Neuroscience

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Posts tagged brain development

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Scientists Discover Key Signaling Pathway that Makes Young Neurons Connect Neuroscientists at The Scripps Research Institute (TSRI) have filled in a significant gap in the scientific understanding of how neurons mature, pointing to a better understanding of some developmental brain disorders. In the new study, the researchers identified a molecular program that controls an essential step in the fast-growing brains of young mammals. The researchers found that this signaling pathway spurs the growth of neuronal output connections by a mechanism called “mitochondrial capture,” which has never been described before. “Mutations that may affect this signaling pathway already have been found in some autism cases,” said TSRI Professor Franck Polleux, who led the research, published June 20, 2013 in the journal Cell. Branching Out Polleux’s laboratory is focused on identifying the signaling pathways that drive neural development, with special attention to the neocortex—a recently evolved structure that handles the “higher” cognitive functions in the mammalian brain and is highly developed in humans. In a widely cited study published in 2007, Polleux’s team identified a trigger of an early step in the development of the most important class of neocortical neurons. As these neurons develop following asymmetric division of neural stem cells, they migrate to their proper place in the developing brain. Meanwhile they start to sprout a root-like mesh of input branches called dendrites from one end, and, from the other end, a long output stalk called an axon. Polleux and his colleagues found that the kinase LKB1 provides a key signal for the initiation of axon growth in these immature cortical neurons. In the new study, Polleux’s team followed up this discovery and found that LKB1 also is crucially important for a later stage of these neurons’ development: the branching of the end of the axon onto the dendrites of other neurons. “In experiments with mice, we knocked the LKB1 gene out of immature cortical neurons that had already begun growing an axon, and the most striking effect was a drastic reduction in terminal branching,” said Julien Courchet, a research associate in the Polleux laboratory who was a lead co-author of the study. “We saw this also in lab dish experiments, and when we overexpressed the LKB1 gene, the result was a dramatic increase in axon branching.” Further experiments by Courchet showed that LKB1 drives axonal branching by activating another kinase, NUAK1. The next step was to try to understand how this newly identified LKB1-NUAK1 signaling pathway induced the growth of new axon branches. Stopping the Train in Its Tracks Following a thin trail of clues, the researchers decided to look at the dynamics of microtubules. These tiny railway-like tracks are laid down within axons for the efficient transport of molecular cargoes and are altered and extended during axonal branching. Although they could find no major change in microtubule dynamics within immature axons lacking LKB1 or NUAK1, the team did discover one striking abnormality in the transport of cargoes along these microtubules. Tiny oxygen-reactors called mitochondria, which are the principal sources of chemical energy in cells, were transported along axons much more actively—and by contrast, became almost immobile when LKB1 and NUAK1 were overexpressed. But the LKB1-NUAK1 signals weren’t just immobilizing mitochondria randomly. They were effectively inducing their capture at points on the axons where axons form synaptic connections with other neurons. “When we removed LKB1 or NUAK1 in cortical neurons, the mitochondria were no longer captured at these points,” said Tommy Lewis, Jr., a research associate in the Polleux Laboratory who was co-lead author of the study. “We argue that there must be an active ‘homing factor’ that specifies where these mitochondria stop moving,” said Polleux. “And we think that this is essentially what the LKB1-NAUK1 signaling pathway does here.” Looking Ahead Precisely how the capture of mitochondria at nascent synapses promotes axonal branching is the object of a further line of investigation in the Polleux laboratory. “We think that we have uncovered something very interesting about mitochondrial function at synapses,” Polleux said. In addition to its basic scientific importance, the work is likely to be highly relevant medically. Developmentally related brain disorders such as epilepsy, autism and schizophrenia typically involve abnormalities in neuronal connectivity. Recent genetic surveys have found NUAK1-related gene mutations in some children with autism, for example. “Our study is the first one to identify that NUAK1 plays a crucial role during the establishment of cortical connectivity and therefore suggests why this gene might play a role in autistic disorder,” Polleux says. He notes, too, that declines in normal mitochondrial transport within axons have been observed in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. “In the light of our findings, we wonder if the decreased mitochondrial mobility observed in these cases might be due not to a transport defect, but instead to a defect in mitochondrial capture in aging neurons,” he said. “We’re eager to start doing experiments to test such possibilities.” (Image: Shutterstock)

Scientists Discover Key Signaling Pathway that Makes Young Neurons Connect

Neuroscientists at The Scripps Research Institute (TSRI) have filled in a significant gap in the scientific understanding of how neurons mature, pointing to a better understanding of some developmental brain disorders.

In the new study, the researchers identified a molecular program that controls an essential step in the fast-growing brains of young mammals. The researchers found that this signaling pathway spurs the growth of neuronal output connections by a mechanism called “mitochondrial capture,” which has never been described before.

“Mutations that may affect this signaling pathway already have been found in some autism cases,” said TSRI Professor Franck Polleux, who led the research, published June 20, 2013 in the journal Cell.

Branching Out

Polleux’s laboratory is focused on identifying the signaling pathways that drive neural development, with special attention to the neocortex—a recently evolved structure that handles the “higher” cognitive functions in the mammalian brain and is highly developed in humans.

In a widely cited study published in 2007, Polleux’s team identified a trigger of an early step in the development of the most important class of neocortical neurons. As these neurons develop following asymmetric division of neural stem cells, they migrate to their proper place in the developing brain. Meanwhile they start to sprout a root-like mesh of input branches called dendrites from one end, and, from the other end, a long output stalk called an axon. Polleux and his colleagues found that the kinase LKB1 provides a key signal for the initiation of axon growth in these immature cortical neurons.

In the new study, Polleux’s team followed up this discovery and found that LKB1 also is crucially important for a later stage of these neurons’ development: the branching of the end of the axon onto the dendrites of other neurons.

“In experiments with mice, we knocked the LKB1 gene out of immature cortical neurons that had already begun growing an axon, and the most striking effect was a drastic reduction in terminal branching,” said Julien Courchet, a research associate in the Polleux laboratory who was a lead co-author of the study. “We saw this also in lab dish experiments, and when we overexpressed the LKB1 gene, the result was a dramatic increase in axon branching.”

Further experiments by Courchet showed that LKB1 drives axonal branching by activating another kinase, NUAK1. The next step was to try to understand how this newly identified LKB1-NUAK1 signaling pathway induced the growth of new axon branches.

Stopping the Train in Its Tracks

Following a thin trail of clues, the researchers decided to look at the dynamics of microtubules. These tiny railway-like tracks are laid down within axons for the efficient transport of molecular cargoes and are altered and extended during axonal branching. Although they could find no major change in microtubule dynamics within immature axons lacking LKB1 or NUAK1, the team did discover one striking abnormality in the transport of cargoes along these microtubules. Tiny oxygen-reactors called mitochondria, which are the principal sources of chemical energy in cells, were transported along axons much more actively—and by contrast, became almost immobile when LKB1 and NUAK1 were overexpressed.

But the LKB1-NUAK1 signals weren’t just immobilizing mitochondria randomly. They were effectively inducing their capture at points on the axons where axons form synaptic connections with other neurons. “When we removed LKB1 or NUAK1 in cortical neurons, the mitochondria were no longer captured at these points,” said Tommy Lewis, Jr., a research associate in the Polleux Laboratory who was co-lead author of the study.

“We argue that there must be an active ‘homing factor’ that specifies where these mitochondria stop moving,” said Polleux. “And we think that this is essentially what the LKB1-NAUK1 signaling pathway does here.”

Looking Ahead

Precisely how the capture of mitochondria at nascent synapses promotes axonal branching is the object of a further line of investigation in the Polleux laboratory. “We think that we have uncovered something very interesting about mitochondrial function at synapses,” Polleux said.

In addition to its basic scientific importance, the work is likely to be highly relevant medically. Developmentally related brain disorders such as epilepsy, autism and schizophrenia typically involve abnormalities in neuronal connectivity. Recent genetic surveys have found NUAK1-related gene mutations in some children with autism, for example. “Our study is the first one to identify that NUAK1 plays a crucial role during the establishment of cortical connectivity and therefore suggests why this gene might play a role in autistic disorder,” Polleux says.

He notes, too, that declines in normal mitochondrial transport within axons have been observed in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. “In the light of our findings, we wonder if the decreased mitochondrial mobility observed in these cases might be due not to a transport defect, but instead to a defect in mitochondrial capture in aging neurons,” he said. “We’re eager to start doing experiments to test such possibilities.”

(Image: Shutterstock)

Filed under neurons neural development neurodegeneration brain development neurodegenerative diseases genetics neuroscience science

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Fetal Neuromaturation Associated with Mother’s Exposure to DDT and Other Environmental Contaminants

Study is the first to show association between mother’s chemical exposure and fetal motor activity and heart rate

A study led by researchers at the Johns Hopkins Bloomberg School of Public Health has for the first time found that a mother’s higher exposure to some common environmental contaminants was associated with more frequent and vigorous fetal motor activity. Some chemicals were also associated with fewer changes in fetal heart rate, which normally parallel fetal movements. The study of 50 pregnant women found detectable levels of organochlorines in all of the women participating in the study—including DDT, PCBs and other pesticides that have been banned from use for more than 30 years. The study is available online in advance of publication in the Journal of Exposure Science and Environmental Epidemiology.

“Both fetal motor activity and heart rate reveal how the fetus is maturing and give us a way to evaluate how exposures may be affecting the developing nervous system. Most studies of environmental contaminants and child development wait until children are much older to evaluate effects of things the mother may have been exposed to during pregnancy; here we have observed effects in utero,” said Janet A. DiPietro, PhD, lead author of the study and Associate Dean for Research at the Bloomberg School of Public Health.

For the study, DiPietro and her colleagues followed a sample of 50 high- and low- income pregnant women living in and around Baltimore, Md. At 36 weeks of pregnancy, blood samples were collected from the mothers and measurements were taken of fetal heart rate and motor activity. The blood samples were tested for levels of 11 pesticides and 36 polychlorinated biphenyl (PCB) compounds.

According to the findings, all participants had detectable concentrations of at least one-quarter of the analyzed chemicals, despite the fact that they have been banned for more than three decades. Fetal heart rate effects were not consistently observed across all of the compounds analyzed; when effects were seen, higher chemical exposures were associated with reductions in fetal heart rate accelerations, an indicator of fetal wellbeing. However, associations with fetal motor activity measures were more consistent and robust: higher concentrations of 7 of 10 organochlorine compounds were positively associated with one of more measures of more frequent and more vigorous fetal motor activity. These chemicals included hexachlorobenzene, DDT, and several PCB congeners. Women of higher socioeconomic status in the study had a greater concentration of chemicals compared to the women of lower socioeconomic status

“There is tremendous interest in how the prenatal period sets the stage for later child development.  These results show that the developing fetus is susceptible to environmental exposures and that we can detect this by measuring fetal neurobehavior. This is yet more evidence for the need to protect the vulnerable developing brain from effects of environmental contaminants both before and after birth,” said DiPietro.

“Fetal heart rate and motor activity associations with maternal organochlorine levels: results of an exploratory study” was written by Janet A. DiPietro, Meghan F. Davis, Kathleen A. Costigan, and Dana Boyd Barr.

(Source: jhsph.edu)

Filed under fetal brain motor activity brain development environmental contaminants neuromaturation neuroscience science

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Scientists Map Process by Which Brain Cells Form Long-Term Memories Scientists at the Gladstone Institutes have deciphered how a protein called Arc regulates the activity of neurons – providing much-needed clues into the brain’s ability to form long-lasting memories. These findings, reported Sunday in Nature Neuroscience, also offer newfound understanding as to what goes on at the molecular level when this process becomes disrupted. Led by Gladstone senior investigator Steve Finkbeiner, MD, PhD, this research delved deep into the inner workings of synapses. Synapses are the highly specialized junctions that process and transmit information between neurons. Most of the synapses our brain will ever have are formed during early brain development, but throughout our lifetimes these synapses can be made, broken and strengthened. Synapses that are more active become stronger, a process that is essential for forming new memories. However, this process is also dangerous, as it can overstimulate the neurons and lead to epileptic seizures. It must therefore be kept in check. Neuroscientists recently discovered one important mechanism that the brain uses to maintain this important balance: a process called “homeostatic scaling.” Homeostatic scaling allows individual neurons to strengthen the new synaptic connections they’ve made to form memories, while at the same time protecting the neurons from becoming overly excited. Exactly how the neurons pull this off has eluded researchers, but they suspected that the Arc protein played a key role. “Scientists knew that Arc was involved in long-term memory, because mice lacking the Arc protein could learn new tasks, but failed to remember them the next day,” said Finkbeiner, who is also a professor of neurology and physiology at UC San Francisco, with which Gladstone is affiliated. “Because initial observations showed Arc accumulating at the synapses during learning, researchers thought that Arc’s presence at these synapses was driving the formation of long-lasting memories.” But Finkbeiner and his team thought there was something else in play. The Role of Arc in Homeostatic Scaling In laboratory experiments, first in animal models and then in greater detail in the petri dish, the researchers tracked Arc’s movements. And what they found was surprising. “When individual neurons are stimulated during learning, Arc begins to accumulate at the synapses – but what we discovered was that soon after, the majority of Arc gets shuttled into the nucleus,” said Erica Korb, PhD, the paper’s lead author who completed her graduate work at Gladstone and UCSF. “A closer look revealed three regions within the Arc protein itself that direct its movements: one exports Arc from the nucleus, a second transports it into the nucleus, and a third keeps it there,” she said. “The presence of this complex and tightly regulated system is strong evidence that this process is biologically important.” In fact, the team’s experiments revealed that Arc acted as a master regulator of the entire homeostatic scaling process. During memory formation, certain genes must be switched on and off at very specific times in order to generate proteins that help neurons lay down new memories.  From inside the nucleus, the authors found that it was Arc that directed this process required for homeostatic scaling to occur. This strengthened the synaptic connections without overstimulating them – thus translating learning into long-term memories.  Implications for a Variety of Neurological Diseases “This discovery is important not only because it solves a long-standing mystery on the role of Arc in long-term memory formation, but also gives new insight into the homeostatic scaling process itself – disruptions in which have already been implicated in a whole host of neurological diseases,” said Finkbeiner. “For example, scientists recently discovered that Arc is depleted in the hippocampus, the brain’s memory center, in Alzheimer’s disease patients. It’s possible that disruptions to the homeostatic scaling process may contribute to the learning and memory deficits seen in Alzheimer’s.” Dysfunctions in Arc production and transport may also be a vital player in autism. For example, the genetic disorder Fragile X syndrome – a common cause of both mental retardation and autism, directly affects the production of Arc in neurons. “In the future,” added Dr. Korb, “we hope further research into Arc’s role in human health and disease can provide even deeper insight into these and other disorders, and also lay the groundwork for new therapeutic strategies to fight them.” (Image: Wikimedia)

Scientists Map Process by Which Brain Cells Form Long-Term Memories

Scientists at the Gladstone Institutes have deciphered how a protein called Arc regulates the activity of neurons – providing much-needed clues into the brain’s ability to form long-lasting memories.

These findings, reported Sunday in Nature Neuroscience, also offer newfound understanding as to what goes on at the molecular level when this process becomes disrupted.

Led by Gladstone senior investigator Steve Finkbeiner, MD, PhD, this research delved deep into the inner workings of synapses. Synapses are the highly specialized junctions that process and transmit information between neurons. Most of the synapses our brain will ever have are formed during early brain development, but throughout our lifetimes these synapses can be made, broken and strengthened. Synapses that are more active become stronger, a process that is essential for forming new memories.

However, this process is also dangerous, as it can overstimulate the neurons and lead to epileptic seizures. It must therefore be kept in check.

Neuroscientists recently discovered one important mechanism that the brain uses to maintain this important balance: a process called “homeostatic scaling.” Homeostatic scaling allows individual neurons to strengthen the new synaptic connections they’ve made to form memories, while at the same time protecting the neurons from becoming overly excited. Exactly how the neurons pull this off has eluded researchers, but they suspected that the Arc protein played a key role.

“Scientists knew that Arc was involved in long-term memory, because mice lacking the Arc protein could learn new tasks, but failed to remember them the next day,” said Finkbeiner, who is also a professor of neurology and physiology at UC San Francisco, with which Gladstone is affiliated. “Because initial observations showed Arc accumulating at the synapses during learning, researchers thought that Arc’s presence at these synapses was driving the formation of long-lasting memories.”

But Finkbeiner and his team thought there was something else in play.

The Role of Arc in Homeostatic Scaling

In laboratory experiments, first in animal models and then in greater detail in the petri dish, the researchers tracked Arc’s movements. And what they found was surprising.

“When individual neurons are stimulated during learning, Arc begins to accumulate at the synapses – but what we discovered was that soon after, the majority of Arc gets shuttled into the nucleus,” said Erica Korb, PhD, the paper’s lead author who completed her graduate work at Gladstone and UCSF.

“A closer look revealed three regions within the Arc protein itself that direct its movements: one exports Arc from the nucleus, a second transports it into the nucleus, and a third keeps it there,” she said. “The presence of this complex and tightly regulated system is strong evidence that this process is biologically important.”

In fact, the team’s experiments revealed that Arc acted as a master regulator of the entire homeostatic scaling process. During memory formation, certain genes must be switched on and off at very specific times in order to generate proteins that help neurons lay down new memories.  From inside the nucleus, the authors found that it was Arc that directed this process required for homeostatic scaling to occur. This strengthened the synaptic connections without overstimulating them – thus translating learning into long-term memories. 

Implications for a Variety of Neurological Diseases

“This discovery is important not only because it solves a long-standing mystery on the role of Arc in long-term memory formation, but also gives new insight into the homeostatic scaling process itself – disruptions in which have already been implicated in a whole host of neurological diseases,” said Finkbeiner. “For example, scientists recently discovered that Arc is depleted in the hippocampus, the brain’s memory center, in Alzheimer’s disease patients. It’s possible that disruptions to the homeostatic scaling process may contribute to the learning and memory deficits seen in Alzheimer’s.”

Dysfunctions in Arc production and transport may also be a vital player in autism. For example, the genetic disorder Fragile X syndrome – a common cause of both mental retardation and autism, directly affects the production of Arc in neurons.

“In the future,” added Dr. Korb, “we hope further research into Arc’s role in human health and disease can provide even deeper insight into these and other disorders, and also lay the groundwork for new therapeutic strategies to fight them.”

(Image: Wikimedia)

Filed under arc protein neurons synapses memory brain development epileptic seizures neuroscience science

173 notes

Evidence from a quiet MRI: Breastfeeding benefits babies’ brains A study using brain images from “quiet” MRI machines adds to the growing body of evidence that breastfeeding improves brain development in infants. Breastfeeding alone produced better brain development than a combination of breastfeeding and formula, which produced better development than formula alone. A new study by researchers from Brown University finds more evidence that breastfeeding is good for babies’ brains. The study made use of specialized, baby-friendly magnetic resonance imaging (MRI) to look at the brain growth in a sample of children under the age of 4. The research found that by age 2, babies who had been breastfed exclusively for at least three months had enhanced development in key parts of the brain compared to children who were fed formula exclusively or who were fed a combination of formula and breastmilk. The extra growth was most pronounced in parts of the brain associated with language, emotional function, and cognition, the research showed. This isn’t the first study to suggest that breastfeeding aids babies’ brain development. Behavioral studies have previously associated breastfeeding with better cognitive outcomes in older adolescents and adults. But this is the first imaging study that looked for differences associated with breastfeeding in the brains of very young and healthy children, said Sean Deoni, assistant professor of engineering at Brown and the study’s lead author. “We wanted to see how early these changes in brain development actually occur,” Deoni said. “We show that they’re there almost right off the bat.” The findings are in press in the journal NeuroImage and available now online. Deoni leads Brown’s Advanced Baby Imaging Lab. He and his colleagues use quiet MRI machines that image babies’ brains as they sleep. The MRI technique Deoni has developed looks at the microstructure of the brain’s white matter, the tissue that contains long nerve fibers and helps different parts of the brain communicate with each other. Specifically, the technique looks for amounts of myelin, the fatty material that insulates nerve fibers and speeds electrical signals as they zip around the brain. Deoni and his team looked at 133 babies ranging in ages from 10 months to four years. All of the babies had normal gestation times, and all came from families with similar socioeconomic statuses. The researchers split the babies into three groups: those whose mothers reported they exclusively breastfed for at least three months, those fed a combination of breastmilk and formula, and those fed formula alone. The researchers compared the older kids to the younger kids to establish growth trajectories in white matter for each group. The study showed that the exclusively breastfed group had the fastest growth in myelinated white matter of the three groups, with the increase in white matter volume becoming substantial by age 2. The group fed both breastmilk and formula had more growth than the exclusively formula-fed group, but less than the breastmilk-only group. “We’re finding the difference [in white matter growth] is on the order of 20 to 30 percent, comparing the breastfed and the non-breastfed kids,” said Deoni. “I think it’s astounding that you could have that much difference so early.” Deoni and his team then backed up their imaging data with a set of basic cognitive tests on the older children. Those tests found increased language performance, visual reception, and motor control performance in the breastfed group. The study also looked at the effects of the duration of breastfeeding. The researchers compared babies who were breastfed for more than a year with those breastfed less than a year, and found significantly enhanced brain growth in the babies who were breastfed longer — especially in areas of the brain dealing with motor function. Deoni says the findings add to a substantial body of research that finds positive associations between breastfeeding and children’s brain health. “I think I would argue that combined with all the other evidence, it seems like breastfeeding is absolutely beneficial,” he said.

Evidence from a quiet MRI: Breastfeeding benefits babies’ brains

A study using brain images from “quiet” MRI machines adds to the growing body of evidence that breastfeeding improves brain development in infants. Breastfeeding alone produced better brain development than a combination of breastfeeding and formula, which produced better development than formula alone.

A new study by researchers from Brown University finds more evidence that breastfeeding is good for babies’ brains.

The study made use of specialized, baby-friendly magnetic resonance imaging (MRI) to look at the brain growth in a sample of children under the age of 4. The research found that by age 2, babies who had been breastfed exclusively for at least three months had enhanced development in key parts of the brain compared to children who were fed formula exclusively or who were fed a combination of formula and breastmilk. The extra growth was most pronounced in parts of the brain associated with language, emotional function, and cognition, the research showed.

This isn’t the first study to suggest that breastfeeding aids babies’ brain development. Behavioral studies have previously associated breastfeeding with better cognitive outcomes in older adolescents and adults. But this is the first imaging study that looked for differences associated with breastfeeding in the brains of very young and healthy children, said Sean Deoni, assistant professor of engineering at Brown and the study’s lead author.

“We wanted to see how early these changes in brain development actually occur,” Deoni said. “We show that they’re there almost right off the bat.”

The findings are in press in the journal NeuroImage and available now online.

Deoni leads Brown’s Advanced Baby Imaging Lab. He and his colleagues use quiet MRI machines that image babies’ brains as they sleep. The MRI technique Deoni has developed looks at the microstructure of the brain’s white matter, the tissue that contains long nerve fibers and helps different parts of the brain communicate with each other. Specifically, the technique looks for amounts of myelin, the fatty material that insulates nerve fibers and speeds electrical signals as they zip around the brain.

Deoni and his team looked at 133 babies ranging in ages from 10 months to four years. All of the babies had normal gestation times, and all came from families with similar socioeconomic statuses. The researchers split the babies into three groups: those whose mothers reported they exclusively breastfed for at least three months, those fed a combination of breastmilk and formula, and those fed formula alone. The researchers compared the older kids to the younger kids to establish growth trajectories in white matter for each group.

The study showed that the exclusively breastfed group had the fastest growth in myelinated white matter of the three groups, with the increase in white matter volume becoming substantial by age 2. The group fed both breastmilk and formula had more growth than the exclusively formula-fed group, but less than the breastmilk-only group.

“We’re finding the difference [in white matter growth] is on the order of 20 to 30 percent, comparing the breastfed and the non-breastfed kids,” said Deoni. “I think it’s astounding that you could have that much difference so early.”

Deoni and his team then backed up their imaging data with a set of basic cognitive tests on the older children. Those tests found increased language performance, visual reception, and motor control performance in the breastfed group.

The study also looked at the effects of the duration of breastfeeding. The researchers compared babies who were breastfed for more than a year with those breastfed less than a year, and found significantly enhanced brain growth in the babies who were breastfed longer — especially in areas of the brain dealing with motor function.

Deoni says the findings add to a substantial body of research that finds positive associations between breastfeeding and children’s brain health.

“I think I would argue that combined with all the other evidence, it seems like breastfeeding is absolutely beneficial,” he said.

Filed under brain development breastfeeding white matter neuroimaging neuroscience psychology science

109 notes

Researchers Discover How Brain Circuits Can Become Miswired During Development Researchers at Weill Cornell Medical College have uncovered a mechanism that guides the exquisite wiring of neural circuits in a developing brain — gaining unprecedented insight into the faulty circuits that may lead to brain disorders ranging from autism to mental retardation. In the journal Cell, the researchers describe, for the first time, that faulty wiring occurs when RNA molecules embedded in a growing axon are not degraded after they give instructions that help steer the nerve cell. So, for example, the signal that tells the axon to turn — which should disappear after the turn is made — remains active, interfering with new signals meant to guide the axon in other directions. The scientists say that there may be a way to use this new knowledge to fix the circuits. "Understanding the basis of brain miswiring can help scientists come up with new therapies and strategies to correct the problem," says the study’s senior author, Dr. Samie Jaffrey, a professor in the Department of Pharmacology. "The brain is quite ‘plastic’ and changeable in the very young, and if we know why circuits are miswired, it may be possible to correct those pathways, allowing the brain to build new, functional wiring," he says. Disorders associated with faulty neuronal circuits include epilepsy, autism, schizophrenia, mental retardation and spasticity and movement disorders, among others. In their study, the scientists describe a process of brain wiring that is much more dynamic than was previously known — and thus more prone to error. Proteins Sense the Environment to Steer the Axon During brain development, neurons have to connect to each other, which they do by extending their long axons to touch one another. Ultimately, these neurons form a circuit between the brain and the target tissue through which chemical and electrical signals are relayed. In this study, researchers investigated neurons that travel up the spinal cord into the brain. “It is very critical that axons are precisely positioned in the spinal cord,” Dr. Jaffrey says. “If they are improperly positioned, they will form the wrong connections, which can lead to signals being sent to the wrong target cells in the brain.” The way that an axon guides and finds its proper target is through so-called growth cones located at the tips of axons. “These growth cones have the ability to sense the environment, determine where the targets are and navigate toward them. The question has always been — how do they know how to do this? Where do the instructions come from that tell them how to find their proper target?” Dr. Jaffrey says. The team found that RNA molecules embedded in the growth cone are responsible for instructing the axon to move left or right, up or down. These RNAs are translated in growth cones to produce antenna-like proteins that steer the axon like a self-guided missile. "As a circuit is being built, RNAs in the neuron’s growth cones are mostly silent. We found that specific RNAs are only read at precise stages in order to produce the right protein needed to steer the axon at the right time. After the protein is produced, we saw that the RNA instruction is degraded and disappears," he says. "If these RNAs do not disappear when they should, the axon does not position itself properly — it may go right instead of left — and the wiring will be incorrect and the circuit may be faulty," Dr. Jaffrey says. RNAs have Tremendous Power over Brain Development The research finding answers a long-standing puzzle in the quest to understand brain wiring, says Dr. Dilek Colak, a postdoctoral associate in Dr. Jaffrey’s laboratory. "There have been a series of discoveries over the last five years showing that proteins that control RNA degradation are very important for brain development and, when they are mutated, you can have spasticity or other movement disorders," Dr. Colak says. "That has raised a major question — why would RNA degradation pathways be so critical for properly creating brain circuits? "What we show here is that not only does RNA need to be present in growth cones to give instructions, it then also needs to be removed from the growth cones to take away those instructions at the right time," she says. "Both those processes are critical and it may explain why there are so many different brain disorders associated with ineffective RNA regulation." "The idea that control of brain wiring is located in these RNA molecules that are constantly being dynamically turned over is something that we didn’t anticipate," Dr. Jaffrey adds. "This tells us that regulating these RNA degradation pathways could have a tremendous impact on brain development. Now we know where to look to tease apart this process when it goes awry, and to think about how we can repair it." (Image: Chad Baker)

Researchers Discover How Brain Circuits Can Become Miswired During Development

Researchers at Weill Cornell Medical College have uncovered a mechanism that guides the exquisite wiring of neural circuits in a developing brain — gaining unprecedented insight into the faulty circuits that may lead to brain disorders ranging from autism to mental retardation.

In the journal Cell, the researchers describe, for the first time, that faulty wiring occurs when RNA molecules embedded in a growing axon are not degraded after they give instructions that help steer the nerve cell. So, for example, the signal that tells the axon to turn — which should disappear after the turn is made — remains active, interfering with new signals meant to guide the axon in other directions.

The scientists say that there may be a way to use this new knowledge to fix the circuits.

"Understanding the basis of brain miswiring can help scientists come up with new therapies and strategies to correct the problem," says the study’s senior author, Dr. Samie Jaffrey, a professor in the Department of Pharmacology.

"The brain is quite ‘plastic’ and changeable in the very young, and if we know why circuits are miswired, it may be possible to correct those pathways, allowing the brain to build new, functional wiring," he says.

Disorders associated with faulty neuronal circuits include epilepsy, autism, schizophrenia, mental retardation and spasticity and movement disorders, among others.

In their study, the scientists describe a process of brain wiring that is much more dynamic than was previously known — and thus more prone to error.

Proteins Sense the Environment to Steer the Axon

During brain development, neurons have to connect to each other, which they do by extending their long axons to touch one another. Ultimately, these neurons form a circuit between the brain and the target tissue through which chemical and electrical signals are relayed. In this study, researchers investigated neurons that travel up the spinal cord into the brain. “It is very critical that axons are precisely positioned in the spinal cord,” Dr. Jaffrey says. “If they are improperly positioned, they will form the wrong connections, which can lead to signals being sent to the wrong target cells in the brain.”

The way that an axon guides and finds its proper target is through so-called growth cones located at the tips of axons. “These growth cones have the ability to sense the environment, determine where the targets are and navigate toward them. The question has always been — how do they know how to do this? Where do the instructions come from that tell them how to find their proper target?” Dr. Jaffrey says. The team found that RNA molecules embedded in the growth cone are responsible for instructing the axon to move left or right, up or down. These RNAs are translated in growth cones to produce antenna-like proteins that steer the axon like a self-guided missile.

"As a circuit is being built, RNAs in the neuron’s growth cones are mostly silent. We found that specific RNAs are only read at precise stages in order to produce the right protein needed to steer the axon at the right time. After the protein is produced, we saw that the RNA instruction is degraded and disappears," he says.

"If these RNAs do not disappear when they should, the axon does not position itself properly — it may go right instead of left — and the wiring will be incorrect and the circuit may be faulty," Dr. Jaffrey says.

RNAs have Tremendous Power over Brain Development

The research finding answers a long-standing puzzle in the quest to understand brain wiring, says Dr. Dilek Colak, a postdoctoral associate in Dr. Jaffrey’s laboratory.

"There have been a series of discoveries over the last five years showing that proteins that control RNA degradation are very important for brain development and, when they are mutated, you can have spasticity or other movement disorders," Dr. Colak says. "That has raised a major question — why would RNA degradation pathways be so critical for properly creating brain circuits?

"What we show here is that not only does RNA need to be present in growth cones to give instructions, it then also needs to be removed from the growth cones to take away those instructions at the right time," she says. "Both those processes are critical and it may explain why there are so many different brain disorders associated with ineffective RNA regulation."

"The idea that control of brain wiring is located in these RNA molecules that are constantly being dynamically turned over is something that we didn’t anticipate," Dr. Jaffrey adds. "This tells us that regulating these RNA degradation pathways could have a tremendous impact on brain development. Now we know where to look to tease apart this process when it goes awry, and to think about how we can repair it."

(Image: Chad Baker)

Filed under brain development plasticity neural circuits autism RNA molecules brain wiring neuroscience science

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Down syndrome neurons grown from stem cells show signature problems

Down syndrome, the most common genetic form of intellectual disability, results from an extra copy of one chromosome. Although people with Down syndrome experience intellectual difficulties and other problems, scientists have had trouble identifying why that extra chromosome causes such widespread effects.

In new research published this week, Anita Bhattacharyya, a neuroscientist at the Waisman Center at UW-Madison, reports on brain cells that were grown from skin cells of individuals with Down syndrome.

"Even though Down syndrome is very common, it’s surprising how little we know about what goes wrong in the brain," says Bhattacharyya. "These new cells provide a way to look at early brain development."

The study began when those skin cells were transformed into induced pluripotent stem cells, which can be grown into any type of specialized cell. Bhattacharyya’s lab, working with Su-Chun Zhang and Jason Weick, then grew those stem cells into brain cells that could be studied in the lab.

One significant finding was a reduction in connections among the neurons, Bhattacharyya says. “They communicate less, are quieter. This is new, but it fits with what little we know about the Down syndrome brain.”  Brain cells communicate through connections called synapses, and the Down neurons had only about 60 percent of the usual number of synapses and synaptic activity. “This is enough to make a difference,” says Bhattacharyya. “Even if they recovered these synapses later on, you have missed this critical window of time during early development.”

The researchers looked at genes that were affected in the Down syndrome stem cells and neurons, and found that genes on the extra chromosome were increased 150 percent, consistent with the contribution of the extra chromosome.

However, the output of about 1,500 genes elsewhere in the genome was strongly affected. “It’s not surprising to see changes, but the genes that changed were surprising,” says Bhattacharyya. The predominant increase was seen in genes that respond to oxidative stress, which occurs when molecular fragments called free radicals damage a wide variety of tissues.

"We definitely found a high level of oxidative stress in the Down syndrome neurons," says Bhattacharyya. "This has been suggested before from other studies, but we were pleased to find more evidence for that. We now have a system we can manipulate to study the effects of oxidative stress and possibly prevent them."

Down syndrome includes a range of symptoms that could result from oxidative stress, Bhattacharyya says, including accelerated aging. “In  their 40s, Down syndrome individuals age very quickly. They suddenly get gray hair; their skin wrinkles, there is rapid aging in many organs, and a quick appearance of Alzheimer’s disease. Many of these processes may be due to increased oxidative stress, but it remains to be directly tested.”

Oxidative stress could be especially significant, because it appears right from the start in the stem cells. “This suggests that these cells go through their whole life with oxidative stress,” Bhattacharyya adds, “and that might contribute to the death of neurons later on, or increase susceptibility to Alzheimer’s.”

Other researchers have created neurons with Down syndrome from induced pluripotent stem cells, Bhattacharyya notes. “However, we are the first to report this synaptic deficit, and to report the effects on genes on other chromosomes in neurons. We are also the first to use stem cells from the same person that either had or lacked the extra chromosome. This allowed us to look at the difference just caused by extra chromosome, not due to the genetic difference among people.”

The research, published the week of May 27 in the Proceedings of the National Academy of Sciences, was a basic exploration of the roots of Down syndrome. Bhattacharyya says that while she did not intend to explore treatments in the short term, “we could potentially use these cells to test or intelligently design drugs to target symptoms of Down syndrome.”

(Source: news.wisc.edu)

Filed under down syndrome stem cells brain cells brain development synapses oxidative stress neuroscience science

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Premature birth interrupts brain development

Imaging technique shows premature birth interrupts vital brain development processes, leading to reduced cognitive abilities in infants

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Researchers from King’s College London have for the first time used a novel form of MRI to identify crucial developmental processes in the brain that are vulnerable to the effects of premature birth. This new study, published today in the Proceedings of the National Academy of Sciences (PNAS), shows that disruption of these specific processes can have an impact on cognitive function.

The researchers say the new techniques developed here will enable them to explore how the disruption of key processes can also cause conditions such as autism, and will be used in future studies to test possible treatments to prevent brain damage.

Scientists from King’s College London and Imperial College London used diffusion MRI – a type of imaging which looks at the natural diffusion of water – to observe the maturation of the cerebral cortex where much of the brain’s computing power resides. By analysing the diffusion of water in the cerebral cortex of 55 premature infants and 10 babies born at full term they mapped the growing complexity and density of nerve cells across the whole of the cortex in the months before the normal time of birth.

They found that during this period maturation was most rapid in areas of the brain relating to social and emotional processing, decision making, working memory and visual-spatial processing. These functions are often impaired after premature birth, and the researchers found that cortical development was reduced in preterm compared to full term infants, with the greatest effect in the most premature infants. When they re-examined the infants at two years of age, the preterm infants with the slowest cortical development performed less well on neurodevelopmental testing, demonstrating the longer-term impact of prematurity on cortical maturation.

Professor David Edwards, Director of the Centre for the Developing Brain at King’s, based at the Evelina Children’s Hospital, said: ‘The number of babies born prematurely is increasing, so it has never been more important to improve our understanding of how preterm birth affects brain development and causes brain damage. We know that prematurity is extremely stressful for an infant, but by using a new technique we are able to track brain maturation in babies to pinpoint the exact processes that might be affected by premature birth. Here we have used innovative ways to understand how the development of the cerebral cortex is affected.

‘These findings highlight a key stage of brain development where the neurons branch out to create a complex, mature structure. We can now see that this happens in the latter stages of development that would usually take place in healthy babies when they are still in the womb. This suggests that premature birth can interrupt this vital developmental process. It may explain why we sometimes see adverse effects on brain development in those born only slightly prematurely as we now know that this process is happening right up to the normal time of birth. With this study we found that the earlier a baby is born, the less mature the cortex structure. The weeks a baby loses in the womb really matter.

‘These new techniques we’ve developed to identify these crucial processes will allow us to examine how disruption caused by premature birth can lead to conditions such as autism and learning difficulties. We will also use the technique in future studies to test new treatments to prevent brain damage. It’s an extremely exciting step forward.’

(Source: kcl.ac.uk)

Filed under brain development infants premature birth cerebral cortex nerve cells neuroscience science

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Researchers Discover Dynamic Behavior Of Progenitor Cells In Brain

By monitoring the behavior of a class of cells in the brains of living mice, neuroscientists at Johns Hopkins discovered that these cells remain highly dynamic in the adult brain, where they transform into cells that insulate nerve fibers and help form scars that aid in tissue repair.

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Published online April 28 in the journal Nature Neuroscience, their work sheds light on how these multipurpose cells communicate with each other to maintain a highly regular, grid-like distribution throughout the brain and spinal cord. The disappearance of one of these so-called progenitor cells causes a neighbor to quickly divide to form a replacement, ensuring that cell loss and cell addition are kept in balance.

“There is a widely held misconception that the adult nervous system is static or fixed, and has a limited capacity for repair and regeneration,” says Dwight Bergles, Ph.D., professor of neuroscience and otolaryngology at the Johns Hopkins University School of Medicine. “But we found that these progenitor cells, called oligodendrocyte precursor cells (OPCs), are remarkably dynamic. Unlike most other adult brain cells, they are able to respond to the repair needs around them while maintaining their numbers.”

OPCs can mature to become oligodendrocytes — support cells in the brain and spinal cord responsible for wrapping nerve fibers to create insulation known as myelin. Without myelin, the electrical signals sent by neurons travel poorly and some cells die due to the lack of metabolic support from oligodendrocytes. It is the death of oligodendrocytes and the subsequent loss of myelin that leads to neurological disability in diseases such as multiple sclerosis.

During brain development, OPCs spread throughout the central nervous system and make large numbers of oligodendrocytes. Scientists know that few new oligodendrocytes are born in the healthy adult brain, yet the brain is flush with OPCs. However, the function of OPCs in the adult brain wasn’t clear.

To find out, Bergles and his team genetically modified mice so that their OPCs contained a fluorescent protein along their edges, giving crisp definition to their many fine branches that extend in every direction. Using special microscopes that allow imaging deep inside the brain, the team watched the activity of individual cells in living mice for over a month.

The researchers discovered that, far from being static, the OPCs were continuously moving through the brain tissue, extending their “tentacles” and repositioning themselves. Even though these progenitors are dynamic, each cell maintains its own area by repelling other OPCs when they come in contact.

“The cells seem to sense each other’s presence and know how to control the number of cells in their population,” says Bergles. “It looks like this process goes wrong in multiple sclerosis lesions, where there are reduced numbers of OPCs, a loss that may impair the cells’ ability to sense whether demyelination has occurred. We don’t yet know what molecules are involved in this process, but it’s something we’re actively working on.”

To see if OPCs do more than form new oligodendrocytes in the adult brain, the team tested their response to injury by using a laser to create a small wound in the brain. Surprisingly, OPCs migrated to the injury site and contributed to scar formation, a previously unsuspected role. The empty space in the OPC grid, created by the loss of the scar-forming OPCs, was then filled by cell division of neighboring OPCs, providing an explanation for why brain injury is often accompanied by proliferation of these cells.

“Scar cells are not oligodendrocytes, so the term ‘oligodendrocyte precursor cell’ may now be outdated,” says Bergles. “These cells are likely to have a broader role in tissue regeneration and repair than we thought. Because traumatic brain injuries, multiple sclerosis and other neurodegenerative diseases require tissue regeneration, we are eager to learn more about the functions of these enigmatic cells.”

Filed under brain cells brain development precursor cells myelin tissue repair neuroscience science

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Mathematicians help to unlock brain function

Mathematicians from Queen Mary, University of London will bring researchers one-step closer to understanding how the structure of the brain relates to its function in two recently published studies.

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Publishing in Physical Review Letters the researchers from the Complex Networks group at Queen Mary’s School of Mathematical Sciences describe how different areas in the brain can have an association despite a lack of direct interaction. 

The team, in collaboration with researchers in Barcelona, Pamplona and Paris, combined two different human brain networks - one that maps all the physical connections among brain areas known as the backbone network, and another that reports the activity of different regions as blood flow changes, known as the functional network. They showed that the presence of symmetrical neurons within the backbone network might be responsible for the synchronised activity of physically distant brain regions.

Lead author Vincenzo Nicosia, said “We don’t fully understand how the human brain works. So far the focus has been more on the analysis of the function of single, localised regions. However, there isn’t a complete model that brings the whole functionality of the brain together. Hopefully, our research will help neuroscientists to develop a more accurate map of the brain and investigate its functioning beyond single areas.”

The research adds to the recent findings published in Proceedings of the National Academy of Sciences in which the QM researchers along with the Department of Psychiatry at University of Cambridge analysed the development of the brain of a small worm called Caenorhabditis elegans. In this paper, the team examined the number of links formed in the brain during the worm’s lifespan, and observed an unexpected abrupt change in the pattern of growth, corresponding with the time of egg hatching.

“The research is important as it’s the first time that a sharp transition in the growth of a neural network has ever been observed,” added Dr Nicosia.

“Although we don’t know which biological factors are responsible for the change in the growth pattern, we were able to reproduce the pattern using a simple economical model of synaptic formation. This result can pave the way to a deeper understanding of how neural networks grow in more complex organisms.” 

(Source: qmul.ac.uk)

Filed under brain brain function c. elegans brain development synaptic formation neural networks neuroscience science

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Pathway Competition Affects Early Differentiation of Higher Brain Structures Sand-dwelling and rock-dwelling cichlids living in East Africa’s Lake Malawi share a nearly identical genome, but have very different personalities. The territorial rock-dwellers live in communities where social interactions are important, while the sand-dwellers are itinerant and less aggressive. Those behavioral differences likely arise from a complex region of the brain known as the telencephalon, which governs communication, emotion, movement and memory in vertebrates – including humans, where a major portion of the telencephalon is known as the cerebral cortex. A study published this week in the journal Nature Communications shows how the strength and timing of competing molecular signals during brain development has generated natural and presumably adaptive differences in the telencephalon much earlier than scientists had previously believed. In the study, researchers first identified key differences in gene expression between rock- and sand-dweller brains during development, and then used small molecules to manipulate developmental pathways to mimic natural diversity. “We have shown that the evolutionary changes in the brains of these fishes occur really early in development,” said Todd Streelman, an associate professor in the School of Biology and the Petit Institute for Bioengineering and Biosciences at the Georgia Institute of Technology. “It’s generally been thought that early development of the brain must be strongly buffered against change. Our data suggest that rock-dweller brains differ from sand-dweller brains – before there is a brain.” For humans, the research could lead scientists to look for subtle changes in brain structures earlier in the development process. This could provide a better understanding of how disorders such as autism and schizophrenia could arise during very early brain development. The research was supported by the National Science Foundation and published online April 23 by the journal. “We want to understand how the telencephalon evolves by looking at genetics and developmental pathways in closely-related species from natural populations,” said Jonathan Sylvester, a postdoctoral researcher in the Georgia Tech School of Biology and lead author of the paper. “Adult cichlids have a tremendous amount of variation within the telencephalon, and we investigated the timing and cause of these differences. Unlike many previous studies in laboratory model organisms that focus on large, qualitative effects from knocking out single genes, we demonstrated that brain diversity evolves through quantitative tuning of multiple pathways.” In examining the fish from embryos to adulthood, the researchers found that the mbuna, or rock-dwellers, tended to exhibit a larger ventral portion of the telencephalon, called the subpallium – while the sand-dwellers tended to have a larger version of the dorsal structure known as the pallium. These structures seem to have evolved differently over time to meet the behavioral and ecological needs of the fishes. The team showed that early variation in the activity of developmental signals expressed as complementary dorsal-ventral gradients, known technically as “Wingless” and “Hedgehog,” are involved in creating those differences during the neural plate stage, as a single sheet of neural tissue folds to form the neural tube. To specifically manipulate those two pathways, Sylvester removed clutches of between 20 and 40 eggs from brooding female cichlids, which normally incubate fertilized eggs in their mouths. At about 36 to 48 hours after fertilization, groups of eggs were exposed to small-molecule chemicals that either strengthened or weakened the Hedgehog signal, or strengthened or weakened the Wingless signal. The chemical treatment came while the structures that would become the brain were little more than a sheet of cells. After treatment, water containing the chemicals was replaced with fresh water, and the embryos were allowed to continue their development. “We were able to artificially manipulate these pathways in a way that we think evolution might have worked to shift the process of rock-dweller telencephalon development to sand-dweller development, and vice-versa. Treatment with small molecules allows us incredible temporal and dose precision in manipulating natural development,” Sylvester explained. “We then followed the development of the embryos until we were able to measure the anatomical structures – the size of the pallium and subpallium – to see that we had transformed one to the other.” The two different brain regions, the dorsal pallium and ventral subpallium, give rise to excitatory and inhibitory neurons in the forebrain. Altering the relative sizes of these regions might change the balance between these neuronal types, ultimately producing behavioral changes in the adult fish. “Evolution has fine-tuned some of these developmental mechanisms to produce diversity,” Streelman said. “In this study, we have figured out which ones.” The researchers studied six different species of East African cichlids, and also worked with collaborators at King’s College in London to apply similar techniques in the zebrafish. As a next step, the researchers would like to follow the embryos through to adulthood to see if the changes seen in embryonic and juvenile brain structures actually do change behavior of adults. It’s possible, said Streelman, that later developmental events could compensate for the early differences. The results could be of interest to scientists investigating human neurological disorders that result from an imbalance between excitatory and inhibitory neurons. Those disorders include autism and schizophrenia. “We think it is particularly interesting that there may be some adaptive variation in the natural proportions of excitatory versus inhibitory neurons in the species we study, correlated with their natural behavioral differences,” said Streelman.

Pathway Competition Affects Early Differentiation of Higher Brain Structures

Sand-dwelling and rock-dwelling cichlids living in East Africa’s Lake Malawi share a nearly identical genome, but have very different personalities. The territorial rock-dwellers live in communities where social interactions are important, while the sand-dwellers are itinerant and less aggressive.

Those behavioral differences likely arise from a complex region of the brain known as the telencephalon, which governs communication, emotion, movement and memory in vertebrates – including humans, where a major portion of the telencephalon is known as the cerebral cortex. A study published this week in the journal Nature Communications shows how the strength and timing of competing molecular signals during brain development has generated natural and presumably adaptive differences in the telencephalon much earlier than scientists had previously believed.

In the study, researchers first identified key differences in gene expression between rock- and sand-dweller brains during development, and then used small molecules to manipulate developmental pathways to mimic natural diversity.

“We have shown that the evolutionary changes in the brains of these fishes occur really early in development,” said Todd Streelman, an associate professor in the School of Biology and the Petit Institute for Bioengineering and Biosciences at the Georgia Institute of Technology. “It’s generally been thought that early development of the brain must be strongly buffered against change. Our data suggest that rock-dweller brains differ from sand-dweller brains – before there is a brain.”

For humans, the research could lead scientists to look for subtle changes in brain structures earlier in the development process. This could provide a better understanding of how disorders such as autism and schizophrenia could arise during very early brain development.

The research was supported by the National Science Foundation and published online April 23 by the journal.

“We want to understand how the telencephalon evolves by looking at genetics and developmental pathways in closely-related species from natural populations,” said Jonathan Sylvester, a postdoctoral researcher in the Georgia Tech School of Biology and lead author of the paper. “Adult cichlids have a tremendous amount of variation within the telencephalon, and we investigated the timing and cause of these differences. Unlike many previous studies in laboratory model organisms that focus on large, qualitative effects from knocking out single genes, we demonstrated that brain diversity evolves through quantitative tuning of multiple pathways.”

In examining the fish from embryos to adulthood, the researchers found that the mbuna, or rock-dwellers, tended to exhibit a larger ventral portion of the telencephalon, called the subpallium – while the sand-dwellers tended to have a larger version of the dorsal structure known as the pallium. These structures seem to have evolved differently over time to meet the behavioral and ecological needs of the fishes. The team showed that early variation in the activity of developmental signals expressed as complementary dorsal-ventral gradients, known technically as “Wingless” and “Hedgehog,” are involved in creating those differences during the neural plate stage, as a single sheet of neural tissue folds to form the neural tube.

To specifically manipulate those two pathways, Sylvester removed clutches of between 20 and 40 eggs from brooding female cichlids, which normally incubate fertilized eggs in their mouths. At about 36 to 48 hours after fertilization, groups of eggs were exposed to small-molecule chemicals that either strengthened or weakened the Hedgehog signal, or strengthened or weakened the Wingless signal. The chemical treatment came while the structures that would become the brain were little more than a sheet of cells. After treatment, water containing the chemicals was replaced with fresh water, and the embryos were allowed to continue their development.

“We were able to artificially manipulate these pathways in a way that we think evolution might have worked to shift the process of rock-dweller telencephalon development to sand-dweller development, and vice-versa. Treatment with small molecules allows us incredible temporal and dose precision in manipulating natural development,” Sylvester explained. “We then followed the development of the embryos until we were able to measure the anatomical structures – the size of the pallium and subpallium – to see that we had transformed one to the other.”

The two different brain regions, the dorsal pallium and ventral subpallium, give rise to excitatory and inhibitory neurons in the forebrain. Altering the relative sizes of these regions might change the balance between these neuronal types, ultimately producing behavioral changes in the adult fish.

“Evolution has fine-tuned some of these developmental mechanisms to produce diversity,” Streelman said. “In this study, we have figured out which ones.”

The researchers studied six different species of East African cichlids, and also worked with collaborators at King’s College in London to apply similar techniques in the zebrafish.

As a next step, the researchers would like to follow the embryos through to adulthood to see if the changes seen in embryonic and juvenile brain structures actually do change behavior of adults. It’s possible, said Streelman, that later developmental events could compensate for the early differences.

The results could be of interest to scientists investigating human neurological disorders that result from an imbalance between excitatory and inhibitory neurons. Those disorders include autism and schizophrenia. “We think it is particularly interesting that there may be some adaptive variation in the natural proportions of excitatory versus inhibitory neurons in the species we study, correlated with their natural behavioral differences,” said Streelman.

Filed under brain development cichlids gene expression evolution telencephalon cerebral cortex neuroscience science

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