Posts tagged cerebral cortex
Articles and news from the latest research reports.
Researchers map brain areas vital to understanding language
When reading text or listening to someone speak, we construct rich mental models that allow us to draw conclusions about other people, objects, actions, events, mental states and contexts. This ability to understand written or spoken language, called “discourse comprehension,” is a hallmark of the human mind and central to everyday social life. In a new study, researchers uncovered the brain mechanisms that underlie discourse comprehension.
The study appears in Brain: A Journal of Neurology.
With his team, study leader Aron Barbey, a professor of neuroscience, of psychology, and of speech and hearing science at the University of Illinois, previously had mapped general intelligence, emotional intelligence and a host of other high-level cognitive functions. Barbey is the director of the Decision Neuroscience Laboratory at the Beckman Institute for Advanced Science and Technology at Illinois.
To investigate the brain regions that underlie discourse comprehension, the researchers studied a group of 145 American male Vietnam War veterans who sustained penetrating head injuries during combat. Barbey said these shrapnel-induced injuries typically produced focal brain damage, unlike injuries caused by stroke or other neurological disorders that affect multiple regions. These focal injuries allowed the researchers to pinpoint the structures that are critically important to discourse comprehension.
“Neuropsychological patients with focal brain lesions provide a valuable opportunity to study how different brain structures contribute to discourse comprehension,” Barbey said.
A technique called voxel-based lesion-symptom mapping allowed the team to pool data from the veterans’ CT scans to create a collective, three-dimensional map of the cerebral cortex. They divided this composite brain into units called voxels (the three-dimensional counterparts of two-dimensional pixels). This allowed them to compare the discourse comprehension abilities of patients with damage to a particular voxel or cluster of voxels with those of patients without injuries to those brain regions.
The researchers identified a network of brain areas in the frontal and parietal cortex that are essential to discourse comprehension.
“Rather than engaging brain regions that are classically involved in language processing, our results indicate that discourse comprehension depends on an executive control network that helps integrate incoming language with prior knowledge and experience,” Barbey said. Executive control, also known as executive function, refers to the ability to plan, organize and regulate one’s behavior.
“The findings help us understand the neural foundations of discourse comprehension, and suggest that core elements of discourse processing emerge from a network of brain regions that support language processing and executive functions. The findings offer new insights into basic questions about the nature of discourse comprehension,” Barbey said, “and could offer new targets for clinical interventions to help patients with cognitive-communication disorders.
“Discourse comprehension is a hallmark of human social behavior,” Barbey said. “By studying the mechanisms that underlie these abilities, we’re able to advance our understanding of the remarkable cognitive and neural architecture from which language comprehension emerges.”
Researchers gain new insights into brain neuronal networks
A paper published in a special edition of the journal Science proposes a novel understanding of brain architecture using a network representation of connections within the primate cortex. Zoltán Toroczkai, professor of physics at the University of Notre Dame and co-director of the Interdisciplinary Center for Network Science and Applications, is a co-author of the paper “Cortical High-Density Counterstream Architectures.”
Using brain-wide and consistent tracer data, the researchers describe the cortex as a network of connections with a “bow tie” structure characterized by a high-efficiency, dense core connecting with “wings” of feed-forward and feedback pathways to the rest of the cortex (periphery). The local circuits, reaching to within 2.5 millimeters and taking up more than 70 percent of all the connections in the macaque cortex, are integrated across areas with different functional modalities (somatosensory, motor, cognitive) with medium- to long-range projections.
The authors also report on a simple network model that incorporates the physical principle of entropic cost to long wiring and the spatial positioning of the functional areas in the cortex. They show that this model reproduces the properties of the connectivity data in the experiments, including the structure of the bow tie. The wings of the bow tie emerge from the counterstream organization of the feed-forward and feedback nature of the pathways. They also demonstrate that, contrary to previous beliefs, such high-density cortical graphs can achieve simultaneously strong connectivity (almost direct between any two areas), communication efficiency, and economy of connections (shown via optimizing total wire cost) via weight-distance correlations that are also consequences of this simple network model.
This bow tie arrangement is a typical feature of self-organizing information processing systems. The paper notes that the cortex has some analogies with information-processing networks such as the World Wide Web, as well as metabolism, the immune system and cell signaling. The core-periphery bow tie structure, they say, is “an evolutionarily favored structure for a wide variety of complex networks” because “these systems are not in thermodynamic equilibrium and are required to maintain energy and matter flow through the system.” The brain, however, also shows important differences from such systems. For example, destination addresses are encoded in information packets sent along the Internet, apparently unlike in the brain, and location and timing of activity are critical factors of information processing in the brain, unlike in the Internet.
“Biological data is extremely complex and diverse,” Toroczkai said. “However, as a physicist, I am interested in what is common or invariant in the data, because it may reveal a fundamental organizational principle behind a complex system. A minimal theory that incorporates such principle should reproduce the observations, if not in great detail, but in extent. I believe that with additional consistent data, as those obtained by the Kennedy team, the fundamental principles of massive information processing in brain neuronal networks are within reach.”
(Source: news.nd.edu)
Critical Gene in Retinal Development and Motion Sensing Identified
Our vision depends on exquisitely organized layers of cells within the eye’s retina, each with a distinct role in perception. Johns Hopkins researchers say they have taken an important step toward understanding how those cells are organized to produce what the brain “sees.” Specifically, they report identification of a gene that guides the separation of two types of motion-sensing cells, offering insight into how cellular layering develops in the retina, with possible implications for the brain’s cerebral cortex. A report on the discovery is published in the Nov. 1 issue of the journal Science.
“The separation of different types of cells into layers is critical to their ability to form the precise sets of connections with each other — the circuitry — that lets us process visual information,” says Alex Kolodkin, Ph.D., a professor in the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience and an investigator at the Howard Hughes Medical Institute. “There is still much to learn about how that separation happens during development, but we’ve identified for the first time proteins that enable two very similar types of cells to segregate into their own distinct neuronal layers.”
Kolodkin’s research group specializes in studying how circuitry forms among neurons (brain and nerve cells). Past experiments revealed that two types of proteins, called semaphorins and plexins, help guide this process. In the current study, Lu Sun, a graduate student in Kolodkin’s laboratory, focused on the genes that carry the blueprint for these proteins in two of the 10 layers of cells in the mammalian retina.
Those two layers are made up of so-called starburst amacrine cells (SACs). One type of SAC, known as “Off,” detects motion by sensing decreases in the amount of light hitting the retina, while the other type, “On,” detects increases in light. Sun examined the amounts of several semaphorin and plexin proteins being made by each type of cell, and found that only the “On” SACs were making a semaphorin called Sema6A. Sema6A can only work in the retina by interacting with its receptor, a plexin called PlexA2, but Sun found both types of SAC were churning out roughly equal amounts of PlexA2.
Reasoning that Sema6A might be the key difference that enabled the “On” and “Off” SACs to segregate from one another, Kolodkin’s team analyzed mice in which the genes for either Sema6A, PlexA2 or both could be switched off, and looked at the effects of this manipulation on their retinas. “Knocking out” either gene during development led the “On” and “Off” layers to run together, the team found, and caused abnormalities in the “On” SACs’ tree-like extensions. However, the “Off” SACs, which hadn’t been using their Sema6A gene in the first place, still looked and functioned normally.
“When signaling between Sema6A and PlexA2 was lost, not only was layering compromised, but the ‘On’ SACs lost both their distinctive symmetrical appearance, and, importantly, their motion-detecting ability,” Sun says. “This is evidence that the beautiful symmetric shape that gives starburst amacrine cells their name is necessary for their function.”
Adds Kolodkin, “We hope that learning how layering occurs in these very specific cell types will help us begin sorting out how connections are made not just in the retina, but also in neurons throughout the nervous system. Layering also occurs in the cerebral cortex, for example, which is responsible for thought and consciousness, and we really want to know how this is organized during neural development.”
(Source: newswise.com)
Unravelling the true identity of the brain of Carl Friedrich Gauss
Preserved specimens of the brains of mathematician Carl Friedrich Gauss and Göttingen physician Conrad Heinrich Fuchs, taken over 150 years ago, were switched – and this probably happened soon after the death of both men in 1855. This is the surprising conclusion reached by Renate Schweizer, a neuroscientist at Biomedizinische NMR Forschungs GmbH at the Max Planck Institute for Biophysical Chemistry. She has now correctly identified the two brains, both of which are archived in a collection at the University Medical Center Göttingen. Working with experts from other disciplines, she extensively documented brain slices with a magnetic resonance imaging scanner.
Walnut-like structures appear on the computer screen. They reveal what’s inside the MRI scanner at Biomedizinische NMR Forschungs GmbH: a 150-year-old slice from the brain of mathematician Carl Friedrich Gauss. Renate Schweizer monitors the measurements as the internal tissue comes into view layer by layer. Then she carefully places another brain on the examination table, more commonly used to slowly move test subjects into the “tube”. This is the brain of Conrad Heinrich Fuchs – who, like Gauss, died in 1855 and was a medical scholar and founder of the University of Göttingen’s anatomical pathology collection. There is a specific reason for this latest examination of the historical brains from the collection at the Institute of Ethics and History of Medicine at University Medical Center Göttingen: “What scientists had long been examining in the belief that it was Gauss’s brain was not his brain at all, but actually belonged to Fuchs. The two scientists’ brains had been switched many years ago, and so they need to be documented again,” says Schweizer, a biologist and psychologist, describing the surprising findings of her investigations.
The scientist made this unexpected discovery while working in her research field – the region of the brain around the so-called central fissure. The gyri running along the central fissure are where the brain processes stimuli, like touch, heat or pain, and where it controls movements. Renate Schweizer suspected that Gauss’s brain featured a rare anatomical variation: a visible division of the central fissure. This is found in less than one percent of the population. Normally, it is of no significance to the people affected, though in a few cases it can cause minimal changes in motor and sensory function.
Schweizer spotted one of those central fissure divisions in the MRI scans believed to be of Gauss’s brain, taken in 1998 by Jens Frahm and his team at Biomedizinische NMR Forschungs GmbH and searched through the primary literature to confirm her findings. Rudolf Wagner, an anatomist in Göttingen and friend of Gauss, had prepared the brain slices of both Gauss and Fuchs before studying them and documenting the images in publications dating back to 1860 and 1862. But contrary to what she expected to see, Schweizer did not find the divided central fissure in the images of Gauss’s brain. Instead, her MRI images were a perfect match for Wagner’s picture of Fuchs’s brain.
When Schweizer visited the collection at the Institute of Ethics and History of Medicine, her initial suspicion was confirmed: the original brain taken from Gauss was indeed in a glass jar labelled ‘C. H. Fuchs’, while Fuchs’s brain was in a jar marked ‘C. F. G__ss’. “My theory, according to the information currently available, is that the brains were probably put into the wrong jars relatively soon after Wagner’s examinations, at the time when the surface of the cerebral cortex was being measured again,” says the neuroscientist. After that, there were no further comparative studies of the brains of Gauss and Fuchs, which is why no one noticed the subsequent mix-up. It is also significant for the Göttingen-based Gauss Society to know that the brains of Gauss and Fuchs are now assigned to their proper owners once more. “The Gauss Society’s Director, Axel Wittmann, was an active supporter of the project from the start and his extensive knowledge was extremely helpful in uncovering the mistake made so many years ago,” reports Schweizer.
Her discovery shows how important historic collections are for modern-day research. Schweizer confirms: “It’s a stroke of luck that the brains in the collection, which are in perfect condition, are still accessible to researchers more than 150 years down the line.” That is what enabled the mix-up to be identified without a shadow of a doubt and the historical brains to be examined in the MRI scanner. Schweizer collaborated closely with former team colleague Gunther Helms, who works with brain slice MRIs in the MR Research Service Unit at the Department of Cognitive Neurology at University Medical Center Göttingen. As Jens Frahm, Director of Biomedizinische NMR Forschungs GmbH, emphasises: “We are not looking for the genie in the gyri of the brain. What we are most interested in is documenting specimens for the long term future to provide a foundation for continuing basic research.” All MRI images and photographs of the historic brains are therefore being digitally archived, thus protecting them as long-term scientific assets. They are a significant impetus for new research projects: Schweizer herself is currently using the MRI images to study the divided central fissure in Fuchs’s brain both above and below the surface of the cerebral cortex.
The MRI images also enable the scientists to demonstrate that earlier publications on what was believed to be Gauss’s brain did not contain incorrect information. In those works, the mathematician’s brain was described as normal. Walter Schulz-Schaeffer, who is head of the Prion and Dementia Research Unit of the Institute of Neuropathology at University Medical Center Göttingen, made a first examination of the recent MRI images and was able to confirm that the brain of the brilliant mathematician and astronomer Gauss, like that of the physician Fuchs, is largely anatomically unremarkable. The two organs are also similar in size and weight. “The age-related changes in Gauss’s brain are normal for a man of 78. Changes in the basal ganglia are indicative of high blood pressure,” comments the neuropathologist.
Not every MRI scan of a historical slice allows for such a clear assertion. That is why neuropathologists and MRI scientists are currently working together to study how tissue and organs change as a result of decades or centuries of storage in alcohol, and how adapted MRI methods can improve the interpretation of the images obtained.
The historical brains have, meanwhile, again found their well-earned rest in the university collection – with no chance of a mix-up ever again.
Birth gets the brain ready to sense the world
Neurons that process sensory information such as touch and vision are arranged in precise, well-characterized maps that are crucial for translating perception into understanding. A study published by Cell Press on October 14 in the journal Developmental Cell reveals that the actual act of birth in mice causes a reduction in a brain chemical called serotonin in the newborn mice, triggering sensory maps to form. The findings shed light on the key role of a dramatic environmental event in the development of neural circuits and reveal that birth itself is one of the triggers that prepares the newborn for survival outside the womb.
"Our results clearly demonstrate that birth has active roles in brain formation and maturation," says senior study author Hiroshi Kawasaki of Kanazawa University in Japan. "We found that birth regulates neuronal circuit formation not only in the somatosensory system but also in the visual system. Therefore, it seems reasonable to speculate that birth actually plays a wider role in various brain regions."
Mammals ranging from mice to humans have brain maps that represent various types of sensory information. In a region of the rodent brain known as the barrel cortex, neurons that process tactile information from whiskers are arranged in a map corresponding to the spatial pattern of whiskers on the snout, with neighboring columns of neurons responding to stimulation of adjacent whiskers. Although previous studies have shown that the neurotransmitter serotonin influences the development of sensory maps, its specific role during normal development has not been clear until now.
In this new study, Kawasaki and his team find that the birth of mouse pups leads to a drop in serotonin levels in the newborn’s brain, triggering the formation of neural circuits in the barrel cortex and in the lateral geniculate nucleus (LGN), a brain region that processes visual information. When mice were treated with drugs that either induced preterm birth or decreased serotonin signaling, neural circuits in the barrel cortex as well as in the LGN formed more quickly. Conversely, neural circuits in the barrel cortex failed to form when the mice were treated with a drug that increased serotonin signaling, suggesting that a reduction in levels of this neurotransmitter is crucial for sensory map formation.
Because serotonin also plays a key role in mental disorders, it is possible that abnormalities in birth processes and the effects on subsequent serotonin signaling and brain development could increase the risk of psychiatric diseases. “Uncovering the entire picture of the downstream signaling pathways of birth may lead to the development of new therapeutic methods to control the risk of psychiatric diseases induced by abnormal birth,” Kawasaki says.
(Source: eurekalert.org)
Human Cortical Neurons with interconnecting dendrites, 4,200X by David Scharf.
Cortical Neurons make up the brain’s cortex which in part makes up the cerebral cortex, responsible for memory, attention, perceptual awareness, thought, language, and consciousness.
(Image Credit: BNPS/RPS/David Scharf)
Egoism and narcissism appear to be on the rise in our society, while empathy is on the decline. And yet, the ability to put ourselves in other people’s shoes is extremely important for our coexistence. A research team headed by Tania Singer from the Max Planck Institute for Human Cognitive and Brain Sciences has discovered that our own feelings can distort our capacity for empathy. This emotionally driven egocentricity is recognised and corrected by the brain. When, however, the right supramarginal gyrus doesn’t function properly or when we have to make particularly quick decisions, our empathy is severely limited.
When assessing the world around us and our fellow humans, we use ourselves as a yardstick and tend to project our own emotional state onto others. While cognition research has already studied this phenomenon in detail, nothing is known about how it works on an emotional level. It was assumed that our own emotional state can distort our understanding of other people’s emotions, in particular if these are completely different to our own. But this emotional egocentricity had not been measured before now.
This is precisely what the Max Planck researchers have accomplished in a complex marathon of experiments and tests. They also discovered the area of the brain responsible for this function, which helps us to distinguish our own emotional state from that of other people. The area in question is the supramarginal gyrus, a convolution of the cerebral cortex which is approximately located at the junction of the parietal, temporal and frontal lobe. “This was unexpected, as we had the temporo-parietal junction in our sights. This is located more towards the front of the brain,” explains Claus Lamm, one of the publication’s authors.
On the empathy trail with toy slime and synthetic fur
Using a perception experiment, the researchers began by showing that our own feelings actually do influence our capacity for empathy, and that this egocentricity can also be measured. The participants, who worked in teams of two, were exposed to either pleasant or unpleasant simultaneous visual and tactile stimuli.
While participant 1, for example, could see a picture of maggots and feel slime with her hand, participant 2 saw a picture of a puppy and could feel soft, fleecy fur on her skin. “It was important to combine the two stimuli. Without the tactile stimulus, the participants would only have evaluated the situation ‘with their heads’ and their feelings would have been excluded,” explains Claus Lamm. The participants could also see the stimulus to which their team partners were exposed at the same time.
The two participants were then asked to evaluate either their own emotions or those of their partners. As long as both participants were exposed to the same type of positive or negative stimuli, they found it easy to assess their partner’s emotions. The participant who was confronted with a stinkbug could easily imagine how unpleasant the sight and feeling of a spider must be for her partner.
Differences only arose during the test runs in which one partner was confronted with pleasant stimuli and the other with unpleasant ones. Their capacity for empathy suddenly plummeted. The participants’ own emotions distorted their assessment of the other person’s feelings. The participants who were feeling good themselves assessed their partners’ negative experiences as less severe than they actually were. In contrast, those who had just had an unpleasant experience assessed their partners’ good experiences less positively.
Particularly quick decisions cause a decline in empathy
The researchers pinpointed the area of the brain responsible for this phenomenon with the help of functional magnetic resonance imaging, generally referred to as a brain scanning. The right supramarginal gyrus ensures that we can decouple our perception of ourselves from that of others. When the neurons in this part of the brain were disrupted in the course of this task, the participants found it difficult not to project their own feelings onto others. The participants’ assessments were also less accurate when they were forced to make particularly quick decisions.
Up to now, the social neuroscience models have assumed that we mainly draw on our own emotions as a reference for empathy. This only works, however, if we are in a neutral state or the same state as our counterpart – otherwise, the brain must counteract and correct.
Neuroscientists identify class of cortical inhibitory neurons that specialize in disinhibition
An inhibitory neuron type is found to specifically suppress the activation of other inhibitory neurons in cerebral cortex.
The cerebral cortex contains two major types of neurons: principal neurons that are excitatory and interneurons that are inhibitory, all interconnected within the same network. New research now reveals that one class of inhibitory neurons – called VIP interneurons — specializes in inhibiting other inhibitory neurons in multiple regions of cortex, and does so under specific behavioral conditions.
The new research finds that VIP interneurons, when activated, release principal cells from inhibition, thus boosting their responses. This provides an additional layer of control over cortical processing, much like a dimmer switch can fine-tune light levels.
The discovery was made by a team of neuroscientists at Cold Spring Harbor Laboratory (CSHL) led by Associate Professor Adam Kepecs, Ph.D. Their research, published online today in Nature, shows that neurons expressing vasoactive intestinal polypeptide, or VIP, provide disinhibition in the auditory cortex and the medial prefrontal cortex.
The researchers used molecular tagging techniques developed by team member Z. Josh Huang, a CSHL Professor, to single out VIP-expressing neurons in the vast diversity of cortical neurons. This enabled Kepecs’ group, led by postdocs Hyun Jae Pi and Balazs Hangya, to employ advanced optogenetic techniques using color-coded laser light to specifically activate VIP neurons. The activity of the cells was monitored via electrophysiological recordings in behaving animals to study their function, and in vitro to probe their circuit properties.
These VIP neurons are long sought “disinhibitory” cells: they inhibit other classes of inhibitory neurons; but they do not directly cause excitation to occur in brain. Dr. Kepecs and colleagues propose that the disinhibitory control mediated by VIP neurons represents a fundamental “motif” in cerebral cortex.
The difference between neural excitation and disinhibition is akin to the difference between hitting the gas pedal and taking your foot off the breaks. Cells that specialize in releasing the brakes, Dr. Kepecs explains, provide the means for balancing between excitation and inhibition. Kepecs calls this function “gain modulation,” which brings to mind the fine control that a dimmer switch provides.
The team wondered when VIP neurons are activated during behavior. When, in other words, is the “cortical dimmer switch” engaged? To learn the answer the scientists recorded VIP neurons while mice were making simple decisions, discriminating between sounds of different pitches. When they made correct choices, the mice earned a drop of water; for incorrect choices, a mild puff of air. Surprisingly, the team found that in auditory cortex, a region involved in processing sounds, VIP neurons were activated by rewards and punishments. Thus these neurons appeared to mediate the impact of reinforcements and “turn up the lights” on principal cells, to use the dimmer-switch analogy.
“Linking specific neuronal types to well-defined behaviors has proved extremely difficult,” says Kepecs. These results, he says, potentially link the circuit-function of VIP neurons in gain control to an important behavioral function: learning.
(Source: cshl.edu)
Study reveals information about the genetic architecture of brain’s grey matter
Findings may one day provide clues to understanding neuropsychiatric disorders
An international research team studying the structure and organization of the brain has found that different genetic factors may affect the thickness of different parts of the cortex of the brain.
The findings of this basic neuroscience study provide clues to better understanding the complex structure of the human brain. Ultimately, knowledge of genetic factors that underlie brain structure may help to identify individuals at risk for neuropsychiatric disorders, such as autism, schizophrenia or dementia. However, further research is necessary and the road to preventing or treating these conditions based on this work remains a long one.
The team was led by researchers at the University of California, San Diego, and included scientists from Virginia Commonwealth University, Boston University, Harvard Medical School and Massachusetts General Hospital, the University of Helsinki in Finland and the Veterans Affairs San Diego Healthcare System.
In the study, published online this week in the Proceedings of the National Academy of Sciences Online Early Edition, the team used MRI brain scan data collected from more than 200 pairs of twins between the ages of 55 and 65 and created a map based on genetic correlations between measures of thickness at different places on the cortex.
Using software developed by Michael Neale, Ph.D., professor of psychiatry and human genetics in the VCU School of Medicine, the team drew a genetic correlation map based on cortical thickness at thousands of points on the surface of the brain. These correlations were then analyzed to identify regions where the same genetic factors seem to have been operating. Twelve such regions in each hemisphere were identified, similar to an earlier study of measures of surface area.
“Our team has mapped genetic factors that influence the thickness of the cortex of the human brain,” said Neale who was a study contributor and co-author.
“Knowledge of the genetic organization of brain structures may guide the identification of risk factors for psychiatric disorders,” he said.
According to Neale, individuals differ in the thickness of these regions, and a twin study can help differentiate genetic from environmental factors that cause these differences at any one location. Twin studies also can estimate the degree to which the same versus different genetic factors affect two different characteristics.
Traditionally, maps of the human brain have been drawn using one of two types of information. The first is anatomical, such as the wrinkles on the surface, or cortex, of the brain. A second type of map, which may be called functional, is drawn from knowledge of how different parts of the brain are associated with particular functions. For example, Wernicke’s area on the left side of the brain is associated with the understanding of language.
The research builds on work published last year in Science by the same research team. That article reported on the initial development of the new software tool to study and explain how the brain works. It was considered the first map of the surface of the brain based on the basis of genetic information.
Next steps for this research will include correlating measures of these regions with outcomes, such as change in cognitive abilities since age 20, or lifetime cigarette smoking.
For nearly 30 years, Neale, an internationally known expert in statistical methodology, has developed and applied statistical models in genetic studies, primarily of twins and their relatives, with the goal of better understanding the brain and behavior.
Researchers find how viral infection disrupts neural development in offspring, increasing risk of autism
Activating a mother’s immune system during her pregnancy disrupts the development of neural cells in the brain of her offspring and damages the cells’ ability to transmit signals and communicate with one another, researchers with the UC Davis Center for Neuroscience and Department of Neurology have found. They said the finding suggests how maternal viral infection might increase the risk of having a child with autism spectrum disorder or schizophrenia.
The research, “MHCI Requires MEF2 Transcription Factors to Negatively Regulate Synapse Density during Development and in Disease,” is published in the Journal of Neuroscience.
The study’s senior author is Kimberley McAllister, professor in the Center for Neuroscience with appointments in the departments of Neurology and Neurobiology, Physiology and Behavior, and a researcher with the UC Davis MIND Institute.
“This is the first evidence that neurons in the developing brain of newborn offspring are altered by maternal immune activation,” McAllister said. “Until now, very little has been known about how maternal immune activation leads to autism spectrum disorder and schizophrenia-like pathophysiology and behaviors in the offspring.”
The study was conducted in mice and rats and compared the brains of the offspring of rodents whose immune systems had been activated and those of animals whose immune systems had not been activated. The pups of animals that were exposed to viral infection had much higher brain levels of immune molecules known as the major histocompatibility complex I (MHCI) molecules.
“This is the first evidence that MHCI levels on the surface of young cortical neurons in offspring are altered by maternal immune activation,” McAllister said.
The researchers found that the high MHCI levels impaired the ability of the neurons from the newborn mice’s brains to form synapses, the tiny gaps separating brain cells through which signals are transmitted. Earlier research has suggested that ASD and schizophrenia may be caused by changes in the development of connections in the brain, especially the cerebral cortex.
The researchers experimentally reduced MHCI to normal levels in neurons from offspring following maternal immune activation.
“Remarkably, synapse density returned to normal levels in those neurons,” McAllister said.
“These results indicate that maternal immune activation does indeed alter connectivity during prenatal development, causing a profound deficit in the ability of cortical neurons to form synapses that is caused by changes in levels of MHCI on the neurons,” she said.
MHCI did not work alone to limit the development of synapses. In a series of experiments, the UC Davis researchers determined that MHCI interacted with calcineurin and myocyte enhancer factor-2 (Mef2), a protein that is a critical determinant of neuronal specialization.
MHCI, calcineurin and Mef2 form a biological signaling pathway that had not been previously identified. McAllister’s team showed that in the offspring of the maternal immune activation mothers, this novel signaling pathway was much more active than it was in the offspring of non-MIA animals.
“This finding provides a potential mechanism linking maternal immune activation to disease-linked behaviors,” McAllister said.
It also is a mechanism that may help McAllister and other scientists to develop diagnostic tests and eventually therapies to improve the lives of individuals with these neurodevelopmental disorders.
(Source: ucdmc.ucdavis.edu)