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Posts Tagged ‘brain’

Researchers reveal types of genes necessary for brain development

Josh: This had to be painstaking work. It’s exciting that this type of work is being done though, because this should give some insight into how the brain develops. As we apply it to other organ development, it should help with regeneration or growing organs for transplant.

Researchers from Harvard Medical School and Brandeis University have successfully completed a full-genome RNAi screen in neurons, showing what types of genes are necessary for brain development. Details of the screen and its novel methodology are published July 4th in the open-access journal PLoS Genetics.

Recent advances in genomics, such as the sequencing of entire genomes and the discovery of RNA-interference as a means of testing the effects of gene loss, have opened up the possibility to systematically analyze the function of all known and predicted genes in an organism. Until now, this type of functional genomics approach has not been applied to the study of very complex cells, such as the brain’s neurons, on a full-genome scale. … Continue Reading »

Researchers find an evolutionarily preserved signature in the primate brain

Researchers from Uppsala University, Karolinska Institute, and the University of Chicago, have determined that there are hundreds of biological differences between the sexes when it comes to gene expression in the cerebral cortex of humans and other primates. These findings, published June 20th in the open-access journal PLoS Genetics, indicate that some of these differences arose a very long time ago and have been preserved through the evolution of primates. These conserved differences constitute a signature of sex differences in the brain.

More obvious gender differences have been preserved throughout primate evolution; examples include average body size and weight, and genitalia design. This novel study focuses on gene expression within the cerebral cortex – that area of the brain that is involved in such complex functions in humans and other primates as memory, attentiveness, thought processes, and language.

The researchers measured gene expression in the brains of male and female primates from three species: humans, macaques, and marmosets. To measure activity of specific genes, the products of genes (RNA) obtained from the brain of each animal were hybridized to microarrays containing thousands of DNA clones coding for thousands of genes. The authors also investigated DNA sequence differences among primates for genes showing different levels of expression between the sexes.

“Knowledge about gender differences is important for many reasons. For example, this information may be used in the future to calculate medical dosages, as well as for other treatments of diseases or damage to the brain,” says Professor Elena Jazin of Uppsala University.

Lead author Björn Reinius notes that the study does not determine whether these differences in gene expression are in any way functionally significant. Such questions remain to be answered by future studies.

Source: Public Library of Science

Reinius B, Saetre P, Leonard JA, Blekhman R, Merino-Martinez R, et al. (2008) An Evolutionarily Conserved Sexual Signature in the Primate Brain. PLoS Genet 4(6): e1000100. doi:10.1371/journal.pgen.1000100

Josh says:

I’d be curious to see how these differences compare to the expression levels in homosexual males and females.

Neuroscientists show insulin receptor signaling regulates structure of brain circuits

A team of neuroscientists at Cold Spring Harbor Laboratory (CSHL) has demonstrated for the first time in living animals that insulin receptors in the brain can initiate signaling that regulates both the structure and function of neural circuits.

The finding suggests a significant role for this class of receptors and perhaps for insulin, not only in brain development, but also in cognition and in pathological processes in which cognition is impaired, as in Alzheimer’s disease, for example.

Insulin receptors on the surface of cells throughout the body have long been understood to play a central role in controlling metabolism through the regulation of glucose. When a molecule of insulin, a hormone, “docks” with the receptor, a complex signaling cascade is set in motion inside a cell, culminating in the cell’s uptake of insulin.

The Brain Is Not “Insulin-Insensitive” After All

Although insulin receptors are observed in certain parts of the mammalian brain, most scientists, until a few years ago, had assumed the organ was “insulin-insensitive,” knowing that glucose could be taken up by brain cells without the involvement of either insulin or insulin receptors.

In recent years, however, it has been shown that the brain is indeed an insulin target, and in cell-culture experiments that insulin receptor signaling in neurons can have an impact on the formation and development of neural circuits. This had never been demonstrated in living organisms until it was shown in experiments performed in the laboratory of CSHL Professor Hollis Cline, Ph.D., and reported this week in the journal Neuron.

These experiments, in Xenopus tadpoles, show that insulin receptor signaling in neurons regulates the maintenance of synapses, contributes to the processing of sensory information and is also involved in adjusting the plasticity of brain circuits in response to experience. The latter function is particularly interesting, notes Dr. Cline, since “it is required for the incorporation of neurons into brain circuits.”

Blocking the Receptor

To test the idea that insulin receptor signaling regulates the formation of brain circuits during development, the Cold Spring Harbor team used two different techniques to block the function of the receptor in neurons located in the visual pathway of tadpoles. One method “knocked down” expression of the receptors genetically, while the other left them in place but prevented them from initiating signaling cascades within the cell.

“Tadpoles are wonderful creatures for such experiments,” Dr. Cline explained, “in part because they have translucent bodies, which makes it easy for us to visualize and record what happens to individual neurons as we manipulate the insulin receptors on their surface.”

When insulin receptor function was blocked, neurons in the visual pathway connecting the tadpole’s retina to a brain region called the tectum responded very poorly to light stimuli. The tectum is the area in which brain cells process incoming visual signals. “We showed that the insulin receptor is critical for the proper operation of this circuit, and also that defects in receptor signaling cause a reduction in the animal’s visual responses,” Dr. Cline said.

Time-Lapse Images of Dendritic Branching

The team went on to perform other experiments that demonstrated two remarkable facts. One is that insulin receptor signaling correlates with the density of the synapses, or neuron-to-neuron connections, in brain circuits. In more technical terms, they found that insulin receptors maintain synaptic density and that synapse density decreases when insulin receptors are removed or dysfunctional.

The team also secured time-lapse images of dendritic formations, the ethereal, branch-like structures that receive chemical signals sent from one neuron to the next. Again, they found that when insulin receptors are engaged and sending signals inside the neuron, dendritic growth is enhanced, specifically in response to visual stimulation.

In this, as in the findings about synaptic density, the team found that insulin receptor signaling regulates the form and function of brain circuits in response to incoming visual information. Another way to put this is that the receptor regulates brain circuits in response to “experience.”

Possible Links to Disease

This suggests that insulin receptors in the brain may play a key role not only in the brain’s development early in life, but also in disease processes that usually occur late in life. People with advanced diabetes suffer memory loss and cognitive deficits, possibly because insulin receptor signaling in the brain is disrupted, synaptic connections are lost and brain circuits don’t work optimally.

In addition, other researchers have found a correlation between diminished insulin receptor signaling and Alzheimer’s disease. Results of the Cold Spring Harbor team’s research raise the question of whether deficits in learning and memory associated with Alzheimer’s might be linked causally to decreased synaptic density as a consequence of lowered insulin receptor signaling. “We are a long way from knowing this for sure, but it’s the direction in which our work now takes us,” Dr. Cline said.

Source: Cold Spring Harbor Laboratory

Shu-Ling Chiu, Chih-Ming Chen and Hollis T. Cline. “Insulin Receptor Signaling Regulates Synapse Number, Dendritic Plasticity, and Circuit Function In Vivo”. Neuron. June 11, 2008. doi:10.1016/j.neuron.2008.04.014.

Josh says:

If this turned out to be true, it could have huge implications for our eating habits and offer an even larger incentive to eat healthier other than the risk of type II diabetes.

Origins of the brain

One of the great scientific challenges is to understand the design principles and origins of the human brain. New research has shed light on the evolutionary origins of the brain and how it evolved into the remarkably complex structure found in humans.

The research suggests that it is not size alone that gives more brain power, but that, during evolution, increasingly sophisticated molecular processing of nerve impulses allowed development of animals with more complex behaviors.

The study shows that two waves of increased sophistication in the structure of nerve junctions could have been the force that allowed complex brains – including our own – to evolve. The big building blocks evolved before big brains.

Current thinking suggests that the protein components of nerve connections – called synapses – are similar in most animals from humble worms to humans and that it is increase in the number of synapses in larger animals that allows more sophisticated thought.

“Our simple view that ‘more nerves’ is sufficient to explain ‘more brain power’ is simply not supported by our study,” explained Professor Seth Grant, Head of the Genes to Cognition Programme at the Wellcome Trust Sanger Institute and leader of the project. “Although many studies have looked at the number of neurons, none has looked at the molecular composition of neuron connections. We found dramatic differences in the numbers of proteins in the neuron connections between different species”.

“We studied around 600 proteins that are found in mammalian synapses and were surprised to find that only 50 percent of these are also found in invertebrate synapses, and about 25 percent are in single-cell animals, which obviously don’t have a brain.”

Synapses are the junctions between nerves where electrical signals from one cell are transferred through a series of biochemical switches to the next. However, synapses are not simply soldered joints, but mini-processors that give the nervous systems the property of learning and memory.

Remarkably, the study shows that some of the proteins involved in synapse signalling and learning and memory are found in yeast, where they act to respond to signals from their environment, such as stress due to limited food or temperature change.

“The set of proteins found in single-cell animals represents the ancient or ‘protosynapse’ involved with simple behaviors,” continues Professor Grant. “This set of proteins was embellished by addition of new proteins with the evolution of invertebrates and vertebrates and this has contributed to the more complex behaviors of these animals.

“The number and complexity of proteins in the synapse first exploded when multicellular animals emerged, some billion years ago. A second wave occurred with the appearance of vertebrates, perhaps 500 million years ago”

One of the team’s major achievements was to isolate, for the first time, the synapse proteins from brains of flies, which confirmed that invertebrates have a simpler set of proteins than vertebrates.

Most important for understanding of human thought, they found the expansion in proteins that occurred in vertebrates provided a pool of proteins that were used for making different parts of the brain into the specialized regions such as cortex, cerebellum and spinal cord.

Since the evolution of molecularly complex, ‘big’ synapses occurred before the emergence of large brains, it may be that these molecular evolutionary events were necessary to allow evolution of big brains found in humans, primates and other vertebrates.

Behavioral studies in animals in which mutations have disrupted synapse genes support the conclusion that the synapse proteins that evolved in vertebrates give rise to a wider range of behaviors including those involved with the highest mental functions. For example, one of the ‘vertebrate innovation’ genes called SAP102 is necessary for a mouse to use the correct learning strategy when solving mazes, and when this gene is defective in human it results in a form of mental disability.

“The molecular evolution of the synapse is like the evolution of computer chips – the increasing complexity has given them more power and those animals with the most powerful chips can do the most,” continues Professor Grant.

Simple invertebrate species have a set of simple forms of learning powered by molecularly simple synapses, and the complex mammalian species show a wider range of types of learning powered by molecularly very complex synapses.

“It is amazing how a process of Darwinian evolution by tinkering and improvement has generated, from a collection of sensory proteins in yeast, the complex synapse of mammals associated with learning and cognition,” said Dr Richard Emes, Lecturer in Bioinformatics at Keele University, and joint first author on the paper.

The new findings will be important in understanding normal functioning of the human brain and will be directly relevant to disease studies. Professor Grant’s team have identified recently evolved genes involved in impaired human cognition and modeled those deficits in the mouse.

“This work leads to a new and simple model for understanding the origins and diversity of brains and behavior in all species” says Professor Grant, adding that “we are one step closer to understanding the logic behind the complexity of human brains”

Source: Wellcome Trust Sanger Institute

Emes RD, Pocklington AJ, Anderson CNG, Bayes A, Collins MO, Vickers CA, Croning MDR, Malik BR, Choudhary JS, Armstrong JD and Grant SGN (2008). Evolutionary expansion and anatomical specialization of synapse proteome complexity. Nature Neuroscience published online Sunday 8 June 2008

Josh says:

I can’t say that I’m at all surprised. Higher level organisms began using more complex neurotransmitters, even though these are just simple derivitives of normal metabolic molecules or amino acids. A lot of studies like this seem obvious to me, but I realize that it’s bad to just assume things, and it’s usually always worth conducting the study anyway. You then gain more knowledge about the topic. I’m wondering if their research could be of any help to the Blue Brain Project, which is trying to reverse engineer the mammalian brain by simulating neuronal ion channels.

Mammalian neurogenesis breaks into the most static brain region

Fifteen years ago, the discovery of adult neurogenesis (the production of new neurons) in the highly static, non-renewable mammalian brain was a breakthrough in neuroscience. Most emphasis was put on the possibility to figure out new strategies for brain repair against the threath of neurodegenerative diseases. Yet, unlike lower vetebrates, which are characterized by widespread postnatal neurogenesis, neurogenic sites in mammals are highly restricted within two very small regions. Hence, the fact that protracted neurogenesis in mammals is an exception rather than the rule slowes down hopes for generalized brain repair.

Work carried out in the recent past at the University of Turin, involving Federico Luzzati and Paolo Peretto at the Department of Animal Biology, and Giovanna Ponti and Luca Bonfanti at the Department of Veterinary Morphophysiology, revealed striking examples of structural plasticity and neurogenesis in the nervous system of rabbits. These Lagomorphs show remarkable differences under the profile of neurogenesis with respect to their close relatives Rodents (mice and rats).

Now, in a work published in this week’s issue of PLoS ONE and coordinated by senior author Luca Bonfanti, new neuronal progenitors were found to be produced in the cerebellum of young and adult rabbits. This is rather astonishing since the mammalian cerebellum is known as one of the most static brain regions, wherein microscopic synaptic remodelling has long been considered as the only type of plasticity.

In addition, unlike the two ‘classic’ neurogenic sites, the ‘alternative’ neurogenic sites discovered in rabbits are not remnants of embryonic germinal layers. These new cells are produced from neural progenitors localized within the mature brain parenchyma, thus representing a more widespread source of neurons and glial cells. This fact supports the emerging hypothesis that the existence of actively dividing parenchymal cell progenitors could be more interesting than stem cells located in neurogenic sites, at least for future perspectives of brain repair.

Under the functional profile, the unusual neurogenesis observed in rabbits could be related to a relatively longer lifespan of these animals, if compared to the short lived Rodents. This hypothesis opens new fields of research in humans, wherein adult neurogenic sites are known to exist, but less it is known about other regions of their large-sized brain.

Source: Public Library of Science

Ponti G, Peretto P, Bonfanti L (2008) Genesis of Neuronal and Glial Progenitors in the Cerebellar Cortex of Peripuberal and Adult Rabbits. PLoS ONE 3(6): e2366. doi:10.1371/journal.pone.0002366

Sleep-deprived brains alternate between normal activity and ‘power failure’

New imaging research shows that brain activity differs in sleep-deprived and well-rested people. The study, in the May 21 issue of The Journal of Neuroscience, shows that individuals who are sleep-deprived experience periods of near-normal brain function, but these periods are interspersed with severe drops in attention and visual processing.

This study shows what happens in the sleep-deprived brain and may explain why sleep-deprived people fail to stay alert. “The main finding is that the brain of the sleep-deprived individual is working normally sometimes, but intermittently suffers from something akin to power failure,” said Clifford Saper, MD, PhD, of Harvard University, an expert unaffiliated with the study. STL-B

The research team, led by Michael Chee, MBBS, at the Duke–National University of Singapore Graduate Medical School in Singapore (Duke-NUS), used functional magnetic resonance imaging (fMRI) to measure brain blood flow in people who were either kept awake all night or allowed a good night’s sleep. Researchers tested the same participants in both conditions.

During imaging, participants did a task that required visual attention. Researchers showed them large letters composed of many smaller letters. Participants were asked to identify either the large or small letters and to indicate their responses by pushing a button.

Well-rested and sleep-deprived volunteers showed a range of reaction times. Those participants with the fastest responses, both in sleep-deprived and well-rested conditions, showed similar patterns of brain activity. However, well-rested and sleep-deprived participants with the slowest responses—also called attentional lapses—showed different patterns of brain activity.

Previous research showed that attentional lapses normally induce activity in frontal and parietal regions of the brain, “command centers” that may compensate for lost focus by increasing attention. However, during attentional lapses, Chee and colleagues found reduced activity in these brain command centers in sleep-deprived compared to well-rested volunteers. This finding suggests that sleep deprivation reduces the brain’s ability to compensate for lost focus.

Sleep-deprived people also showed reduced activity in brain regions involved in visual processing during attentional lapses. Because the brain becomes less responsive to sensory stimuli during sleep, reduced activity in these regions suggests that, during attentional lapses, the sleep-deprived brain enters a sleep-like state.

“To my knowledge, this is one of the first studies to look carefully at brain imaging during lapses of consciousness after sleep deprivation, the equivalent of ‘blanking out,’” said Emmanuel Mignot, MD, PhD, at Stanford University, who was not involved in the study. Although attentional lapses result in the same behaviors, “lapses due to sleep deprivation are clearly different neurobiologically than lapses in well-rested people,” Mignot said.

Saper says the study highlights the importance of preventing sleep deprivation in people who are doing critical tasks, like night driving. Although sleep deprivation harms decision making and may increase on-the-job errors, sleep-deprived workers may not know they are impaired. “The periods of apparently normal functioning could give a false sense of competency and security when, in fact, the brain’s inconsistency could have dire consequences,” study author Chee said.

Source: Society for Neuroscience

Andrew says:

This seems to be true in my experience… especially when programming. It’s the morning-after thousand-yard stare. So after an all-nighter, while trying to work the next morning, 6am to 1pm seem to fly by with little productivity. Tens of minutes will pass before my brain “wakes itself up.” However, if there is some emergency demanding my all my focus, like a morning exam, my brain never has an opportunity to “fail to compensate” and I perform fine.

Disturbances in brain circuitry linked to chronic exposure to solvents

Chronic occupational exposure to organic solvents, found in materials such as paints, printing and dry cleaning agents, is widespread all over the world, and is thought to damage the central nervous system. The pattern of cognitive impairment, involving memory, attention and psychomotor function, frequently persists even after exposure has ceased, is usually referred to as chronic solvent-induced encephalopathy (CSE). Although CSE is an acknowledged occupational disease in an increasing number of western countries, and is classified according to the World Health Organization criteria and is included in the Diagnostic and Statistical Manual for Mental Disorders, it is still a controversial diagnosis, with still some debating whether or not it is a bonafide condition.

Various studies have attempted to pinpoint brain abnormalities caused by CSE, but their methodologies have been questioned. It has been proposed that deterioration within the frontal-striatal-thalamic (FST) circuitry, which is also associated with the psychomotor and attention impairment that takes place with natural aging, may play a role in CSE. A new study was the first to show that disturbances in this region are related to the clinical characteristics of CSE as well as to the severity of exposure. The study was published in the April 2008 issue of Annals of Neurology, the official journal of the American Neurological Association. … Continue Reading »

Brain DNA ‘remodeled’ in alcoholism

Reshaping of the DNA scaffolding that supports and controls the expression of genes in the brain may play a major role in the alcohol withdrawal symptoms, particularly anxiety, that make it so difficult for alcoholics to stop using alcohol.

The finding is reported by researchers at the University of Illinois at Chicago and the Jesse Brown VA Medical Center in the April 2 issue of the Journal of Neuroscience.

DNA can undergo changes in function without any changes in inheritance or coded sequence. These “epigenetic” changes are minor chemical modifications of chromatin — dense bundles of DNA and proteins called histones. … Continue Reading »