TL;DR
• Study identifies universal blueprint for mammalian brain shape
• Researchers capture brain proteins “dance” with Cryo-EM technology
• Fingerprint-like brain patterns in the blind offer new insights for sight restoration
• Rapid tagging method reveals psychedelics’ immediate effects on neurons
• Exercise or snack? Orexin neurons steer healthy habits
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
Neuro-evolutionary evidence for a universal fractal primate brain shape
by Yujiang Wang, Karoline Leiberg, Nathan Kindred, Christopher R. Madan, Colline Poirier, Christopher I. Petkov, Peter N. Taylor, Bruno Mota in eLife
Researchers have developed a new approach for describing the shape of the cerebral cortex, and provide evidence that cortices across mammalian species resemble a universal, fractal pattern.
The study, published as a Reviewed Preprint in eLife and appearing as a revised version, is described by the editors as a valuable framework to our understanding of the brain cortex as a fractal shape. They describe the strength of evidence as convincing for a universal blueprint for mammalian cerebral cortex folding.
With further research and validation, the approach could be used to grant insights into the development of various degenerative and congenital neuropathic conditions.
The cerebral cortex is the outermost layer of the brain, and is responsible for complex functions such as thought, perception and decision-making. Cerebral cortex folding, known as gyrification, is the process by which the brain’s surface develops grooves (sulci) and ridges (gyri). This folding increases the surface area of the brain, allowing for a greater number of neurons and more complex information processing. The cortex displays a wide diversity of shapes and sizes across and within species.
“We set out to find a way to define the shape of the cortex, and express what is unique about the complex shapes and folds that comprise each cortex,” says lead author Yujiang Wang, a Future Leaders Fellow at the Computational Neurology, Neuroscience & Psychiatry (CNNP) Lab in the School of Computing, Newcastle University, UK. “One can look at an image of a cerebral cortex, and recognize what it is. But how can we tell apart your cortex from mine? Or how can we distinguish a giraffe’s cerebral cortex from that of a marmoset? This requires a more expressive way to describe the shape of the cortex.”
Wang and colleagues began by establishing two key principles. Firstly, they knew that cortices cannot simply assume any folded shape — cortices are thin sheets of grey matter folded in complex ways around the white matter and the degree of folding they undergo is precisely determined by the thickness and size of this sheet. This principle is called universal scaling. They then devised a way to ‘melt’ the cerebral cortex, by removing folds that were smaller than a certain threshold, allowing them to study the remaining folds individually. This revealed the second principle; that cortices are composed of folds of various sizes, where the small folds resemble their larger folds — a property called self-similarity. This resembles fractal scaling, where a complex geometric shape exhibits intricate patterns that repeat at progressively smaller scales.
The team then combined these principles of universal scaling and self-similarity to study the cerebral cortex of 11 different primate species, including humans, chimpanzees and marmosets. This revealed that, despite the clear visual differences between the species’ cortices, all of them follow a universal scaling law, and resemble the same fractal shape. So, if you take the most complex cortex studied, that of a human, and use the team’s process of ‘melting’ to eliminate the smallest folds, it begins to resemble that of a chimpanzee. If you ‘melt’ the cortex of a chimpanzee, it resembles that of a rhesus monkey, and so on.
These findings suggest that, regardless of species, there is only one way for a cerebral cortex to undergo folding. So why are they so clearly different when observed through an MRI scan? They appear different in size, and some are highly folded, like the human cortex, and some are much smoother, like the marmoset cortex.
“The key here is to precisely define what we mean by ‘resemble’,” explains senior author Bruno Mota, a Professor at the metaBIO Lab, Instituto de Física, Universidade Federal do Rio de Janeiro, Brazil. “One can imagine a shape that looks like a human cortex, but, as you zoom in, you find within each fold there are infinitely smaller folds. Such a shape cannot exist in nature, but it can be defined mathematically as a fractal shape, as we have done here. What we have shown is that all cortices of the species we have studied resemble this fractal shape for a certain range of fold sizes.”
Therefore, Mota adds, the differences observed in cortical shapes across these species are largely due to the fact that each has a different range of fold sizes for which the resemblance holds. For a smoother cortex, like in a marmoset, this range is narrower; for a more folded one, like a chimpanzee, it is broader.
The authors note that their study was limited to descriptions of entire cortical hemispheres, and that in future work they will look to explore more specific cortical regions. They will also investigate how neurodegenerative diseases such as Alzheimer’s affect the fractal shape of the cortex. This may eventually allow the identification of more detailed biomarkers for various neurological conditions and diseases, and grant further understanding for how they develop.
“Our results suggest a universal blueprint for mammalian brain shape, and a common set of mechanisms governing cortical folding,” concludes Mota. “We hope that our framework for expressing and analysing cortical shape can become a powerful tool to characterize and compare cortices of different species and individuals, across development and aging, and across health and disease.”
Molecular mechanism of ligand gating and opening of NMDA receptor
by Chou TH, Epstein M, Fritzemeier RG, et al. in Nature
Proteins are constantly performing a kind of dance. They move and contort their bodies to fulfill specific functions inside our bodies. The NMDAR protein executes an especially hard dance routine in our brains. One wrong step can lead to a range of neurological disorders. NMDAR binds to the neurotransmitter, glutamate, and another compound, glycine. These bindings control NMDAR’s dance steps. When their routine is over, the NMDAR opens. This open ion channel generates electrical signals critical for cognitive functions like memory.
The problem is that scientists couldn’t figure out the last step in NMDAR’s routine — until now. Cold Spring Harbor Laboratory Professor Hiro Furukawa and his team have deciphered the critical dance move in which NMDAR rotates into an open formation. In other words, they’ve learned the NMDAR “Twist.”
To capture this key step, Furukawa and his team used a technique called electron cryo-microscopy (cryo-EM), which freezes and visualizes proteins in action. First, the team had to find a way to keep a type of NMDAR called GluN1–2B in its open pose long enough to image it. So, Furukawa teamed up with Professors Stephen Traynelis and Dennis Liotta at Emory University. Together, they discovered a molecule that favors NMDAR in an open position.
“It’s not the most stable conformation,” Furukawa explains. “There are many pieces dancing independently in NMDAR. They have to coordinate with each other. Everything has to go perfectly to open the ion channel. We need a precise amount of electrical signals at the right time for proper behaviors and cognitions.”
The cryo-EM images allow researchers to see precisely how the NMDAR’s atoms move during its “Twist.” This may one day lead to drug compounds that can teach the correct moves to NMDARs that have lost a step. Better drugs that target NMDARs might have applications for neurological disorders like Alzheimer’s and depression.
“Compounds bind to pockets within proteins and are imperfect, initially. This will allow us and chemists to find a way to fill those pockets more perfectly. That would improve the potency of the drug. Also, the shape of the pocket is unique. But there could be something similarly shaped in other proteins. That would cause side effects. So, specificity is key,” Furukawa explains.
Indeed, there are many types of NMDARs in the brain. Another recent study from Furukawa’s lab offers the first view of the GluN1–3A NMDAR. Surprisingly, its dance moves are completely different. This routine results in unusual patterns of electrical signals.
Longitudinal stability of individual brain plasticity patterns in blindness
by Amaral L, Thomas P, Amedi A, Striem-Amit E. in Proc Natl Acad Sci USA
A study led by Georgetown University neuroscientists reveals that the part of the brain that receives and processes visual information in sighted people develops a unique connectivity pattern in people born blind. They say this pattern in the primary visual cortex is unique to each person — akin to a fingerprint.
The findings, described July 30, 2024, in PNAS, have profound implications for understanding brain development and could help launch personalized rehabilitation and sight restoration strategies.
For decades, scientists have known that the visual cortex in people born blind responds to a myriad of stimuli, including touch, smell, sound localization, memory recall and response to language. However, the lack of a common thread linking the tasks that activate primary areas in the visual cortex has perplexed researchers. The new study, led by Lenia Amaral, PhD, a postdoctoral researcher; and Ella Striem-Amit, PhD, the Edwin H. Richard and Elisabeth Richard von Matsch Assistant Professor of Neuroscience at Georgetown University’s School of Medicine, offers a compelling explanation: differences in how each individual’s brain organizes itself.
“We don’t see this level of variation in the visual cortex connectivity among individuals who can see — the connectivity of the visual cortex is usually fairly consistent,” said Striem-Amit, who leads the Sensory and Motor Plasticity Lab at Georgetown. “The connectivity pattern in people born blind is more different across people, like an individual fingerprint, and is stable over time — so much so that the individual person can be identified from the connectivity pattern.”
The study included a small sample of people born blind who underwent repeated functional MRI scans over two years. The researchers used a neuroimaging technique to analyze neural connectivity across the brain.
“The visual cortex in people born blind showed remarkable stability in its connectivity patterns over time,” Amaral explained. “Our study found that these patterns did not change significantly based on the task at hand — whether participants were localizing sounds, identifying shapes, or simply resting. Instead, the connectivity patterns were unique to each individual and remained stable over the two-year study period.”
Striem-Amit said these findings tell us how the brain develops. “Our findings suggest that experiences after birth shape the diverse ways our brains can develop, especially if growing up without sight. Brain plasticity in these cases frees the brain to develop, possibly even for different possible uses for the visual cortex among different people born blind,” Striem-Amit said.
The researchers posit that understanding each person’s individual connectivity may be important to better tailor solutions for rehabilitation and sight restoration to individuals with blindness, each based on their own individual brain connectivity pattern.
Rapid, biochemical tagging of cellular activity history in vivo
by Zhang R, Anguiano M, Aarrestad IK, et al. in Nat Methods
Amidst the psychedelic “renaissance”, a prominent challenge somewhat limits the adoption of psychedelic-based compounds in a clinical setting. While a flurry of studies have demonstrated some efficacy using psychedelics for treating psychiatric disorders, how these effects are achieved isn’t so clear.
“It’s important to think about the cellular mechanisms that these psychedelics act upon,” Christina Kim, an assistant professor of neurology at the University of California (UC) Davis Center for Neuroscience and School of Medicine, and an affiliate of the UC Davis Institute for Psychedelics and Neurotherapeutics, said.
Equipped with this knowledge, researchers could improve patient outcomes by designing different versions of the compounds that carry fewer side effects.
Kim’s lab at UC Davis develops molecular and optical approaches that aid in the study of neuronal organization and function. In collaboration with David Olson, founding director of the Institute for Psychedelics and Neurotherapeutics and a professor in the departments of Chemistry and Biochemistry and Molecular Medicine, her research group developed a non-invasive protein-based tool capable of tracking neurons and biomolecules that are activated by psychedelic drugs.
Ca2+-activated Split-TurboID, or CaST for short, enables scientists to tag and follow molecular signaling processes in the brain quickly with a run time of 10 to 30 minutes, compared to several hours.
Calcium concentration is a gold-standard marker for tracking activity in neurons. When neurons are highly active, their intracellular calcium concentrations increase.
“We designed an activity-dependent enzyme that can attach a small, biochemical handle to activated cells exhibiting high intracellular calcium. Our strategy was to reengineer and repurpose a proximity-labeling enzyme, split-TurboID16, to report increased intracellular calcium in living cells by tagging proteins with an exogenously delivered biotin molecule,” the researchers described.
Proximity-labeling enzymes like split-TurboID16 have been used to tag proteins for downstream analysis and enrichment over a period of several days. Kim and colleagues engineered this system so that neurons can be enzymatically tagged in brief, user-defined time windows. Once tagged, the neurons can then be detected using existing methods for biotin detection.
“We designed these proteins in the lab that can be packaged into DNA and then put into harmless adeno-associated viruses,” Kim said. “Once we deliver the CaST tool and these proteins into neurons, then they incubate inside the cells and start expressing.”
CaST was used to tag prefrontal cortex neurons in the mouse brain after administering psilocybin. This area of the brain is associated with several brain disorders and also experiences neuronal growth and strengthened connectivity after psychedelic administration.
Mouse neurons treated with the new CaST labeling technique developed at UC Davis. CaST enables rapid labeling of brain cells as they respond to psychedelic drugs such as psilocybin or LSD. Credit: Run Zhang/UC Davis.
Kim and colleagues could measure how psilocybin modulates neuronal activity in this area of the brain while simultaneously measuring a hallucinogenic behavioral correlate of psychedelic drugs in animals, the head-twitch response (HTR).
“What’s nice about CaST is that it can be used in a freely behaving animal,” Kim said. Other tagging techniques require laboratory models’ heads to be stabilized to achieve high-quality images.
She continued, “Biotin is also a great tagging substrate because there are many pre-existing commercial tools that can report whether biotin is present or not just by a simple staining and imaging method.”
How do psychedelics benefit the cellular profiles of people with brain disorders?
The research team is further developing the CaST tool to achieve brain-wide cellular labeling, while also investigating novel ways to enrich proteins that are produced through psychedelics affecting neurons. Overall, they aim to understand why and how psychedelics can be beneficial for individuals with brain disorders and their cellular phenotypes.
“We can send those samples to the UC Davis Proteomics Core Facility and they can give us an unbiased picture of all the proteins we identified,” Kim said. “We want to examine their entire contents in terms of what proteins they express, what genes they express, and try to see what’s different in psilocybin-treated animals versus control animals or animal models of diseases.”
Orexin neurons mediate temptation-resistant voluntary exercise
by Tesmer AL, Li X, Bracey E, et al. in Nature Neuroscience
Should I go and exercise, or would I rather go to the café and enjoy a delectable strawberry milkshake? Until now, what exactly happens in our brain when we make this decision has been a mystery to science, but researchers at ETH Zurich have found the solution. They deciphered which brain chemical and which nerve cells mediate this decision: the messenger substance orexin and the neurons that produce it.
These neuroscientific fundamentals are relevant because many people don’t get enough exercise. Most of us have probably already decided once or even several times to skip exercising in favour of one of the numerous alternative temptations of daily life. According to the World Health Organization, 80 percent of adolescents and 27 percent of adults don’t get enough exercise. And obesity is increasing at an alarming rate not only among adults but also among children and adolescents.
“Despite these statistics, many people manage to resist the constantly present temptations and get enough exercise,” says Denis Burdakov, Professor of Neuroscience at ETH Zurich. “We wanted to know what it is in our brain that helps us make these decisions.”
In their experiments with mice, the researchers were able to show that orexin plays a key role in this process. It’s one of over a hundred messenger substances that are active in the brain. Other chemical messengers, such as serotonin and dopamine, were discovered a long time ago and their role has largely been decoded. The situation for orexin is different: researchers discovered it relatively late, around 25 years ago, and they are now clarifying its functions step by step. Burdakov is one of the scientists who have devoted their efforts to studying orexin.
“In neuroscience, dopamine is a popular explanation for why we choose to do some things but avoid others,” says Burdakov. This brain messenger is critical for our general motivation. “However, our current knowledge about dopamine does not easily explain why we decide to exercise instead of eating,” the scientist continues. “Our brain releases dopamine both when we eat and when we exercise, which does not explain why we choose one over the other.”
To find out what does, the researchers devised a sophisticated behavioral experiment for mice, which were able to choose freely from among eight different options in ten-minute trials. These included a wheel they could run on and a “milkshake bar” where they could enjoy a standard strawberry-flavored milkshake.
“Mice like a milkshake for the same reason people do: it contains lots of sugar and fat and tastes good,” says Burdakov.
In their experiment, the scientists compared different groups of mice: one made up of normal mice and one in which the mice’s orexin systems were blocked, either with a drug or through genetic modification of their cells.
The mice with an intact orexin system spent twice as much time on the running wheel and half as much time at the milkshake bar as the mice whose orexin system had been blocked. Interestingly, however, the behaviour of the two groups didn’t differ in experiments in which the scientists only offered the mice either the running wheel or the milkshake.
“This means that the primary role of the orexin system is not to control how much the mice move or how much they eat,” Burdakov says. “Rather, it seems central to making the decision between one and the other, when both options are available.” Without orexin, the decision was strongly in favour of the milkshake, and the mice gave up exercising in favour of eating.
The ETH researchers expect that orexin may also be responsible for this decision in humans; the brain functions involved here are known to be practically the same in both species. “It will now be a matter of verifying our results in humans”, says Daria Peleg-Raibstein, group leader at ETH Zurich. She led the study together with Denis Burdakov. This could involve examining patients who have a restricted orexin system for genetic reasons — this is the case in around one in two thousand people. These people suffer from narcolepsy (a sleeping disorder). Another possibility would be to observe people who receive a drug that blocks orexin. Such drugs are authorised for patients with insomnia.
“If we understand how the brain arbitrates between food consumption and physical activity, we can develop more effective strategies for addressing the global obesity epidemic and related metabolic disorders,” says Peleg-Raibstein.
In particular, interventions could be developed to help overcome exercise barriers in healthy individuals and those whose physical activity is limited. However, Burdakov points out that these would be important questions for scientists involved in clinical research in humans. He and his group have dedicated themselves to basic neuroscientific research. Next he wants to find out how the orexin neurons interact with the rest of the brain when making decisions like the one between exercise and snacking.
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