Posts tagged "biology"
Homolog of Mammalian Neocortex Found in Bird Brain
A seemingly unique part of the human and mammalian brain is the neocortex, a layered structure on the outer surface of the organ where most higher-order processing is thought to occur. But new research at the University of Chicago has found the cells similar to those of the mammalian neocortex in the brains of birds, sitting in a vastly different anatomical structure.

The work, published in Proceedings of the National Academy of Sciences, confirms a 50-year-old hypothesis about the identity of a mysterious structure in the bird brain that has provoked decades of scientific debate. The research also sheds new light on the evolution of the brain and opens up new animal models for studying the neocortex.
"If you want to study motor neurons or dopamine cells, which are biomedically important, you can study them in mammals, in chick embryos, in zebrafish. But for these neurons of the cerebral cortex, we could only do that in mammals before," said Clifton Ragsdale, PhD, associate professor of neurobiology at University of Chicago Biological Sciences and senior author of the study. "Now, we can take advantage of these other experimental systems to ask how they are specified, can they regenerate, and other questions."
Both the mammalian neocortex and a structure in the bird brain called the dorsal ventricular ridge (DVR) originate from an embryonic region called the telencephalon. But the two regions mature into very different shapes, with the neocortex made up of six distinct cortical layers while the DVR contains large clusters of neurons called nuclei.
Because of this divergent anatomy, many scientists proposed that the bird DVR does not correspond to the mammalian cortex, but is analogous to another mammalian brain structure called the amygdala.
"All mammals have a neocortex, and it’s virtually identical across all of them," said Jennifer Dugas-Ford, PhD, postdoctoral researcher at the University of Chicago and first author on the paper. "But when you go to the next closest group, the birds and reptiles, they don’t have anything that looks remotely similar to neocortex."
But in the 1960s, neuroscientist Harvey Karten studied the neural inputs and outputs of the DVR, finding that they were remarkably similar to the pathways traveling to and from the neocortex in mammals. As a result, he proposed that the DVR performs a similar function to the neocortex despite its dramatically different anatomy.
Dugas-Ford, Ragsdale and co-author Joanna Rowell decided to test Karten’s hypothesis by using recently discovered sets of molecular markers that can identify specific layers of mammalian cortex: the layer 4 “input” neurons or layer 5 “output” neurons. The researchers then looked for whether these marker genes were expressed in the DVR nuclei.
In two different bird species — chicken and zebra finch — the level 4 and 5 markers were expressed by distinct nuclei of the DVR, supporting Karten’s hypothesis that the structure contains cells homologous to those of mammalian neocortex.
"Here was a completely different line of evidence," Ragsdale said. "There were molecular markers that picked out specific layers of cortex; whereas the original Karten theory was based just on connections, and some people dismissed that. But in two very distant birds, all of the gene expression fits together very nicely with the connections."
Dugas-Ford called the evidence “really incredible.”
"All of our markers were exactly where they thought they would be in the DVR when you’re comparing them to the neocortex," she said.
A similar experiment was conducted in a species of turtle, and revealed yet another anatomical possibility for these neocortex-like cells. Instead of a six-layer neocortex or a cluster of nuclei, the turtle brain had layer 4- and 5-like cells distributed along a single layer of the species’ dorsal cortex.
"I think that’s the interesting part, that you can have all these different morphologies built with the same cell types, just in different conformations," Rowell said. "It’s a neocortex or a big clump of nuclei, and then in reptiles they have an unusual dorsal cortex unlike either of those."
Future experiments will test the developmental steps that shape these neurons into various structures, and the relative pros and cons of these anatomical differences. The complex language and tool-use of some bird species suggests that the nuclear organization of this pathway is also capable of supporting advanced functions — and even may offer advantages over the mammalian brain.
"If you wanted to have a special nuclear processing center in Broca’s area to carry out language processing, you can’t do that in a mammal," Ragsdale said. "But in a bird they have these special nuclei that are involved in vocalization. It’s as if you have additional flexibility: You can have shorter circuits, longer circuits, you can have specialized processing centers."
Beyond the structural differences, the discovery of homologous neocortex cell types will allow scientists to study cortical neurons in bird species such as the chicken, a common model used for examining embryonic development. Such research could help scientists more easily study the neurons lost in paralysis, deafness, blindness, and other neurological conditions.

Homolog of Mammalian Neocortex Found in Bird Brain


A seemingly unique part of the human and mammalian brain is the neocortex, a layered structure on the outer surface of the organ where most higher-order processing is thought to occur. But new research at the University of Chicago has found the cells similar to those of the mammalian neocortex in the brains of birds, sitting in a vastly different anatomical structure.

The work, published in Proceedings of the National Academy of Sciences, confirms a 50-year-old hypothesis about the identity of a mysterious structure in the bird brain that has provoked decades of scientific debate. The research also sheds new light on the evolution of the brain and opens up new animal models for studying the neocortex.

"If you want to study motor neurons or dopamine cells, which are biomedically important, you can study them in mammals, in chick embryos, in zebrafish. But for these neurons of the cerebral cortex, we could only do that in mammals before," said Clifton Ragsdale, PhD, associate professor of neurobiology at University of Chicago Biological Sciences and senior author of the study. "Now, we can take advantage of these other experimental systems to ask how they are specified, can they regenerate, and other questions."

Both the mammalian neocortex and a structure in the bird brain called the dorsal ventricular ridge (DVR) originate from an embryonic region called the telencephalon. But the two regions mature into very different shapes, with the neocortex made up of six distinct cortical layers while the DVR contains large clusters of neurons called nuclei.

Because of this divergent anatomy, many scientists proposed that the bird DVR does not correspond to the mammalian cortex, but is analogous to another mammalian brain structure called the amygdala.

"All mammals have a neocortex, and it’s virtually identical across all of them," said Jennifer Dugas-Ford, PhD, postdoctoral researcher at the University of Chicago and first author on the paper. "But when you go to the next closest group, the birds and reptiles, they don’t have anything that looks remotely similar to neocortex."

But in the 1960s, neuroscientist Harvey Karten studied the neural inputs and outputs of the DVR, finding that they were remarkably similar to the pathways traveling to and from the neocortex in mammals. As a result, he proposed that the DVR performs a similar function to the neocortex despite its dramatically different anatomy.

Dugas-Ford, Ragsdale and co-author Joanna Rowell decided to test Karten’s hypothesis by using recently discovered sets of molecular markers that can identify specific layers of mammalian cortex: the layer 4 “input” neurons or layer 5 “output” neurons. The researchers then looked for whether these marker genes were expressed in the DVR nuclei.

In two different bird species — chicken and zebra finch — the level 4 and 5 markers were expressed by distinct nuclei of the DVR, supporting Karten’s hypothesis that the structure contains cells homologous to those of mammalian neocortex.

"Here was a completely different line of evidence," Ragsdale said. "There were molecular markers that picked out specific layers of cortex; whereas the original Karten theory was based just on connections, and some people dismissed that. But in two very distant birds, all of the gene expression fits together very nicely with the connections."

Dugas-Ford called the evidence “really incredible.”

"All of our markers were exactly where they thought they would be in the DVR when you’re comparing them to the neocortex," she said.

A similar experiment was conducted in a species of turtle, and revealed yet another anatomical possibility for these neocortex-like cells. Instead of a six-layer neocortex or a cluster of nuclei, the turtle brain had layer 4- and 5-like cells distributed along a single layer of the species’ dorsal cortex.

"I think that’s the interesting part, that you can have all these different morphologies built with the same cell types, just in different conformations," Rowell said. "It’s a neocortex or a big clump of nuclei, and then in reptiles they have an unusual dorsal cortex unlike either of those."

Future experiments will test the developmental steps that shape these neurons into various structures, and the relative pros and cons of these anatomical differences. The complex language and tool-use of some bird species suggests that the nuclear organization of this pathway is also capable of supporting advanced functions — and even may offer advantages over the mammalian brain.

"If you wanted to have a special nuclear processing center in Broca’s area to carry out language processing, you can’t do that in a mammal," Ragsdale said. "But in a bird they have these special nuclei that are involved in vocalization. It’s as if you have additional flexibility: You can have shorter circuits, longer circuits, you can have specialized processing centers."

Beyond the structural differences, the discovery of homologous neocortex cell types will allow scientists to study cortical neurons in bird species such as the chicken, a common model used for examining embryonic development. Such research could help scientists more easily study the neurons lost in paralysis, deafness, blindness, and other neurological conditions.

Brain Parts Can Evolve Independently, Shows Analysis of Brains of 10,000 Mice
An evolutionary biologist at The University of Manchester, working with scientists in the United States, has found compelling evidence that parts of the brain can evolve independently from each other. It’s hoped the findings will significantly advance our understanding of the brain.
The unique 15-year study with researchers at the University of Tennessee and Harvard Medical School also identified several genetic loci that control the size of different brain parts.
The aim of the research was to find out if different parts of the brain can respond independently of each other to evolutionary stimulus (mosaic evolution) or whether the brain responds as a whole (concerted evolution). Unlike previous studies the researchers compared the brain measurements within just one species. The findings have been published in the journal Nature Communications.
The brains of approximately 10,000 mice were analysed. Seven individual parts of each brain were measured by volume and weight. The entire genome, except the Y chromosome, was scanned for each animal and the gene set for each brain part identified.
Dr Reinmar Hager from the Faculty of Life Sciences compared variation in the size of the brain parts to variation in the genes. He found that the variation in the size of brain parts is controlled by the specific gene set for that brain part and not a shared set of genes.
He also compared the measurements for each mouse to the overall size of its brain. Surprisingly he found very little correlation between the sizes of the brain parts and the overall size of the brain.
Dr Hager says: “If all the different brain parts evolved as a whole we would expect that the same set of genes influences size in all parts. However, we found many gene variations for each different part of the brain supporting a mosaic scenario of brain evolution. We also found very little correlation between the size of the brain parts and the overall size of the brain. This again supports the mosaic evolutionary hypothesis.”
Using the data collected from the mice Dr Hager and colleagues analysed the genes that influence the size of the brain to the genes that control the size of the body. They wanted to find out how independent size regulation of the brain is to that of the body.
They found evidence that the size of the brain is governed by an independent gene set to the one that controls the size of the body. Again they found vey little correlation between variations in the size of the body and the brain.
The evidence means that overall brain size can evolve independently of body size.
Following this research more work will be carried out to identify the specific genes that underlie the size of different parts in the brain
Dr Hager says: “If we can identify the specific genes that cause variations in the size of brain parts then there will be big implications for researchers looking at neuronal disease and brain development. We hope this research will significantly advance our understanding of the brain.”

Brain Parts Can Evolve Independently, Shows Analysis of Brains of 10,000 Mice

An evolutionary biologist at The University of Manchester, working with scientists in the United States, has found compelling evidence that parts of the brain can evolve independently from each other. It’s hoped the findings will significantly advance our understanding of the brain.

The unique 15-year study with researchers at the University of Tennessee and Harvard Medical School also identified several genetic loci that control the size of different brain parts.

The aim of the research was to find out if different parts of the brain can respond independently of each other to evolutionary stimulus (mosaic evolution) or whether the brain responds as a whole (concerted evolution). Unlike previous studies the researchers compared the brain measurements within just one species. The findings have been published in the journal Nature Communications.

The brains of approximately 10,000 mice were analysed. Seven individual parts of each brain were measured by volume and weight. The entire genome, except the Y chromosome, was scanned for each animal and the gene set for each brain part identified.

Dr Reinmar Hager from the Faculty of Life Sciences compared variation in the size of the brain parts to variation in the genes. He found that the variation in the size of brain parts is controlled by the specific gene set for that brain part and not a shared set of genes.

He also compared the measurements for each mouse to the overall size of its brain. Surprisingly he found very little correlation between the sizes of the brain parts and the overall size of the brain.

Dr Hager says: “If all the different brain parts evolved as a whole we would expect that the same set of genes influences size in all parts. However, we found many gene variations for each different part of the brain supporting a mosaic scenario of brain evolution. We also found very little correlation between the size of the brain parts and the overall size of the brain. This again supports the mosaic evolutionary hypothesis.”

Using the data collected from the mice Dr Hager and colleagues analysed the genes that influence the size of the brain to the genes that control the size of the body. They wanted to find out how independent size regulation of the brain is to that of the body.

They found evidence that the size of the brain is governed by an independent gene set to the one that controls the size of the body. Again they found vey little correlation between variations in the size of the body and the brain.

The evidence means that overall brain size can evolve independently of body size.

Following this research more work will be carried out to identify the specific genes that underlie the size of different parts in the brain

Dr Hager says: “If we can identify the specific genes that cause variations in the size of brain parts then there will be big implications for researchers looking at neuronal disease and brain development. We hope this research will significantly advance our understanding of the brain.”

The lab is focusing on cortex to cortex projections in preparation for a paper on this connectomic subject. Here’s an example from images I’ve been working on.
(Mouse Connectome Project)

The lab is focusing on cortex to cortex projections in preparation for a paper on this connectomic subject. Here’s an example from images I’ve been working on.

(Mouse Connectome Project)

Rich Club of the Brain: Not all Regions of the Brain are Created Equal.

"We’ve known for a while that the brain has some regions that are ‘rich’ in the sense of being highly connected to many other parts of the brain," said Olaf Sporns, professor in the Department of Psychological and Brain Sciences in IU’s College of Arts and Sciences. "It now turns out that these regions are not only individually rich, they are forming a ‘rich club.’ They are strongly linked to each other, exchanging information and collaborating."

The study, “Rich-Club Organization of the Human Connectome,” is published in the Nov. 2 issue of the Journal of Neuroscience. The research is part of an ongoing intensive effort to map the intricate networks of the human brain, casting the brain as an integrated dynamic system rather than a set of individual regions.

Using diffusion imaging, which is a form of MRI, Martijn van den Heuvel, a professor at the Rudolf Magnus Institute of Neuroscience at University Medical Center Utrecht, and Sporns examined the brains of 21 healthy men and women and mapped their large-scale network connectivity. They found a group of 12 strongly interconnected bihemispheric hub regions, comprising the precuneus, superior frontal and superior parietal cortex, as well as the subcortical hippocampus, putamen and thalamus. Together, these regions form the brain’s “rich club.”

Most of these areas are engaged in a wide range of complex behavioral and cognitive tasks, rather than more specialized processing such as vision and motor control. If the brain network involving the rich club is disrupted or damaged, said Sporns, the negative impact would likely be disproportionate because of its central position in the network and the number of connections it contains. By contrast, damage to regions outside of the rich club would likely cause specific impairments but would likely have little influence on the global flow of information throughout the brain.

Sporns said the cohesive nature of the rich club’s interconnections was surprising and unexpected. It would not have been implausible to have highly connected nodes that did not interact or influence each other to the same degree.

"You sort of wonder what they’re talking about when they’re communicating with each other," he said. "All these regions are getting all kinds of highly processed information, from virtually all parts of the brain."

The rich club, said van den Heuvel, might be the “G8 summit of our brain.”

"It’s a group of highly influential regions that keep each other informed and likely collaborate on issues that concern whole brain functioning," he said. "Figuring out what is discussed at this summit might be an important step in understanding how our brain works."

Sporns said he and van den Heuvel hope the findings and subsequent research could shed light on the network basis of brain disorders affecting mental health. Van den Heuvel’s prior research has already shown characteristic disturbances of brain networks in schizophrenia. Whether these disturbances specifically affect the brain’s rich club is an open question.

Interest in creating a comprehensive map of the human brain’s neural connections, the connectome, has accelerated in the last few years. In the U.S., the National Institutes of Health are currently funding a project involving a consortium of more than 70 scientists, including Sporns, who are working together to create a first map of the human connectome. Similar projects are planned or already under way in Europe and Asia.

"People are coming around to the idea that mapping the connectome is not only technically feasible but also very important to do," Sporns said. "It’s a fundamental step towards understanding the brain as a networked system. Networks are everywhere these days, found in technology, social media and economics, ecology and systems biology — They’re becoming more and more central in many areas of science. The human brain is perhaps the most challenging example to date."

How the Brain Cell Works: A Dive Into Its Inner Network 
 University of Miami (UM) biology professor Akira Chiba is leading a multidisciplinary team to develop the first systematic survey of protein interactions within brain cells. The team is aiming to reconstruct genome-wide in situ protein-protein interaction networks (isPIN) within the neurons of a multicellular organism. Preliminary data were presented at the American Society for Cell Biology annual meeting, December 3 through 7, 2011, in Denver, Colorado.
 
"This work brings us closer to understanding the mechanics of molecules that keep us functioning," says Chiba, principal investigator of this project. "Knowing how our cells work will improve medicine. Most importantly, we will gain a better understanding of what life is at the molecular level."
Neurons are the cells that are mainly responsible for signaling in the brain. Like all other cells, each neuron produces millions of individual proteins that associate with one another and form a complex communication network. Until recently, observing these protein-protein interactions had not been possible due to technical difficulties. Individual proteins are small and typically less than 10 nm (nanometer) in diameter. Yet, this nano-scale distance was considered to be off-limits even with super-resolution microscopy.
Now, Chiba and his collaborators have developed a novel methodology to examine interaction of individual proteins in the fruit fly — the model organism of choice for this project. The researchers are creating genetically engineered insects that are capable of expressing over 500 fluorescently-tagged assorted proteins, two at a time. The fluorescent tags make it possible to visualize the exact spot where a given pair of proteins associates with each other.
The team utilizes a custom- built 3D FLIM (fluorescent lifetime imaging microscopy) system to quantify this association event within the cells of a live animal. FLIM shows the location and time of such protein interaction, providing the data that allow creation of a point-by-point map of protein-protein interactions.
The pilot phase of this multidisciplinary project is being funded by the National Institutes of Health. It employs advanced genetics, molecular imaging technology and high-performance computation, among other fields. “Collaborating fluorescent chemistry, laser optics and artificial intelligence, my team is working in the ‘jungle’ of the molecules of life within the living cells,” Chiba says. “This is a new kind of ecology played out at the scale of nanometers — creating a sense of deja vu 80 years after the birth of modern ecology.”
At present, the researchers still need to extrapolate from data obtained in test tubes. In the future, they will begin to visualize directly how the individual proteins interact with one another in their ‘native environment,’ which are the cells in our body.

How the Brain Cell Works: A Dive Into Its Inner Network

University of Miami (UM) biology professor Akira Chiba is leading a multidisciplinary team to develop the first systematic survey of protein interactions within brain cells. The team is aiming to reconstruct genome-wide in situ protein-protein interaction networks (isPIN) within the neurons of a multicellular organism. Preliminary data were presented at the American Society for Cell Biology annual meeting, December 3 through 7, 2011, in Denver, Colorado.

"This work brings us closer to understanding the mechanics of molecules that keep us functioning," says Chiba, principal investigator of this project. "Knowing how our cells work will improve medicine. Most importantly, we will gain a better understanding of what life is at the molecular level."

Neurons are the cells that are mainly responsible for signaling in the brain. Like all other cells, each neuron produces millions of individual proteins that associate with one another and form a complex communication network. Until recently, observing these protein-protein interactions had not been possible due to technical difficulties. Individual proteins are small and typically less than 10 nm (nanometer) in diameter. Yet, this nano-scale distance was considered to be off-limits even with super-resolution microscopy.

Now, Chiba and his collaborators have developed a novel methodology to examine interaction of individual proteins in the fruit fly — the model organism of choice for this project. The researchers are creating genetically engineered insects that are capable of expressing over 500 fluorescently-tagged assorted proteins, two at a time. The fluorescent tags make it possible to visualize the exact spot where a given pair of proteins associates with each other.

The team utilizes a custom- built 3D FLIM (fluorescent lifetime imaging microscopy) system to quantify this association event within the cells of a live animal. FLIM shows the location and time of such protein interaction, providing the data that allow creation of a point-by-point map of protein-protein interactions.

The pilot phase of this multidisciplinary project is being funded by the National Institutes of Health. It employs advanced genetics, molecular imaging technology and high-performance computation, among other fields. “Collaborating fluorescent chemistry, laser optics and artificial intelligence, my team is working in the ‘jungle’ of the molecules of life within the living cells,” Chiba says. “This is a new kind of ecology played out at the scale of nanometers — creating a sense of deja vu 80 years after the birth of modern ecology.”

At present, the researchers still need to extrapolate from data obtained in test tubes. In the future, they will begin to visualize directly how the individual proteins interact with one another in their ‘native environment,’ which are the cells in our body.

scipsy:

Brain Development:

The embryonic and fetal brains of all mammals develop in similar ways. The embryonic spinal cord develops along common sequences and patterns. The nervous system emerges from a simple elongated tube of cells, called the neural tube. The head (cranial) end of the embryonic tube expands and differentiates more robustly (than does the spinal end) into several clusters of cells which emerge as the forebrain (telencephalon and diencephalon), midbrain (mesencephalon) and hindbrain (metencephalon and myelencephalon) portions. (via Comparative Mammalian Brain Collections)

scipsy:

Brain Development:

The embryonic and fetal brains of all mammals develop in similar ways. The embryonic spinal cord develops along common sequences and patterns. The nervous system emerges from a simple elongated tube of cells, called the neural tube. The head (cranial) end of the embryonic tube expands and differentiates more robustly (than does the spinal end) into several clusters of cells which emerge as the forebrain (telencephalon and diencephalon), midbrain (mesencephalon) and hindbrain (metencephalon and myelencephalon) portions. (via Comparative Mammalian Brain Collections)

(via biognosis)

eudaimonist:

2,500-Year-Old Brain Examined:

First dug up in 2008 by archaeologists in York, England, the well-preserved brain prompted experts to investigate how the tissue had stayed in such good shape. Above, a computer-generated scan of the 2,500-year-old human skull shows brain matter in dark gray. The lighter gray colors in the skull represent soil. Protein analysis confirmed the ancient brain matter—dated to between 673 and 482 B.C.—belonged to a human, said study co-author Matthew Collins, an archaeologist at the University of York.

“The majority of the mass of the brain is still there, but it’s quite reduced in volume—it’s lost a lot of water,” he said. A new study released in March suggests that the skull had been quickly buried in a pit full of thick, wet clay—among several factors that may have helped prevent the brain from decomposing. The cool, low-oxygen conditions of the soil may have aided in the brain’s preservation, according to the study, published in the Journal of Archaeological Science. Analyses of the tissue and remains of the surrounding skull suggest the Iron Age brain belonged to a male between 26 and 45 who was hanged and then ritually decapitated. The rest of the man’s body hasn’t been located.

(via biognosis)

 
Fundamental Discovery About Neurons May Radically Alter Current View of Neurotransmission
A fundamental new discovery about how nerve cells in the brain store and release tiny sacs filled with chemicals may radically alter the way scientists think about neurotransmission — the electrical signaling in the brain that enables everything from the way we move, to how we remember and sense the world.
According to the scientists at the University of California, San Francisco (UCSF) who conducted the research, the discovery doesn’t change the players involved so much as it reveals that the rules of the game are very different than previously assumed. Better understanding these rules may help researchers find new ways of addressing neurological diseases like Parkinson’s, which may arise in part because these normal brain processes go awry.
The players in question are known as vesicles — tiny sacs filled with neurotransmitters, the chemicals that neurons release to transmit a signal to the next neuron in the circuit.
Scientists have known about these vesicles and the important role they play in brain function for decades, but mystery remained because there appear to be two distinct pools of vesicles, with no understanding of what accounts for the distinction. All the tiny vesicles in an average neuron look the same, even to a trained eye peering through a powerful microscope — the same way a bunch of players wearing the same color on a given field of play would seem to belong to the same team.
In the journal Neuron this month UCSF professor Robert Edwards and his colleagues present the first evidence that, despite their appearance, vesicles in the two pools have distinct identities and fates, which are defined by the particular proteins on their surfaces.
"They look identical, but they contain different proteins," Edwards said.
How the Brain Transmits Information
Neurons, which make up the white matter in the brain and the nerves that run throughout the body, are basically just specialized cells with very long extensions — sometimes a meter or more in length.
Down these spaghetti-like nerve fibers travel electrical impulses, which will cause the neuron to release some of these tiny vesicle sacs, spilling their chemical contents into the synapse, a gap between the nerve ending and the next neuron. The chemicals then seep over to the adjoining neuron, sometimes triggering it to fire in turn.
This basic game of neurotransmission is played trillions of times over by the 10 billion or so neurons in the human brain. Some neurons are so active that they fire as many as 100 times a second, requiring mechanisms to sustain these high rates.
The vesicles play a crucial role in this process because they allow neurons to fire when ready. Neurons use the vesicles to package the chemicals and transport them in advance so that they can release as soon as an electrical impulse arrives. Since the release sites are far away from the cell center, the vesicles must recycle locally to maintain high rates of release.
For years, scientists have observed that while all vesicles appear identical, they actually exist in two different pools. The smaller pool, found at the extreme land’s end of the neuron, holds the ones that release neurotransmitters when an electrical impulse arrives. After release, the vesicles are quickly recycled for continued use, and for this reason scientists have called this the “recycling” pool of vesicles.
The second pool of vesicles can be much larger, accounting for up to 80 percent of all the vesicles at a synapse. Surprisingly, these vesicles do not respond to electrical impulses. Instead they sit dormant when the signal arrives and, because of this, scientists have dubbed this the “resting” pool.
"It’s not clear what they respond to or what their function is," Edwards said.
Because the vesicles in the two pools appear to be identical under the microscope, nobody knew if there was actually any difference between them. In the past, many scientists hypothesized that the difference was simply a matter of location — the recycling ones come into play when an electrical impulse arrives simply because they happen to be at the right spot for release.
But some scientists pondered whether the identity of the vesicles determines their behavior and not the other way around — that the recycling ones are in the right spot because they are the ones destined to be released. It’s sort of like asking whether a soccer player is a goalie because he happens to block shots near the goal, or because he’s designated to be the goalie.
The new work essentially shows that goalies block shots because they’re goalies.
Proteins Determine the Fate
In their paper, Edwards and his colleagues show that vesicles in the two different pools contain different proteins and that these differences determine how they behave. Using a technique for labeling proteins with glowing molecules derived from jellyfish, they were able to show that a protein called VAMP7 is present at high levels in the resting pool rather than the recycling pool, which contains more of other synaptic vesicle proteins.
This shows that the body makes and maintains different pools of vesicles containing different proteins for different purposes: release or some other function. According to Edwards, the observation has far-reaching implications for our understanding of how neurotransmitters are packaged, transported and released from neurons.
"What’s happening is not a simple, monolithic process," he said.
The observation gives new insight into the function of the brain at the most basic, microscopic level. It also may help unravel some of the secrets of neurological diseases, aspects of which may be related to how vesicles are produced and released.
According to Edwards, resting vesicles are involved in a separate not-well-understood process in which neurons spontaneously release vesicles, which may help them adjust the types of connections they make with each other as well as the strength of those connections. This process may play a role in neurological diseases, many of which are characterized by changes in the type and strength of synapses.
(Source: http://www.sciencedaily.com/releases/2011/08/110823154038.htm)

 

Fundamental Discovery About Neurons May Radically Alter Current View of Neurotransmission

A fundamental new discovery about how nerve cells in the brain store and release tiny sacs filled with chemicals may radically alter the way scientists think about neurotransmission — the electrical signaling in the brain that enables everything from the way we move, to how we remember and sense the world.

According to the scientists at the University of California, San Francisco (UCSF) who conducted the research, the discovery doesn’t change the players involved so much as it reveals that the rules of the game are very different than previously assumed. Better understanding these rules may help researchers find new ways of addressing neurological diseases like Parkinson’s, which may arise in part because these normal brain processes go awry.

The players in question are known as vesicles — tiny sacs filled with neurotransmitters, the chemicals that neurons release to transmit a signal to the next neuron in the circuit.

Scientists have known about these vesicles and the important role they play in brain function for decades, but mystery remained because there appear to be two distinct pools of vesicles, with no understanding of what accounts for the distinction. All the tiny vesicles in an average neuron look the same, even to a trained eye peering through a powerful microscope — the same way a bunch of players wearing the same color on a given field of play would seem to belong to the same team.

In the journal Neuron this month UCSF professor Robert Edwards and his colleagues present the first evidence that, despite their appearance, vesicles in the two pools have distinct identities and fates, which are defined by the particular proteins on their surfaces.

"They look identical, but they contain different proteins," Edwards said.

How the Brain Transmits Information

Neurons, which make up the white matter in the brain and the nerves that run throughout the body, are basically just specialized cells with very long extensions — sometimes a meter or more in length.

Down these spaghetti-like nerve fibers travel electrical impulses, which will cause the neuron to release some of these tiny vesicle sacs, spilling their chemical contents into the synapse, a gap between the nerve ending and the next neuron. The chemicals then seep over to the adjoining neuron, sometimes triggering it to fire in turn.

This basic game of neurotransmission is played trillions of times over by the 10 billion or so neurons in the human brain. Some neurons are so active that they fire as many as 100 times a second, requiring mechanisms to sustain these high rates.

The vesicles play a crucial role in this process because they allow neurons to fire when ready. Neurons use the vesicles to package the chemicals and transport them in advance so that they can release as soon as an electrical impulse arrives. Since the release sites are far away from the cell center, the vesicles must recycle locally to maintain high rates of release.

For years, scientists have observed that while all vesicles appear identical, they actually exist in two different pools. The smaller pool, found at the extreme land’s end of the neuron, holds the ones that release neurotransmitters when an electrical impulse arrives. After release, the vesicles are quickly recycled for continued use, and for this reason scientists have called this the “recycling” pool of vesicles.

The second pool of vesicles can be much larger, accounting for up to 80 percent of all the vesicles at a synapse. Surprisingly, these vesicles do not respond to electrical impulses. Instead they sit dormant when the signal arrives and, because of this, scientists have dubbed this the “resting” pool.

"It’s not clear what they respond to or what their function is," Edwards said.

Because the vesicles in the two pools appear to be identical under the microscope, nobody knew if there was actually any difference between them. In the past, many scientists hypothesized that the difference was simply a matter of location — the recycling ones come into play when an electrical impulse arrives simply because they happen to be at the right spot for release.

But some scientists pondered whether the identity of the vesicles determines their behavior and not the other way around — that the recycling ones are in the right spot because they are the ones destined to be released. It’s sort of like asking whether a soccer player is a goalie because he happens to block shots near the goal, or because he’s designated to be the goalie.

The new work essentially shows that goalies block shots because they’re goalies.

Proteins Determine the Fate

In their paper, Edwards and his colleagues show that vesicles in the two different pools contain different proteins and that these differences determine how they behave. Using a technique for labeling proteins with glowing molecules derived from jellyfish, they were able to show that a protein called VAMP7 is present at high levels in the resting pool rather than the recycling pool, which contains more of other synaptic vesicle proteins.

This shows that the body makes and maintains different pools of vesicles containing different proteins for different purposes: release or some other function. According to Edwards, the observation has far-reaching implications for our understanding of how neurotransmitters are packaged, transported and released from neurons.

"What’s happening is not a simple, monolithic process," he said.

The observation gives new insight into the function of the brain at the most basic, microscopic level. It also may help unravel some of the secrets of neurological diseases, aspects of which may be related to how vesicles are produced and released.

According to Edwards, resting vesicles are involved in a separate not-well-understood process in which neurons spontaneously release vesicles, which may help them adjust the types of connections they make with each other as well as the strength of those connections. This process may play a role in neurological diseases, many of which are characterized by changes in the type and strength of synapses.

(Source: http://www.sciencedaily.com/releases/2011/08/110823154038.htm)

approachingsignificance:

 
In Cajal’s time, the dominant belief was that the brain and nervous system formed a “reticulum,” a web of fibers that conducted nerve signals continuously, through a network of connections that linked it all together. It is certainly a simpler and more plausible idea than the truth that Cajal saw in his microscope: that the brain is stuffed with billions of tiny cells of many different sizes and shapes. Each nerve impulse—each twitch, each thought—travels through the brain by leaping from cell to cell. For that insight, he was awarded the Nobel Prize in 1906, shared with Golgi. Cajal also figured out that nerve cells are polar, meaning that signals enter the cell through the shrubbery of the dendrites at one end and leave through the other end at the whiplike axon.
More than a century later, we have machines that can visualize living structures smaller than the wavelength of light. Yet today’s students of neuroscience recognize Cajal’s artful and elaborately detailed illustrations of neurons. He is often called one of the fathers of neuroscience but is probably better described as one of its true artists. Thanks to his vision, we all see a new truth.
This is a portrait of Cajal at age 31.

Edit: We studied his representations and schematics in a 3rd level neuroscience class to cross-check for accuracy against electron microscope shots. Cajal was a true genius. 

approachingsignificance:

In Cajal’s time, the dominant belief was that the brain and nervous system formed a “reticulum,” a web of fibers that conducted nerve signals continuously, through a network of connections that linked it all together. It is certainly a simpler and more plausible idea than the truth that Cajal saw in his microscope: that the brain is stuffed with billions of tiny cells of many different sizes and shapes. Each nerve impulse—each twitch, each thought—travels through the brain by leaping from cell to cell. For that insight, he was awarded the Nobel Prize in 1906, shared with Golgi. Cajal also figured out that nerve cells are polar, meaning that signals enter the cell through the shrubbery of the dendrites at one end and leave through the other end at the whiplike axon.

More than a century later, we have machines that can visualize living structures smaller than the wavelength of light. Yet today’s students of neuroscience recognize Cajal’s artful and elaborately detailed illustrations of neurons. He is often called one of the fathers of neuroscience but is probably better described as one of its true artists. Thanks to his vision, we all see a new truth.

This is a portrait of Cajal at age 31.

Edit: We studied his representations and schematics in a 3rd level neuroscience class to cross-check for accuracy against electron microscope shots. Cajal was a true genius. 

How Memory Is Read out in the Fly Brain: MB-V2 Nerve Cells Enable the Read-Out of Associative Memories
What happens if you cannot recall your memory correctly? You are able to associate and store the name and face of a person, yet you might be unable to remember them when you meet that person. In this example, the recall of the information is temporarily impaired. How such associative memories are “read out” in the brain remains one of the great mysteries of modern neurobiology.
Now, scientists from the Max Planck Institute of Neurobiology in Martinsried and from the Ecole Supérieure de Physique et de Chimie Industrielles in Paris, with an international team of colleagues, took the first step to unravel this mechanism.
Fruit flies have the ability to remember. The brain of these minute animals can store different pieces of information and associations and can recall these for a long time. In comparison to the human brain, which boasts about 100 billion cells, the brain of the fruit fly is, of course, a lot smaller. However, many of the basic principles are the same in both species. Thus, the straightforward structure of the fly brain, with its modest hundred thousand cells, enables the scientists to decode processes at their point of origin: in other words, on the individual cell level.
Nerve cells with read-out function
In their experiments, the neurobiologists conditioned the fruit flies to associate a certain odor with a mild electrical stimulus. After repeating this classical conditioning experiment only once, the flies had already got the message and turned away from the pertaining odor. The key in this experiment was that the scientists could temporarily deactivate specific nerve cells. This was done by a combination of special genetic techniques which allowed certain nerve cells to be deactivated through a change of ambient temperature. In this way, the scientists could show that the behavior of the flies was not altered, when certain nerve cells were deactivated only while the flies recalled the associated memory. The responsible nerve cells, known as MB-V2 cells, had to be intact in order for the flies to fully retrieve the associative memory. These cells were, however, not important for the flies’ ability to associate odor and electrical stimulus or to stabilize the formed memory. The results thus indicated that MB-V2 cells are involved in a memory ‘read-out’ pathway.
Alternative pathways of memory processing
Prior to this experiment, it was known that olfactory information is processed in the lateral horn of the fly’s brain. As a result of such processing, certain behavior, such as innate odor avoidance or approach, can be released. In contrast, the mushroom body is the site in the fly brain, where a positive or negative value is given to the odor information. Here, the neutral odor is associated with the negative sensation of the electric stimulus to form an aversive odor memory. The neurobiologists’ results, which were now published in Nature Neuroscience, showed that MB-V2 cells receive information from the mushroom body and that they, in turn, relay to the nerve cells in the lateral horn.
"For the first time, we demonstrated the function of this alternative pathway via which a learned odor directs avoidance behavior for the memory recall," Hiromu Tanimoto, one of the two leaders of the study, explains. Instinctive behavior, such as the avoidance of certain odors, operates directly via the lateral horn and, as such, remains unperturbed by deactivation of the MB-V2 cells.
"The identification of these cells and the role they play in recalling the contents of the memory are significant milestones on the way to gaining an understanding of how memory guides animal behavior," Tanimoto explains. Perhaps one day, science will thus be able to explain why our brains sometimes get stuck, when trying to call up certain pieces of information. Such knowledge would, for example, be an important prerequisite in the development of drugs to combat certain memory deficiencies.
http://www.sciencedaily.com/releases/2011/07/110708123935.htm

How Memory Is Read out in the Fly Brain: MB-V2 Nerve Cells Enable the Read-Out of Associative Memories

What happens if you cannot recall your memory correctly? You are able to associate and store the name and face of a person, yet you might be unable to remember them when you meet that person. In this example, the recall of the information is temporarily impaired. How such associative memories are “read out” in the brain remains one of the great mysteries of modern neurobiology.

Now, scientists from the Max Planck Institute of Neurobiology in Martinsried and from the Ecole Supérieure de Physique et de Chimie Industrielles in Paris, with an international team of colleagues, took the first step to unravel this mechanism.

Fruit flies have the ability to remember. The brain of these minute animals can store different pieces of information and associations and can recall these for a long time. In comparison to the human brain, which boasts about 100 billion cells, the brain of the fruit fly is, of course, a lot smaller. However, many of the basic principles are the same in both species. Thus, the straightforward structure of the fly brain, with its modest hundred thousand cells, enables the scientists to decode processes at their point of origin: in other words, on the individual cell level.

Nerve cells with read-out function

In their experiments, the neurobiologists conditioned the fruit flies to associate a certain odor with a mild electrical stimulus. After repeating this classical conditioning experiment only once, the flies had already got the message and turned away from the pertaining odor. The key in this experiment was that the scientists could temporarily deactivate specific nerve cells. This was done by a combination of special genetic techniques which allowed certain nerve cells to be deactivated through a change of ambient temperature. In this way, the scientists could show that the behavior of the flies was not altered, when certain nerve cells were deactivated only while the flies recalled the associated memory. The responsible nerve cells, known as MB-V2 cells, had to be intact in order for the flies to fully retrieve the associative memory. These cells were, however, not important for the flies’ ability to associate odor and electrical stimulus or to stabilize the formed memory. The results thus indicated that MB-V2 cells are involved in a memory ‘read-out’ pathway.

Alternative pathways of memory processing

Prior to this experiment, it was known that olfactory information is processed in the lateral horn of the fly’s brain. As a result of such processing, certain behavior, such as innate odor avoidance or approach, can be released. In contrast, the mushroom body is the site in the fly brain, where a positive or negative value is given to the odor information. Here, the neutral odor is associated with the negative sensation of the electric stimulus to form an aversive odor memory. The neurobiologists’ results, which were now published in Nature Neuroscience, showed that MB-V2 cells receive information from the mushroom body and that they, in turn, relay to the nerve cells in the lateral horn.

"For the first time, we demonstrated the function of this alternative pathway via which a learned odor directs avoidance behavior for the memory recall," Hiromu Tanimoto, one of the two leaders of the study, explains. Instinctive behavior, such as the avoidance of certain odors, operates directly via the lateral horn and, as such, remains unperturbed by deactivation of the MB-V2 cells.

"The identification of these cells and the role they play in recalling the contents of the memory are significant milestones on the way to gaining an understanding of how memory guides animal behavior," Tanimoto explains. Perhaps one day, science will thus be able to explain why our brains sometimes get stuck, when trying to call up certain pieces of information. Such knowledge would, for example, be an important prerequisite in the development of drugs to combat certain memory deficiencies.

http://www.sciencedaily.com/releases/2011/07/110708123935.htm

Nervous System Stem Cells Can Replace Themselves, Give Rise to Variety of Cell Types, Even Amplify

A Johns Hopkins team has discovered in young adult mice that a lone brain stem cell is capable not only of replacing itself and giving rise to specialized neurons and glia – important types of brain cells – but also of taking a wholly unexpected path: generating two new brain stem cells.
A report on their study appears June 24 in Cell.
Although it was known that the brain has the capacity to generate both neurons, which send and receive signals, and the glial cells that surround them, it was unclear whether these various cell types came from a single source. In addition to demonstrating that a single radial glia-like (RGL) brain cell is able to generate two very different functional cell types, the Hopkins researchers, by following the fates of single cells over time, found that a single brain stem cell can even produce two stem cells like itself.
“Now we know they don’t just maintain their numbers, or go down in number, but that stem cells can amplify,” says Hongjun Song, Ph.D., professor of neurology and neuroscience and director of the Stem Cell Program in the Institute for Cell Engineering, the Johns Hopkins University School of Medicine. “If we can somehow cash in on this newly discovered property of stem cells in the brain, and find ways to intervene so they divide more, then we might actually increase their numbers instead of losing them over time, which is what normally happens, perhaps due to aging or diseases.”
The researchers’ findings hinged on a decision to single out and follow lone, radial glia-like cells, instead of labeling and monitoring entire stem cell populations in the mouse brain. They took this approach because they suspected radial glia-like cells were essentially stem cells, having been shown in previous studies to give rise to neurons.
Using mice genetically modified with special genes that color-code cells for easy labeling and tracking, the Hopkins team injected a very small amount of a chemical into about 50 mouse brains to induce extremely limited cell labeling.
“It’s a simple idea that forced us to confront a lot of complex technical issues,” Song says. “With so many millions of cells in the relatively large mouse brain, labeling a single stem cell and then chasing its family history was like finding a needle in a haystack.”
The scientists developed computer programs and devised a new imaging technique that allowed them to examine stained slices of the mouse brain and, ultimately, follow single, randomly chosen radial glia-like stem cells over time. The method allowed them to track down all the new cells derived from a single original stem cell.
“We reconstituted single stem cells’ family trees to look at the progeny they gave rise to,” says Guo-li Ming, associate professor of neurology and neuroscience and a member of the Neuroregeneration Program in the Institute for Cell Engineering. “We discovered that single cells in an intact animal nervous system absolutely do exhibit stem-cell properties; they are capable of both replicating themselves and producing different types of differentiated neural progeny.”
The team followed the fates of all the marked radial glia-like stem cells for at least a month or two, and examined some a full year later to discover that even over the long term, the “mother” cell was still generating itself as well as different kinds of progeny.
In addition, the researchers investigated how these RGLs were activated on a molecular level, focusing, in particular, on the regulatory role of an autism-associated gene called PTEN. Conventional wisdom was that deleting this gene led to an increase in stem-cell activation. However, the scientists demonstrated that was a transient effect in the mouse brains, and that, ultimately, PTEN deletion leads to stem-cell depletion.
(Johns-Hopkins)

Nervous System Stem Cells Can Replace Themselves, Give Rise to Variety of Cell Types, Even Amplify

A Johns Hopkins team has discovered in young adult mice that a lone brain stem cell is capable not only of replacing itself and giving rise to specialized neurons and glia – important types of brain cells – but also of taking a wholly unexpected path: generating two new brain stem cells.

A report on their study appears June 24 in Cell.

Although it was known that the brain has the capacity to generate both neurons, which send and receive signals, and the glial cells that surround them, it was unclear whether these various cell types came from a single source. In addition to demonstrating that a single radial glia-like (RGL) brain cell is able to generate two very different functional cell types, the Hopkins researchers, by following the fates of single cells over time, found that a single brain stem cell can even produce two stem cells like itself.

“Now we know they don’t just maintain their numbers, or go down in number, but that stem cells can amplify,” says Hongjun Song, Ph.D., professor of neurology and neuroscience and director of the Stem Cell Program in the Institute for Cell Engineering, the Johns Hopkins University School of Medicine. “If we can somehow cash in on this newly discovered property of stem cells in the brain, and find ways to intervene so they divide more, then we might actually increase their numbers instead of losing them over time, which is what normally happens, perhaps due to aging or diseases.”

The researchers’ findings hinged on a decision to single out and follow lone, radial glia-like cells, instead of labeling and monitoring entire stem cell populations in the mouse brain. They took this approach because they suspected radial glia-like cells were essentially stem cells, having been shown in previous studies to give rise to neurons.

Using mice genetically modified with special genes that color-code cells for easy labeling and tracking, the Hopkins team injected a very small amount of a chemical into about 50 mouse brains to induce extremely limited cell labeling.

“It’s a simple idea that forced us to confront a lot of complex technical issues,” Song says. “With so many millions of cells in the relatively large mouse brain, labeling a single stem cell and then chasing its family history was like finding a needle in a haystack.”

The scientists developed computer programs and devised a new imaging technique that allowed them to examine stained slices of the mouse brain and, ultimately, follow single, randomly chosen radial glia-like stem cells over time. The method allowed them to track down all the new cells derived from a single original stem cell.

“We reconstituted single stem cells’ family trees to look at the progeny they gave rise to,” says Guo-li Ming, associate professor of neurology and neuroscience and a member of the Neuroregeneration Program in the Institute for Cell Engineering. “We discovered that single cells in an intact animal nervous system absolutely do exhibit stem-cell properties; they are capable of both replicating themselves and producing different types of differentiated neural progeny.”

The team followed the fates of all the marked radial glia-like stem cells for at least a month or two, and examined some a full year later to discover that even over the long term, the “mother” cell was still generating itself as well as different kinds of progeny.

In addition, the researchers investigated how these RGLs were activated on a molecular level, focusing, in particular, on the regulatory role of an autism-associated gene called PTEN. Conventional wisdom was that deleting this gene led to an increase in stem-cell activation. However, the scientists demonstrated that was a transient effect in the mouse brains, and that, ultimately, PTEN deletion leads to stem-cell depletion.

(Johns-Hopkins)

Roots of Memory Impairment Resulting from Sleep Deprivation Identified 
From high-school students to surgeons, anyone who has pulled an all-nighter knows there is a price to be paid the next day: trouble focusing, a fuzzy memory and other cognitive impairments. Now, researchers at Penn have found the part of the brain and the neurochemical basis for sleep deprivation’s effects on memory.
Ted Abel, a professor of biology in Penn’s School of Arts and Sciences and director of the University’s interdisciplinary Biological Basis of Behavior program, led the research team. His partners included Cédrick Florian, a postdoctoral fellow in biology, and Christopher Vecsey, a neuroscience graduate student, as well as researchers from the Massachusetts Institute of Technology and Tufts University.
Their research was published in The Journal of Neuroscience.
Abel’s group aimed to better understand the role of the nucleoside adenosine in the hippocampus, the part of the brain associated with memory function.
“For a long time, researchers have known that sleep deprivation results in increased levels of adenosine in the brain, and has this effect from fruit flies to mice to humans.” Abel said. “There is accumulating evidence that this adenosine is really the source of a number of the deficits and impact of sleep deprivation, including memory loss and attention deficits. One thing that underscores that evidence is that caffeine is a drug that blocks the effects of adenosine, so we sometimes refer to this as ‘the Starbucks experiment.’”
Abel’s research actually involved two parallel experiments on sleep-deprived mice, designed to test adenosine’s involvement in memory impairment in different ways.
One experiment involved genetically engineered mice. These mice were missing a gene involved in the production of glial transmitters, chemicals signals that originate from glia, the brain cells that support the function of neurons. Without these gliatransmitters, the engineered mice could not produce the adenosine the researchers believed might cause the cognitive effects associated sleep deprivation.
The other experiment involved a pharmacological approach. The researchers grafted a pump into the brains of mice that hadn’t been genetically engineered; the pump delivered a drug that blocked a particular adenosine receptor in the hippocampus. If the receptor was indeed involved in memory impairment, sleep-deprived mice would behave as if the additional adenosine in their brains was not there.
To see whether these mice showed the effects of sleep deprivation, the researchers used an object recognition test. On the first day, mice were placed in a box with two objects and were allowed to explore them while being videotaped. That night, the researchers woke some of the mice halfway through their normal 12-hour sleep schedule.
On the second day, the mice were placed back in the box, where one of the two objects had been moved, and were once again videotaped as they explored to see how they reacted to the change.
“Mice would normally explore that moved object more than other objects, but, with sleep deprivation, they don’t,” Abel said. “They literally don’t know where things are around them.”
Both sets of treated mice explored the moved object as if they had received a full night’s sleep.
“These mice don’t realize they’re sleep-deprived,” Abel said.
Abel and his colleagues also examined the hippocampi of the mice, using electrical current to measure their synaptic plasticity, or how strong and resilient their memory-forming synapses were. The pharmacologically and genetically protected mice showed greater synaptic plasticity after being sleep deprived than the untreated group.
Combined, the two experiments cover both halves of the chemical pathway involved in sleep deprivation. The genetic engineering experiment shows where the adenosine comes from: glia’s release of adenosine triphosphate, or ATP, the chemical by which cells transfer energy to one another. And the pharmacological experiment shows where the adenosine goes: the A1 receptor in the hippocampus.
The knowledge that interrupting the pathway at either end results in mice that show no memory impairments is a major step forward in understanding how to manage those impairments in humans.
“To be able to reverse a particular aspect of sleep-deprivation, such as its effect on memory storage, we really want to understand the molecular pathways and targets,” Abel said. “Here, we’ve identified the molecule, the cellular circuit and the brain region by which sleep deprivation affects memory storage.”
Such treatments would be especially enticing, given how sensitive the brain is to sleep deprivation’s effects.
“Our sleep deprivation experiments are the equivalent of losing half of a night sleep for a single night,” Abel said. “Most of us would think that’s pretty minor, but it shows just how critical the need for sleep is for things like cognition.”
(UPenn)

Roots of Memory Impairment Resulting from Sleep Deprivation Identified

From high-school students to surgeons, anyone who has pulled an all-nighter knows there is a price to be paid the next day: trouble focusing, a fuzzy memory and other cognitive impairments. Now, researchers at Penn have found the part of the brain and the neurochemical basis for sleep deprivation’s effects on memory.

Ted Abel, a professor of biology in Penn’s School of Arts and Sciences and director of the University’s interdisciplinary Biological Basis of Behavior program, led the research team. His partners included Cédrick Florian, a postdoctoral fellow in biology, and Christopher Vecsey, a neuroscience graduate student, as well as researchers from the Massachusetts Institute of Technology and Tufts University.

Their research was published in The Journal of Neuroscience.

Abel’s group aimed to better understand the role of the nucleoside adenosine in the hippocampus, the part of the brain associated with memory function.

“For a long time, researchers have known that sleep deprivation results in increased levels of adenosine in the brain, and has this effect from fruit flies to mice to humans.” Abel said. “There is accumulating evidence that this adenosine is really the source of a number of the deficits and impact of sleep deprivation, including memory loss and attention deficits. One thing that underscores that evidence is that caffeine is a drug that blocks the effects of adenosine, so we sometimes refer to this as ‘the Starbucks experiment.’”

Abel’s research actually involved two parallel experiments on sleep-deprived mice, designed to test adenosine’s involvement in memory impairment in different ways.

One experiment involved genetically engineered mice. These mice were missing a gene involved in the production of glial transmitters, chemicals signals that originate from glia, the brain cells that support the function of neurons. Without these gliatransmitters, the engineered mice could not produce the adenosine the researchers believed might cause the cognitive effects associated sleep deprivation.

The other experiment involved a pharmacological approach. The researchers grafted a pump into the brains of mice that hadn’t been genetically engineered; the pump delivered a drug that blocked a particular adenosine receptor in the hippocampus. If the receptor was indeed involved in memory impairment, sleep-deprived mice would behave as if the additional adenosine in their brains was not there.

To see whether these mice showed the effects of sleep deprivation, the researchers used an object recognition test. On the first day, mice were placed in a box with two objects and were allowed to explore them while being videotaped. That night, the researchers woke some of the mice halfway through their normal 12-hour sleep schedule.

On the second day, the mice were placed back in the box, where one of the two objects had been moved, and were once again videotaped as they explored to see how they reacted to the change.

“Mice would normally explore that moved object more than other objects, but, with sleep deprivation, they don’t,” Abel said. “They literally don’t know where things are around them.”

Both sets of treated mice explored the moved object as if they had received a full night’s sleep.

“These mice don’t realize they’re sleep-deprived,” Abel said.

Abel and his colleagues also examined the hippocampi of the mice, using electrical current to measure their synaptic plasticity, or how strong and resilient their memory-forming synapses were. The pharmacologically and genetically protected mice showed greater synaptic plasticity after being sleep deprived than the untreated group.

Combined, the two experiments cover both halves of the chemical pathway involved in sleep deprivation. The genetic engineering experiment shows where the adenosine comes from: glia’s release of adenosine triphosphate, or ATP, the chemical by which cells transfer energy to one another. And the pharmacological experiment shows where the adenosine goes: the A1 receptor in the hippocampus.

The knowledge that interrupting the pathway at either end results in mice that show no memory impairments is a major step forward in understanding how to manage those impairments in humans.

“To be able to reverse a particular aspect of sleep-deprivation, such as its effect on memory storage, we really want to understand the molecular pathways and targets,” Abel said. “Here, we’ve identified the molecule, the cellular circuit and the brain region by which sleep deprivation affects memory storage.”

Such treatments would be especially enticing, given how sensitive the brain is to sleep deprivation’s effects.

“Our sleep deprivation experiments are the equivalent of losing half of a night sleep for a single night,” Abel said. “Most of us would think that’s pretty minor, but it shows just how critical the need for sleep is for things like cognition.”

(UPenn)