Scientists breach brain barriers to attack tumors

Illustration of human brain and tumor (stock image).

The brain is a sort of fortress, equipped with barriers designed to keep out dangerous pathogens. But protection comes at a cost: These barriers interfere with the immune system when faced with dire threats such glioblastoma, a deadly brain tumor for which there are few effective treatments.

Yale researchers have found a novel way to circumvent the brain's natural defenses when they're counterproductive by slipping immune system rescuers through the fortresses' drainage system, they report Jan. 15 in the journal Nature.

"People had thought there was very little the immune system could do to combat brain tumors," said senior corresponding author Akiko Iwasaki. "There has been no way for glioblastoma patients to benefit from immunotherapy."

Iwasaki is the Waldemar Von Zedtwitz Professor of Immunobiology and professor of molecular, cellular, and developmental biology and an investigator for the Howard Hughes Medical Institute.

While the brain itself has no direct way for disposing of cellular waste, tiny vessels lining the interior of the skull collect tissue waste and dispose of it through the body's lymphatic system, which filters toxins and waste from the body. It is this disposal system that researchers exploited in the new study.

These vessels form shortly after birth, spurred in part by the gene known as vascular endothelial growth factor C, or VEGF-C.

Yale's Jean-Leon Thomas, associate professor of neurology at Yale and senior co-corresponding author of the paper, wondered whether VEGF-C might increase immune response if lymphatic drainage was increased. And lead author Eric Song, a student working in Iwasaki's lab, wanted to see if VEGF-C could specifically be used to increase the immune system's surveillance of glioblastoma tumors. Together, the team investigated whether introducing VEGF-C through this drainage system would specifically target brain tumors.

The team introduced VEGF C into the cerebrospinal fluid of mice with glioblastoma and observed an increased level of T cell response to tumors in the brain. When combined with immune system checkpoint inhibitors commonly used in immunotherapy, the VEGF-C treatment significantly extended survival of the mice. In other words, the introduction of VEGF-C, in conjunction with cancer immunotherapy drugs, was apparently sufficient to target brain tumors.

"These results are remarkable," Iwasaki said. "We would like to bring this treatment to glioblastoma patients. The prognosis with current therapies of surgery and chemotherapy is still so bleak."

The study was primarily funded by the Howard Hughes Medical Institute and the National Institutes of Health.

Other Yale authors are Tianyang Mao, Huiping Dong, Ligia Simoes,Braga Boisserand, and Marcus Bosenberg. Salli Antila and Kari Alitalo of the University of Helsinki are also authors.

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Story Source:

Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.

Scientists breach brain barriers to attack tumors

Illustration of human brain and tumor (stock image).

The brain is a sort of fortress, equipped with barriers designed to keep out dangerous pathogens. But protection comes at a cost: These barriers interfere with the immune system when faced with dire threats such glioblastoma, a deadly brain tumor for which there are few effective treatments.

Yale researchers have found a novel way to circumvent the brain's natural defenses when they're counterproductive by slipping immune system rescuers through the fortresses' drainage system, they report Jan. 15 in the journal Nature.

"People had thought there was very little the immune system could do to combat brain tumors," said senior corresponding author Akiko Iwasaki. "There has been no way for glioblastoma patients to benefit from immunotherapy."

Iwasaki is the Waldemar Von Zedtwitz Professor of Immunobiology and professor of molecular, cellular, and developmental biology and an investigator for the Howard Hughes Medical Institute.

While the brain itself has no direct way for disposing of cellular waste, tiny vessels lining the interior of the skull collect tissue waste and dispose of it through the body's lymphatic system, which filters toxins and waste from the body. It is this disposal system that researchers exploited in the new study.

These vessels form shortly after birth, spurred in part by the gene known as vascular endothelial growth factor C, or VEGF-C.

Yale's Jean-Leon Thomas, associate professor of neurology at Yale and senior co-corresponding author of the paper, wondered whether VEGF-C might increase immune response if lymphatic drainage was increased. And lead author Eric Song, a student working in Iwasaki's lab, wanted to see if VEGF-C could specifically be used to increase the immune system's surveillance of glioblastoma tumors. Together, the team investigated whether introducing VEGF-C through this drainage system would specifically target brain tumors.

The team introduced VEGF C into the cerebrospinal fluid of mice with glioblastoma and observed an increased level of T cell response to tumors in the brain. When combined with immune system checkpoint inhibitors commonly used in immunotherapy, the VEGF-C treatment significantly extended survival of the mice. In other words, the introduction of VEGF-C, in conjunction with cancer immunotherapy drugs, was apparently sufficient to target brain tumors.

"These results are remarkable," Iwasaki said. "We would like to bring this treatment to glioblastoma patients. The prognosis with current therapies of surgery and chemotherapy is still so bleak."

The study was primarily funded by the Howard Hughes Medical Institute and the National Institutes of Health.

Other Yale authors are Tianyang Mao, Huiping Dong, Ligia Simoes,Braga Boisserand, and Marcus Bosenberg. Salli Antila and Kari Alitalo of the University of Helsinki are also authors.

---

Story Source:

Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.

Researchers discover brain circuit linked to food impulsivity

Eating popcorn at a movie (stock image).

Credit: © Zoriana / Adobe Stock

You're on a diet, but the aroma of popcorn in the movie theater lobby triggers a seemingly irresistible craving.

Within seconds, you've ordered a tub of the stuff and have eaten several handfuls.

Impulsivity, or responding without thinking about the consequences of an action, has been linked to excessive food intake, binge eating, weight gain and obesity, along with several psychiatric disorders including drug addiction and excessive gambling.

A team of researchers that includes a faculty member at the University of Georgia has now identified a specific circuit in the brain that alters food impulsivity, creating the possibility scientists can someday develop therapeutics to address overeating.

The team's findings were published recently in the journal Nature Communications.

"There's underlying physiology in your brain that is regulating your capacity to say no to (impulsive eating)," said Emily Noble, an assistant professor in the UGA College of Family and Consumer Sciences who served as lead author on the paper. "In experimental models, you can activate that circuitry and get a specific behavioral response."

Using a rat model, researchers focused on a subset of brain cells that produce a type of transmitter in the hypothalamus called melanin concentrating hormone (MCH).

While previous research has shown that elevating MCH levels in the brain can increase food intake, this study is the first to show that MCH also plays a role in impulsive behavior, Noble said.

"We found that when we activate the cells in the brain that produce MCH, animals become more impulsive in their behavior around food," Noble said.

To test impulsivity, researchers trained rats to press a lever to receive a "delicious, high-fat, high-sugar" pellet, Noble said. However, the rat had to wait 20 seconds between lever presses. If the rat pressed the lever too soon, it had to wait an additional 20 seconds.

Researchers then used advanced techniques to activate a specific MCH neural pathway from the hypothalamus to the hippocampus, a part of the brain involved with learning and memory function.

Results indicated MCH doesn't affect how much the animals liked the food or how hard they were willing to work for the food. Rather, the circuit acted on the animals' inhibitory control, or their ability to stop themselves from trying to get the food."Activating this specific pathway of MCH neurons increased impulsive behavior without affecting normal eating for caloric need or motivation to consume delicious food," Noble said. "Understanding that this circuit, which selectively affects food impulsivity, exists opens the door to the possibility that one day we might be able to develop therapeutics for overeating that help people stick to a diet without reducing normal appetite or making delicious foods less delicious."

---

Story Source:

Materials provided by University of Georgia. Original written by Cal Powell. Note: Content may be edited for style and length.

Dogs process numerical quantities in similar brain region as humans

Dog and chalkboard addition (stock image).

Dogs spontaneously process basic numerical quantities, using a distinct part of their brains that corresponds closely to number-responsive neural regions in humans, finds a study at Emory University.

Biology Letters published the results, which suggest that a common neural mechanism has been deeply conserved across mammalian evolution.

"Our work not only shows that dogs use a similar part of their brain to process numbers of objects as humans do -- it shows that they don't need to be trained to do it," says Gregory Berns, Emory professor of psychology and senior author of the study.

"Understanding neural mechanisms -- both in humans and across species -- gives us insights into both how our brains evolved over time and how they function now," says co-author Stella Lourenco, an associate professor of psychology at Emory.

Such insights, Lourenco adds, may one day lead to practical applications such as treating brain abnormalities and improving artificial intelligence systems.

Lauren Aulet, a PhD candidate in Lourenco's lab, is first author of the study.

The study used functional magnetic resonance imaging (fMRI) to scan dogs' brains as they viewed varying numbers of dots flashed on a screen. The results showed that the dogs' parietotemporal cortex responded to differences in the number of the dots. The researchers held the total area of the dots constant, demonstrating that it was the number of the dots, not the size, that generated the response.

The approximate number system supports the ability to rapidly estimate a quantity of objects in a scene, such as the number of predators approaching or the amount of food available for foraging. Evidence suggests that humans primarily draw on their parietal cortex for this ability, which is present even in infancy.

This basic sensitivity to numerical information, known as numerosity, does not rely on symbolic thought or training and appears to be widespread throughout the animal kingdom. Much of the research in non-humans, however, has involved intensive training of the subjects.

Previous research, for example, has found that particular neurons in the parietal cortex of monkeys are attuned to numerical values. Such studies had not clarified whether numerosity is a spontaneous system in non-human primates, because the subjects underwent many trials and received rewards for selecting scenes with greater numbers of dots in preparation for the experiments.

Behavioral studies in dogs that were trained in the task of discriminating between different quantities of objects have also indicated that dogs are sensitive to numerosity.

The Emory researchers wanted to delve further into the neural underpinnings of canine number perception using fMRI.

Berns is founder of the Dog Project, which is researching evolutionary questions surrounding man's best, and oldest friend. The project was the first to train dogs to voluntarily enter an fMRI scanner and remain motionless during scanning, without restraint or sedation.

Lourenco primarily researches human visual perception, cognition and development.

Eleven dogs of varying breeds were involved in the current fMRI experiments. The dogs did not receive advance training in numerosity. After entering the fMRI, they passively viewed dot arrays that varied in numerical value. Eight of the 11 dogs showed greater activation in the parietotemporal cortex when the ratio between alternating dot arrays was more dissimilar than when the numerical values were constant.

"We went right to the source, observing the dogs' brains, to get a direct understanding of what their neurons were doing when the dogs viewed varying quantities of dots," Aulet says. "That allowed us to bypass the weaknesses of previous behavioral studies of dogs and some other species."

Humans and dogs are separated by 80 million years of evolution, Berns notes. "Our results provide some of the strongest evidence yet that numerosity is a shared neural mechanism that goes back at least that far," he says.

Unlike dogs and other animals, humans are able to build on basic numerosity in order to do more complex math, drawing primarily on the prefrontal cortex. "Part of the reason that we are able to do calculus and algebra is because we have this fundamental ability for numerosity that we share with other animals," Aulet says. "I'm interested in learning how we evolved that higher math ability and how these skills develop over time in individuals, starting with basic numerosity in infancy."

Additional authors of the study include Veronica Chiu and Ashley Prichard, Emory graduate students in psychology, and Mark Spivak, CEO of Comprehensive Pet Therapy. Spivak and Berns co-founded Dog Star Technologies to develop techniques to study how dogs perceive the world.

The work was supported by the National Institutes of Health, the John Merck Fund and the Office of Naval Research.

---

Story Source:

Materials provided by Emory Health Sciences. Original written by Carol Clark. Note: Content may be edited for style and length.

Dogs process numerical quantities in similar brain region as humans

Dog and chalkboard addition

Dogs spontaneously process basic numerical quantities, using a distinct part of their brains that corresponds closely to number-responsive neural regions in humans, finds a study at Emory University.

Biology Letters published the results, which suggest that a common neural mechanism has been deeply conserved across mammalian evolution.

"Our work not only shows that dogs use a similar part of their brain to process numbers of objects as humans do -- it shows that they don't need to be trained to do it," says Gregory Berns, Emory professor of psychology and senior author of the study.

"Understanding neural mechanisms -- both in humans and across species -- gives us insights into both how our brains evolved over time and how they function now," says co-author Stella Lourenco, an associate professor of psychology at Emory.

Such insights, Lourenco adds, may one day lead to practical applications such as treating brain abnormalities and improving artificial intelligence systems.

Lauren Aulet, a PhD candidate in Lourenco's lab, is first author of the study.

The study used functional magnetic resonance imaging (fMRI) to scan dogs' brains as they viewed varying numbers of dots flashed on a screen. The results showed that the dogs' parietotemporal cortex responded to differences in the number of the dots. The researchers held the total area of the dots constant, demonstrating that it was the number of the dots, not the size, that generated the response.

The approximate number system supports the ability to rapidly estimate a quantity of objects in a scene, such as the number of predators approaching or the amount of food available for foraging. Evidence suggests that humans primarily draw on their parietal cortex for this ability, which is present even in infancy.

This basic sensitivity to numerical information, known as numerosity, does not rely on symbolic thought or training and appears to be widespread throughout the animal kingdom. Much of the research in non-humans, however, has involved intensive training of the subjects.

Previous research, for example, has found that particular neurons in the parietal cortex of monkeys are attuned to numerical values. Such studies had not clarified whether numerosity is a spontaneous system in non-human primates, because the subjects underwent many trials and received rewards for selecting scenes with greater numbers of dots in preparation for the experiments.

Behavioral studies in dogs that were trained in the task of discriminating between different quantities of objects have also indicated that dogs are sensitive to numerosity.

The Emory researchers wanted to delve further into the neural underpinnings of canine number perception using fMRI.

Berns is founder of the Dog Project, which is researching evolutionary questions surrounding man's best, and oldest friend. The project was the first to train dogs to voluntarily enter an fMRI scanner and remain motionless during scanning, without restraint or sedation.

Lourenco primarily researches human visual perception, cognition and development.

Eleven dogs of varying breeds were involved in the current fMRI experiments. The dogs did not receive advance training in numerosity. After entering the fMRI, they passively viewed dot arrays that varied in numerical value. Eight of the 11 dogs showed greater activation in the parietotemporal cortex when the ratio between alternating dot arrays was more dissimilar than when the numerical values were constant.

"We went right to the source, observing the dogs' brains, to get a direct understanding of what their neurons were doing when the dogs viewed varying quantities of dots," Aulet says. "That allowed us to bypass the weaknesses of previous behavioral studies of dogs and some other species."

Humans and dogs are separated by 80 million years of evolution, Berns notes. "Our results provide some of the strongest evidence yet that numerosity is a shared neural mechanism that goes back at least that far," he says.

Unlike dogs and other animals, humans are able to build on basic numerosity in order to do more complex math, drawing primarily on the prefrontal cortex. "Part of the reason that we are able to do calculus and algebra is because we have this fundamental ability for numerosity that we share with other animals," Aulet says. "I'm interested in learning how we evolved that higher math ability and how these skills develop over time in individuals, starting with basic numerosity in infancy."

Additional authors of the study include Veronica Chiu and Ashley Prichard, Emory graduate students in psychology, and Mark Spivak, CEO of Comprehensive Pet Therapy. Spivak and Berns co-founded Dog Star Technologies to develop techniques to study how dogs perceive the world.

The work was supported by the National Institutes of Health, the John Merck Fund and the Office of Naval Research.

---

Story Source:

Materials provided by Emory Health Sciences. Original written by Carol Clark. Note: Content may be edited for style and length.

A week in the dark rewires brain cell networks and changes hearing in adult mice

A week in the dark rewires brain cell networks and changes hearing in adult mice

Scientists have known that depriving adult mice of vision can increase the sensitivity of individual neurons in the part of the brain devoted to hearing. New research from biologists at the University of Maryland revealed that sight deprivation also changes the way brain cells interact with one another, altering neuronal networks and shifting the mice's sensitivity to different frequencies. The research was published in the November 11, 2019 issue of the journal eNeuro.

"This study reinforces what we are learning about how manipulating vision can have a significant effect on the ability of an animal to hear long after the window for auditory learning was thought to have closed," said Patrick Kanold, professor of biology at UMD and senior author of the study.

It was once thought that the sensory regions of the brain were not adaptable after a critical period in childhood. This is why children learn languages much more readily than adults. Kanold's earlier research disproved this idea by showing that depriving adult mice of vision for a short period increased the sensitivity of individual neurons in the auditory cortex, which is devoted to hearing.

The current study expands on that earlier work. Kanold and his team investigated how exposure to darkness affects the way groups of neurons in the auditory cortex work together in response to a given sound -- which neurons are connected and which fire more powerfully or faster. The researchers placed adult mice in a dark space for one week and then played 17 different tones while measuring brain activity in the auditory cortex. Based on their earlier work, Kanold and his team expected to see changes in the neural networks, but they were surprised to find that groups of neurons changed in different ways.

Young brains wire themselves according to the sounds they hear frequently, allocating areas of the auditory cortex for specific frequencies based on what they are used to hearing. The researchers found that, in adult mice, a week in the dark also redistributed the allocation of space to different frequencies. In the areas of the auditory cortex they examined, the researchers saw an increase in the proportion of neurons that were sensitive to high and low frequencies and a decrease in proportion of neurons that were sensitive to mid-range frequencies.

"We don't know why we are seeing these patterns," Kanold said. "We speculate that it may have to do with what the mice are paying attention to while they are in the dark. Maybe they pay attention to the noises or voices from the other mice, or maybe they're paying more attention to the footsteps they are making."

Kanold said his next steps include manipulating the sounds the mice are exposed to during the darkness phase of the experiment and monitoring brain activity to determine what aspects of their soundscape the mice are listening to. This will help the researchers understand the role of focus and attention in promoting change to the auditory neurons. Such information could be very useful in helping people adapt to cochlear implants or hearing aids.

Other authors of the study from UMD include biological sciences graduate student Zac Bowen, biophysics graduate student Ji Liu, and alumna Krystyna Solarana (Ph.D. '16, neuroscience and cognitive science) now at USAID.

---

Story Source:

Materials provided by University of Maryland. Note: Content may be edited for style and length.

Researchers discover brain circuit linked to food impulsivity

Eating popcorn at a movie 

You're on a diet, but the aroma of popcorn in the movie theater lobby triggers a seemingly irresistible craving.

Within seconds, you've ordered a tub of the stuff and have eaten several handfuls.

Impulsivity, or responding without thinking about the consequences of an action, has been linked to excessive food intake, binge eating, weight gain and obesity, along with several psychiatric disorders including drug addiction and excessive gambling.

A team of researchers that includes a faculty member at the University of Georgia has now identified a specific circuit in the brain that alters food impulsivity, creating the possibility scientists can someday develop therapeutics to address overeating.

The team's findings were published recently in the journal Nature Communications.

"There's underlying physiology in your brain that is regulating your capacity to say no to (impulsive eating)," said Emily Noble, an assistant professor in the UGA College of Family and Consumer Sciences who served as lead author on the paper. "In experimental models, you can activate that circuitry and get a specific behavioral response."

Using a rat model, researchers focused on a subset of brain cells that produce a type of transmitter in the hypothalamus called melanin concentrating hormone (MCH).

While previous research has shown that elevating MCH levels in the brain can increase food intake, this study is the first to show that MCH also plays a role in impulsive behavior, Noble said.

"We found that when we activate the cells in the brain that produce MCH, animals become more impulsive in their behavior around food," Noble said.

To test impulsivity, researchers trained rats to press a lever to receive a "delicious, high-fat, high-sugar" pellet, Noble said. However, the rat had to wait 20 seconds between lever presses. If the rat pressed the lever too soon, it had to wait an additional 20 seconds.

Researchers then used advanced techniques to activate a specific MCH neural pathway from the hypothalamus to the hippocampus, a part of the brain involved with learning and memory function.

Results indicated MCH doesn't affect how much the animals liked the food or how hard they were willing to work for the food. Rather, the circuit acted on the animals' inhibitory control, or their ability to stop themselves from trying to get the food."Activating this specific pathway of MCH neurons increased impulsive behavior without affecting normal eating for caloric need or motivation to consume delicious food," Noble said. "Understanding that this circuit, which selectively affects food impulsivity, exists opens the door to the possibility that one day we might be able to develop therapeutics for overeating that help people stick to a diet without reducing normal appetite or making delicious foods less delicious."

---

Story Source:

Materials provided by University of Georgia. Original written by Cal Powell. Note: Content may be edited for style and length.

A week in the dark rewires brain cell networks and changes hearing in adult mice

A week in the dark rewires brain cell networks

Scientists have known that depriving adult mice of vision can increase the sensitivity of individual neurons in the part of the brain devoted to hearing. New research from biologists at the University of Maryland revealed that sight deprivation also changes the way brain cells interact with one another, altering neuronal networks and shifting the mice's sensitivity to different frequencies. The research was published in the November 11, 2019 issue of the journal eNeuro.

"This study reinforces what we are learning about how manipulating vision can have a significant effect on the ability of an animal to hear long after the window for auditory learning was thought to have closed," said Patrick Kanold, professor of biology at UMD and senior author of the study.

It was once thought that the sensory regions of the brain were not adaptable after a critical period in childhood. This is why children learn languages much more readily than adults. Kanold's earlier research disproved this idea by showing that depriving adult mice of vision for a short period increased the sensitivity of individual neurons in the auditory cortex, which is devoted to hearing.

The current study expands on that earlier work. Kanold and his team investigated how exposure to darkness affects the way groups of neurons in the auditory cortex work together in response to a given sound -- which neurons are connected and which fire more powerfully or faster. The researchers placed adult mice in a dark space for one week and then played 17 different tones while measuring brain activity in the auditory cortex. Based on their earlier work, Kanold and his team expected to see changes in the neural networks, but they were surprised to find that groups of neurons changed in different ways.

Young brains wire themselves according to the sounds they hear frequently, allocating areas of the auditory cortex for specific frequencies based on what they are used to hearing. The researchers found that, in adult mice, a week in the dark also redistributed the allocation of space to different frequencies. In the areas of the auditory cortex they examined, the researchers saw an increase in the proportion of neurons that were sensitive to high and low frequencies and a decrease in proportion of neurons that were sensitive to mid-range frequencies.

"We don't know why we are seeing these patterns," Kanold said. "We speculate that it may have to do with what the mice are paying attention to while they are in the dark. Maybe they pay attention to the noises or voices from the other mice, or maybe they're paying more attention to the footsteps they are making."

Kanold said his next steps include manipulating the sounds the mice are exposed to during the darkness phase of the experiment and monitoring brain activity to determine what aspects of their soundscape the mice are listening to. This will help the researchers understand the role of focus and attention in promoting change to the auditory neurons. Such information could be very useful in helping people adapt to cochlear implants or hearing aids.

Other authors of the study from UMD include biological sciences graduate student Zac Bowen, biophysics graduate student Ji Liu, and alumna Krystyna Solarana (Ph.D. '16, neuroscience and cognitive science) now at USAID.

---

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Materials provided by University of Maryland. Note: Content may be edited for style and length.

Lack of oxygen doesn't kill infant brain cells

Nearly 15 million babies are born prematurely, or before 37 weeks of pregnancy, around the world each year. When born too early, a baby's immature respiratory center in the brain often fails to signal it to breathe, resulting in low oxygen levels, or hypoxia, in the brain.

Research published in the Journal of Neuroscience shows that even a brief 30-minute period of hypoxia is enough to persistently disrupt the structure and function of the brain region known as the hippocampus, which is vital for learning and memory.

"Our findings raise new concerns about the vulnerability of the preterm brain to hypoxia. They are concerning for the long-term impact that oxygen deprivation can have on the ability of these preterm babies to learn as they grow to school age and adulthood," said the study's principal investigator, Stephen Back, M.D., Ph.D., Clyde and Elda Munson Professor of Pediatric Research and Pediatrics, OHSU School of Medicine, OHSU Doernbecher Children's Hospital.

In the neonatal intensive care unit, preemies can experience up to 600 short, but impactful periods of hypoxia each week. Consequently, more than one-third of babies who survive preterm birth are likely to have smaller brains, presumably due to brain cell loss, compared with the brains of full-term infants. This can increase the risk of significant life-long neurodevelopmental challenges that will affect learning, memory, attention and behavior.

Using a twin preterm fetal sheep model, Back and colleagues studied the impact of both hypoxia alone, as well as in combination with ischemia -- or insufficient blood flow -- on the developing hippocampus. The results confirm that, similar to human preterm survivors, growth of the hippocampus is impaired. However, brain cells do not die as previously believed. Rather, hippocampal cells fail to mature normally, causing a reduction in long-term potentiation, or the cellular basis of how the brain learns.

Remarkably, the severity of the hypoxia predicted the degree to which cells in the hippocampus failed to mature normally, explains Back. These findings are all the more unexpected because it was not appreciated that the preterm hippocampus was already capable of these learning processes.

"We want to understand next how very brief or prolonged exposure to hypoxia affects the ability for optimal learning and memory, " says Back. "This will allow us to understand how the hippocampus responds to a lack of oxygen, creating new mechanisms of care and intervention both at the hospital, and at home."

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Materials provided by Oregon Health & Science University. Note: Content may be edited for style and length.

MRI reveals brain damage in obese teens

Researchers using MRI have found signs of damage that may be related to inflammation in the brains of obese adolescents, according to a study being presented next week at the annual meeting of the Radiological Society of North America (RSNA).

Obesity in young people has become a significant public health problem. In the U.S., the percentage of children and adolescents affected by obesity has more than tripled since the 1970s, according to the Centers for Disease Control and Prevention. Data from the World Health Organization indicates that the number of overweight or obese infants and young children ages five years or younger increased from 32 million globally in 1990 to 41 million in 2016.

While obesity is primarily associated with weight gain, recent evidence suggests that the disease triggers inflammation in the nervous system that could damage important regions of the brain. Developments in MRI like diffusion tensor imaging (DTI), a technique that tracks the diffusion of water along the brain's signal-carrying white matter tracts, have enabled researchers to study this damage directly.

For the new study, researchers compared DTI results in 59 obese adolescents and 61 healthy adolescents, ages 12 to 16 years. From DTI, the researchers derived a measure called fractional anisotropy (FA), which correlates with the condition of the brain's white matter. A reduction in FA is indicative of increasing damage in the white matter.

The results showed a reduction of FA values in the obese adolescents in regions located in the corpus callosum, a bundle of nerve fibers that connects the left and right hemispheres of the brain. Decrease of FA was also found in the middle orbitofrontal gyrus, a brain region related to emotional control and the reward circuit. None of the brain regions in obese patients had increased FA.

"Brain changes found in obese adolescents related to important regions responsible for control of appetite, emotions and cognitive functions," said study co-author Pamela Bertolazzi, a biomedical scientist and Ph.D. student from the University of São Paulo in Brazil.

This pattern of damage correlated with some inflammatory markers like leptin, a hormone made by fat cells that helps regulate energy levels and fat stores. In some obese people, the brain does not respond to leptin, causing them to keep eating despite adequate or excessive fat stores. This condition, known as leptin resistance, makes the fat cells produce even more leptin.

Worsening condition of the white matter was also associated with levels of insulin, a hormone produced in the pancreas that helps regulate blood sugar levels. Obese people often suffer from insulin resistance, a state in which the body is resistant to the effects of the hormone.

"Our maps showed a positive correlation between brain changes and hormones such as leptin and insulin," Dr. Bertolazzi said. "Furthermore, we found a positive association with inflammatory markers, which leads us to believe in a process of neuroinflammation besides insulin and leptin resistance."

Dr. Bertolazzi noted that additional studies are needed to determine if this inflammation in young people with obesity is a consequence of the structural changes in the brain.

"In the future, we would like to repeat brain MRI in these adolescents after multi-professional treatment for weight loss to assess if the brain changes are reversible or not," she added.

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Materials provided by Radiological Society of North America. Note: Content may be edited for style and length.

Brain waves detected in mini-brains grown in a dish

Brain waves detected

Scientists have created miniature brains from stem cells that developed functional neural networks. Despite being a million times smaller than human brains, these lab-grown brains are the first observed to produce brain waves that resemble those of preterm babies. The study, published August 29 in the journal Cell Stem Cell, could help scientists better understand human brain development.

"The level of neural activity we are seeing is unprecedented in vitro," says Alysson Muotri, a biologist at the University of California, San Diego. "We are one step closer to have a model that can actually generate these early stages of a sophisticated neural network."

The pea-sized brains, called cerebral organoids, are derived from human pluripotent stem cells. By putting them in culture that mimics the environment of brain development, the stem cells differentiate into different types of brain cells and self-organize into a 3D structure resembling the developing human brain.

Scientists have successfully grown organoids with cellular structures similar to those of human brains. However, none of the previous models developed human-like functional neural networks. Networks appear when neurons are mature and become interconnected, and they are essential for most brain activities.

"You can use brain organoids for several things, including understand normal human neurodevelopment, disease modeling, brain evolution, drug screening, and even to inform artificial intelligence," Muotri says.

Muotri and colleagues designed a better procedure to grow stem cells, including optimizing the culture medium formula. These adjustments allowed their organoids to become more mature than previous models. The team grew hundreds of organoids for 10 months and used multi-electrode arrays to monitor their neural activities.

The team began to detect bursts of brain waves from organoids at about two months. The signals were sparse and had the same frequency, a pattern seen in very immature human brains. As the organoids continued to grow, they produced brain waves at different frequencies, and the signals appeared more regularly. This suggests the organoids have further developed their neural networks.

"This is a result of having more functional synapses, and you are forming more connections between the neurons," Muotri says. The interactions between neurons contribute to signals at various frequencies, he says.

To compare the brain wave patterns of organoids with those of human brains early in development, the team trained a machine learning algorithm with brain waves recorded from 39 premature babies between six and nine-and-a-half months old. The algorithm was able to predict how many weeks the organoids have developed in culture, which suggests these organoids and human brain share a similar growth trajectory.

However, it's not likely these organoids have mental activities, such as consciousness, Muotri says. "The organoid is still a very rudimentary model -- we don't have other brain parts and structures. So these brain waves might not have anything to do with activities in real brains."

"It might be that in the future, we will get something that is really close to the signals in the human brains that control behaviors, thoughts, or memory," Muotri says. "But I don't think we have any evidence right now to say we have any of those."

Looking forward, the team aims to further improve the organoids and use them to understand diseases associated with neural network malfunctioning, such as autism, epilepsy, and schizophrenia.

"As a scientist, I want to get closer and closer to the human brain," Muotri says. "I want to do that because I see the good in it. I can help people with neurological conditions by giving them better treatments and better quality of life. But it's up to us to decide where the limit is. It might be that the technology is not ready yet, or we don't know how to control the technology. This is the same kind of discussion around CRISPR in babies, and that's why we have ethics committees to represent all parts of the society."

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Materials provided by Cell Press. Note: Content may be edited for style and length.

The difference between an expert's brain and a novice's

Neurons illustration

When mice learn to do a new task, their brain activities change over time as they advance from 'novice' to 'expert.' The changes are reflected in the wiring of cell circuits and activities of neurons.

Using a two-photon imaging microscope and a wealth of genetic tools, researchers from Cold Spring Harbor Laboratory (CSHL), Columbia University, University College London, and Flatiron Institute found that neural networks become more focused as mice got better at performing a trained task. They used the data to construct computational models that can inform their understanding of the neuroscience behind decision-making.

"We recorded the activity from hundreds of neurons all at the same time, and studied what the neurons did over learning," said CSHL Associate Professor Anne Churchland. "Nobody really knew how animals or humans learn the structure of a task and how the neural activity supports that."

The team, including Farzaneh Najafi, the first author on the study and a postdoctoral fellow in Churchland's lab, started by training mice on perceptual decision-making tasks. The mice received multisensory stimuli in the form of a sequence of clicks and flashes that were presented together. Their job was to tell researchers whether those are happening at a high or low rate by licking one of three waterspouts in front of them.

They licked the middle spout to start the trial, one side to report a high-rate decision and the other side for a low-rate decision. When the mice made the correct decision, they received a reward.

"Most decision-making studies focused on the period where the animals are really experts. But we were able to see how they arrive at the state by measuring the neurons in their brain all the way through learning," said Churchland, the senior author on the study. "We found that in all the animals, their learning occurs gradually over about four weeks. And we found that what supports learning is activity changes in a whole bunch of neurons."

The neurons, the team discovered, became more selective in responding to an activity associated with a particular task. The also started reacting faster and more immediately.

"They'll respond really strongly in advance of one choice and much less so in advance of the other choice," Churchland said.

When the animals are just beginning to learn, the neurons don't respond until around the time it makes the choice. But as the animal gains expertise, the neurons respond much further in advance.

"We can kind of read the animal's mind in a way, we can predict what the animal is going to do before he does it," Churchland said. "When you're a novice at something your brain is doing all different things, so you have neurons engaged in all different things. But then when you're an expert, you hone in on exactly what you're going to do and we can pick up that activity."

The researchers decoded neural activity by training a small artificial network called the 'Linear Support Vector Machine' using machine learning algorithms. It collects performance data from multiple trials and combines it with the activity of all the neurons, weighing them to make a guess about what the animal's going to do. As the animal gets better at the task, its neural networks get more refined, precise and specific. The researchers are able to mirror that onto the artificial network, which can then predict the animal's decision with about 90 percent accuracy.

The learning models also offer another way of looking at specific types of neurons in the brain involved in cognition, like excitatory and inhibitory neurons, which trigger positive and negative changes, respectively. In this study, published in Neuron (Cell Press), the team found that the inhibitory neurons are part of very selective sub-networks in the brain, and they're strongly selective for the choice that the animal's going to make.

These neurons are part of a biophysical model that helps researchers understand how decision making works. As researchers refine these models, they're able to make more sense of how cognition informs behavior.

"We've learned a lot about perceptual decision-making-the decisions that a subject would get right and wrong, how long it takes to make those decisions, what the neural activity would look like during decision-making-by making different kinds of models that make really concrete predictions," Churchland said. "Now we can understand, hopefully better, why these very selective sub-networks are there, how they help us make better decisions, and how they are wired up during learning."

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Materials provided by Cold Spring Harbor Laboratory. Original written by Charlotte Hu. Note: Content may be edited for style and length.