NS/ Creating mice with hybrid rat brains for enhanced sensory abilities

Paradigm

Published in

Paradigm

32 min readMay 8, 2024

Neuroscience biweekly vol. 109, 24th April — 8th May

TL;DR

If mice ever wonder what it’s like to experience the world as a rat, some are now able to live that dream, at least when it comes to the sense of smell. Researchers led by Columbia’s Kristin Baldwin have created mice with hybrid brains — part mouse, part rat — that sense the odors of the world with their rat neurons. It is the first time that an animal has been able to use the sensory apparatus of another to sense and respond accurately to the world and is one indication of how flexible the brain can be in integrating outside brain cells.
In a new study published in Neuron, neuroscientists artificially increased neuronal activity in the LC by briefly shining light on genetically modified neurons. They saw that this manipulation selectively enhanced performance in non-human primates performing a visual attention task, underscoring the crucial role that attention plays in sensory perception.
Researchers at the Univesity of Minnesota have developed a new neurostimulation device — the MagPatch — that is capable of single-neuron precision. This extra precision could be highly beneficial for future cochlear implants or vagus nerve stimulators, the researchers say. A research paper demonstrating the use of the prototype MagPatch on human neuroblastoma cells is published in the Journal of Vacuum Science & Technology B.
A new imaging technique developed by engineers at Washington University in St. Louis can give scientists a much closer look at fibril assemblies — stacks of peptides that include amyloid beta, most notably associated with Alzheimer’s disease.
Two complementary research articles reveal that central and peripheral circadian clocks coordinate to regulate the daily activity of skin and muscles. The coordination between the two clocks (central and peripheral) guarantees 50% of the circadian functions of tissues, including vital processes such as the cell cycle, DNA repair, mitochondrial activity, and metabolism. Synchronization between the central brain clock and peripheral ones prevents premature muscle aging and improves muscle function, suggesting new strategies to tackle age-related decline through circadian rhythm modulation.
Scientists have discovered how glioblastoma evades the immune system by inducing pro-tumor macrophages via a glucose-based epigenetic modification.
A new study involved high-resolution scans that enabled the researchers to visualize brain connections at submillimeter spatial resolution. Together, these pathways form a ‘default ascending arousal network’ that sustains wakefulness in the resting, conscious human brain.
A brief episode of anger triggered by remembering past experiences may negatively impact the blood vessels’ ability to relax, which is essential for proper blood flow, according to new research published today in the Journal of the American Heart Association.
During sleep, the brain weakens the new connections between neurons that had been forged while awake — but only during the first half of a night’s sleep, according to a new study.
Seagull species that have bigger brains are more likely to nest on coastal cliffs and may also be better adapted to breed in urban environments such as on the roofs of buildings. New research has found that more than half of cliff-nesting gull species have been recorded as nesting in towns and cities, compared to just 11% of those that do not, and these species have bigger brains than their non-cliff-nesting counterparts.

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Functional sensory circuits built from neurons of two species

by Throesch BT, bin Imtiaz MK, Muñoz-Castañeda R, et al. in Cell

If mice ever wonder what it’s like to experience the world as a rat, some are now able to live that dream, at least when it comes to the sense of smell. Researchers led by Columbia’s Kristin Baldwin have created mice with hybrid brains — part mouse, part rat — that sense the odors of the world with their rat neurons. It is the first time that an animal has been able to use the sensory apparatus of another to sense and respond accurately to the world and is one indication of how flexible the brain can be in integrating outside brain cells.

“This research is starting to show us how we can expand the flexibility of a brain so that it can accommodate other kinds of inputs, from human-machine interfaces or transplanted stem cells,” says Baldwin, professor of genetics & development at Columbia University Vagelos College of Physicians and Surgeons and in the Columbia Stem Cell Initiative.

One of the biggest challenges in understanding and treating diseases of the human brain is that it is impossible to fully understand these disorders with current research methods.

“We have beautiful models of cells in dishes and 3D cultures called organoids and they both have their advantages,” Baldwin says, “But none of them allow you to determine if the cells are really functioning at the highest level.”

Hybrid brains will allow researchers to better understand how brain cells get sick or die and better understand the rules of repairing and replacing parts of the brain.

“Right now, researchers are transplanting stem cells and neurons into people with Parkinson’s and epilepsy. But we do not really understand how well that will work,” she adds. “With hybrid brain models, we can start to get some answers and at a faster pace than a clinical trial.”

Researchers have previously created hybrid brains by injecting neurons or transplanting pea-sized brain organoids from one species into either a developing brain or a fully formed one, either a mouse or rat.

“These experiments have told us that we are somewhat limited in when and how we can add brain cells to an existing brain,” Baldwin says. “If the brain has developed to a certain point, the transplanted cells don’t necessarily wire together appropriately.”

Instead, Baldwin’s team introduced rat stem cells into mouse blastocysts, an early stage in development that occurs just hours after fertilization, so that the rat and mouse cells could grow together and integrate on their own.

The technique, called blastocyst complementation, is similar to a technique used to create mice with human immune systems, which have proved to be powerful research tools. But until this study, the technique had not been successful in creating hybrid brains of two different species.

“What we’re doing is really cutting edge,” Baldwin says.

In the team’s first hybrid experiments, researchers examined where rat neurons appeared in the mouse brain. Rats develop at a slower pace and have bigger brains, but in the mouse, the rat cells followed the mouse’s instructions, accelerating their development and making the same kinds of connections as their mouse counterparts.

“You could see rat cells throughout almost the entire mouse brain, which was fairly surprising to us,” Baldwin says. “It tells us that there are few barriers to insertion, suggesting that many kinds of mouse neurons can be replaced by a similar rat neuron.”

The researchers then looked to see if the rat neurons had been integrated in a functional neural circuit, in this case part of the olfactory system, which is essential to mice for finding food and avoiding predators. By engineering the mouse embryo to kill or inactivate its own olfactory neurons, the researchers could easily determine if rat neurons had restored the animals’ sense of smell.

“We hid a cookie in each mouse cage, and we were very surprised to see that they could find it with the rat neurons,” Baldwin says.

Some mice did better at finding the cookie than others, however. The researchers found that mice that retained their own silenced olfactory neurons were less successful at finding hidden cookies than mice whose olfactory neurons were engineered to disappear during development.

“This suggests that adding replacement neurons isn’t plug and play,” Baldwin says. “If you want a functional replacement, you may need to empty out dysfunctional neurons that are just sitting there, which could be the case in some neurodegenerative diseases and also in some neurodevelopmental disorders like autism and schizophrenia.”

With the hybrid brain system created by Baldwin’s team, researchers can now use the mice to carefully dissect what happened in the different models, which may eventually help improve the success of human cell transplantation.

One downside of the new hybrid brain system is that the rat cells were randomly distributed in each different animal, a hurdle in extending these studies to other sensory and neural systems in the brain.

Baldwin’s lab is currently trying to find ways to drive the inserted cells to develop into just one cell type, which may allow for more precise experimentation.

If inserted cells can be constrained in their development within hybrid brains, it could also open the door to creating hybrid brains with primate neurons.

“This would help us get even closer to understanding human disease,” Baldwin says.

Locus coeruleus norepinephrine contributes to visual-spatial attention by selectively enhancing perceptual sensitivity

by Ghosh S, Maunsell JHR. in Neuron

The locus coeruleus (LC) is a small region of the brainstem that produces norepinephrine, a chemical with powerful effects on arousal and wakefulness which plays an important role in the body’s response to stress or panic. Now, research from the University of Chicago shows it plays a specific role in visual sensory processing as well. In a new study published in Neuron, neuroscientists artificially increased neuronal activity in the LC by briefly shining light on genetically modified neurons. They saw that this manipulation selectively enhanced performance in non-human primates performing a visual attention task, underscoring the crucial role that attention plays in sensory perception.

“We want to understand what changes in your brain when you pay attention to something in the environment, because attention greatly affects your ability to discern stimuli,” said John Maunsell, PhD, the Albert D. Lasker Distinguished Service Professor of Neurobiology and Director of the Neuroscience Institute at the University of Chicago, and co-author of the study. “Now we have found a brain structure that has strong signals related to whether the subjects are paying attention to a stimulus or not, and we see big differences in how its neurons respond depending on where that attention is directed.”

Maunsell and co-author Supriya Ghosh, PhD, a postdoctoral researcher, focus their studies on how neurons in different areas of the brain change to represent sensory input when a subject is paying attention to a stimulus or not. For example, activity of neurons in the cerebral cortex may increase by 10–25% when a subject pays attention to the stimuli those neurons represent. Previous research has shown that LC activation, coupled with its ensuing norepinephrine production, might improve performance on tasks that require attention to discern between visual stimuli.

Ghosh, who specializes in subcortical brain structures, suggested that the LC might be a good candidate to study for these effects. The team trained two monkeys to perform a visual task in which they paid attention to the left or right side of a screen. First, a sample image would appear on both sides of the screen. Next, after a delay, a test image would appear on one side of the screen. The monkey would report if that image was oriented differently than the sample shown earlier on that side of the screen by moving its eyes to one of two targets. The researchers recorded neuron activity in the LC during the task and saw that activity increased greatly — and only — when the animal attended to the image that appeared on the side of the screen monitored by those neurons.

To see if there was a causal relationship between this increased activity and performance, they also used a method called optogenetics to increase activity in the LC while the animals were performing the task. Optogenetics allows researchers to selectively control the activity of norepinephrine-expressing cells via light. First, they introduce a genetic modification that causes neurons to produce a light-sensitive protein called opsin, the same type of protein that photoreceptors in the eye use to detect light. When they shine a special light on these neurons, the opsin causes the neurons to fire. Optogenetically boosting the responses of the neurons drastically improved the animals’ ability to differentiate the shapes on the corresponding half of the screen, without affecting motor processing.

“This kind of artificial enhancement of that activity did not interfere with other cognitive factors either, such as motor actions or decision-related activities,” Ghosh said. “So, it could selectively contribute to the perceptual sensitivity in a very precise way.”

Distinguishing the effects of attention from other factors, like decision-making or motor movements, is crucial, Ghosh said. Those processes take place in other parts of the brain, and can contribute to performance independently. Understanding how a relatively small brain structure like the LC impacts such an important function as attention is also one step toward solving the overall puzzle of the brain.

“Every time we get more information about the likely contribution of a given brain structure, or how broad the range of functions of a given structure might be, that gives us much more power to understand the relationships among them,” Maunsell said. “No one part of the brain does interesting behaviors by itself.”

Planar microcoil arrays for in vitro cellular-level micromagnetic activation of neurons

by Saha R, Benally OJ, Faramarzi S, et al. in J Vac Sci Technol B.

The MagPatch is an array of magnetic microcoils, promising single-neuron precision for cochlear implants and vagus nerve stimulation.

For those suffering from neurological or severe psychiatric disorders, neurostimulation therapy can be a promising avenue for treatment. This therapy relies on the use of neurostimulation devices, which apply energy to neurons in the brain to encourage them to grow or make new connections.

Epilepsy treatment is one common application for neurostimulation devices, though similar treatment can also be used for Parkinson’s disease, chronic pain and psychiatric disorders, such as depression.

Now, researchers at the Univesity of Minnesota have developed a new neurostimulation device — the MagPatch — that is capable of single-neuron precision. This extra precision could be highly beneficial for future cochlear implants or vagus nerve stimulators, the researchers say. A research paper demonstrating the use of the prototype MagPatch on human neuroblastoma cells is published in the Journal of Vacuum Science & Technology B.

While there are already several neurostimulation devices and treatments that have received approval from the US Food and Drug Administration (FDA) to be used on patients, these devices have a rather large effect range.

“The motivation behind this study originated when the National Institute of Health (NIH) released a call for proposals on designing and fabricating stimulator devices for cellular-level interventions,” said lead study author Renata Saha. Now a senior scientist at DuPont, Saha was a MnDRIVE neuromodulation fellow at the University of Minnesota during this research.
“There are several neurostimulation devices in the market — some were already FDA approved for patient trials, some were pending approvals. But each of them had one caveat — they stimulated a large population of neurons, including neighboring cells that weren’t supposed to be stimulated,” Saha explained.

Around the same time as the NIH call for proposals, Saha and her team at the University of Minnesota Department of Electrical and Computer Engineering were already actively developing new neurostimulation technologies using microscopically-sized magnetic coils, or microcoils, that promised to deliver a more precise effect.

“Our preliminary animal studies had already shown that micromagnetic stimulation is highly directional in nature,” Saha said. “We planned on exploiting this highly directional nature of the induced electric field from these microcoils to use it for cellular-level neuron stimulation. This particular thought laid the foundations of the design, fabrication and testing of the MagPatch array reported in this work.”

The MagPatch is an array of eight magnetic microcoils that use electric current to create a magnetic field powerful enough to affect nearby neurons.

“Essentially, the devices in MagPatch are micrometer-sized coils or microcoils that can be implanted in the brain or in the periphery of a nerve and operate based on a physics law taught in high school — Faraday’s laws of electromagnetic induction,” Saha explained. “Upon applying a time-varying current through these microcoils, they generate a time-varying magnetic field, which generates an induced electric field that stimulates the neurons.”

In addition to being much more precise than the traditional electrodes used in other neurostimulation systems, the implantable MagPatch is also designed to function for longer without degradation.

“This induced electric field is not in direct galvanic contact with the neurons,” Saha said. “Hence, there is less biofouling effect from the adjacent neurons and supporting cells causing the electrodes to degrade significantly less.”

But making the MagPatch was not without its challenges. One of the reasons that the patch consists of eight microcoils instead of just one, is that the amount of current needed to drive these microcoils is extremely high. By increasing the number of microcoils in use, the researchers were able to induce magnetic fields using significantly less current per coil.

To further improve the efficiency of their device, the researchers also added certain soft magnetic materials to the core of the microcoils.

“A more effective way for reducing the power of driving these microcoils is to use soft magnetic materials (SMM) at the core of these microcoils in the array,” Saha explained. “Adding these SMM materials at the core of these microcoils increases the [strength of the] electric field without increasing the current that is required to drive these microcoils.”

To demonstrate the effectiveness of the MagPatch, Saha and her team created a prototype of the device primarily using titanium, gold and silicon nitride — all materials that are already commonly used in medical implants. To improve the device’s biocompatibility even further, it was also encased in a watertight biocompatible coating of parylene-C polymer.

They tested the device using human neuroblastoma cells, finding that the MagPatch was able to stimulate the cells without harming them, suggesting the device could be safe for future clinical use.

“By fabricating a proof-of-concept prototype for such an array and encapsulating it in a biocompatible coating, we were successful in adhering human neuroblastoma cells to that coating,” Saha said. “When the adhered cells responded to the stimulation applied to those cells, we confirmed that the cells adhering to the fabricated prototype were alive. This implied the preliminary biocompatibility of the MagPatch devices.”

Following the success of the prototype, the researchers say they plan to continue developing the MagPatch device to further explore its safety and utility. Such a device could help to improve future generations of cochlear implants, they suggest, or neural stimulation technologies that more selectively target the vagus nerve.

Resolving the nanoscale structure of β-sheet peptide self-assemblies using single-molecule orientation–localization microscopy

by Zhou W, O’Neill CL, Ding T, Zhang O, Rudra JS, Lew MD. in ACS Nano

A new imaging technique developed by engineers at Washington University in St. Louis can give scientists a much closer look at fibril assemblies — stacks of peptides that include amyloid beta, most notably associated with Alzheimer’s disease.

These cross-β fibril assemblies are also useful building blocks within designer biomaterials for medical applications, but their resemblance to their amyloid beta cousins, whose tangles are a symptom of neurodegenerative disease, is concerning. Researchers want to learn how different sequences of these peptides are linked to their varying toxicity and function, for both naturally occurring peptides and their synthetically engineered cousins.

Now, scientists can get a close enough look at fibril assemblies to see there are notable differences in how synthetic peptides stack compared with amyloid beta. These results stem from a fruitful collaboration between lead author Matthew Lew, associate professor in the Preston M. Green Department of Electrical & Systems Engineering, and Jai Rudra, associate professor of biomedical engineering, in WashU’s McKelvey School of Engineering.

In a paper published recently in ACS Nano, Lew and colleagues outline how they used the Nile red chemical probe to light up cross-β fibrils. Their technique, called single-molecule orientation–localization microscopy (SMOLM), uses the flashes of light from Nile red to visualize the fiber structures formed by synthetic peptides and by amyloid beta.

The bottom line: these assemblies are much more complicated and heterogenous than anticipated. That’s good news because it means there’s more than one way to safely stack proteins. With better measurements and images of fibril assemblies, bioengineers can better understand the rules that dictate how protein grammar affects toxicity and biological function, leading to more effective and less toxic therapeutics.

First, scientists need to see the difference between them, something very challenging because of the tiny scale of these assemblies.

“The helical twist of these fibers is impossible to discern using an optical microscope, or even some super-resolution microscopes, because these things are just too small,” Lew said.

With high-dimensional imaging technology developed in Lew’s lab the past couple years, they are able to see the differences.

A typical fluorescence microscope uses florescent molecules as light bulbs to highlight certain aspects of a biological target. In the case of this work, they used one of those probes, Nile red, as a sensor for what was around it. As Nile red randomly explores its environment and collides with the fibrils, it emits flashes of light that they can measure to determine where the fluorescent probe is and its orientation. From that data, they can piece together the full picture of engineered fibrils that stack very differently from natural ones such as amyloid beta.

Their image of these fibril assemblies made the cover of the ACS Nano and was put together by first author Weiyan Zhou, who color-coded the image based on where the Nile reds were pointing. The resulting image is a blueish, red flowing assembly of peptides that looks like a river valley.

They plan to continue to develop techniques such as SMOLM to open new avenues of studying biological structures and processes at the nanoscale.

“We are seeing things you can’t see with existing technology,” Lew said.

Brain-muscle communication prevents muscle aging by maintaining daily physiology

by Arun Kumar, Mireia Vaca-Dempere, Thomas Mortimer, Oleg Deryagin, Jacob G. Smith, Paul Petrus, Kevin B. Koronowski, Carolina M. Greco, Jessica Segalés, Eva Andrés, Vera Lukesova, Valentina M. Zinna, Patrick-Simon Welz, Antonio L. Serrano, Eusebio Perdiguero, Paolo Sassone-Corsi, Salvador Aznar Benitah, Pura Muñoz-Cánoves. in Science

The epidermal circadian clock integrates and subverts brain signals to guarantee skin homeostasis

by Thomas Mortimer, Valentina M. Zinna, Muge Atalay, Carmelo Laudanna, Oleg Deryagin, Guillem Posas, Jacob G. Smith, Elisa García-Lara, Mireia Vaca-Dempere, Leonardo Vinícius Monteiro de Assis, Isabel Heyde, Kevin B. Koronowski, Paul Petrus, Carolina M. Greco, Stephen Forrow, Henrik Oster, Paolo Sassone-Corsi, Patrick-Simon Welz, Pura Muñoz-Cánoves, Salvador Aznar Benitah in Cell Stem Cell

Discovered in the 1970s, circadian clocks are essential for the regulation of biological time in most cells in the human body. These internal mechanisms adjust biological processes to a 24-hour cycle, allowing the synchronisation of cellular functions with daily variations in the environment. Circadian rhythms, which are coordinated by a central clock in the brain that communicates with clocks in different peripheral tissues, influence many functions, from our sleep patterns to our ability to metabolise food.

A team led by Dr. Salvador Aznar Benitah, an ICREA researcher at IRB Barcelona, and Dr. Pura Muñoz-Cánoves, an ICREA researcher in the Department of Medicine and Life Sciences at the Pompeu Fabra University (UPF), has described how the synchronisation between the central clock and peripheral clocks in muscle and skin plays a key role in ensuring the correct function of these tissues, as well as preventing degenerative processes associated with ageing.

The results of this work have been published in two articles in high-impact journals. In this regard, the research on the synchronisation between the central and peripheral clocks appears in Science, while the work on the coordination between the central clock and skin peripheral clock has been released in Cell Stem Cell. Both studies reveal the common mechanisms that underscore the importance of this coordination to uphold the optimal functionality of muscle and skin.

The work also describes the remarkable degree of autonomy of the peripheral clocks, which can maintain 24-h cycles and manage approximately 15% of circadian functions in the absence of the central clock.

“It is fascinating to see how synchronisation between the brain and peripheral circadian clocks plays a critical role in skin and muscle health, while peripheral clocks alone are autonomous in carrying out the most basic tissue functions,” says Dr. Aznar Benitah, head of the Stem Cell and Cancer laboratory at IRB Barcelona.
“Our study reveals that minimal interaction between only two tissue clocks (one central and the other peripheral) is needed to maintain optimal functioning of tissues like muscles and skin and to avoid their deterioration and ageing. Now, the next step is to identify the signalling factors involved in this interaction, with potential therapeutic applications in mind,” explains Dr. Muñoz-Cánoves, a UPF Professor who is now a Principal Investigator at Altos Labs (San Diego, US).

The study published in Science on the communication between the brain and muscle confirmed that the coordination between the central and peripheral clocks is crucial for maintaining daily muscle function and preventing the premature ageing of this tissue. Restoration of the circadian rhythm reduces the loss of muscle mass and strength, thereby improving deteriorated motor functions in experimental mouse models.

The results of the study have also demonstrated that time-restricted feeding (TRF), which involves eating only in the active phase of the day, can partially replace the central clock and enhance the autonomy of the muscle clock. More relevant still is that this restoration of the circadian rhythm through TRF can mitigate muscle loss, the deterioration of metabolic and motor functions, and the loss of muscle strength in aged mice.

These findings have significant implications for the development of therapies for muscular ageing and the enhancement of physical performance in older age. Drs. Arun Kumar and Mireia Vaca Dempere, both from the UPF, are the first authors of this study, which has also received contributions from Drs. Eusebio Perdiguero and Antonio Serrano, previously at the UPF and now at Altos Labs.

In the study published in Cell Stem Cell, the team has demonstrated that the skin circadian clock is pivotal in coordinating the daily physiology of this tissue. By integrating brain signals, and sometimes by modifying them, this coordination ensures the correct functioning of the skin.

A surprising discovery was that, in the absence of the peripheral clock, the central body clock maintains the circadian rhythm of the skin but it works in the opposite way as usual (that is to say, on an opposite schedule). For example, the researchers observed that DNA replication, if regulated only by the central clock, would occur during the daytime, when skin is exposed to ultraviolet light, which would increase the risk of accumulating mutations. This phenomenon highlights the importance of the peripheral clock, which not only receives signals from the central clock — which coordinates the rhythms of the entire organism — but also adapts these signals to the specific needs of the tissue in which they are (in the case of skin stem cells, DNA replication peaks after exposure to ultraviolet light during the day).

Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma

by Alessandra De Leo, Alessio Ugolini, Xiaoqing Yu, Fabio Scirocchi, Delia Scocozza, Barbara Peixoto, Angelica Pace, Luca D’Angelo, James K.C. Liu, Arnold B. Etame, Aurelia Rughetti, Marianna Nuti, Antonio Santoro, Michael A. Vogelbaum, Jose R. Conejo-Garcia, Paulo C. Rodriguez, Filippo Veglia in Immunity

The Wistar Institute assistant professor Filippo Veglia, Ph.D., and team, have discovered a key mechanism of how glioblastoma — a serious and often fatal brain cancer — suppresses the immune system so that the tumor can grow unimpeded by the body’s defenses. The lab’s discovery was published in the paper, “Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma,” in the journal Immunity.

“Our study shows that the cellular mechanisms of cancer’s self-preservation, when sufficiently understood, can be used against the disease very effectively,” said Dr. Veglia. “I look forward to future research on metabolism-driven mechanisms of immunosuppression in glioblastoma, and I’m hopeful for all that we will continue to learn about how to best understand and fight this cancer.”

Until now, it has been poorly understood how monocyte-derived macrophages and microglia create an immunosuppressive tumor microenvironment in glioblastoma. The Veglia lab investigated the cellular “how” of glioblastoma immunosuppression and identified that, as glioblastoma progressed, monocyte-derived macrophages came to outnumber microglia — which indicated that monocyte-derived macrophages’ eventuality to becoming the majority in the tumor microenvironment was advantageous to the cancer’s goal of evading immune response. Indeed, monocyte-derived macrophages, but not microglia, blocked the activity of T cells (immune cells that destroy tumor cells), in preclinical models and patients. The team confirmed this finding when they assessed preclinical models of glioblastoma with artificially reduced numbers of monocyte-derived macrophages. And as the group expected, the models with fewer malicious macrophages in the tumor microenvironment showed improved outcomes relative to the standard glioblastoma models.

Glioblastoma accounts for slightly more than half of all malignancies that originate in the brain, and the prognosis for those diagnosed with the cancer is quite poor: only 25% of patients who receive a glioblastoma diagnosis will survive beyond a year. Glioblastoma is inherently dangerous due to its location in the brain and its immunosuppressive tumor microenvironment, which renders glioblastoma resistant to promising immunotherapies. By programming certain immune cells like macrophages, (such as monocyte-derived macrophages and microglia), to work for — rather than against — the tumor, glioblastoma fosters a tumor microenvironment for itself that enables the cancer to grow aggressively while evading anticancer immune responses.

Having confirmed the role of monocyte-derived macrophages, the Veglia lab then sought to understand just how the cancer-allied immune cells were working against the immune system. They sequenced the macrophages in question to see whether the cells had any aberrant gene expression patterns that could point to which gene(s) could be playing a role in immunosuppression, and they also investigated the metabolic patterns of macrophages to see whether the macrophages’ nonstandard gene expression could be tied to metabolism.

The team’s twin gene expression & metabolic analysis led them to glucose metabolism. Through a series of tests, the Veglia lab was able to determine that monocyte-derived macrophages with enhanced glucose metabolism and expressing GLUT1, a major transporter for glucose (a key metabolic compound), blocked T cells’ function by releasing interleukin-10 (IL-10). The team demonstrated that glioblastoma-perturbed glucose metabolism in these macrophages induced their immunosuppressive activity.

The team discovered the key to macrophages’ glucose-metabolism-driven immunosuppressive potency lies in a process called “histone lactylation.” Histones are structural proteins in the genome that play a key role in which genes — like IL-10 — are expressed in which contexts. As rapidly glucose-metabolizing cells, monocyte-derived macrophages produce lactate, a by-product of glucose metabolism. And histones can become “lactylated” (which is when lactate becomes incorporated into histones) in such a way that the histones’ organization further promotes the expression of IL-10 — which is effectively produced by monocyte-derived macrophages to help cancer cells to grow.

But how can the glucose-driven immunosuppressive activity of monocyte-derived macrophages be stopped? Dr. Veglia and his research team identified a possible solution: PERK, an enzyme they had identified as regulating glucose metabolism and GLUT1 expression in macrophages. In preclinical models of glioblastoma, targeting PERK impaired histone lactylation and immunosuppressive activity of macrophages, and in combination with immunotherapy blocked glioblastoma progression and induced long-lasting immunity that protected the brain from tumor re-growth — a sign that targeting PERK-histone lactylation axis may be a viable strategy for fighting this deadly brain cancer.

Multimodal MRI reveals brainstem connections that sustain wakefulness in human consciousness

by Brian L. Edlow, Mark Olchanyi, Holly J. Freeman, Jian Li, Chiara Maffei, Samuel B. Snider, Lilla Zöllei, J. Eugenio Iglesias, Jean Augustinack, Yelena G. Bodien, Robin L. Haynes, Douglas N. Greve, Bram R. Diamond, Allison Stevens, Joseph T. Giacino, Christophe Destrieux, Andre van der Kouwe, Emery N. Brown, Rebecca D. Folkerth, Bruce Fischl, Hannah C. Kinney in Science Translational Medicine

Human consciousness requires arousal (i.e., wakefulness) and awareness. Brain imaging studies over the last decade have produced connectivity maps of the cortical networks that sustain awareness, but maps of the subcortical networks that sustain wakefulness are lacking, due to the small size and anatomic complexity of subcortical structures such as the brainstem. In a magnetic resonance imaging (MRI) study that integrated high-resolution structural and functional connectivity data, researchers mapped a subcortical brain network that is believed to integrate arousal and awareness in human consciousness.

In a paper published today in Science Translational Medicine, a group of researchers at Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, and Boston Children’s Hospital, created a connectivity map of a brain network that they propose is critical to human consciousness.

The study involved high-resolution scans that enabled the researchers to visualize brain connections at submillimeter spatial resolution. This technical advance allowed them to identify previously unseen pathways connecting the brainstem, thalamus, hypothalamus, basal forebrain, and cerebral cortex.

Together, these pathways form a “default ascending arousal network” that sustains wakefulness in the resting, conscious human brain. The concept of a “default” network is based on the idea that specific networks within the brain are most functionally active when the brain is in a resting state of consciousness. In contrast, other networks are more active when the brain is performing goal-directed tasks.

To investigate the functional properties of this default brain network, the researchers analyzed 7 Tesla resting-state functional MRI data from the Human Connectome Project. These analyses revealed functional connections between the subcortical default ascending arousal network and the cortical default mode network that contributes to self-awareness in the resting, conscious brain.

The complementary structural and functional connectivity maps provide a neuroanatomic basis for integrating arousal and awareness in human consciousness. The researchers released the MRI data, brain mapping methods, and a new Harvard Ascending Arousal Network Atlas, to support future efforts to map the connectivity of human consciousness.

“Our goal was to map a human brain network that is critical to consciousness and to provide clinicians with better tools to detect, predict, and promote recovery of consciousness in patients with severe brain injuries,” explains lead-author Brian Edlow, MD, co-director of Mass General Neuroscience, associate director of the Center for Neurotechnology and Neurorecovery (CNTR) at Mass General, an associate professor of Neurology at Harvard Medical School and a Chen Institute MGH Research Scholar 2023–2028.
Dr. Edlow explains, “Our connectivity results suggest that stimulation of the ventral tegmental area’s dopaminergic pathways has the potential to help patients recover from coma because this hub node is connected to many regions of the brain that are critical to consciousness.”
Senior author Hannah Kinney, MD, Professor Emerita at Boston Children’s Hospital and Harvard Medical School, adds that “the human brain connections that we identified can be used as a roadmap to better understand a broad range of neurological disorders associated with altered consciousness, from coma, to seizures, to sudden infant death syndrome (SIDS).”

The authors are currently conducting clinical trials to stimulate the default ascending arousal network in patients with coma after traumatic brain injury, with the goal of reactivating the network and restoring consciousness.

Translational research of the acute effects of negative emotions on vascular endothelial health: Findings From a Randomized Controlled Study.

by Shimbo D, Cohen MT, McGoldrick M, et al. in J Am Heart Assoc

A brief episode of anger triggered by remembering past experiences may negatively impact the blood vessels’ ability to relax, which is essential for proper blood flow, according to new research published today in the Journal of the American Heart Association, an open access, peer-reviewed journal of the American Heart Association.

Previous research has found that impairment of blood vessels’ ability to relax may increase the risk of developing atherosclerosis, which may, in turn, increase the risk of heart disease and stroke.

“Impaired vascular function is linked to an increased risk of heart attack and stroke,” said lead study author Daichi Shimbo, M.D., a professor of medicine at the Columbia University Irving Medical Center in New York City. “Observational studies have linked feelings of negative emotions with having a heart attack or other cardiovascular disease events. The most common negative emotion studied is anger, and there are fewer studies on anxiety and sadness, which have also been linked to heart attack risk.”

In this study, the researchers investigated whether negative emotions — anger, sadness and anxiety — may have an adverse impact on blood vessel function compared to a neutral emotion. The 280 adults in the study were randomly assigned to one of four emotional tasks for 8 minutes: recalling a personal memory that made them angry; recalling a personal memory of anxiety; reading a series of depressing sentences that evoked sadness; or repeatedly counting to 100 to induce an emotionally neutral state. This protocol, “Putative mechanisms Underlying Myocardial infarction onset and Emotions (PUME),” was described by the researchers in a previous paper.

Researchers assessed the cells lining each study participant’s blood vessels before the tasks and at several points after, looking for evidence of impaired blood vessel dilation, increased cell injury and/or reduced cell repair capacity. The measurements taken before the emotional tasks were repeated after tasks were completed.

Measurements were taken for each participant at baseline (0 minutes) and at four different timepoints after experiencing the assigned emotional task: 3 minutes, 40 minutes, 70 minutes and 100 minutes. The analysis found:

Tasks that recalled past events causing anger led to an impairment in blood vessel dilation, from zero to 40 minutes after the task. The impairment was no longer present after the 40-minute mark.
There were no statistically significant changes to participants’ blood vessel linings at any time points after experiencing the anxiety and sadness emotional tasks.

“We saw that evoking an angered state led to blood vessel dysfunction, though we don’t yet understand what may cause these changes,” Shimbo said. “Investigation into the underlying links between anger and blood vessel dysfunction may help identify effective intervention targets for people at increased risk of cardiovascular events.”

According to an American Heart Association 2021 scientific statement, Psychological Health, Well-Being, and the Mind-Heart-Body Connection, mental well-being can positively or negatively impact a person’s health and risk factors for heart disease and stroke.

“This study adds nicely to the growing evidence base that mental well-being can affect cardiovascular health, and that intense acute emotional states, such as anger or stress, may lead to cardiovascular events,” said Glenn Levine, M.D., FAHA, writing committee chair of the scientific statement, and master clinician and professor of medicine at Baylor College of Medicine, and chief of the cardiology section at the Michael E. DeBakey VA Medical Center, both in Houston.
“For instance, we know that intense sadness or similar emotions are a common trigger for Takatsubo cardiomyopathy, and events such as earthquakes or even as a fan watching a world soccer match, which provoke stress, may lead to myocardial infarction and/or to arrhythmias. This current study very eloquently shows how anger can negatively impact vascular endothelial health and function, and we know the vascular endothelium, the lining of blood vessels, is a key player in myocardial ischemia and atherosclerotic heart disease. While not all the mechanisms on how psychological states and health impact cardiovascular health have been elucidated, this study clearly takes us one step closer to defining such mechanisms.”

The study’s limitations included that participants were young and apparently healthy, “making it unclear whether the results would apply to older adults with other health conditions, who would most likely be taking medications,” Shimbo noted. In addition, participants were observed in a health care setting, rather than in real-world situations, and the study only assessed the short-term effects of evoked emotions.

Sleep pressure modulates single-neuron synapse number in zebrafish

by Anya Suppermpool, Declan G. Lyons, Elizabeth Broom, Jason Rihel. in Nature

During sleep, the brain weakens the new connections between neurons that had been forged while awake — but only during the first half of a night’s sleep, according to a new study in fish by UCL scientists.

The researchers say their findings, published in Nature, provide insight into the role of sleep, but still leave an open question around what function the latter half of a night’s sleep serves.

The researchers say the study supports the Synaptic Homeostasis Hypothesis, a key theory on the purpose of sleep which proposes that sleeping acts as a reset for the brain.

Lead author Professor Jason Rihel (UCL Cell & Developmental Biology) said: “When we are awake, the connections between brain cells get stronger and more complex. If this activity were to continue unabated, it would be energetically unsustainable. Too many active connections between brain cells could prevent new connections from being made the following day.

“While the function of sleep remains mysterious, it may be serving as an ‘off-line’ period when those connections can be weakened across the brain, in preparation for us to learn new things the following day.”

For the study, the scientists used optically translucent zebrafish, with genes enabling synapses (structures that communicate between brain cells) to be easily imaged. The research team monitored the fish over several sleep-wake cycles.

The researchers found that brain cells gain more connections during waking hours, and then lose them during sleep. They found that this was dependent on how much sleep pressure (need for sleep) the animal had built up before being allowed to rest; if the scientists deprived the fish from sleeping for a few extra hours, the connections continued to increase until the animal was able to sleep.

Professor Rihel added: “If the patterns we observed hold true in humans, our findings suggest that this remodelling of synapses might be less effective during a mid-day nap, when sleep pressure is still low, rather than at night, when we really need the sleep.”

The researchers also found that these rearrangements of connections between neurons mostly happened in the first half of the animal’s nightly sleep. This mirrors the pattern of slow-wave activity, which is part of the sleep cycle that is strongest at the beginning of the night.

First author Dr Anya Suppermpool (UCL Cell & Developmental Biology and UCL Ear Institute) said: “Our findings add weight to the theory that sleep serves to dampen connections within the brain, preparing for more learning and new connections again the next day. But our study doesn’t tell us anything about what happens in the second half of the night. There are other theories around sleep being a time for clearance of waste in the brain, or repair for damaged cells — perhaps other functions kick in for the second half of the night.”

From the sea to the city: explaining gulls’ use of urban habitats.

by Goumas M, Berkin CR, Rayner CW, Boogert NJ. Front Ecol Evol

Seagull species that have bigger brains are more likely to nest on coastal cliffs and may also be better adapted to breed in urban environments such as on the roofs of buildings. New research has found that more than half of cliff-nesting gull species have been recorded as nesting in towns and cities, compared to just 11% of those that do not, and these species have bigger brains than their non-cliff-nesting counterparts.

The findings come in a broad-ranging study by ecologists at the University of Exeter looking at potential relationships between brain size, wing shape, nesting habits and the use of urban areas.

It suggests that species such as the Herring Gull, the Lesser Black-backed Gull and the Black-legged Kittiwake possess a behavioural flexibility that enables them to nest in more challenging locations.

“Many people will be familiar with gulls nesting and foraging in urban areas,” says lead author Dr Madeleine Goumas, formerly a Postdoctoral Research Associate in the Centre for Ecology and Conservation, based at Exeter’s Cornwall campus in Penryn. “It’s not something you might expect from a seabird, so we wanted to try to understand why they do it.”

Thirteen of the 50 gull species were recorded as using urban areas to breed, while 13 gull species are known as urban foragers — with nine both breeding and foraging. When they compared the figures for breeding with the known habits of the birds, the team identified 10 of the 19 (53%) cliff-nesting gull species among those found to have nested in urban settlements, whereas only three of 28 (11%) non-cliff-nesting species were found to have done likewise.

“We found that gull species with larger brains are more likely to be cliff-nesters, and cliff-nesting species are more likely to breed in urban areas,” says Dr Neeltje Boogert, Royal Society Dorothy Hodgkin Research Fellow. “We also found that cliff-nesting is probably not something that was shared by the ancestor of gulls, so it is a relatively recent adaptation.”
“It’s also not a fixed behaviour in most gulls,” adds Dr Goumas. “While non-cliff-nesting species nest exclusively on the ground, most cliff-nesting species nest either on cliffs or the ground. This suggests that bigger brains enable these gull species to be flexible with regard to where they choose to nest, and this allows them to use unconventional sites, like buildings, for raising their young.”

When it came to foraging, the researchers found that neither brain size nor the shape of the wing, which affects manoeuvrability, were robust indictors of seagull behaviour in urban environments.

Finally, the researchers looked at the status of the gulls on the International Union on Conservation of Nature and found that those with stable or increasing populations were more than twice as likely to have been recorded using urban habitats than those that are decreasing. Of the ten Threatened or Near Threatened species, only one — the Black-legged Kittiwake — was known to use urban habitats.

“Whether or not species use urban areas has important implications for conservation,” says Dr Boogert. “If we can understand the factors that allow animals to use urban areas, we can better understand how to help those that aren’t faring so well.”
“Urbanisation is a major problem for a lot of animals,” concludes Dr Goumas. “It looks like some gull species have managed to overcome some of the challenges that prevent other animals from using urban areas, but we need more long-term studies as well as comparative studies on other taxa to fully understand the impacts of urban living.”

The study builds on a body of research conducted by the team on gull behavior, including how they favor food humans have handled and how staring at them makes them less likely to steal your food.