NS/ Modified virtual reality tech can measure brain activity
Neuroscience biweekly vol. 91, 2nd August — 16th August
TL;DR
- The research team at The University of Texas at Austin created a noninvasive electroencephalogram (EEG) sensor that they installed in a Meta VR headset that can be worn comfortably for long periods. The EEG measures the brain’s electrical activity during immersive VR interactions.
- Scientists discovered that anti-CTLA-4 immunotherapy extended the lives of mice with glioblastoma by causing specialized CD4+ T immune cells to 1) infiltrate the brain and 2) tell brain-resident immune cells called microglia to destroy tumor cells. Their findings show the benefit of harnessing the body’s own immune cells to fight brain cancer and could lead to more effective immunotherapies.
- Two distinct neurodevelopmental abnormalities that arise just weeks after the start of brain development have been associated with the emergence of autism spectrum disorder, according to a new study in which researchers developed brain organoids from the stem cells of boys diagnosed with the disorder.
- Unlike previously thought, it turns out that speech production and singing are supported by the same circuitry in the brain. Observations in a new study can help develop increasingly effective rehabilitation methods for patients with aphasia.
- Researchers have developed a technique for simultaneously measuring electrical signals from 128 areas of the brain in awake rats. They then used the information to measure what happens to the neurons when the rats are given psychedelic drugs. The results show an unexpected and simultaneous synchronization among neurons in several regions of the brain.
- Alzheimer’s, stroke, multiple sclerosis and other neurological diseases cause severe damage due to neuroinflammation mediated by immune cells. Managing this inflammation poses a significant medical challenge because the brain is protected by the skull and additional surrounding membranes that make the brain less accessible for treatment approaches. Scientists had previously discovered pathways going from the bone marrow of the skull toward the brain, allowing immune cell movement. Now, new research revealed that cells in the skull’s bone marrow are unique in their composition and in their disease response. These findings offer new possibilities for the diagnosis and treatment of neurological diseases and revolutionize brain health monitoring in the future with non-invasive skull imaging.
- Researchers have discovered that a subcategory of brain cells responds to stress in a totally different manner in males and females. The findings could lead to a better understanding of health conditions affected by chronic stress, such as anxiety, depression and even obesity and diabetes, and they could pave the way toward personalized therapies for these disorders.
- Trying to finish your homework while the big game is on TV? “Visual-movement” neurons in the front of your brain can help you stay focused, according to a new study from neuroscientists in the Perelman School of Medicine at the University of Pennsylvania.
- Researchers have long thought that rewards like food or money encourage learning in the brain by causing the release of the ‘feel-good’ hormone dopamine, known to reinforce the storage of new information. Now, a new study in rodents describes how learning still occurs in the absence of an immediate incentive.
- Scientists at Stanford University have identified a brain hub that controls sexual arousal in male mice. By tweaking signaling in this area, the team was able to enhance or extinguish sexual desire and even let male mice engage in sexual activity immediately after ejaculation. Researchers hope that this line of study could lead to treatments for sexual problems in human men.
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
Hair-compatible sponge electrodes integrated on VR headset for electroencephalography
by Hongbian Li, Hyonyoung Shin, Minsu Zhang, Andrew Yu, Heeyong Huh, Gubeum Kwon, Nicholas Riveira, Sangjun Kim, Susmita Gangopadahyay, Jessie Peng, Zhengjie Li, Yifan Rao, Luis Sentis, Jośe del R. Millán, Nanshu Lu in Soft Science
Researchers have modified a commercial virtual reality headset, giving it the ability to measure brain activity and examine how we react to hints, stressors and other outside forces.
The research team at The University of Texas at Austin created a noninvasive electroencephalogram (EEG) sensor that they installed in a Meta VR headset that can be worn comfortably for long periods. The EEG measures the brain’s electrical activity during immersive VR interactions.
The device could be used in many ways, from helping people with anxiety to measuring the attention or mental stress of aviators using a flight simulator, to giving a human the chance to see through the eyes of a robot.
“Virtual reality is so much more immersive than just doing something on a big screen,” said Nanshu Lu, a professor in the Cockrell School of Engineering’s Department of Aerospace Engineering and Engineering Mechanics who led the research. “It gives the user a more realistic experience, and our technology enables us to get better measurements of how the brain is reacting to that environment.”
The pairing of VR and EEG sensors has made its way into the commercial sphere already. However, the devices that exist today are costly, and the researchers say their electrodes are more comfortable for the user, extending the potential wearing time and opening up additional applications.
The best EEG devices today consist of a cap covered in electrodes, but that does not work well with the VR headset. And individual electrodes struggle to get a strong reading because our hair blocks them from connecting with the scalp. The most popular electrodes are rigid and comb-shaped, inserting through the hairs to connect with the skin, an uncomfortable experience for the user.
“All of these mainstream options have significant flaws that we tried to overcome with our system,” said Hongbian Li, a research associate in Lu’s lab.
For this project, the researchers created a spongy electrode made of soft, conductive materials that overcome those issues, an effort led by Li. The modified headset features electrodes across the top strap and forehead pad, a flexible circuit with conductive traces similar to Lu’s electronic tattoos, and an EEG recording device attached to the back of the headset.
This technology will play into another major research project at UT Austin: A new robot delivery network that will also serve as the largest study to date on human-robot interactions.
Lu is a part of that project, and the VR headsets will be used by people either traveling with robots or in a remote “observatory.” They will be able to watch along from the robot’s perspective, and the device will also measure the mental load of this observation for long periods.
“If you can see through the eyes of the robot, it paints a clearer picture of how people are reacting to it and lets operators monitor their safety in case of potential accidents,” said Luis Sentis, a professor in the Department of Aerospace Engineering and Engineering Mechanics who is co-leading the robot delivery project and is a co-author on the VR EEG paper.
To test the viability of the VR EEG headset, the researchers created a game. They worked with José del R. Millán, a faculty member in the Chandra Family Department of Electrical and Computer Engineering and the Dell Medical School and an expert in brain-machine interfaces, to develop a driving simulation that has the user press a button to react to turn commands.
The EEG measures the brain activity of the users as they make driving decisions. In this case, it shows how closely the subjects are paying attention.
The researchers have filed preliminary patent paperwork for the EEG, and they’re open to partnering with VR companies to create a built-in version of the technology.
CTLA-4 blockade induces CD4+ T cell IFNγ-driven microglial phagocytosis and anti-tumor function in glioblastoma
by Dan Chen, Siva Karthik Varanasi, Toshiro Hara, Kacie Traina, Ming Sun, Bryan McDonald, Yagmur Farsakoglu, Josh Clanton, Shihao Xu, Lizmarie Garcia-Rivera, Thomas H. Mann, Victor Du, H. Kay Chung, Ziyan Xu, Victoria Tripple, Eduardo Casillas, Shixin Ma, Carolyn O’Connor, Qiyuan Yang, Ye Zheng, Tony Hunter, Greg Lemke, Susan M. Kaech in Immunity
Glioblastoma, the most common and deadly form of brain cancer, grows rapidly to invade and destroy healthy brain tissue. The tumor sends out cancerous tendrils into the brain that make surgical tumor removal extremely difficult or impossible.
Now, Salk scientists have found the immunotherapy treatment anti-CTLA-4 leads to considerably greater survival of mice with glioblastoma. Furthermore, they discovered that this therapy was dependent on immune cells called CD4+ T cells infiltrating the brain and triggering the tumor-destructive activities of other immune cells called microglia, which permanently reside in the brain.
The findings show the benefit of harnessing the body’s own immune cells to fight brain cancer and could lead to more effective immunotherapies for treating brain cancer in humans.
“There are currently no effective treatments for glioblastoma — a diagnosis today is basically a death sentence,” says Professor Susan Kaech, senior author and director of the NOMIS Center for Immunobiology and Microbial Pathogenesis. “We’re extremely excited to find an immunotherapy regimen that uses the mouse’s own immune cells to fight the brain cancer and leads to considerable shrinkage, and in some cases elimination, of the tumor.”
When standard cancer treatments like surgery, chemotherapy, and radiation cease to be effective, doctors increasingly turn to immunotherapy. Immunotherapy encourages the body’s own immune cells to seek and destroy cancer cells. Though not universal, immunotherapy works on many tumors and has provided many patients with strong, long-lasting anti-cancer responses. Kaech wanted to find new ways of harnessing the immune system to develop more safe and durable treatments for brain cancer.
Her team found three cancer-fighting tools that have been somewhat overlooked in brain cancer research that may cooperate and effectively attack glioblastoma: an immunotherapy drug called anti-CTLA-4 and specialized immune cells called CD4+ T cells and microglia.
Anti-CTLA-4 immunotherapy works by blocking cells from making the CTLA-4 protein, which, if not blocked, inhibits T cell activity. It was the first immunotherapy drug designed to stimulate our immune system to fight cancer, but it was quickly followed by another, anti-PD-1, that was less toxic and became more widely used. Whether anti-CTLA-4 is an effective treatment for glioblastoma remains unknown since anti-PD-1 took precedence in clinical trials. Unfortunately, anti-PD-1 was found to be ineffective in multiple clinical trials for glioblastoma — a failure that inspired Kaech to see whether anti-CTLA-4 would be any different.
As for the specialized immune cells, CD4+ T cells are often overlooked in cancer research in favor of a similar immune cell, the CD8+ T cell, because CD8+ T cells are known to directly kill cancer cells. Microglia live in the brain full time, where they patrol for invaders and respond to damage — whether they play any role in tumor death was not clear.
First, the researchers compared the life spans of mice with glioblastoma when treated with anti-CTLA-4 versus anti-PD-1. After discovering that blocking CTLA-4 prolonged their life spans considerably, but blocking PD-1 did not, the team moved on to figure out what made that outcome possible.
They found that after anti-CTLA-4 treatment, CD4+ T cells secreted a protein called interferon gamma that caused the tumor to throw up “stress flags” while simultaneously alerting microglia to start eating up those stressed tumor cells. As they gobbled up the tumor cells, the microglia would present scraps of tumor on their surface to keep the CD4+ T cells attentive and producing more interferon gamma — creating a cycle that repeats until the tumor is destroyed.
“Our study demonstrates the promise of anti-CTLA-4 andoutlines a novel process where CD4+ T cells and other brain-resident immune cells team up to kill cancerous cells,” says co-first author Dan Chen, a postdoctoral researcher in Kaech’s lab.
To understand the role of microglia in this cycle, the researchers collaborated with co-author and Salk Professor Greg Lemke, holder of the Françoise Gilot-Salk Chair. For decades, Lemke has investigated critical molecules, called TAM receptors, used by microglia to send and receive crucial messages. The researchers found that TAM receptors told microglia to gobble up cancer cells in this novel cycle.
“We were stunned by this novel codependency between microglia and CD4+ T cells,” says co-first author Siva Karthik Varanasi, a postdoctoral researcher in Kaech’s lab. “We are already excited about so many new biological questions and therapeutic solutions that could radically change treatment for deadly cancers like glioblastoma.”
Connecting the pieces of this cancer-killing puzzle brings researchers closer than ever to understanding and treating glioblastoma.
“We can now reimagine glioblastoma treatment by trying to turn the local microglia that surround brain tumors into tumor killers,” says Kaech, holder of the NOMIS Chair. “Developing a partnership between CD4+ T cells and microglia is creating a new type of productive immune response that we have not previously known about.”
Next, the researchers will examine whether this cancer-killing cell cycle is present in human glioblastoma cases. Additionally, they aim to look at other animal models with differing glioblastoma subtypes, expanding their understanding of the disease and optimal treatments.
Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis
by Alexandre Jourdon, Feinan Wu, Jessica Mariani, Davide Capauto, Scott Norton, Livia Tomasini, Anahita Amiri, Milovan Suvakov, Jeremy D. Schreiner, Yeongjun Jang, Arijit Panda, Cindy Khanh Nguyen, Elise M. Cummings, Gloria Han, Kelly Powell, Anna Szekely, James C. McPartland, Kevin Pelphrey, Katarzyna Chawarska, Pamela Ventola, Alexej Abyzov, Flora M. Vaccarino in Nature Neuroscience
Two distinct neurodevelopmental abnormalities that arise just weeks after the start of brain development have been associated with the emergence of autism spectrum disorder, according to a new Yale-led study in which researchers developed brain organoids from the stem cells of boys diagnosed with the disorder.
And, researchers say, the specific abnormalities seem to be dictated by the size of the child’s brain, a finding that could help doctors and researchers to diagnosis and treat autism in the future.
“It’s amazing that children with the same symptoms end up with two distinct forms of altered neural networks,” said Dr. Flora Vaccarino, the Harris Professor in the Child Study Center at Yale School of Medicine and co-senior author of the paper.
Using stem cells collected from 13 boys diagnosed with autism — including eight boys with macrocephaly, a condition in which the head is enlarged — a Yale team created brain organoids (small, three-dimensional replicas of the developing brain) in a lab dish that mimic neuronal growth in the fetus. They then compared brain development of these affected children with their fathers. (Patients were recruited from clinician colleagues at the Yale Child Study Center, which conducts research, service, and training to improve understanding of health issues facing children and their families.)
The study was co-led by Alexandre Jourdon, Feinan Wu, and Jessica Mariani, all from Vaccarino’s lab at the Yale School of Medicine.
About 20% of autism cases involve individuals with macrocephaly, a condition in which a child’s head size is in the 90th percentile or greater at birth. Among autism cases these tend to be more severe.
Intriguingly, the researchers found that children with autism and macrocephaly exhibited excessive growth of excitatory neurons compared with their fathers while organoids of other children with autism showed a deficit of the same type of neurons.
The ability to track the growth of specific types of neurons could help doctors diagnose autism, symptoms of which generally appear 18 to 24 months after birth, the authors say.
The findings may also help identify autism cases that might benefit from existing drugs designed to ameliorate symptoms of disorders marked by excessive excitatory neuron activity, such as epilepsy, Vaccarino said. Autism patients with macrocephaly might benefit from such drugs while those without enlarged brains may not, she said.
Creating biobanks of patient-derived stem cells could be essential to tailor therapeutics to specific individuals, or personalized medicine.
Hodological organization of spoken language production and singing in the human brain
by Anni Pitkäniemi, Teppo Särkämö, Sini-Tuuli Siponkoski, Sonia L. E. Brownsett, David A. Copland, Viljami Sairanen, Aleksi J. Sihvonen in Communications Biology
Unlike previously thought, speech production and singing are supported by the same circuitry in the brain. Observations in a new study can help develop increasingly effective rehabilitation methods for patients with aphasia.
The neural network related to speech is mostly located in the left cerebral hemisphere, while singing has been primarily associated with the structures of both hemispheres. However, a new study indicates that the left hemisphere has a greater significance, including in terms of singing than previously thought.
“According to a notion prevalent for more than 50 years, the potential preservation of singing ability in aphasia is based on the fact that the right hemisphere of the brain offers, as it were, a detour to expressing sung words,” says Doctoral Researcher Anni Pitkäniemi from the University of Helsinki.
This theory has also served as a basis for the development of singing-based rehabilitation strategies for patients with aphasia, or difficulty producing speech due to cerebrovascular disease.
However, a recently published study carried out by the Cognitive Brain Research Unit at the University of Helsinki found that, contrary to the researchers’ expectations, the ability to produce words by singing was associated not with the structures of the right hemisphere, but, with speech, with the language network of the left hemisphere.
Another key finding in the study was that, while the results indicate that the production of speech and singing are centrally linked to the language network of the brain, they are partially dispersed into distinct circuits under that network.
In fact, it was found that the production of sung words was linked to a specific part of the language network, the ventral stream associated with understanding speech.
In contrast, the fluent speech was connected in patients with aphasia not only with what is known as the dorsal stream of the left hemisphere, associated with speech production but also with other connections. These include the above-mentioned ventral stream as well as pathways entirely outside the language network, which are more commonly associated with information processing and motor functions in the brain.
“The scale of the network demonstrates the complexity of conversation-level speech,” Pitkäniemi points out. “The observation also now explains why the ability to produce familiar lyrics is preserved only in certain patients,” she adds. The extent of damage within the language network, she further remarks, has the largest effect on this.
According to Pitkäniemi, the structures of the right hemisphere considered central to singing are likely to play a more important role in other significant factors associated with singing, including the production of melody and rhythm.
For centuries, researchers have been interested in the relationship between music and language.
“There are cases in research literature dating back to the eighteenth century of persons with stroke losing their ability to speak due to aphasia, while unexpectedly retaining the ability to sing the words of familiar songs fluently,” Pitkäniemi says.
Next, the researchers at the University of Helsinki intend to investigate which brain networks are connected, for example, to learning new songs or producing melody and rhythm. The goal is to find methods based on singing for rehabilitating people with aphasia, which could be applied in an increasingly personalized and effective manner.
“The findings of the recently published study can already help define biological markers that could be useful, for example, in assessing the effectiveness of treatment or rehabilitation,” Pitkäniemi muses. “The findings also provide indications of the at least partly parallel development of speech and singing, which is interesting from the perspective of evolutionary neuroscience,” she adds.
5-HT2AR and NMDAR psychedelics induce similar hyper-synchronous states in the rat cognitive-limbic cortex-basal ganglia system
by Ivani Brys, Sebastian A. Barrientos, Jon Ezra Ward, Jonathan Wallander, Per Petersson, Pär Halje in Communications Biology
Researchers at Lund University have developed a technique for simultaneously measuring electrical signals from 128 areas of the brain in awake rats. They have then used the information to measure what happens to the neurons when the rats are given psychedelic drugs. The results show an unexpected and simultaneous synchronisation among neurons in several regions of the brain.
The idea that electrical oscillations in the brain could be used to teach us more about our experiences was conceived several years ago. Pär Halje and the research team was studying rats with Parkinson’s disease that had problems with involuntary movements. The researchers discovered a tone — an oscillation or wave in the electrical fields — of 80 hertz in the brains of rats with Parkinson’s disease. It turned out that the wave was closely connected to the involuntary movements.
“A Polish researcher had observed similar waves after giving rats the anesthetic ketamine. The ketamine was given at a low dose so that the rats were conscious, and the equivalent dose in a human causes psychedelic experiences. The waves they saw were in more cognitive regions of the brain than in the rats with Parkinson’s, and the frequency was higher, but that still made us consider whether there were links between the two phenomena. Perhaps excessive brain waves in the motor regions of the brain cause motor symptoms, while excessive waves in cognitive regions give cognitive symptoms,” says Pär Halje, researcher in neurophysiology at Lund University.
The research team that Pär Halje belongs to has developed a method that uses electrodes to simultaneously measure oscillations from 128 separate areas of the brain in awake rats. The electrical waves are caused by the cumulative activity in thousands of neurons, but the researchers also succeeded in isolating signals from individual neurons.
“For several of these areas, it is the first time anyone has successfully shown how individual neurons are affected by LSD in awake animals. When we gave the rats the psychedelic substances LSD and ketamine, the waves were clearly registered.”
Despite ketamine and LSD affecting different receptors in the brain — they have completely different ways into the nervous system — they resulted in the same wave patterns even if the signals from individual cells differed. When the rats were given LSD, researchers saw that their neurons were inhibited — they signaled less — in all parts of the brain. Ketamine seemed to have a similar effect on the large neurons — pyramidal cells — which saw their expression inhibited, while interneurons, which are smaller neurons that are only collected locally in tissue, increased their signaling.
Pär Halje interprets the results seen in the study, which is published in Communication Biology, to mean that the wave phenomenon is connected to the psychedelic experience.
“Activity in the individual neurons caused by ketamine and LSD looks quite different, and as such cannot be directly linked to the psychedelic experience. Instead, it seems to be this distinctive wave phenomenon — how the neurons behave collectively — that is most strongly linked to the psychedelic experience.”
Even if what is happening in individual cells is interesting, Pär Halje argues that the whole is bigger and more exciting than the individual parts.
“The oscillations behave in a strange way. One might think that a strong wave starts somewhere, which then spreads to other parts of the brain. But instead, we see that the neurons’ activity synchronises itself in a special way — the waves in the brain go up and down essentially simultaneously in all parts of the brain where we are able to take measurements. This suggests that there are other ways in which the waves are communicated than through chemical synapses, which are relatively slow.”
Pär Halje emphasises that it is difficult to know whether the waves cause hallucinations or are merely an indication of them. But, he argues, it opens up the possibility that this could be used as a research model for psychoses, where no good models exist today.
“Given how drastically a psychosis manifests itself, there ought to be a common pattern that we can measure. So far, we have not had that, but we now see a very specific oscillation pattern in rats that we are able to measure.”
There is also a dream — that the model will help us in the hunt for the mechanisms behind consciousness and that the measurements may be a way to study how consciousness is shaped.
“In light of the development of AI, it is becoming increasingly important to clarify what we mean by intelligence and what we mean by consciousness. Can self-awareness occur spontaneously, or is it something that needs to be built in? We do not know this today, because we do not know what the required ingredients for consciousness in our brains are. This is where it is exciting, the synchronised pattern we see, and whether this can help us to track down the neural foundations of consciousness,” says Pär Halje.
Distinct molecular profiles of skull bone marrow in health and neurological disorders
by Zeynep Ilgin Kolabas, Louis B. Kuemmerle, Robert Perneczky, Benjamin Förstera, Selin Ulukaya, Mayar Ali et al in Cell
Alzheimer’s, stroke, multiple sclerosis and other neurological diseases cause severe damage due to neuroinflammation mediated by immune cells. Managing this inflammation poses a significant medical challenge because the brain is protected by the skull and additional surrounding membranes that make the brain less accessible for treatment approaches. Scientists had previously discovered pathways going from the bone marrow of the skull towards the brain, allowing immune cell movement. Now, new research revealed that cells in the skull’s bone marrow are unique in their composition and in their disease response. These findings offer new possibilities for the diagnosis and treatment of neurological diseases and revolutionize brain health monitoring in the future with non-invasive skull imaging. The results are now published in Cell.
Neurological diseases such as Alzheimer’s, stroke, and multiple sclerosis have a devastating impact on the lives of millions worldwide. A common feature is neuroinflammation, an internal “fire” in the brain that can cause severe damage by activation of immune cells and release of inflammatory molecules. However, due to the brain’s relative inaccessibility, as it is shielded by the skull and three additional layers of protection in the form of membranes, controlling and monitoring this inflammation has been a major challenge. A team of scientists around Prof. Ali Ertürk at Helmholtz Munich in collaboration with researchers from the Ludwig-Maximilians-Universität München (LMU) and the Technical University of Munich (TUM) sought to address this unmet need.
Defying traditional understanding that the skull and the brain have no direct interchange, recent studies have unveiled direct connections between the skull’s bone marrow and the brain’s outermost surface of the protective membranes, the meningeal surface. These connections act as conduits, facilitating the movement of immune cells back and forth. The team of scientists found that these connections often traverse even through the outermost and toughest layer of membrane, the dura, opening up even closer to the brain surface than previously thought. To achieve these significant findings, the team utilized a specialized method called tissue clearing in combination with 3D imaging to visualize the conduits. During the tissue clearing process biological tissues are treated with a specific solution to render them transparent enabling the passage of light for the examination of both brain tissue and the skull under a microscope. As a result, 3D images of structures and cells were generated, leading to a comprehensive visual analysis.
The research team probed even deeper into the distinct role the skull-based immune cells play in brain physiology and diseases. They began by questioning if the skull harbors unique brain-specific cells and molecules that cannot be found in other bones. Extensive analysis of the RNA and protein content in the form of transcriptomics and proteomics analyses of both mouse and human bones affirmed this — the skull is indeed exceptional, hosting unique neutrophil immune cells, which are a type of white blood cell that play a critical role in the immune system’s defense.
“These findings carry profound implications, suggesting a far more complex connection between the skull and the brain than previously believed” highlights the first author of the study Ilgin Kolabas, Ph.D.-student at the Ertürk lab at Helmholtz Munich.
Ali Ertürk, corresponding author, adds: “This opens up a myriad of possibilities for diagnosing and treating brain diseases and has the potential to revolutionize our understanding of neurological diseases. This breakthrough could lead to more effective monitoring of conditions such as Alzheimer’s and stroke, and potentially even aid in preventing the onset of these diseases by enabling early detection.”
Another impactful finding was that using PET imaging, the researchers discovered that signals from the skull mirrored those from the underlying brain, with changes in these signals corresponding to disease progression in patients with Alzheimer’s and stroke. Thereby showcasing a new potential to monitor brain inflammation simply by scanning the surface of the patient’s head.
Looking forward, the researchers envision that their findings could translate to clinical practice in the form of non-invasive skull imaging.
Ali Ertürk explains the impact on disease monitoring: “This could potentially be done using portable and wearable devices, offering a more accessible and practical way to monitor brain health.”
The team hopes that this approach will greatly improve the diagnosis, monitoring, and possibly even treatment of neurological disorders, bringing us a step closer to more effective management of these devastating conditions.
Sex shapes cell-type-specific transcriptional signatures of stress exposure in the mouse hypothalamus
by Elena Brivio, Aron Kos, Alessandro Francesco Ulivi, Stoyo Karamihalev, Andrea Ressle, Rainer Stoffel, Dana Hirsch, Gil Stelzer, Mathias V. Schmidt, Juan Pablo Lopez, Alon Chen in Cell Reports
Scientific excellence requires diversity — research conducted by men and women, by people from different backgrounds and with varied worldviews. The need for diversity extends to scientific experiments themselves, but even today the vast majority of studies in the life sciences are done on male mice only, which could harm the findings, as well as our ability to extrapolate from them to humans. A new study by researchers from the Weizmann Institute of Science addresses this challenge, revealing in unprecedented detail how the brains of male and female mice respond differently to stress. In the study, published in Cell Reports, researchers from Prof. Alon Chen’s joint laboratory at the Weizmann Institute and the Max Planck Institute of Psychiatry in Munich discovered that a subcategory of brain cells responds to stress in a totally different manner in males and females. The findings could lead to a better understanding of health conditions affected by chronic stress, such as anxiety, depression and even obesity and diabetes, and they could pave the way toward personalized therapies for these disorders.
Mental and physical disorders caused by chronic stress are constantly on the rise, putting a significant strain on society. They affect both men and women, but not necessarily in the same way. Although plenty of evidence suggests that men and women deal differently with stress, the causes of these differences are not yet fully understood, and in any event, personalized treatments for men and women are still beyond the reach of medicine. But researchers from Chen’s laboratory, which specializes in studying the response to stress, hypothesized that innovative research methods could help to change the picture. Previous studies in other labs had uncovered certain sex differences in the response to stress, but those findings were obtained using research methods that could mask significant differences in the responses of specific cells or even entirely erase the roles played by relatively rare cells. Chen’s laboratory, in contrast, uses advanced methods that allow scientists to analyze brain activity at an unprecedented resolution — on the level of the individual cell — and could therefore shed new light on the differences between the sexes.
“We turned the most sensitive research lens possible onto the area of the brain that acts as a central hub of the stress response in mammals, the paraventricular nucleus (PVN) of the hypothalamus,” says Dr. Elena Brivio, who led the study. “By sequencing the RNA molecules in that part of the brain on the level of the individual cell, we were able to map the stress response in male and female mice along three main axes: how each cell type in that part of the brain responds to stress, how each cell type previously exposed to chronic stress responds to a new stress experience and how these responses differ between males and females.”
The researchers mapped out gene expression in more than 35,000 individual cells, generating a huge amount of data that provides a picture of stress response that’s unprecedented in its scope and in highlighting the differences between how males and females perceive and process stress. As part of the study, and in keeping with the principles of open-access science, the researchers decided to make the entire detailed mapping publicly available on a dedicated interactive website, which went live at the same time the study was published, providing other researchers with convenient, user-friendly access to the data.
“The website will, for example, allow researchers who are focusing on a specific gene to see how that gene’s expression changes in a certain cell type in response to stress, in males as well as females,” Brivio explains.
The comprehensive mapping has already allowed the researchers to identify a long list of differences in gene expression — between males and females, and between chronic and acute stress. The data showed, inter alia, that certain brain cells respond differently to stress in males and females: Some cells are more susceptible to stress in females and some to stress in males. The most significant difference was found in a type of brain cell called the oligodendrocyte — a subtype of glial cell that provides support to nerve cells and plays an important role in regulating brain activity. In males, exposure to stress conditions, especially chronic stress, changed not only the gene expression in these cells and their interactions with surrounding nerve cells but also their very structure. In females, however, no significant change was observed in these cells, and they were not susceptible to stress exposure.
“Neurons attract most of the scientific attention, but they only make up approximately a third of all cells in the brain. The method we implemented allows us to see a much richer and fuller picture, including all the cell types and their interactions in the part of the brain under study,” says Dr. Juan Pablo Lopez, a former postdoctoral fellow in Chen’s group and now the head of a research group at the Department of Neuroscience of the Karolinska Institute in Sweden.
Until the 1980s, clinical trials of new drugs were conducted on men alone. The accepted view was that including women was unnecessary, and that it would only complicate the research, bringing into play new variables such as menstruation and hormonal changes. For the same reasons, preclinical studies avoided using female animals until very recently. But it’s now known that the variability among male animals, on a molecular and behavioral level, is usually greater than among females, so there is no reason to suppose that females would complicate the experiments any more than males. Nonetheless, in basic research it’s still common to conduct experiments only on males.
“Our findings show that, when it comes to stress-related health conditions, from depression to diabetes, it’s very important to take the sex variable into account, since it has a significant impact on how different brain cells respond to stress,” Chen explains. “Even if a study does not specifically focus on the differences between males and females, it’s essential to include female animals in the research, especially in neuroscience and behavioral science, just as it is important to implement the most sensitive research methods, in order to obtain as complete a picture of brain activity as possible,” Brivio adds.
Top-down control of exogenous attentional selection is mediated by beta coherence in prefrontal cortex
by Agrita Dubey, David A. Markowitz, Bijan Pesaran in Neuron
Trying to finish your homework while the big game is on TV? “Visual-movement” neurons in the front of your brain can help you stay focused, according to a new study from neuroscientists in the Perelman School of Medicine at the University of Pennsylvania.
In the study, published recently in Neuron, the scientists sought to illuminate the neural mechanism that helps the brain decide whether to focus visual attention on a rewarding task or an alluring distraction. By analyzing neuron activity in animal models as they faced this kind of attentional conflict, the researchers discovered that a pattern of coordinated activity called “beta bursts” in a set of neurons in the lateral prefrontal cortex (LPFC) — a section in the front of the brain responsible for motivation and rewards — appears to have a major role in keeping attention task-focused, essentially by suppressing the influence of the distracting stimulus.
“Our research suggests that while all brains have the ability to focus on a rewarding task and filter out distractions, some are better at it than others,” said senior author Bijan Pesaran PhD, the Robert A Groff II Professor of Neurosurgery at Penn Medicine. “By understanding how our brains process rewarding stimuli, we hope to be able to also understand failures to do so in a variety of cognitive and psychiatric disorders, including attention deficit disorder, schizophrenia, and obsessive-compulsive disorder.”
Humans and other large mammals can tune out distractions to keep their attention focused on actions that further goals. This is called “top-down” control, in which attention is directed towards a task with the intention of accomplishing a rewarding goal. Large mammals like primates also have brain circuitry that automatically redirects their attention based on incoming sights and sounds and other “salient” sensory stimuli, otherwise known as “bottom-up” control. How the brain suppresses such distractions to keep attention focused on a goal-related task has never been fully clear, until now.
In the new study, the researchers sought to understand what directs attention to some stimuli, but suppresses others in more detail. Using animal models, researchers recorded how activity in the LPFC shifts while completing a task while being presented with visual distractions. The neuroscientists found strong evidence that one specific type of LPFC neurons, called visual-movement neurons, direct attention towards either the rewarding shape or the distracting one.
The researchers also observed that visual-movement neurons in the LPFC fired together at the same frequency, called “beta bursts” during periods of focus (when ignoring visual distractions and completing tasks). When these beta bursts occurred in the moments before the visual stimuli were presented, subjects were far more likely to ignore the visual stimuli and complete the task. In contrast, when the beta bursts were weak or absent before visual stimuli were presented, subjects were more likely to move their attention to the bright but unrewarding shapes.
“This suggests to us that the beta-bursts originate in a network of visual-movement neurons, and act as ‘traffic directors’ for the neurons that process different visual stimuli,” said first author Agrita Dubey, PhD, a postdoctoral researcher in the Pesaran laboratory. “It also suggests that focusing on a rewarding task takes a great deal of energy, and that it may be something that can be improved, especially in individuals with attention deficits.”
Intrinsic dopamine and acetylcholine dynamics in the striatum of mice
by Anne C. Krok, Marta Maltese, Pratik Mistry, Xiaolei Miao, Yulong Li, Nicolas X. Tritsch in Nature
Researchers have long thought that rewards like food or money encourage learning in the brain by causing the release of the “feel-good” hormone dopamine, known to reinforce storage of new information. Now, a new study in rodents describes how learning still occurs in the absence of an immediate incentive.
Led by researchers at NYU Grossman School of Medicine, the study explored the relationship between dopamine and the brain chemical acetylcholine, also known to play a role in learning and memory. Past research had shown that these two hormones compete with one another, so that a boost in one causes a decline in the other. Rewards were thought to promote learning by simultaneously triggering an increase in dopamine and a decrease in acetylcholine.
This sudden hormone imbalance is believed to open a window of opportunity for brain cells to adjust to new circumstances and form memories for later use. Known as neuroplasticity, this process is a major feature of learning as well as recovery after injury. However, the question had remained whether food and other external rewards are the only drivers for this memory system, or whether our brains instead are able to create the same conditions that are favorable to learning without outside help.
To provide some clarity, the study authors focused on when and under what circumstances dopamine levels are high at the same time as acetylcholine levels are low. They found that this situation occurs frequently, even in the absence of rewards. In fact, it turns out that the hormones constantly ebb and flow in the brain, with dopamine levels regularly raised while acetylcholine levels are low, setting the stage for continual learning.
“Our findings challenge the current understanding of when and how dopamine and acetylcholine work together in the brain,” said study lead author Anne Krok, PhD. “Rather than creating unique conditions for learning, rewards take advantage of a mechanism that is already in place and is constantly at work,” added Krok, who is also a medical student at NYU Grossman School of Medicine.
For the research the study team gave dozens of mice access to a wheel on which they could run or rest at will. On occasion, the researchers offered the animals a drink of water. Then they recorded rodent brain activity and measured the amount of dopamine and acetylcholine released at different moments.
As expected, the drink treats created the typical patterns of dopamine and acetylcholine release that are prompted by rewards. However, the team also observed that well before receiving water treats, dopamine and acetylcholine already followed “ebb and flow” cycles approximately twice every second, during which the levels of one hormone dipped while the other surged. Krok notes that this pattern continued regardless of whether the rodents were running or standing still. Similar brain waves have been observed in humans during periods of introspection and rest, she adds.
“These results may help explain how the brain learns and rehearses on its own, without the need for external incentives,” said study senior author and neuroscientist Nicolas Tritsch, PhD. “Perhaps this pulsing circuit triggers the brain to reflect on past events and to learn from them.”
That said, Tritsch, an assistant professor in the Department of Neuroscience and Physiology at NYU Langone Health, cautions that their research was not designed to tell whether mouse brains process information the same way as human brains do during this “self-driven” learning, as he describes it.
Nevertheless, he says, the results of the study may also offer insight into new ways of understanding neuropsychiatric conditions that have been tied to incorrect levels of dopamine, such as schizophrenia, attention-deficit/hyperactivity disorder (ADHD), and depression.
In schizophrenia, for example, patients often experience delusions that contradict reality. If the dopamine-acetylcholine circuit is constantly strengthening connections in the brain, says Tritsch, then problems with this mechanism might lead to the formation of too many, and incorrect, connections, causing them to “learn” of events that did not really occur.
Similarly, lack of motivation is a common symptom of depression, making it challenging to perform basic tasks such as getting out of bed, brushing teeth, or going to work. It is possible that a disruption in the internal-drive system might be contributing to these issues, the authors say.
As a result, Tritsch says the research team next plans to examine how dopamine-acetylcholine cycles behave in animal models of such mental illnesses, as well as during sleep, which is important for memory consolidation.
A neural circuit for male sexual behavior and reward
by Bayless DW, Davis C ha O, Yang R, et al. in Cell
Researchers at Stanford University have identified a brain hub that controls sexual arousal in male mice. By tweaking signaling in this area, the team was able to enhance or extinguish sexual desire and even let male mice engage in sexual activity immediately after ejaculation. Researchers hope that this line of study could lead to treatments for sexual problems in human men.
“We’ve singled out a circuit in male mammals’ brains that controls sexual recognition, libido and mating behavior and pleasure,” said Dr. Nirao Shah, a professor of psychiatry and of neurobiology at Stanford and the senior author of the study.
The study meticulously explored the function and connections of this brain circuit. The researchers bred a group of male, virgin mice who were kept in isolation from female mice after they were weaned a few weeks after birth to rule out any social influences on their behavior. When these mice encountered a stranger animal and realized it was female, a brain circuit lit up. This appears to be the key location for determining mouse libido.
Once this region was activated, a series of related circuits were stimulated, including those that encouraged the mice to engage in the voluntary movements required for mating behavior and those that help anticipate and produce pleasure for the animal in response.
Shah’s previous work explored connections from the brain’s emotional center — the amygdala. His team showed that altering neurons that extended from a subregion called the bed nucleus of the stria terminalis (BNST) to another brain area — the preoptic hypothalamus — could turn male mice’s ability to recognize the sex of another mouse on and off like a light switch.
This latest work furthered this line of study. “We wanted to know exactly which of these neurons were talking to exactly which neurons in the preoptic hypothalamus once that recognition occurred,” said Shah.
Within the BNST, Shah’s team tracked down a set of brain cells that behaved differently by secreting a protein called substance P. Looking in the preoptic hypothalamus, the team found these cells’ complement — a linked group of neurons that expressed receptors activated by substance P.
When this neuronal circuit was stimulated, a 10-to-15-minute timer appeared to start ticking. Once this time had elapsed, the mice started the full glut of mating behaviors: mounting, penetration and ejaculation. The team was able to speed this process up further by injecting substance P directly into the circuit area. If the receptors themselves were directly stimulated, the urge to mate became so strong that mice would attempt to copulate with anything around them, inanimate objects included. The stimulation appeared to be pleasurable for the mice, judging by the release of the hormone dopamine and the mice’s tendency to self-stimulate if given the option.
The influence of this brain circuit appears to extend beyond a simple desire for sex. Nearly all male mammals, humans very much included, have a “refractory period” built into their sexual brain hardware. After ejaculation, a waiting period ensues before full sexual drive and performance is restored.
This delay may have been the cause for an occasional frustration among enthusiastic human partners, but perhaps we should consider ourselves fortunate — mice have to wait a remarkable four days after ejaculation before their sex drive is restored.
But when substance P-sensitive neurons were stimulated in mice who had just ejaculated, barely a second’s pause was required before the mice were once again ready to do the deed.
“It took one second or less for them to resume sexual activity,” Shah said. “That’s a more than 400,000-fold reduction in the refractory period.” Importantly, the intervention did not affect other key mouse behaviors, like aggression.
These changes were not a one-way street, however. “If you silence just this set of preoptic-hypothalamus neurons,” Shah said, “the males don’t mate, period.” The mice were also otherwise unaffected by this libido loss.
Does this almanac of amorous rodent behavior have any uses in humans? Shah reckons that our brain circuitry could look very similar in this area.
“It’s very likely there are similar sets of neurons in the human hypothalamus that regulate sexual reward, behavior and gratification,” he said. “And they’re probably quite similar to the ones we’ve observed in mice.”
“If these centers exist in humans — and now we know where to look — it should be possible to design small molecules that can be used to regulate these circuits,” Shah said.
Currently used drugs for low sex drive, like Viagra, work by altering blood flow throughout the body. You can make a broken-down car move again by towing it with a repair truck, but the stricken vehicle isn’t fixed. Treatments that target the substance P brain circuit directly would be more precisely targeted, the equivalent of a new engine and a recharged car battery.
MISC
Subscribe to Paradigm!
Medium, Twitter, Telegram, Telegram Chat, LinkedIn, and Reddit.
Main sources
Research articles
