found that the brains of goggle-wearing mice were activated in very similar ways as in freely moving animals. And, in side-by-side comparisons, the researchers noticed that goggle-wearing mice engaged with the scene much more quickly than mice with traditional VR systems.
“We went through the same kind of training paradigms that we have done in the past, but mice with the goggles learned more quickly,” Dombeck said. “After the first session, they could already complete the task. They knew where to run and looked to the right places for rewards. We think they actually might not need as much training because they can engage with the environment in a more natural way.”
Next, the researchers used the goggles to simulate an overhead threat — something that had been previously impossible with current systems. Because hardware for imaging technology already sits above the mouse, there is nowhere to mount a computer screen. The sky above a mouse, however, is an area where animals often look for vital — sometimes life-or-death — information.
“The top of a mouse’s field of view is very sensitive to detect predators from above, like a bird,” said co-first author Dom Pinke, a research specialist in Dombeck’s lab. “It’s not a learned behavior; it’s an imprinted behavior. It’s wired inside the mouse’s brain.”
To create a looming threat, the researchers projected a dark, expanding disk into the top of the goggles — and the top of the mice’s fields of view. In experiments, mice — upon noticing the disk — either ran faster or froze. Both behaviors are common responses to overhead threats. Researchers were able to record neural activity to study these reactions in detail.
“In the future, we’d like to look at situations where the mouse isn’t prey but is the predator,” Issa said. “We could watch brain activity while it chases a fly, for example. That activity involves a lot of depth perception and estimating distances. Those are things that we can start to capture.”
In addition to opening the door for more research, Dombeck hopes the goggles open the door to new researchers. Because the goggles are relatively inexpensive and require less intensive laboratory setups, he thinks they could make neurobiology research more accessible.
“Traditional VR systems are pretty complicated,” Dombeck said. “They’re expensive, and they’re big. They require a big lab with a lot of space. And, on top of that, if it takes a long time to train a mouse to do a task, that limits how many experiments you can do. We’re still working on improvements, but our goggles are small, relatively cheap and pretty user friendly as well. This could make VR technology more available to other labs.”
Ultrasound trapping and navigation of microrobots in the mouse brain vasculature
by Del Campo Fonseca A, Glück C, Droux J, et al. in Nature Communications
ETH Zurich researchers have shown for the first time that microvehicles can be steered through blood vessels in the brains of mice using ultrasound. They hope that this will eventually lead to treatments capable of delivering drugs with pinpoint precision.
Brain tumours, brain haemorrhages and neurological and psychological conditions are often hard to treat with medication. And even when effective drugs are available, these tend to have severe side effects because they circulate throughout the brain and not just the area they are meant to treat. In light of this situation, researchers have high hopes of one day being able to provide a more targeted approach that would deliver medications to very specifically defined locations. To this end, they are in the process of developing mini-transporters that can be guided through the dense maze of blood vessels.
Researchers at ETH Zurich, the University of Zurich and the University Hospital Zurich have now managed for the first time to guide microvehicles through the blood vessels in the brain of an animal using ultrasound.
Compared to alternative navigation technologies such as those based on magnetic fields, ultrasound offers certain benefits. Daniel Ahmed, Professor of Acoustic Robotics at ETH Zurich and supervisor of the study, explains:
“In addition to being widely used in the medical field, ultrasound is safe and penetrates deep into the body.”
For their microvehicle, Ahmed and his colleagues used gas-filled microbubbles coated in lipids — the same substances that biological cell membranes are made of. The bubbles have a diameter of 1.5 micrometres and are currently used as contrast material in ultrasound imaging.
As the researchers have now shown, these microbubbles can be guided through blood vessels.
“Since these bubbles, or vesicles, are already approved for use in humans, it’s likely that our technology will be approved and used in treatments for humans more quickly than other types of microvehicles currently in development,” Ahmed says.
He was awarded a Starting Grant by the European Research Council ERC in 2019 for his project to research and develop this technology.
Another benefit of ultrasound-guided microbubbles is that they dissolve in the body once they’ve done their job. When using another approach, magnetic fields, the microvehicles have to be magnetic, and it’s not easy to develop biodegradable microvehicles. Moreover, the microbubbles developed by the ETH Zurich researchers are small and smooth.
“This makes it easy for us to guide them along narrow capillaries,” says Alexia Del Campo Fonseca, a doctoral student in Ahmed’s group and lead author of the study.
Over the past few years, Ahmed and his group have been working in the lab to develop their method for guiding microbubbles through narrow vessels. Now, in collaboration with researchers from the University of Zurich and University Hospital Zurich, they have tested this method on blood vessels in the brains of mice. The researchers injected the bubbles into the rodents’ circulatory system, where they are swept along in the bloodstream without any outside help. However, the researchers managed to use ultrasound to hold the vesicles in place and guide them through the brain vessels against the direction of blood flow. The researchers were even able to guide the bubbles through convoluted blood vessels or get them to change direction multiple times in order to steer them into the narrowest branches of the bloodstream.
To control the microvehicles’ movements, the researchers also attached four small transducers to the outside of each mouse’s skull. These devices generate vibrations in the ultrasonic range, which spread through the brain as waves. At certain points in the brain, the waves emitted by two or more transducers can either amplify each other or cancel each other out. The researchers guide the bubbles using a sophisticated method of adjusting the output of each individual transducer. Real-time imaging shows them what direction the bubbles are moving in.
To create the imaging for this study, the researchers used two-photon microscopy. In the future, they also want to use ultrasound itself for imaging and plan to enhance ultrasound technology for this purpose.
In this study, the microbubbles were not equipped with medications. The researchers first wanted to show that they could guide the microvehicles along blood vessels and that this technology is suitable for use in the brain. That’s where there are promising medical applications, including in the treatment of cancer, stroke and psychological conditions. The researchers’ next step will be to attach drug molecules to the outside of the bubble casing for transport. They want to enhance the entire method to the point at which it can be used in humans, hoping it will one day provide the basis for the development of new treatments.
A global view of aging and Alzheimer’s pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains
by Sziraki A, Lu Z, Lee J, et al. in Nat Genet.
A single drop of rain is undetectable in the ocean. It couldn’t even be found in a bucket of salty water. But if a single container outfitted with extraordinarily precise sensors could scoop up the entire ocean, it would suddenly be possible to locate that one tiny drop. Tracking rare cell types in the brain has proved equally elusive. And yet alterations in some of these cells may be associated with a variety of diseases, including Alzheimer’s. Being able to find and study them could potentially open up a new world of brain analysis and disease intervention. As described in a new paper in Nature Genetics, Rockefeller geneticist Junyue Cao and his colleagues have developed a low-cost, high-throughput technique for finding these secretive cells by scanning an entire mouse brain at once — a digital bucket that captured 1.5 million cells and can hold many more.
A type of single-cell sequencing called EasySci, their method can simultaneously reveal the identity of every cell entered into the system. The researchers used it to illuminate cell populations and dynamics specific to different ages, as well as to Alzheimer’s disease, in both mouse and human brains. Some cellular subtypes have never been seen before.
“A key feature of EasySci is that instead of focusing on specific brain regions, we can scan each cell, one by one, across millions of cells, to create a holistic view of the entire brain — and to identify detailed changes for different cell types,” says Cao, head of the Laboratory of Single-Cell Genomics and Population Dynamics at Rockefeller. “We can use this to understand aging and Alzheimer’s disease.”
When it comes to understanding neurological conditions, access to human brain tissue is essential. But because it’s such a precious, finite resource, most analyses of brain tissues rely on small sections from select areas of the brain. And yet the human brain is a fantastically complex network made up of more than 3,000 types of cells. Being able to see its molecular totality could reveal hidden cells that though rare might produce an outsized effect.
Recent advances in single-cell sequencing — a method of genetic analysis that homes in on the genetic expression and molecular dynamics of individual cells — are making it increasingly possible to find rare cells and explore cell dynamics. And while it’s still not possible to scan an entire human brain using single-cell sequencing, the mouse brain provides a good model for testing the technological potential.
For the current study, led by Cao lab researchers Andras Sziraki, Ziyu Lu, and Jasper Lee, the team used a method called combinatorial indexing to reveal more about these cells and their dynamics. The technique involves attaching ID tags to different molecules, resulting in every molecule having a unique barcode. In this way, they can then identify and tally the number of all the different cell types.
The researchers studied six types of brains: young, adult, and aged mouse brains; mouse brains with neural degeneration that mimics Alzheimer’s disease; and tissues from human brains that were either normal or had Alzheimer’s disease. The human samples came from the hippocampus, associated with learning and memory, and the superior and middle temporal gyrus, both located in the temporal lobe and linked to the processing of language and sound.
Scanning more than 1.5 million cells, the researchers identified 31 cell types and 359 subtypes in the mouse brain; nearly one-third of these subtypes had never been reported before. They discovered that the star-shaped astrocyte cells in one brain region, for example, were different from astrocytes in a different area; some subtypes even within the same region showed variations.
The most common cells were cerebellum granule neurons (32.5%), which pass information from the central nervous system to the cerebellar cortex. Rarest were inferior olivary nucleus neurons (0.05%), which are located in the brainstem and process data about the body’s movements.
“If we had only scanned 100 or even 1000 cells, we never would have seen some of these rare cell types,” Cao says. “We needed to scan millions of cells.”
Another rare cell type they identified was the pinealocyte, a pineal gland cell that secretes the hormone melatonin, which is linked to circadian rhythm. There were just 21 pinealocyte cells in that batch of a million.
They also learned that the olfactory bulbs of young mice brim with a special group of neurons and astrocytes that more than double across the early developmental stages — not surprising for an animal that relies on a highly developed sense of smell to navigate its environment. And they found that “neurons in the olfactory bulb have many different subtypes in the same location with different functions,” Cao says.
Distinct cells — and changes — marked the Alzheimer’s brains, both mouse and human. A rare subtype of choroid plexus epithelial cells, key structural components of the blood-brain barrier that secrete cerebrospinal fluid, had been lost twice as much in Alzheimer’s brains. These cells are associated with mitochondrial genes that protect against neurodegeneration and Tau proteins in cerebrospinal fluid.
They also documented new changes in 20 cell subtypes, some of them in brain regions where they’ve never been seen before. This is important, Cao says, because many Alzheimer researchers focus on cortical regions or the hippocampus, which are associated with common symptoms.
“But as we have shown in both human and mouse AD brains, there are many other regions that see changes,” he says.
Moreover, he adds, with conventional techniques, you can only identify two or three molecular biomarkers of disease inside each cell, but EasySci can potentially identify thousands of them.
“And once you identify those ‘bugs,’” he says, “you can seek ways to correct them.”
In the future, Cao and his team plan to use EasySci to scan mixed tissues.
“We can use this to scan many brains from diverse patients within a single experiment,” he notes. As they describe in a recent paper in Nature, they’ve already tested the approach with 101 mutant mouse embryos, scanning 1.6 million cell nuclei simultaneously.
In an upcoming study, the team shares the results of its scans of every major internal organ of the mouse at once. The mouse brain needs more attention too: the current study covered only around 2% of that total cell population, which is estimated to top out at approximately 100 million. Extending this technology to the human brain — with its staggering 170 billion cells — presents a more complex challenge and will necessitate developing new techniques.
But by focusing on increasing EasySci’s throughput power, Cao is optimistic that the method will soon be able to scan tens of millions of cells at once.
“We want to further refine this method to the extent that it can be used to scan every cell, from those in the brain to the entirety of the body. This could provide critical insights for addressing cellular changes associated with aging and Alzheimer’s disease,” he says.
DeWave: Discrete encoding of EEG Waves for EEG to text translation
by Lin CT, Duan Y, Zhou J, et al. Presented at NeurIPS 2023, December 12, 2023, New Orleans.
In a world-first, researchers from the GrapheneX-UTS Human-centric Artificial Intelligence Centre at the University of Technology Sydney (UTS) have developed a portable, non-invasive system that can decode silent thoughts and turn them into text.
The technology could aid communication for people who are unable to speak due to illness or injury, including stroke or paralysis. It could also enable seamless communication between humans and machines, such as the operation of a bionic arm or robot.
The study has been selected as the spotlight paper at the NeurIPS conference, a top-tier annual meeting that showcases world-leading research on artificial intelligence and machine learning, held in New Orleans on 12 December 2023.
The research was led by Distinguished Professor CT Lin, Director of the GrapheneX-UTS HAI Centre, together with first author Yiqun Duan and fellow PhD candidate Jinzhou Zhou from the UTS Faculty of Engineering and IT.
In the study participants silently read passages of text while wearing a cap that recorded electrical brain activity through their scalp using an electroencephalogram (EEG). A demonstration of the technology can be seen in this video.
The EEG wave is segmented into distinct units that capture specific characteristics and patterns from the human brain. This is done by an AI model called DeWave developed by the researchers. DeWave translates EEG signals into words and sentences by learning from large quantities of EEG data.
“This research represents a pioneering effort in translating raw EEG waves directly into language, marking a significant breakthrough in the field,” said Distinguished Professor Lin.
“It is the first to incorporate discrete encoding techniques in the brain-to-text translation process, introducing an innovative approach to neural decoding. The integration with large language models is also opening new frontiers in neuroscience and AI,” he said.
Previous technology to translate brain signals to language has either required surgery to implant electrodes in the brain, such as Elon Musk’s Neuralink, or scanning in an MRI machine, which is large, expensive, and difficult to use in daily life.
These methods also struggle to transform brain signals into word level segments without additional aids such as eye-tracking, which restrict the practical application of these systems. The new technology is able to be used either with or without eye-tracking.
The UTS research was carried out with 29 participants. This means it is likely to be more robust and adaptable than previous decoding technology that has only been tested on one or two individuals, because EEG waves differ between individuals.
The use of EEG signals received through a cap, rather than from electrodes implanted in the brain, means that the signal is noisier. In terms of EEG translation however, the study reported state-of the art performance, surpassing previous benchmarks.
“The model is more adept at matching verbs than nouns. However, when it comes to nouns, we saw a tendency towards synonymous pairs rather than precise translations, such as ‘the man’ instead of ‘the author’,” said Duan.
“We think this is because when the brain processes these words, semantically similar words might produce similar brain wave patterns. Despite the challenges, our model yields meaningful results, aligning keywords and forming similar sentence structures,” he said.
The translation accuracy score is currently around 40% on BLEU-1. The BLEU score is a number between zero and one that measures the similarity of the machine-translated text to a set of high-quality reference translations. The researchers hope to see this improve to a level that is comparable to traditional language translation or speech recognition programs, which is closer to 90%.
Regulation of stress-induced sleep fragmentation by preoptic glutamatergic neurons
by Jennifer Smith, Adam Honig-Frand, Hanna Antila, Kevin Beier, Franz Weber, Shinjae Chung in Submitted to bioRxiv; accepted by Current Biology
New research reveals that neurons in the preoptic hypothalamus — the region of the brain that regulates sleep and body temperature — are rhythmically activated during non-rapid eye movement sleep (NREM). Stress activates these brain cells out of turn, causing “microarousals,” that interrupt sleep cycles and decrease the duration of sleep episodes, according to research from Perelman School of Medicine at the University of Pennsylvania, published in Current Biology.
While our bodies are at rest when we are asleep, our brains are still very active during four different stages of sleep.
In each 90-minute sleep cycle, there are three stages of NREM sleep, and one stage of rapid eye movement (REM) sleep.
During the first two stages of NREM sleep, brain waves, heartbeat, and breathing slow, and body temperature decreases.
Stage two also includes unique brain activity, called spindles and K-complexes, which are short bursts of activity responsible for processing outside stimuli, as well as for consolidating memory.
Stage three of the NREM sleep cycle is when the body releases growth hormone, which is important for repairing the body, keeping the immune system healthy, and further improving memory.
During phase three, brain waves are larger, called delta waves.
REM sleep, which happens in this phase when dreaming normally occurs, is also critical for memory formation, emotional processing, and brain development.
“When you have a bad night of sleep, you notice that your memory isn’t as good as it normally is, or your emotions are all over the place — but a bad night of sleep interrupts so many other processes throughout your body. This is even more heightened in individuals with stress-related sleep disorders,” said senior author, Shinjae Chung, PhD, an assistant professor of Neuroscience.
“It’s crucial to understand the biology driving the brain activity in these crucial stages of sleep, and how stimuli like stress can disrupt it, so that we might someday develop therapies to help individuals have more restful sleep that allows their brain to complete these important processes.”
The researchers monitored the activity in the preoptic area (POA) of the hypothalamus of mice during their natural sleep and found that glutamatergic neurons (VGLUT2) are rhythmically activated during NREM sleep.
They also found that VGLUT2 neurons were most active during wakefulness, and less active during NREM and REM sleep.
During microarousals in NREM sleep, VGLUT2 neurons were the only active neurons within the POA, and their signals started to increase in the time before a microarousal.
To confirm that active VGLUT2 neurons were indeed the cause of microarousal, the researchers stimulated the VGLUT2 neurons in sleeping subjects, which immediately increased the amount of microarousals and wakefulness.
Next, to illustrate the connection between stress and increased VGLUT2 neuron activation, researchers exposed subjects to a stressor, which increased awake time and microarousals, and decreased overall time spent in REM and NREM sleep.
Researchers also noted increased VGLUT2 neuron activity during NREM sleep in the stressed subjects.
What’s more, when researchers inhibited VGLUT 2 neurons, microarousals during NREM sleep decreased, and NREM sleep episodes were longer.
“The glutamatergic neurons in the hypothalamus give us a promising target for developing treatments for stress-related sleep disorders,” said first author, Jennifer Smith, a graduate researcher in Chung’s lab.
“Being able to reduce interruptions during the important stages of non-REM sleep by suppressing VGLUT2 activity would be groundbreaking for individuals struggling with disrupted sleep from disorders like insomnia or PTSD.”
A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain
by Brian Staats, Ming-Qiang Michael Wang, Carol L. Thompson, Shoaib Mufti, Chelsea M. Pagan, Lauren Kruse, Nick Dee, Susan M. Sunkin, Luke Esposito, Michael J. Hawrylycz, Jack Waters, Lydia Ng, Kimberly Smith, Bosiljka Tasic, Xiaowei Zhuang, Hongkui Zeng in Nature
For the first time ever, an international team of researchers has created a complete cell atlas of a whole mammalian brain. This atlas serves as a map for the mouse brain, describing the type, location, and molecular information of more than 32 million cells and providing information on connectivity between these cells. The mouse is the most commonly used vertebrate experimental model in neuroscience research, and this cellular map paves the way for a greater understanding of the human brain — arguably the most powerful computer in the world. The cell atlas also lays the foundation for the development of a new generation of precision therapeutics for people with mental and neurological disorders of the brain.
The findings were funded by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®, and appear in a collection of 10 papers published in Nature.
“The mouse atlas has brought the intricate network of mammalian brain cells into unprecedented focus, giving researchers the details needed to understand human brain function and diseases,” said Joshua A. Gordon, M.D., Ph.D., Director of the National Institute of Mental Health, part of the National Institutes of Health.
The cell atlas describes the types of cells in each region of the mouse brain and their organization within those regions.
In addition to this structural information, the cell atlas provides an incredibly detailed catalog of the cell’s transcriptome — the complete set of gene readouts in a cell, which contains instructions for making proteins and other cellular products.
The transcriptomic information included in the atlas is hierarchically organized, detailing cell classes, subclasses, and thousands of individual cell clusters within the brain.
The atlas also characterizes the cell epigenome — chemical modifications to a cell’s DNA and chromosomes that alter the way the cell’s genetic information is expressed — detailing thousands of epigenomic cell types and millions of candidate genetic regulation elements for different brain cell types.
Together, the structural, transcriptomic, and epigenetic information included in this atlas provide an unprecedented map of cellular organization and diversity across the mouse brain.
The atlas also provides an accounting of the neurotransmitters and neuropeptides used by different cells and the relationship among cell types within the brain. This information can be used as a detailed blueprint for how chemical signals are initiated and transmitted in different parts of the brain. Those electrical signals are the basis for how brain circuits operate and how the brain functions overall.
“This product is a testament to the power of this unprecedented, cross-cutting collaboration and paves our path for more precision brain treatments,” said John Ngai, Ph.D., Director of the NIH BRAIN Initiative.”
Of the 10 studies included in this collection, seven are funded through the NIH BRAIN Initiative Cell Census Network (BICCN), and two are funded through the larger NIH BRAIN Initiative.
The core aim of the BICCN, a groundbreaking, cross-collaborative effort to understand the brain’s cellular makeup, is to develop a comprehensive inventory of the cells in the brain — where they are, how they develop, how they work together, and how they regulate their activity — to better understand how brain disorders develop, progress, and are best treated.
“By leveraging the unique nature of its multi-disciplinary and international collaboration, the BICCN was able to accomplish what no other team of scientists has been able to before,” said Dr. Ngai. “Now we are ready to take the next big step — completing the cell maps of the human brain and the nonhuman primate brain.”
The BRAIN Initiative Cell Atlas Network (BICAN) is the next stage in the NIH BRAIN Initiative’s effort to understand the cell and cellular functions of the mammalian brain. BICAN is a transformative project that, together with two other large-scale projects — the BRAIN Initiative Connectivity Across Scales and the Armamentarium for Precision Brain Cell Access — aim to revolutionize neuroscience research by illuminating foundational principles governing the circuit basis of behavior and informing new approaches to treating human brain disorders.
A unique cell population expressing the Epithelial-Mesenchymal Transition-transcription factor Snail moderates microglial and astrocyte injury responses
by Cheryl Clarkson-Paredes, Molly T Karl, Anastas Popratiloff, Robert H Miller in PNAS Nexus
A new study published in Proceedings of the National Academy of Sciences Nexus provides a better understanding of how the brain responds to injuries. Researchers at the George Washington University discovered that a protein called Snail plays a key role in coordinating the response of brain cells after an injury.
The study shows that after an injury to the central nervous system (CNS) a group of localized cells start to produce Snail, a transcription factor or protein that has been implicated in the repair process.The GW researchers show that changing how much Snail is produced can significantly affect whether the injury starts to heal efficiently or whether there is additional damage.
“Our findings reveal the intricate ways the brain responds to injuries,” said senior author Robert Miller, the Vivian Gill Distinguished Research Professor and Vice Dean of the GW School of Medicine and Health Sciences.
“Snail appears to be a key player in coordinating these responses, opening up promising possibilities for treatments that can minimize damage and enhance recovery from neurological injuries.”
Key findings:
- This study identifies for the first time a special group of microglial-like cells that produce Snail. Microglial cells are found in the central nervous system.
- Lowering the amount of Snail produced after an injury results in inflammation and increased cell death. During this process, the injury gets worse, not better and there are fewer connections or synapses between brain cells.
- In contrast, when Snail levels are increased the outcome of brain injury improves-suggesting this protein can help limit the spread of injury-induced damage.
The research raises questions about whether an experimental drug that affects Snail production could be used to limit the damage incurred after someone suffers a stroke or has been injured in an accident, Miller said.
Additional studies must be done to show that increasing Snail production could curtail injury or even promote healing of the brain.
Miller and his team also plan to study the regulation of Snail in diseases like multiple sclerosis. Multiple sclerosis is a disease resulting in damage to myelin, the protective layer insulating nerve fibers in the brain. If drugs targeting Snail could be used to stop that damage, many of the future symptoms of this disease could be eased, he says. However researchers have years of work to do before new drugs targeting Snail can be tested in clinical trials.
The payoff ultimately might be drugs that can lead to accelerated healing for stroke damage, head wounds and even neurodegenerative diseases like dementia.
Nanoparticle‐Mediated Delivery of Anti‐PU.1 siRNA via Localized Intracisternal Administration Reduces Neuroinflammation
by William T. Ralvenius, Jason L. Andresen, Margaret M. Huston, Jay Penney, Julia Maeve Bonner, Owen S. Fenton, Robert Langer, Li‐Huei Tsai in Advanced Materials
In mice and human cell cultures, MIT researchers showed that novel nanoparticles can deliver a potential therapy for inflammation in the brain, a prominent symptom in Alzheimer’s disease.
Some Covid-19 vaccines safely and effectively used lipid nanoparticles (LNPs) to deliver messenger RNA to cells. A new MIT study shows that different nanoparticles could be used for a potential Alzheimer’s disease (AD) therapy. In tests in multiple mouse models and with cultured human cells, a newly tailored LNP formulation effectively delivered small interfering RNA (siRNA) to the brain’s microglia immune cells to suppress the expression of a protein linked to excessive inflammation in Alzheimer’s disease.
In a prior study the researchers showed that blocking the consequences of PU.1 protein activity helps to reduce Alzheimer’s disease-related neuroinflammation and pathology. The new results, reported in the journal Advanced Materials achieve a reduction in inflammation by directly tamping down expression of the Spi1 gene that encodes PU.1. More generally, the new study also demonstrates a new way to deliver RNA to microglia, which have been difficult to target so far.
Study co-senior author Li-Huei Tsai, Picower Professor of Neuroscience and Director of The Picower Institute for Learning and Memory and Aging Brain Initiative, said she hypothesized that LNPs might work as a way to bring siRNA into microglia because the cells, which clear waste in the brain, have a strong proclivity to uptake lipid molecules. She discussed this with Robert Langer, David Koch Institute Professor, who widely known for his seminal work on nanoparticle drug delivery, They decided to test the idea of reducing PU.1 expression with an LNP-delivered siRNA.
“I still remember the day when I asked to meet with Bob to discuss the idea of testing LNPs as a payload to target inflammatory microglia,” said Tsai, a faculty member in the Department of Brain and Cognitive Sciences. “I am very grateful to The JPB Foundation who supported this idea without any preliminary evidence.”
Langer Lab graduate student Jason Andresen and former Tsai Lab postdoc William Ralvenius led the work and are the study’s co-lead authors. Owen Fenton, a former Langer Lab postdoc who is now an assistant professor at the University of North Carolina’s Eshelman School of Pharmacy, is a co-corresponding author along with Tsai and Langer. Langer is a Professor in Chemical Engineering, Biological Engineering and the Koch Institute for Integrative Cancer Research.
The simplest way to test whether siRNA could therapeutically suppress PU.1 expression would have been to make use of an already available delivery device, but one of the first discoveries in the study is that none of eight commercially available reagents could safely and effectively transfect cultured human microglia-like cells in the lab.
Instead the team had to optimize an LNP to do the job. LNPs have four main components and by changing the structures of two of them, and by varying the ratio of lipids to RNA, the researchers were able to come up with seven formulations to try. Importantly, their testing included trying their formulations on cultured microglia that they had induced into an inflammatory state. That state, after all, is the one in which the proposed treatment is needed.
Among the seven candidates, one the team named “MG-LNP” stood out for its especially high delivery efficiency and safety of a test RNA cargo.
What works in a dish sometimes doesn’t work in a living organism, so the team next tested their LNP formulations’ effectiveness and safety in mice. Testing two different methods of injection, into the body or into the cerebrospinal fluid (CSF), they found that injection into the CSF ensured much greater efficacy in targeting microglia without affecting cells in other organs. Among the seven formulations, MG-LNP again proved the most effective at transfecting microglia. Langer said he believes this could potentially open new ways of treating certain brain diseases with nanoparticles someday.
Once they knew MG-LNP could deliver a test cargo to microglia both in human cell cultures and mice, the scientists then tested whether using it to deliver a PU.1-suppressing siRNA could reduce inflammation in microglia. In the cell cultures, a relatively low dose achieved a 42 percent reduction of PU.1 expression (which is good because microglia need at least some PU.1 to live). Indeed MG-LNP transfection did not cause the cells any harm. It also significantly reduced the transcription of the genes that PU.1 expression increases in microglia, indicating that it can reduce multiple inflammatory markers.
In all these measures, and others, MG-LNP outperformed a commercially available reagent called RNAiMAX that the scientists tested in parallel.
“These findings support the use of MG-LNP-mediated anti-PU.1 siRNA delivery as a potential therapy for neuroinflammatory diseases,” the researchers wrote.
The final set of tests evaluated MG-LNP’s performance delivering the siRNA in two mouse models of inflammation in the brain. In one, mice were exposed to LPS, a molecule that simulates infection and stimulates a systemic inflammation response. In the other model, mice exhibit severe neurodegeneration and inflammation when an enzyme called CDK5 becomes hyperactivated by a protein called p25.
In both models, injection of MG-LNPs carrying the anti-PU.1 siRNA reduced expression of PU.1 and inflammatory markers, much like in the cultured human cells.
“MG-LNP delivery of anti-PU.1 siRNA can potentially be used as an anti-inflammatory therapeutic in mice with systemic inflammation an in the CK-p25 mouse model of AD-like neuroinflammation,” the scientists concluded, calling the results a “proof-of-principle.” More testing will be required before the idea could be tried in human patients.
Early life adversity shapes social subordination and cell type–specific transcriptomic patterning in the ventral hippocampus
by Aron Kos, Juan Pablo Lopez, Joeri Bordes, Carlo de Donno, Julien Dine, Elena Brivio, Stoyo Karamihalev, Malte D. Luecken, Suellen Almeida-Correa, Serena Gasperoni, Alec Dick, Lucas Miranda, Maren Büttner, Rainer Stoffel, Cornelia Flachskamm, Fabian J. Theis, Mathias V. Schmidt, Alon Chen in Science Advances
The images of Israeli child hostages being freed from Hamas captivity are heartwarming, but for most of these children, the release is just the start of a long rehabilitation process. Countless studies have shown that exposure to warfare, abuse and other traumatic events at a young age significantly raises the risk of ill health, social problems and mental health issues later in life. Now, a new study by researchers at the Weizmann Institute of Science provides a reason for optimism. In research conducted on mice, published in Science Advances, a team headed by Prof. Alon Chen discovered brain mechanisms that go awry as a result of exposure to trauma in infancy and showed that these changes may be reversible if treated early.
Our brains have a wonderful quality known as plasticity, the ability to change throughout our lives. As may be expected, in our early years, when the brain is still developing, it is at peak plasticity. This manifests in, for example, the aptitude for learning languages, but this also entails a heightened sensitivity to traumatic events, which are liable to leave a scar that only intensifies with age. Many studies provide evidence for the latter effect, but very little is known about the way that exposure to trauma at a young age affects the different kinds of brain cells and the communication between them in adulthood.
Chen’s laboratory in Weizmann’s Brain Sciences Department focuses on the molecular and behavioral aspects of the response to stress. In previous studies, Chen’s team examined how stress during pregnancy affects mouse offspring when they reach maturity. In the current research, the scientists, led by Dr. Aron Kos, studied how trauma experienced shortly after birth affects mouse pups later in life. To advance the understanding of this topic, the researchers pulled together the strengths of Chen’s lab: its expertise in exploring the brain’s molecular processes at the highest possible resolution, using genetic sequencing on the level of individual cells; the ability to use cameras to track dozens of behavioral variables in a rich social environment intended to recreate natural living conditions; and the ability to process the massive quantities of data generated in this environment, using machine learning and artificial intelligence tools.
This comprehensive behavioral mapping revealed that mice exposed after birth to a traumatic event — in the case of this study, being neglected by their mothers — displayed a variety of behaviors indicating that they found themselves at the bottom of the dominance hierarchy.
“Equivalent behaviors in humans might include high levels of introversion, social anxiety and having an avoidant personality, all known to be characteristic of posttrauma,” says Dr. Juan Pablo Lopez, a former postdoctoral fellow in Chen’s joint laboratory at Weizmann and the Max Planck Institute of Psychiatry in Munich, and today head of a research group in the Department of Neuroscience at the Karolinska Institute in Stockholm.
In the next stage of the study, the researchers exposed some of the adult mice that had experienced trauma in infancy to a stressful social situation: bullying by other mice. Ultimately, they created four groups of adult mice: those that had not been exposed to any trauma; those that had not been exposed to trauma in infancy but were subjected to bullying as adults; mice that were exposed to trauma only in infancy; and mice that were exposed to both trauma in infancy and bullying as adults. To find out how exposure to early trauma disrupts the brain and what happens as a result of this in adulthood, the researchers carried out a meticulous comparison of the four groups, using RNA sequencing at the single-cell level in the hippocampus, a brain area known to play an important role in social functioning. The comparison revealed that early trauma left a mark on different types of cells, primarily affecting gene expression in two subpopulations of neurons, those belonging to the glutamatergic excitatory system and those belonging to the GABA inhibitory system. This effect was especially strong in mice that had been exposed to both trauma in infancy and bullying as adults.
Cells in the brain communicate with one another using electrical signals, which can be excitatory, that is, stimulating, or inhibitory. An excitatory signal encourages communication between brain cells, whereas an inhibitory signal represses it, like the gas and brake pedals in a car. Normal brain functioning requires a balance between excitatory and inhibitory signals, which is lacking in many psychiatric disorders. One of the ways of assessing the brain’s electrical activity and the balance between excitatory and inhibitory signals is through electrophysiological measurements. Such measurements, performed in the hippocampus of the mice by Dr. Julien Dine, a former staff scientist at the Weizmann Institute and currently a pharmaceutical electrophysiologist, supported the molecular findings: Exposure to trauma in early childhood disrupted the balance between excitatory and inhibitory signals in adulthood.
Having discovered a brain mechanism that is disrupted in adulthood as a result of early trauma — and having identified this disruption as an imbalance between the excitatory and inhibitory signals — the researchers tried to find a way to fix it. During a brief treatment window shortly after the early trauma, they gave the mice a well-known antianxiety drug — diazepam, known commercially as Valium — which affects the GABA inhibitory system. This short course of treatment led to results that were nothing less than stunning: The treated mice were able to fully or almost fully avoid the behavioral future that awaited them and were no longer at the foot of the social ladder.
“Understanding the molecular and functional mechanisms allowed us to neutralize the negative behavioral impact of trauma with a drug given shortly after exposure to traumatic incidents,” Kos explains. “This certainly should not be seen as a recommendation to treat young trauma patients with drugs, but our findings do highlight the importance of early treatment for successful rehabilitation.”
Intense, ongoing stress can, at any age, contribute to disease, from psychiatric disorders to obesity and diabetes. But in the first years of life — and also in the womb — such stress can have dramatic ramifications.
“The wars in Israel, Ukraine, Sudan and elsewhere, and the unprecedented global refugee crisis that is caused, in part, by climate change, alongside an increased understanding of the long-term harm caused by exposure to war and violence at a young age — all these highlight the need for better rehabilitation capabilities,” says Chen. “Our new study identifies a key brain mechanism that is especially sensitive to childhood trauma. But the most exciting part is the prospect of using the plasticity of the young brain to help it recover, avoiding the toll this trauma can exact in adulthood.”
Improved sleep, cognitive processing and enhanced learning and memory task accuracy with Yoga nidra practice in novices
by Datta K et al. in PLOS ONE
Practicing yoga nidra — a kind of mindfulness training — might improve sleep, cognition, learning, and memory, even in novices, according to a pilot study publishing in the open-access journal PLOS ONE by Karuna Datta of the Armed Forces Medical College in India, and colleagues. After a two-week intervention with a cohort of novice practitioners, the researchers found that the percentage of delta-waves in deep sleep increased and that all tested cognitive abilities improved.
Unlike more active forms of yoga, which focus on physical postures, breathing, and muscle control, yoga nidra guides people into a state of conscious relaxation while they are lying down. While it has been reported to improve sleep and cognitive ability, those reports were based more on subjective measures than on objective data. The new study used objective polysomnographic measures of sleep and a battery of cognitive tests. Measurements were taken before and after two weeks of yoga nidra practice, which was carried out during the daytime using a 20-minute audio recording.
Among other things, polysomnography measures brain activity to determine how long each sleep stage lasts and how frequently each stage occurs. After two weeks of yoga nidra, the researchers observed that participants exhibited a significantly increased sleep efficiency and percentage of delta waves in deep sleep. They also saw faster responses in all cognitive tests with no loss in accuracy and faster and more accurate responses in tasks including tests of working memory, abstraction, fear and anger recognition, and spatial learning and memory tasks. The findings support previous studies that link delta-wave sleep to improved sleep quality as well as better attention and memory.
The authors believe their study provides objective evidence that yoga nidra is an effective means of improving sleep quality and cognitive performance. Yoga Nidra is a low-cost and highly accessible activity from which many people might therefore benefit.
The authors add: “Yoga Nidra practice improves sleep and makes brain processing faster. Accuracy also increased, especially with learning and memory related tasks.”
MISC
Subscribe to Paradigm!
Medium, Twitter, Telegram, Telegram Chat, LinkedIn, and Reddit.
Main sources
Research articles
