Neuroscience

Debora A Rothmond, Cynthia S Weickert and Maree J Webster

BMC Neuroscience 2012, 13:18 doi:10.1186/1471-2202-13-18 Published: 15 February 2012           

Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-O-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years).

Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p<0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p<0.001) and D2L (p=0.003) isoforms, monoamine oxidase A (p<0.001) and catechol-O-methyltransferase (p=0.024) were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32kDa, p=0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p=0.002) and dopamine D1 receptor protein expression increased throughout development (p<0.001) with adults having the highest D1 protein levels (p[less than or equal to]0.01). Monoamine oxidase B mRNA and protein (p<0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r=-0.31, p=0.018) in an expression profile opposite to that of the dopamine D1 receptor.

We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function. 

Source: BMC Neuroscience

February 24, 2012 by Stuart Mason Dambrot

Mechanisms of fluorescent voltage sensing. (A) Electrochromic voltage-sensitive dyes (VDSs) sense voltage when the chromophore interacts directly with the electric field. Changes in the energy levels of the chromophore result in small spectral shifts in the emission of the dye. (B) Fluorescence resonance energy transfer-pair voltage sensors use lipophilic anions (red). Depolarization causes translocation of the anion, which can now quench the fluorescence of an immobilized fluorophore (green). (C) Molecular wire photo-induced electron transfer (PeT) VSDs depend upon the voltage-sensitive electron transfer from an electron-rich donor (orange) through a membrane-spanning molecular wire (black) to a fluorescent reporter (green). Image Copyright © PNAS, doi: 10.1073/pnas.1120694109

(Medical Xpress) — Optically monitoring the brain’s neuronal activity can be accomplished in several ways, including electrochromic dyes, hydrophobic anions, calcium imaging, or voltage-sensitive ion channels. Fluorescence imaging is an attractive method due to its ability to map the electrical activity and communication of multiple spatially resolved neurons. While this complements traditional electrophysiological measurements, historically fluorescent voltage imaging has been limited by the difficulty of developing sensors that give both large and fast responses to voltage changes. Recently, however, scientists in the Department of Pharmacology and other areas in the University of California at San Diego’s Howard Hughes Medical Institute have designed, synthesized, and implemented fluorescent sensors in the form of photo-induced electron transfer (PeT)-based molecular wire probes for voltage imaging in neurons. Moreover, they have used these so-called VoltageFluor sensors to perform single-trial detection of synaptic and action potentials in cultured hippocampal neurons and intact leech ganglia.

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Article Date: 24 Feb 2012 - 8:00 PST

A new study, in this week’s online edition of the Proceedings of the National Academy of Sciences , shows an incredible degree of biological diversity in a surprising location, i.e. in a single neural connection in the body wall of flies. The finding opens up a new spectrum of interesting questions regarding the importance of the nervous system structure and the evolution of neural wiring.

Geneticist Barry Ganetzky, Steenbock Professor of Biological Sciences at the University of Wisconsin-Madison declared:

 ”We know almost nothing about the evolution of the nervous system, although we know it has to happen - behaviors change, complexity changes, there is the addition of new neurons, formation of different synaptic connections.”

The finding proves even more astounding given that Ganetzky and his graduate student Megan Campbell discovered the unexpected diversity in a location very familiar to scientists, i.e. the neuromuscular junction 4 (NMJ4), the location where a single motor neuron contacts a particular muscle in the fly body wall to drive its activity. The synapses where neurons link to their neuronal or muscular targets have a complex structural form, looking like miniature trees decorated with tiny bulbs that are the nerve terminals (synaptic boutons).

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February 23rd, 2012

Researchers at the RIKEN-MIT Center for Neural Circuit Genetics have discovered an answer to the long-standing mystery of how brain cells can both remember new memories while also maintaining older ones.

They found that specific neurons in a brain region called the dentate gyrus serve distinct roles in memory formation depending on whether the neural stem cells that produced them were of old versus young age.

The study will appear in the March 30 issue of Cell and links the cellular basis of memory formation to the birth of new neurons – a finding that could unlock a new class of drug targets to treat memory disorders.

The findings also suggest that an imbalance between young and old neurons in the brain could disrupt normal memory formation during post-traumatic stress disorder (PTSD) and aging. “In animals, traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging,” said the study’s senior author Susumu Tonegawa, 1987 Nobel Laureate and Director of the RIKEN-MIT Center.

Other authors include Toshiaki Nakashiba and researchers from the RIKEN-MIT Center and Picower Institute at MIT; the laboratory of Michael S. Fanselow at the University of California at Los Angeles; and the laboratory of Chris J. McBain at the National Institute of Child Health and Human Development.

In the study, the authors tested mice in two types of memory processes. Pattern separation is the process by which the brain distinguishes differences between similar events, like remembering two Madeleine cookies with different tastes. In contrast, pattern completion is used to recall detailed content of memories based on limited clues, like recalling who one was with when remembering the taste of the Madeleine cookies.

Pattern separation forms distinct new memories based on differences between experiences; pattern completion retrieves memories by detecting similarities. Individuals with brain injury or trauma may be unable to recall people they see every day. Others with PTSD are unable to forget terrible events. “Impaired pattern separation due to the loss of young neurons may shift the balance in favor of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients,” Tonegawa said.

Neuroscientists have long thought these two opposing and potentially competing processes occur in different neural circuits. The dentate gyrus, a structure with remarkable plasticity within the nervous system and its role in conditions from depression to epilepsy to traumatic brain injury — was thought to be engaged in pattern separation and the CA3 region in pattern completion. Instead, the MIT researchers found that dentate gyrus neurons may perform pattern separation or completion depending on the age of their cells.

The MIT researchers assessed pattern separation in mice who learned to distinguish between two similar but distinct chambers: one safe and the other associated with an unpleasant foot shock. To test their pattern completion abilities, the mice were given limited cues to escape a maze they had previously learned to negotiate. Normal mice were compared with mice lacking either young neurons or old neurons. The mice exhibited defects in pattern completion or separation depending on which set of neurons was removed.

“By studying mice genetically modified to block neuronal communication from old neurons — or by wiping out their adult-born young neurons — we found that old neurons were dispensable for pattern separation, whereas young neurons were required for it,” co-author Toshiaki Nakashiba said. “Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons.”

Source: Neuroscience News

ScienceDaily (Feb. 23, 2012) — After we sense a threat, our brain center responsible for responding goes into gear, setting off a chain of biochemical reactions leading to the release of cortisol from the adrenal glands.

Dr. Gil Levkowitz and his team in the Molecular Cell Biology Department have now revealed a new kind of ON-OFF switch in the brain for regulating the production of a main biochemical signal from the brain that stimulates cortisol release in the body. This finding, which was recently published in Neuron, may be relevant to research into a number of stress-related neurological disorders.

This signal is corticotropin releasing hormone (CRH). CRH is manufactured and stored in special neurons in the hypothalamus. Within this small brain region the danger is sensed, the information processed and the orders to go into stress-response mode are sent out. As soon as the CRH-containing neurons have depleted their supply of the hormone, they are already receiving the directive to produce more.

The research — on zebrafish — was performed in Levkowitz’s lab and spearheaded by Dr. Liat Amir-Zilberstein together with Drs. Janna Blechman, Adriana Reuveny and Natalia Borodovsky and Maayan Tahor. The team found that a protein called Otp is involved in several stages of CRH production. As well as directly activating the genes encoding CRH, it also regulates the production of two different receptors on the neurons’ surface for receiving and relaying CRH production signals — in effect, ON and OFF switches.

The team found that both receptors are encoded in a single gene. To get two receptors for the price of one, Otp regulates a gene-editing process known as alternative splicing, in which some of the elements in the sequence encoded in a gene can be “cut and pasted” to make slightly different “sentences.” In this case, it generates two variants of a receptor called PAC1: The short version produces the ON receptor; the long version, containing an extra sequence, encodes the OFF receptor. The researchers found that as the threat passed and the supply of CRH was replenished, the ratio between the two types of PAC1 receptor on the neurons’ surface gradually changed from more ON to mostly OFF. In collaboration with Drs Laure Bally-Cuif and William Norton of the Institute of Neurobiology Alfred Fessard at the Centre National de la Recherche Scientifique (CNRS) in France, the researchers showed that blocking the production of the long receptor variant causes an anxiety-like behavior in zebrafish.

Together with Drs. Alon Chen and Yehezkel Sztainberg of the Neurobiology Department, Levkowitz’s team found the same alternatively-spliced switch in mice. This conservation of the mechanism through the evolution of fish and mice implies that a similar means of turning CRH production on and off exists in the human brain.

Faulty switching mechanisms may play a role in a number of stress-related disorders. The action of the PAC1 receptor has recently been implicated in post-traumatic stress disorder, as well as in schizophrenia and depression. Malfunctions in alternative splicing have also been associated with epilepsy, mental retardation, bipolar disorder and autism.

Source: Science Daily

ScienceDaily (Feb. 22, 2012) — While RNA is an appealing drug target, small molecules that can actually affect its function have rarely been found. But now scientists from the Florida campus of The Scripps Research Institute have for the first time designed a series of small molecules that act against an RNA defect directly responsible for the most common form of adult-onset muscular dystrophy.

In two related studies published recently in online-before-print editions of Journal of the American Chemical Society and ACS Chemical Biology, the scientists show that these novel compounds significantly improve a number of biological defects associated with myotonic dystrophy type 1 in both cell culture and animal models.

"Our compounds attack the root cause of the disease and they improve defects in animal models," said Scripps Research Associate Professor Matthew Disney, PhD. "This represents a significant advance in rational design of compounds targeting RNA. The work not only opens up potential therapies for this type of muscular dystrophy, but also paves the way for RNA-targeted therapeutics in general."

Myotonic dystrophy type 1 involves a type of RNA defect known as a “triplet repeat,” a series of three nucleotides repeated more times than normal in an individual’s genetic code. In this case, the repetition of the cytosine-uracil-guanine (CUG) in RNA sequence leads to disease by binding to a particular protein, MBNL1, rendering it inactive. This results in a number of protein splicing abnormalities. Symptoms of this variable disease can include wasting of the muscles and other muscle problems, cataracts, heart defects, and hormone changes.

To find compounds that acted against the problematic RNA in the disease, Disney and his colleagues used information contained in an RNA motif-small molecule database that the group has been developing. By querying the database against the secondary structure of the triplet repeat that causes myotonic dystrophy type 1, a lead compound targeting this RNA was quickly identified. The lead compounds were then custom-assembled to target the expanded repeat or further optimized using computational chemistry. In animal models, one of these compounds improved protein-splicing defects by more than 40 percent.

"There are limitless RNA targets involved in disease; the question is how to find small molecules that bind to them," Disney said. "We’ve answered that question by rationally designing these compounds that target this RNA. There’s no reason that other bioactive small molecules targeting other RNAs couldn’t be developed using a similar approach."

Source: Science Daily

February 22nd, 2012

The notion of a pain switch is an alluring idea, but is it realistic? Well, chemists at LMU Munich, in collaboration with colleagues in Berkeley and Bordeaux, have now shown in laboratory experiments that it is possible to inhibit the activity of pain-sensitive neurons using an agent that acts as a photosensitive switch. For the LMU researchers, the method primarily represents a valuable tool for probing the neurobiology of pain. (Nature Methods, 19.02.2012)

The system developed by the LMU team, led by Dirk Trauner, who is Professor of Chemical Biology and Genetics, is a chemical compound they call QAQ. The molecule is made up of two functional parts, each containing a quaternary ammonium, which are connected by a nitrogen double bond (N=N). This bridge forms the switch, as its conformation can be altered by light. Irradiation with light of a specific wavelength causes the molecule to flip from a bent to an extended form; exposure to light of a different color reverses the effect.

One half of QAQ closely resembles one of the active analogs of lidocaine, a well-known local anesthetic used by dentists. Lidocaine blocks the perception of pain by inhibiting the action of receptors found on specific nerve cells in the skin, which respond to painful stimuli and transmit signals to the spinal cord.

Neuroreceptors are proteins that span the outer membrane of nerve cells. They possess deformable pores that open in response to appropriate stimuli, and function as conduits that permit electrically charged ions to pass into or out of the cells. The ion channel targeted by the lidocaine-like end of QAQ responds to heat by allowing positively charged sodium ions to pass into the cells that express it. This alters the electrical potential across the membrane, which ultimately leads to transmission of the nerve impulse.

In their experiments, the researchers exploited the fact that QAQ can percolate through endogenous ion channels to get the molecule into nerve cells. This is a crucial step, because its site of action is located on the inner face of the targeted ion channel.

Furthermore, the lidocaine-like end of QAQ binds to this site only if the molecule is in an extended conformation. When the cells were irradiated with 380-nm light, which bends the bridge, signal transmission was reactivated within a matter of milliseconds. Exposure to light with a wavelength of 500 nm, on the other hand, reverts the molecule to the extended form and restores its inhibitory action. The analgesic effect of the switch was confirmed using an animal model.
Trauner’s team has been working for some considerable time on techniques with which biologically critical molecular machines such as neuroreceptors can be controlled in living animals by means of light impulses. The researchers themselves regard the new method primarily as a tool for neurobiological studies, particularly for pain research. Therapeutic applications of the principle are “a long way off”, says Timm Fehrentz, one of Dirk Trauner’s PhD students and one of the two equal first authors on the new paper. For one thing, the monochromatic light used to isomerize the QAQ molecule cannot penetrate human skin sufficiently to reach the pain-sensitive neurons. The researchers hope to address that problem by looking for alternatives to QAQ that respond to red light of longer wavelength, which more readily passes through the skin. (math/PH)

Source: Neuroscience News

February 21, 2012

There are a number of drugs and experimental conditions that can block cognitive function and impair learning and memory. However, scientists have recently shown that some drugs can actually improve cognitive function, which may have implications for our understanding of cognitive disorders such as Alzheimer’s disease. The new research is reported 21 February in the open-access journal PLoS Biology.

The study, led by Drs. Jose A. Esteban, Shira Knafo and Cesar Venero, is the result of collaboration between researchers from The Centro de Biología Molecular Severo Ochoa and UNED (Spain), the Brain Mind Institute (EPFL, Switzerland) and the Department of Neuroscience and Pharmacology (Faculty of Health Sciences, Denmark).

The human brain contains trillions of neuronal connections, called synapses, whose pattern of activity controls all our cognitive functions. These synaptic connections are dynamic and constantly changing in their strength and properties. This process, known as synaptic plasticity, has been proposed as the cellular basis for learning and memory. Indeed, alterations in synaptic plasticity mechanisms are thought to be responsible for multiple cognitive deficits, such as autism, Alzheimer’s disease and several forms of mental retardation.

The study by Knafo et al. provides new information on the molecular mechanisms of synaptic plasticity, and how this process may be manipulated to improve cognitive performance. They find that synapses can be made more plastic by using a small protein fragment (peptide) derived from a neuronal protein involved in cell-to-cell communication. This peptide (called FGL) initiates a cascade of events inside the neuron that results in the facilitation of synaptic plasticity. Specifically, the authors found that FGL triggers the insertion of new neurotransmitter receptors into synapses in a region of the brain called the hippocampus, which is known to be involved in multiple forms of learning and memory. Importantly, when this peptide was administered to rats, their ability to learn and retain spatial information was enhanced.

Dr. Esteban remarks: “We have known for three decades that synaptic connections are not fixed from birth, but they respond to neuronal activity modifying their strength. Thus, outside stimuli will lead to the potentiation of some synapses and the weakening of others. It is precisely this code of ups and downs what allows the brain to store information and form memories during learning”.

Within this framework, these new findings demonstrate that synaptic plasticity mechanisms mechanisms can be manipulated pharmacologically in adult animals, with the aim of enhancing cognitive ability. Dr. Knafo adds: “These are basic studies on the molecular and cellular processes that control our cognitive function. Nevertheless, they shed light into potential therapeutic avenues for mental disorders where these mechanisms go awry”.

Source: medicalxpress.com

ScienceDaily (Feb. 21, 2012) — The carnage evident in disasters like car wrecks or wartime battles is oftentimes mirrored within the bodies of the people involved. A severe wound can leave blood vessels and nerves severed, bones broken, and cellular wreckage strewn throughout the body — a debris field within the body itself.

Thriving DRG cells. (Credit: Image courtesy of University of Rochester Medical Center)

It’s scenes like this that neurosurgeon Jason Huang, M.D., confronts every day. Severe damage to nerves is one of the most challenging wounds to treat for Huang and colleagues. It’s a type of wound suffered by people who are the victims of gunshots or stabbings, by those who have been involved in car accidents — or by soldiers injured on the battlefield, like those whom Huang treated in Iraq.

Now, back in his university laboratory, Huang and his team have taken a step forward toward the goal of repairing nerves in such patients more effectively. In a paper published in the journal PLoS ONE, Huang and colleagues at the University of Rochester Medical Center report that a surprising set of cells may hold potential for nerve transplants.

In a study in rats, Huang’s group found that dorsal root ganglion neurons, or DRG cells, help create thick, healthy nerves, without provoking unwanted attention from the immune system.

The finding is one step toward better treatment for the more than 350,000 patients each year in the United States who have serious injuries to their peripheral nerves. Huang’s laboratory is one of a handful developing new technologies to treat such wounds.

"These are very serious injuries, and patients really suffer, many for a very long time," said Huang, associate professor of Neurosurgery and chief of Neurosurgery at Highland Hospital, an affiliate of the University of Rochester Medical Center. "There are a variety of options, but none of them is ideal.

"Our long-term goal is to grow living nerves in the laboratory, then transplant them into patients and cut down the amount of time it takes for those nerves to work," added Huang, whose project was funded by the National Institute of Neurological Disorders and Stroke and by the University of Rochester Medical Center.

For a damaged nerve to repair itself, the two disconnected but healthy portions of the nerve must somehow find each other through a maze of tissue and connect together. This happens naturally for a very small wound — much like our skin grows back over a small cut — but for some nerve injuries, the gap is simply too large, and the nerve won’t grow back without intervention.

For surgeons like Huang, the preferred option is to transplant nerve tissue from elsewhere in the patient’s own body — for instance, a section of a nerve in the leg — into the wounded area. The transplanted nerve serves as scaffolding, a guide of sorts for a new nerve to grow and bridge the gap. Since the tissue comes from the patient, the body accepts the new nerve and doesn’t attack it.

But for many patients, this treatment isn’t an option. They might have severe wounds to other parts of the body, so that extra nerve tissue isn’t available. Alternatives can include a nerve transplant from a cadaver or an animal, but those bring other challenges, such as the lifelong need for powerful immunosuppressant drugs, and are rarely used.

One technology used by Huang and other neurosurgeons is the NeuraGen Nerve Guide, a hollow, absorbable collagen tube through which nerve fibers can grow and find each other. The technology is often used to repair nerve damage over short distances less than half an inch long.

In the PLoS One study, Huang’s team compared several methods to try to bridge a nerve gap of about half an inch in rats. The team transplanted nerve cells from a different type of rat into the wound site and compared results when the NeuraGen technology was was used alone or when it was paired with DRG cells or with other cells known as Schwann cells.

After four months, the team found that the tubes equipped with either DRG or Schwann cells helped bring about healthier nerves. In addition, the DRG cells provoked less unwanted attention from the immune system than the Schwann cells, which attracted twice as many macrophages and more of the immune compound interferon gamma.

While both Schwann and DRG cells are known players in nerve regeneration, Schwann cells have been considered more often as potential partners in the nerve transplantation process, even though they pose considerable challenges because of the immune system’s response to them.

"The conventional wisdom has been that Schwann cells play a critical role in the regenerative process," said Huang, who is a scientist in the Center for Neural Development and Disease. "While we know this is true, we have shown that DRG cells can play an important role also. We think DRG cells could be a rich resource for nerve regeneration."

In a related line of research, Huang along with colleagues in the laboratory of Douglas H. Smith, M.D. , at the University of Pennsylvania are creating DRG cells in the laboratory by stretching them, which coaxes them to grow about one inch every three weeks. The idea is to grow nerves several inches long in the laboratory, then transplant them into the patient, instead of waiting months after surgery for the nerve endings to travel that distance within the patient to ultimately hook up.

Source: Science Daily

Article Date: 20 Feb 2012 - 2:00 PST

New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study published in Nature on February 19 (advance online publication). Led by researchers at the University of California, Santa Cruz, the study reveals details of how brain circuits are rewired during the formation of new motor memories.

The researchers studied mice as they learned new behaviors, such as reaching through a slot to get a seed. They observed changes in the motor cortex, the brain layer that controls muscle movements, during the learning process. Specifically, they followed the growth of new “dendritic spines,” structures that form the connections (synapses) between nerve cells.

“For the first time we are able to observe the spatial distribution of new synapses related to the encoding of memory,” said Yi Zuo, assistant professor of molecular, cell and developmental biology at UC Santa Cruz and corresponding author of the paper.

In a previous study, Zuo and others documented the rapid growth of new dendritic spines on pyramidal neurons in the motor cortex during the learning process. These spines form synapses where the pyramidal neurons receive input from other brain regions involved in motor memories and muscle movements. In the new study, first author Min Fu, a postdoctoral researcher in Zuo’s lab, analyzed the spatial distribution of the newly formed synapses.

Initial results of the spatial analysis showed that one third of the newly formed synapses were located next to another new synapse. These clustered synapses tended to form over the course of a few days during the learning period, when the mouse was repeatedly performing the new behavior. Compared to non-clustered counterparts, the clustered synapses were more likely to persist through the learning sessions and after training stopped.

In addition, the researchers found that after formation of the second spine in a cluster, the first spine grew larger. The size of the spine head correlates with the strength of the synapse. “We found that formation of a second connection is correlated with a strengthening of the first connection, which suggests that they are likely to be involved in the same circuitry,” Zuo said. “The clustering of synapses may serve to magnify the strength of the connections.”

Another part of the study also supported the idea that the clustered synapses are involved in neural circuits specific to the task being learned. The researchers studied mice trained first in one task and then in a different task. Instead of grabbing a seed, the mice had to learn how to handle a piece of capellini pasta. Both tasks induced the formation of clustered spines, but spines formed during the learning of different tasks did not cluster together.

The researchers also looked at mice that were challenged with new motor tasks every day, but did not repeat the same task over and over like the ones trained in seed-grabbing or capellini-handling. These mice also grew lots of new dendritic spines, but few of the new spines were clustered.

“Repetitive activation of the same cortical circuit is really important in learning a new task,” Zuo said. “But what is the optimal frequency of repetition? Ultimately, by studying the relationship between synapse formation and learning, we want to find out the best way to induce new memories.”

The study used mice that had been genetically altered to make a fluorescent protein within certain neurons in the motor cortex. The researchers used a special microscopy technique (two-photon microscopy) to obtain images of those neurons near the surface of the brain. The noninvasive imaging technique enabled them to view changes in individual brain cells of the mice before, during, and after learning a new behavior.  

Source: Medical News Today

ScienceDaily (Feb. 19, 2012) — New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study published in Nature on February 19 (advance online publication). Led by researchers at the University of California, Santa Cruz, the study reveals details of how brain circuits are rewired during the formation of new motor memories.

Rendering of neural network. New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study. (Credit: © nobeastsofierce / Fotolia)

The researchers studied mice as they learned new behaviors, such as reaching through a slot to get a seed. They observed changes in the motor cortex, the brain layer that controls muscle movements, during the learning process. Specifically, they followed the growth of new “dendritic spines,” structures that form the connections (synapses) between nerve cells.

"For the first time we are able to observe the spatial distribution of new synapses related to the encoding of memory," said Yi Zuo, assistant professor of molecular, cell and developmental biology at UC Santa Cruz and corresponding author of the paper.

In a previous study, Zuo and others documented the rapid growth of new dendritic spines on pyramidal neurons in the motor cortex during the learning process. These spines form synapses where the pyramidal neurons receive input from other brain regions involved in motor memories and muscle movements. In the new study, first author Min Fu, a postdoctoral researcher in Zuo’s lab, analyzed the spatial distribution of the newly formed synapses.

Initial results of the spatial analysis showed that one third of the newly formed synapses were located next to another new synapse. These clustered synapses tended to form over the course of a few days during the learning period, when the mouse was repeatedly performing the new behavior. Compared to non-clustered counterparts, the clustered synapses were more likely to persist through the learning sessions and after training stopped.

In addition, the researchers found that after formation of the second spine in a cluster, the first spine grew larger. The size of the spine head correlates with the strength of the synapse. “We found that formation of a second connection is correlated with a strengthening of the first connection, which suggests that they are likely to be involved in the same circuitry,” Zuo said. “The clustering of synapses may serve to magnify the strength of the connections.”

Another part of the study also supported the idea that the clustered synapses are involved in neural circuits specific to the task being learned. The researchers studied mice trained first in one task and then in a different task. Instead of grabbing a seed, the mice had to learn how to handle a piece of capellini pasta. Both tasks induced the formation of clustered spines, but spines formed during the learning of different tasks did not cluster together.

The researchers also looked at mice that were challenged with new motor tasks every day, but did not repeat the same task over and over like the ones trained in seed-grabbing or capellini-handling. These mice also grew lots of new dendritic spines, but few of the new spines were clustered.

"Repetitive activation of the same cortical circuit is really important in learning a new task," Zuo said. "But what is the optimal frequency of repetition? Ultimately, by studying the relationship between synapse formation and learning, we want to find out the best way to induce new memories."

The study used mice that had been genetically altered to make a fluorescent protein within certain neurons in the motor cortex. The researchers used a special microscopy technique (two-photon microscopy) to obtain images of those neurons near the surface of the brain. The noninvasive imaging technique enabled them to view changes in individual brain cells of the mice before, during, and after learning a new behavior.

Source: Science Daily

February 19, 2012 

In two landmark papers in the journal Nature this week, scientists at The Scripps Research Institute report that they have identified a class of proteins that detect “painful touch.”

Scientists have known that sensory nerves in our skin detect pressure, pain, heat, cold, and other stimuli using specialized “ion channel” proteins in their outer membranes. They have only just begun, however, to identify and characterize the specific proteins involved in each of these sensory pathways. The new work provides evidence that a family of sensory nerve proteins known as piezo proteins are ion channel proteins essential to the sensation of painful touch.

The experiments in the new study were conducted in fruit flies, a model system for the sensory nervous system of mammals, where piezo proteins are also expressed, as well as in certain cell types in the ear, kidney, heart, and other tissues. Future studies will focus on the roles of piezo proteins in sensing sound, blood pressure, and related stimuli that press and/or stretch cell membranes.

"Researchers in this field have been trying for decades to identify pressure-transducing ion channel proteins that exist in mammals, and these piezo proteins are exceptionally strong candidates," said Ardem Patapoutian, a professor in the Department of Cell Biology and the Dorris Neuroscience Center at Scripps Research, and a senior investigator for both papers. "We now have solid clues that we can follow up to learn how the mechanotransduction pathway works and how it is disrupted in diseases."

The two papers appear online in Nature on February 19, 2012.

Following the Path of Clues

Patapoutian’s laboratory specializes in the study of sensory ion-channel proteins. When hit by a stimulus to which it is sensitive, one of these proteins typically will open its structure to allow charged calcium, sodium, or potassium molecules (“ions”) to flow from the fluid outside the cell into the cell’s interior. Ion channels that sense mechanical pressure are thought to open when the membrane in which they are embedded is distorted past a certain threshold. The resulting flow of charge can trigger other signals inside the cell, for example a nerve impulse within sensory neurons—and in a human, a sufficient number of these nerve impulses would be interpreted by the brain as a touch- or pressure-related feeling.

 In a highly cited paper published in Science in late 2010, Patapoutian and his colleagues reported that two mouse proteins of previously unknown function exhibited properties of mechanotransducers. Cells to which these proteins were added drew in positively charged ions when subjected to mechanical pressure. Bertrand Coste, the first author of the paper, named the two closely related proteins piezo1 and piezo2—the prefix “piezo-” being derived from the ancient Greek word for pressure or squeezing.

"Since these proteins bore little resemblance to known ion channel proteins, the next step for us was to confirm that they are indeed ion channel proteins," Patapoutian said. The new studies take this step and more.

In the first of the new studies, lead authors Bertrand Coste, Bailong Xiao, and their colleagues confirmed that piezo proteins are indeed ion channel proteins, and very large ones. “It assembles into a ‘tetramer’ complex of four piezo proteins, which appears to be the biggest plasma membrane ion channel yet discovered,” said Coste, a research associate in the Patapoutian lab. The protein sequences within piezo also suggest that its ion channel structure weaves through the cell membrane more than 100 times.

Collaborating researchers in the laboratory of Mauricio Montal, a Distinguished Professor of Neurobiology at the University of California, San Diego, found that even in the absence of other proteins, piezo proteins could self-assemble into this tetramer complex, forming ion channels in artificial membranes known as lipid bilayers.

The second of the new studies involved experiments with the fruit fly Drosophila. Sung Eun Kim, first author of the study, genetically engineered a line of Drosophila that does not express the Drosophila piezo (dpiezo) gene. “We found that their larvae showed a severe loss of responsiveness to mechanical stimuli that would be expected to generate pain-related signals, though they responded normally to other kinds of stimuli such as heat and mild pressure,” she said. Kim is a graduate student who divides her time between the Patapoutian lab and the lab of Scripps Research Assistant Professor Boaz Cook, who was co-principal investigator of this study.

Kim also used genetic “knockdown” techniques in Drosophila to show that interrupting dpiezo expression in certain sensory neurons could reproduce this loss of sensitivity. Finally, when she artificially reinstated dpiezo expression in larvae that had been born without the gene, they displayed normal sensitivity to strong pressure. “It’s the first demonstration of a specific physiological function of a piezo family protein,” said Cook.

The Patapoutian lab now is now conducting detailed follow-up studies of piezo and other possible mechanotransduction proteins. “In the next several years, we’ll be trying to determine all the biological processes and diseases in which these pressure-sensing proteins play a role,” he said.

More information: “Piezos Are Pore-Forming Subunits of Mechanically Activated Channels,” Nature (2012).

Provided by The Scripps Research Institute

Source: medicalxpress.com

February 16, 2012

(Medical Xpress) — Gene therapy not only helps injured brain cells to live longer and regenerate, but also changes the shape of the cells, according to researchers The University of Western Australia. 

The study, published in the international science and medicine journal PLoS One, was led by Winthrop Professor Alan Harvey from UWA’s School of Anatomy, Physiology and Human Biology, and Associate Professor Jennifer Rodger, NHMRC Research Fellow in Experimental and Regenerative Neurosciences at UWA’s School of Animal Biology.  The research was funded primarily by the WA Neurotrauma Research Program.

Professor Harvey said gene therapy was a relatively new strategy that attempted to help injured brain cells survive and regrow.

"Our previous work has shown that when growth-promoting genes are introduced into injured brain cells for long periods of time (up to nine months), the cells’ capacity for survival and regeneration is significantly increased," he said.

"We have now shown that these same neurons have also changed shape in response to persistent over-expression of the growth factors.  Importantly, it is not just neurons containing the introduced growth-promoting gene that are affected, but neighbouring "bystander" neurons."

Professor Harvey said neural morphology was very important in determining how a cell communicated with other cells and formed the circuits that allowed the brain to function.

"Any changes in morphology are therefore likely to alter the way neurons receive and transmit information.  These changes may be beneficial but could also interfere with normal brain circuits, reducing the benefits of improved survival and regeneration."

Professor Harvey said the results were significant for those involved in designing gene therapy-based protocols to treat brain and spinal cord injury and degeneration.

"These new results suggest that we may need to be careful about the types of genes we use in neurotherapy and how long we continue the therapy.  While it may be beneficial for these genes to move around and cause changes in other cells, we need to be able to switch them off once the change has taken place."

Provided by University of Western Australia

Source: medicalxpress.com

February 16th, 2012

Researchers have created a living 3-D model of a brain tumor and its surrounding blood vessels. In experiments, the scientists report that iron-oxide nanoparticles carrying the agent tumstatin were taken by blood vessels, meaning they should block blood vessel growth. The living-tissue model could be used to test the effectiveness of nanoparticles in fighting other diseases. Results appear in Theranostics.

Brown University scientists have created the first three-dimensional living tissue model, complete with surrounding blood vessels, to analyze the effectiveness of therapeutics to combat brain tumors. The 3-D model gives medical researchers more and better information than Petri dish tissue cultures.

The researchers created a glioma, or brain tumor, and the network of blood vessels that surrounds it. In a series of experiments, the team showed that iron-oxide nanoparticles ferrying the chemical tumstatin penetrated the blood vessels that sustain the tumor with oxygen and nutrients. The iron-oxide nanoparticles are important, because they are readily taken up by endothelial cells and can be tracked by magnetic resonance imaging.

Previous experiments have shown that tumstatin was effective at blocking endothelial cell growth in gliomas. The tests by the Brown researchers took it to another level by confirming, in a 3-D, living environment, the iron-oxide nanoparticles’ ability to reach blood vessels surrounding a glioma as well as tumstatin’s ability to penetrate endothelial cells.

“The 3-D glioma model that we have developed offers a facile process to test diffusion and penetration into a glioma that is covered by a blood vessel-like coating of endothelial cells,” said Don Ho, a graduate student in the lab of chemistry professor Shouheng Sun and the lead author of the paper in the journal Theranostics. “This assay would save time and money, while reducing tests in living organisms, to examine an agent’s 3-D characteristics such as the ability for targeting and diffusion.”

The tissue model concept comes from Jeffrey Morgan, a bioengineer at Brown and a corresponding author on the paper. Building on that work, Ho and others created an agarose hydrogel mold in which rat RG2-cell gliomas roughly 200 microns in diameter formed. The team used endothelial cells derived from cow respiratory vessels, which congregated around the tumor and created the blood vessel architecture. The advantage of a 3-D model rather than Petri-dish-type analyses is that the endothelial cells attach to the tumor, rather than being separated from the substrate. This means the researchers can study their formation and growth, as well as the action of anti-therapeutic agents, just as they would in a living organism.

“You want to see nanoparticles that diffuse through the endothelial cells, which is lost in 2-D because you just have diffusion into media,” Ho said.

Other 3-D tissue models have been “forced cell arrangements,” Ho said. The 3-D glioma model, in contrast, allowed the glioma and the endothelial cells to assemble naturally, just as they would in real life. “It more clearly mimics what would actually happen,” Ho explained.

The group then attached tumstatin, part of a naturally occurring protein found in collagen, to iron-oxide nanoparticles and dosed the mold. True to form, the nanoparticles were gobbled up by the endothelial cells. In a series of in vitro experiments, the team reported the tumstatin iron-oxide nanoparticles decreased vasculature growth 2.7 times more than under normal conditions over eight days. “The growth is pretty much flat,” Ho said. “There’s no new growth of endothelial cells.” The next step is to test the tumstatin nanoparticles’ performance in the 3-D environment.

“This model has significant potential to help in the testing and optimization of the design of therapeutic/diagnostic nanocarriers and determine their therapeutic capabilities,” the researchers write.

Source: Neuroscience News

February 16th, 2012

A team of scientists from The Scripps Research Institute, collaborating with members of the drug discovery company Receptos, has created the first high-resolution virtual image of cellular structures called S1P1 receptors, which are critical in controlling the onset and progression of multiple sclerosis and other diseases.

This new molecular map is already pointing researchers toward promising new paths for drug discovery and aiding them in better understanding how certain existing drugs work.

Source: Neuroscience News

Article Date: 16 Feb 2012 - 1:00 PST

Scientists at Emory University School of Medicine have identified a new group of compounds that may protect brain cells from inflammation linked to seizures and neurodegenerative diseases.

The compounds block signals from EP2, one of the four receptors for prostaglandin E2, which is a hormone involved in processes such as fever, childbirth, digestion and blood pressure regulation. Chemicals that could selectively block EP2 were not previously available. In animals, the EP2 blockers could markedly reduce the injury to the brain induced after a prolonged seizure, the researchers showed.

The results were published online this week in the Proceedings of the National Academy of Sciences Early Edition.

“EP2 is involved in many disease processes where inflammation is showing up in the nervous system, such as epilepsy, stroke and neurodegenerative diseases,” says senior author Ray Dingledine, PhD, chairman of Emory’s Department of Pharmacology. “Anywhere that inflammation is playing a role via EP2, this class of compounds could be useful. Outside the brain, EP2 blockers could find uses in other diseases with a prominent inflammatory component such as cancer and inflammatory bowel disease.”

Prostaglandins are the targets for non-steroid anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen. NSAIDSs inhibit enzymes known as cyclooxygenases, the starting point for generating prostaglandins in the body. Previous research indicates that drugs that inhibit cyclooxygenases can have harmful side effects. For example, sustained use of aspirin can weaken the stomach lining, coming from prostaglandins’ role in the stomach. Even drugs designed to inhibit only cyclooxygenases involved in pain and inflammation, such as Vioxx, have displayed cardiovascular side effects.

Dingledine’s team’s strategy was to bypass cyclooxygenase enzymes and go downstream, focusing on one set of molecules that relay signals from prostaglandins. Working with Yuhong Du in the Emory Chemical Biology Discovery Center, postdoctoral fellows Jianxiong Jiang, Thota Ganesh and colleagues sorted through a library of 262,000 compounds to find those that could block signals from the EP2 prostaglandin receptor but not related receptors. One of the compounds could prevent damage to neurons in mice after “status epilepticus,” a prolonged drug-induced seizure used to model the neurodegeneration linked to epilepsy. The team found that a family of related compounds had similar protective effects.

Dingledine says that the compounds could become valuable tools for exploring new ways to treat neurological diseases. However, given the many physiological processes prostaglandins regulate, more tests are needed, he says. Prostaglandin E2 is itself a drug used to induce labor in pregnant women, and female mice engineered to lack the EP2 receptor are infertile, so the compounds would need to be tested for effects on reproductive organs, for example.

View drug information on Vioxx.

Source: Medical News Today

ScienceDaily (Feb. 15, 2012) — Brain scans of two strains of mice imbibing significant quantities of alcohol reveal serious shrinkage in some brain regions — but only in mice lacking a particular type of receptor for dopamine, the brain’s “reward” chemical. The study, conducted at the U.S. Department of Energy’s Brookhaven National Laboratory and published in the May 2012 issue of Alcoholism: Clinical and Experimental Research, now online, provides new evidence that these dopamine receptors, known as DRD2, may play a protective role against alcohol-induced brain damage.

"This study clearly demonstrates the interplay of genetic and environmental factors in determining the damaging effects of alcohol on the brain, and builds upon our previous findings suggesting a protective role of dopamine D2 receptors against alcohol’s addictive effects," said study author Foteini Delis, a neuroanatomist with the Behavioral Neuropharmacology and Neuroimaging Lab at Brookhaven, which is funded through the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Coauthor and Brookhaven/NIAA neuroscientist Peter Thanos stated that, "These studies should help us better understand the role of genetic variability in alcoholism and alcohol-induced brain damage in people, and point the way to more effective prevention and treatment strategies."

The current study specifically explored how alcohol consumption affects brain volume — overall and region-by-region — in normal mice and a strain of mice that lack the gene for dopamine D2 receptors. Half of each group drank plain water while the other half drank a 20 percent ethanol solution for six months. Then scientists performed magnetic resonance imaging (MRI) scans on all the mice and compared the scans of those drinking alcohol with those from the water drinkers in each group.

The scans showed that chronic alcohol drinking induced significant overall brain atrophy and specific shrinkage of the cerebral cortex and thalamus in the mice that lacked dopamine D2 receptors, but not in mice with normal receptor levels. Mice in both groups drank the same amount of alcohol.

"This pattern of brain damage mimics a unique aspect of brain pathology observed in human alcoholics, so this research extends the validity of using these mice as a model for studying human alcoholism," Thanos said.

In humans, these brain regions are critically important for processing speech, sensory information, and motor signals, and for forming long-term memories. So this research helps explain why alcohol damage can be so widespread and detrimental.

"The fact that only mice that lacked dopamine D2 receptors experienced brain damage in this study suggests that DRD2 may be protective against brain atrophy from chronic alcohol exposure," Thanos said. "Conversely, the findings imply that lower-than-normal levels of DRD2 may make individuals more vulnerable to the damaging effects of alcohol."

That would in effect deal people with low DRD2 levels a double whammy of alcohol vulnerability: Previous studies conducted by Thanos and collaborators suggest that individuals with low DRD2 levels may be more susceptible to alcohol’s addictive effects.

"The increased addictive liability and the potentially devastating increased susceptibility to alcohol toxicity resulting from low DRD2 levels make it clear that the dopamine system is an important target for further research in the search for better understanding and treatment of alcoholism," Thanos said.

Source: Science Daily

ScienceDaily (Feb. 14, 2012) — Curcumin, a substance extracted from turmeric, prolongs life and enhances activity of fruit flies with a nervous disorder similar to Alzheimers, according to new research. The study conducted at Linköping University, indicates that it is the initial stages of fibril formation and fragments of the amyloid fibrils that are most toxic to neurons.

Above left are the survival curves for “Alzheimer flies” treated (dashed line) and those not treated with curcumin. The flies that were administered curcumin lived longer and were more active. The scientists identified an accelerated formation of amyloid plaque in the treated flies, which seemed to protect the nerve cells. On the right we see microscopic images of neurons (blue) and plaque (green) in the fruit fly’s brain. The study strengthens the hypothesis that a curcumin-based drug can contribute to toxic fibrils being encapsulated (bottom left of the figure). (Credit: Per Hammarström, Ina Caesar)

Ina Caesar, as the lead author, has published the results of the study in the journal PLoS ONE.

For several years curcumin has been studied as a possible drug candidate to combat Alzheimer’s disease, which is characterized by the accumulation of sticky amyloid-beta and Tau protein fibres. Linköping researchers wanted to investigate how the substance affected transgenic fruit flies (Drosophila melanogaster), which developed evident Alzheimer’s symptoms. The fruit fly is increasingly used as a model for neurodegenerative diseases.

Five groups of diseased flies with different genetic manipulations were administered curcumin. They lived up to 75 % longer and maintained their mobility longer than the sick flies that did not receive the substance.

However, the scientists saw no decrease of amyloid in the brain or eyes. Curcumin did not dissolve the amyloid plaque; on the contrary it accelerated the formation of fibres by reducing the amount of their precursor forms, known as oligomers.

"The results confirm our belief that it is the oligomers that are most harmful to the nerve cells," says Professor Per Hammarstrom, who led the study.

"We now see that small molecules in an animal model can influence the amyloid form. To our knowledge the encapsulation of oligomers is a new and exciting treatment strategy," he said.

Several theories have been established about how oligomers can instigate the disease process. According to one hypothesis, they become trapped at synapses, inhibiting nerve impulse signals. Others claim that they cause cell death by puncturing the cell membrane.

Curcumin is extracted from the root of herbaceous plant turmeric and has been used as medicine for thousands of years. More recently, it has been tested against pain, thrombosis and cancer.

Source: Science Daily

February 14th, 2012

Humans move between ‘patches’ in their memory using the same strategy as bees flitting between flowers for pollen or birds searching among bushes for berries.

Researchers at the University of Warwick and Indiana University have identified parallels between animals looking for food in the wild and humans searching for items within their memory – suggesting that people with the best ‘memory foraging’ strategies are better at recalling items.

Scientists asked people to name as many animals as they could in three minutes and then compared the results with a classic model of optimal foraging in the real world, the marginal value theorem, which predicts how long animals will stay in one patch before jumping to another.

Dr Thomas Hills, associate professor in the psychology department at the University of Warwick, said: “A bird’s food tends to be clumped together in a specific patch – for example on a bush laden with berries.

“But when the berries on a bush are depleted to the point where the bird’s energy is best focused on another more fruitful bush, it will move on.

“This kind of behaviour is predicted by the marginal value theorem, for a wide variety of animals.

“Because of the way human attention has evolved, we wondered if humans might use the same strategies to forage in memory. It turns out, they do.

“When faced with a memory task, we focus on specific clusters of information and jump between them like a bird between bushes. For example, when hunting for animals in memory, most people start with a patch of household pets—like dog, cat and hamster.

“But then as this patch becomes depleted, they look elsewhere. They might then alight on another semantically distinct ‘patch’, for example predatory animals such as lion, tiger and jaguar.”

The study shows that people who either stay too long or not long enough in one ‘patch’ did not recall as many animals as those who better judged the best time to switch between patches.

In other words, people who most closely adhered to the marginal value theorem produced more items.

The study Optimal Foraging in Semantic Memory, published in Psychological Review, asked 141 undergraduates (46 men and 95 women) at Indiana University to name as many animals as they could in three minutes.

They then analysed the responses using a categorisation scheme and also a semantic space model, called BEAGLE, which identifies clusters in the memory landscape based on the way words are related to one another in natural language.

Source: Neuroscience News 

February 14, 2012 

(Medical Xpress) — A UT Dallas undergraduate’s research is revealing new information about a key protein’s role in the development of epilepsy, autism and other neurological disorders. This work could one day lead to new treatments for the conditions.

Senior neuroscience student Francisco Garcia has worked closely with Dr. Marco Atzori, associate professor in the School of Behavioral and Brain Sciences (BBS), on several papers that outline their findings about interleukin 6 (IL-6) and hyper-excitability. An article on the project is slated for publication in Biological Psychiatry later this year.

Scientists know that stress elevates the levels of pro-inflammatory cytokines (signaling molecules used in intercellular communication) and promotes hyper-excitable conditions within the central nervous system. This hyper-excitability is thought to be a factor in epilepsy, autism and anxiety disorders.

Garcia and Atzori hypothesized that the protein IL-6 acutely and directly induces hyper-excitability by altering the balance between excitation and inhibition within synaptic communication. In other words, IL-6 is not just present when hyper-excitability occurs in the nervous system. It may actually cause it in some circumstances, Garcia said.

The UT Dallas research team administered IL-6 to rat brain tissue and monitored its synaptic excitability. The brain tissue exhibited higher than normal excitability in their synapses, a symptom that may lead to misfiring of signals in epilepsy and other conditions.

The researchers then injected sgp130 -a novel drug that acts as an IL-6 blocker- into the laboratory animals’ brains. The substance limited excitability and appeared to prevent the conditions that lead to related neurological and psychiatric disorders, Garcia said.

“This finding has the potential to lead to eventual new treatments for epilepsy, anxiety disorders or autism,” Garcia said.

The next stage of his research will involve looking at how IL-6 might affect development of other types of neurological problems. Human trials could follow sometime in the future.

Garcia is a native of Mexico, and he plans to pursue his master’s degree in neuroscience at UT Dallas after finishing his undergraduate studies. He credits the BBS faculty with allowing him to participate in laboratory experiments and expand his research skills.

“The UT Dallas faculty members have been great about giving me the opportunity to learn the techniques of a lab researcher,” he said. “It’s been a great experience to work as an undergraduate with such highly respected scientists as Dr. Atzori and Dr. Michael Kilgard.”

Atzori also praised Garcia’s efforts.

“Francisco has been an intelligent, hard-working and experimentally gifted student who contributed way more than the average undergraduate to the projects of the laboratory,” Atzori said. “I am proud that a fine piece of research with great potential for research and clinical applications has been carried out thanks to his enthusiasm and dedication. Francisco’s work in my laboratory is an example of the achievements possible when an institution like UT Dallas invests in and nurtures its research environment.”

Provided by University of Texas at Dallas

Source: medicalxpress.com

February 14, 2012 in Neuroscience

The amount and quality of sleep you get at night may affect your memory later in life, according to research that was released today and will be presented at the American Academy of Neurology’s 64th Annual Meeting in New Orleans April 21 to April 28, 2012.

"Disrupted sleep appears to be associated with the build-up of amyloid plaques, a hallmark marker of Alzheimer’s disease, in the brains of people without memory problems," said study author Yo-El Ju, MD, with Washington University School of Medicine in St. Louis and a member of the American Academy of Neurology. "Further research is needed to determine why this is happening and whether sleep changes may predict cognitive decline."

Researchers tested the sleep patterns of 100 people between the ages of 45 and 80 who were free of dementia. Half of the group had a family history of Alzheimer’s disease. A device was placed on the participants for two weeks to measure sleep. Sleep diaries and questionnaires were also analyzed by researchers.

After the study, it was discovered that 25 percent of the participants had evidence of amyloid plaques, which can appear years before the symptoms of Alzheimer’s disease begin. The average time a person spent in bed during the study was about eight hours, but the average sleep time was 6.5 hours due to short awakenings in the night.

The study found that people who woke up more than five times per hour were more likely to have amyloid plaque build-up compared to people who didn’t wake up as much. The study also found those people who slept “less efficiently” were more likely to have the markers of early stage Alzheimer’s disease than those who slept more efficiently. In other words, those who spent less than 85 percent of their time in bed actually sleeping were more likely to have the markers than those who spent more than 85 percent of their time in bed actually sleeping.

"The association between disrupted sleep and amyloid plaques is intriguing, but the information from this study can’t determine a cause-effect relationship or the direction of this relationship. We need longer-term studies, following individuals’ sleep over years, to determine whether disrupted sleep leads to amyloid plaques, or whether brain changes in early Alzheimer’s disease lead to changes in sleep," Ju said. "Our study lays the groundwork for investigating whether manipulating sleep is a possible strategy in the prevention or slowing of Alzheimer disease."

Provided by American Academy of Neurology

Source: medicalxpress.com

February 14, 2012 by Bob Yirka in Neuroscience

(Medical Xpress) — A small team of researchers has found that various forms of child abuse can lead to stunted development in certain regions of the brain. The research carried out by Martin Teicher, Carl Anderson and Ann Polcari, all working in the Boston area, relied on questionnaires and MRI brain scans to determine that certain parts of the hippocampus, all known to be sensitive to stress, were up to six percent smaller in adults who as children had been sexually, verbally or physically abused. The team has published their results in the Proceedings of the National Academy of Sciences.

The three areas affected: the cornu ammonis, the dentate gyrus and the subiculum, all located in the hippocampus, are known to be vulnerable to stress which leads to less cell development than would normally occur in the absence of abuse.

To test the relationship between brain development and childhood abuse, the research team enlisted a group of otherwise healthy adult volunteers: 73 men and 120 women, all between the ages of 18 and 25. All were given questionnaires that delved into their childhood, specifically addressing issues of verbal, mental and physical abuse and other types of stresses such as the death of someone close to them or problems between parents. All were also given brain scans using an MRI machine. The team then compared the answers given on the questionnaires to the possibly impacted areas in the hippocampus of each volunteer. In so doing, they found that the brain regions under study were 5.8 to 6.5 percent smaller than average for those that reported such childhood stresses.

The researchers suggest that smaller brain regions due to childhood stressmay help explain the abnormally high levels of mental illness (depression, bi-polarism, anxiety, etc.) seen in adults who have endured abuse as children and why so many wind up with drug dependency problems. They also noted that one of the regions impacted, the subiculum, serves as a relay, moving information in and out of the hippocampus, which can have a direct impact on dopamine production. Those with reduced volume have been found to have problems with drug addiction and in some cases develop schizophrenia.

The researchers believe that increased stress leads to higher levels of the hormone cortisol, which in turn can slow or even stop the growth of new neurons in the brain which can result in permanently stunting certain brain regions.

The researchers are hoping their results will further highlight the damage that is done when children are subjected to adverse living conditions, leading perhaps to earlier interventions and possibly a means for developing treatments that may aid in preventing the stunting of brain regions, thus helping to pave the way for a better quality of life for those that have been abused as children.

Source: medicalxpress.com

Article Date: 14 Feb 2012 - 1:00 PST

A distinctive pattern of brain activity associated with conditions including deep anesthesia, coma and congenital brain disorders appears to represent the brain’s shift into a protective, low-activity state in response to reduced metabolic energy. A mathematical model developed by a Massachusetts General Hospital (MGH)-based research team accurately predicts and explains for the first time how the condition called burst suppression is elicited when brain cells’ energy supply becomes insufficient. Their report has been released online in PNAS Early Edition.

“The seemingly unrelated brain states that lead to burst suppression - deep anesthesia, coma, hypothermia and some developmental brain disorders - all represent a depressed metabolic state,” says Emery Brown, MD, PhD, of the MGH Department of Anesthesia, Critical Care and Pain Medicine, senior author of the report. “We believe we have identified something fundamental about brain neurochemistry, neuroanatomy and neurophysiology that may help us plan better therapies for brain protection and design future anesthetics.”

Burst suppression is an electroencephalogram (EEG) pattern in which periods of normal, high brain activity - the bursts - are interrupted by stretches of greatly reduced activity that can last 10 seconds or longer. Burst suppression has been observed in deep general anesthesia, in induced hypothermia - used to protect the brain or other structures from damage caused by trauma or reduced blood flow - in coma, and in infants with serious neurodevelopmental disorders. It also has transiently been observed in some premature infants. Previous investigations of burst suppression focused on characterizing the structure of the EEG patterns and understanding the brain’s responsiveness to external stimuli while in this state, not on the underlying mechanism.

Lead author ShiNung Ching, PhD, a postdoctoral fellow in Brown’s lab, had been working with Nancy Kopell, PhD, a professor of Mathematics at Boston University and co-author of the PNAS article, to develop mathematical models of different brain states under general anesthesia. In developing a model for burst suppression, they focused on what the associated conditions have in common - a significant reduction in the brain’s metabolic state. In order for a signal to pass from one nerve cell to another, the balance between sodium ions outside the cell and potassium ions within the cell needs to be correct. Maintaining that balance requires that structures called ion pumps, fueled by the cellular energy molecule ATP, function correctly. The model developed by Ching and his colleagues revealed that, when brain energy supplies drop too low and cause a deficiency in ATP, potassium leaks from the nerve cells and signal transmission halts.

“It looks like burst suppression shifts the brain into an altered physiologic state to allow for the regeneration of ATP, which is the essential metabolic substrate,” Ching explains. “During suppression, the brain is trying to recover enough ATP to restart. If the substrate doesn’t regenerate quickly enough, the system will have these brief bursts of activity, stop and then need to recover again. The length of suppression is governed by how quickly ATP regenerates, which matches the observation that the deeper someone is anesthetized, the longer the periods of suppression.”

Brown adds, “When we use general anesthesia to place patients with serious neurologic injuries into induced comas to allow their brains to heal, we take them down to a level of burst suppression. But there are a lot of questions regarding how deeply anesthetized an individual patient should be - how often the bursts should occur - and how long we should maintain that state. By elucidating what appears to be a fundamental energy-preserving mechanism within the brain, this model may help us think about using burst suppression to guide induced coma and track recovery from brain injuries. This is also a great example of how studying anesthesia can help us learn something very basic about the brain.”  

Source: Medical News Today

ScienceDaily (Feb. 13, 2012) — Only by employing complex machine-learning techniques to decipher repeated advanced brain scans were researchers at NewYork-Presbyterian/Weill Cornell able to provide evidence that a patient with a severe brain injury could, in her way, communicate accurately.

Their study, published in the Feb. 13 issue of the Archives of Neurology, demonstrates how difficult it is to determine whether a patient can communicate using only measured brain activity, even if it is possible for them to generate reliable patterns of brain activation in response to instructed commands. Patients in a minimally conscious state or who have locked-in syndrome (normal cognitive function with severe motor impairment) and can follow commands in the absence of a motor response may not generate clearly interpretable communications using the same patterns of brain activity, the researchers say.

While less sophisticated methods have been shown successful, the authors say their new approach provides important new insights into brain function and level of consciousness. It also identifies mechanisms of variation in brain activity supporting cognitive function after injury.

"In these studies we have reanalyzed earlier published data that demonstrated an effort to communicate using brain activations alone that apparently failed but was nonetheless a clear effort to generate a response," says Dr. Nicholas D. Schiff, professor of neurology and neuroscience and professor of public health at Weill Cornel Medical College, and a neurologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "Importantly, the reanalysis with new, more sensitive methods provides evidence that the problem with communication may reflect a mismatch of our expectations in designing the assessment, rather than a failure on the subject’s part in an attempt to accurately communicate with us."

"Our study shows that multivariate, machine-learning methods can be useful in determining whether patients are attempting to communicate, specifically when applied to data that already show evidence of a signal in univariate, more standard methods of analysis," says the study’s lead author, Jonathan Bardin, a fourth-year neuroscience graduate student at Weill Cornell Medical College.

"It is our clinical and ethical imperative to learn as much as possible about their ability to communicate," he says. "A simple bedside exam is not good enough."

"We need a set of methods that are both powerful and simple, and we are not there yet, as this study shows," adds Dr. Schiff. "We are using quite complex tasks to perhaps detect just the few of many patients who are conscious."

Patients Differ in Abilities

This study is a continuation of NewYork-Presbyterian/Weill Cornell research into how fMRI can establish a line of communication with brain-injured patients in order to understand if they can benefit from rehabilitation, and to gauge their level of pain and other clinical parameters that would improve care and quality of life.

It specifically follows up on a study published in the journal Brain last February that demonstrated use of fMRI to detect consciousness in six patients (either locked-in or minimally conscious) resulted in a wide, and largely unpredictable, variation in the ability of patients to respond to a simple command (such as “imagine swimming — now stop”) and then using the same command to answer simple yes/no or multiple-choice questions. This variation was apparent when compared with their ability to interact at the bedside using gestures or voice.

Some patients unable to communicate by gestures or voice were unable to do the mental tests, while others unable to communicate by gestures or voice were intermittently able to answer the researchers’ questions using mental imagery. And, intriguingly, some patients with the ability to communicate through gestures or voice were unable to do the mental tasks.

The researchers say these findings suggest that no exam yet exists at this time that can accurately assess the higher-level functioning that may be, and certainly seems to be, occurring in a number of severely brain-injured patients.

"There are people whose personal autonomy is abridged because they don’t have a good motor channel to express themselves despite, in some cases, having a clear mind and opinions and desires about themselves and the world," Dr. Schiff says about those results.

"Not all minimally conscious patients are the same, and not all patients with locked-in syndrome are the same," he says.

Sensitive and Flexible Methods Are Needed

This main new result of this study is a reinterpretation of findings from a 25-year-old patient who was the only one of six who showed an ability to use the fMRI signal for communication in the earlier research. But her results were confusing because it seemed that she was consistently responding to the answer that was directly after the correct answer, Bardin says.

"It’s often seen in patients like this — she had a stroke that damaged her brain — that there can be a cognitive delay in some area of the brain. FMRI is a readout of blood flow instead of actual neural activity, so these delays could be caused by an interruption of blood flow due to damage or could just mean they are working on the problem more slowly, and the answer looks wrong because it is given in the next response period."

To understand this, Bardin employed a newer technique, which he says has sprung out of machine-learning research, to instruct a computer to evaluate multiple fMRI scans from the patient after she answered the two questions a number of times.

This so-called multivariate approach used the same data gathered for the first study, which, in the typical “univariate” analysis, specifically looks at functioning in the brain’s Supplementary Motor Area (SMA), which is active when “normal” subjects imagine doing something.

In contrast, the multivariate analysis examines whether there is a pattern of activity in any part of the brain that is consistent from one scan to the next.

"When there is significant damage to the brain, it can rewire itself so that functions associated with SMA could be processed somewhere else," Bardin says.

Using this complex approach, the researchers found that, indeed, the patient had consistently attempted to communicate answers to both questions — but at a delayed speed.

The researchers say that one approach to analyze fMRI scans is not better than the other for all patients and that univariate methods should always be carried out first. Multivariate approaches can be especially sensitive to noise, leading to false positives if used on their own. If the standard approach reveals a signal, the multivariate approach could be used to gain further insights and possibly identify response in patients where the univariate results are ambiguous.

"We did all these things to simply show that we think this patient was trying to communicate," Bardin says. "You have to be very careful in your data analysis before saying anything strongly about what a patient can or cannot do."

"Rigid experimental paradigms like those used in the field can very well miss important information about these patients," Dr. Schiff says. "This is all extremely complex and messy, but we should expect that. Given the injuries some of our patients suffer, their cognitive abilities are very difficult to detect behaviorally or through simplistic tests or scans."

Source: Science Daily

February 13, 2012 

For some, the pain is so great that they can’t even bear to have clothes touch their skin. For others, it means that every step is a deliberate and agonizing choice. Whether the pain is caused by arthritic joints, an injury to a nerve or a disease like fibromyalgia, research now suggests there are new solutions for those who suffer from chronic pain.

A team of researchers led by McGill neuroscientist Terence Coderre, who is also affiliated with the Research Institute of the McGill University Health Centre, has found the key to understanding how memories of pain are stored in the brain. More importantly, the researchers are also able to suggest how these memories can be erased, making it possible to ease chronic pain.

It has long been known that the central nervous system “remembers” painful experiences, that they leave a memory trace of pain. And when there is new sensory input, the pain memory trace in the brain magnifies the feeling so that even a gentle touch can be excruciating.

"Perhaps the best example of a pain memory trace is found with phantom limb pain," suggests Coderre. "Patients may have a limb amputated because of gangrene, and because the limb was painful before it was amputated, even though the limb is gone, the patients continue to feel they are suffering from pain in the absent limb. That’s because the brain remembers the pain. In fact, there’s evidence that any pain that lasts more than a few minutes will leave a trace in the nervous system." It’s this memory of pain, which exists at the neuronal level, that is critical to the development of chronic pain. But until now, it was not known how these pain memories were stored at the level of the neurons.

Recent work has shown that the protein kinase PKMzeta plays a crucial role in building and maintaining memory by strengthening the connections between neurons. Now Coderre and his colleagues have discovered that PKMzeta is also the key to understanding how the memory of pain is stored in the neurons. They were able to show that after painful stimulation, the level of PKMzeta increases persistently in the central nervous system (CNS).

Even more importantly, the researchers found that by blocking the activity of PKMzeta at the neuronal level, they could reverse the hypersensitivity to pain that neurons developed after irritating the skin by applying capsaicin – the active ingredient in hot peppers. Moreover, erasing this pain memory trace was found to reduce both persistent pain and heightened sensitivity to touch.

Coderre and his colleagues believe that building on this study to devise ways to target PKMzeta in pain pathways could have a significant effect for patients with chronic pain. “Many pain medications target pain at the peripheral level, by reducing inflammation, or by activating analgesia systems in the brain to reduce the feeling of pain,” says Coderre. “This is the first time that we can foresee medications that will target an established pain memory trace as a way of reducing pain hypersensitivity. We believe it’s an avenue that may offer new hope to those suffering from chronic pain.”

Provided by McGill University

Source: medicalxpress.com

ScienceDaily (Feb. 10, 2012) — A distinctive pattern of brain activity associated with conditions including deep anesthesia, coma and congenital brain disorders appears to represent the brain’s shift into a protective, low-activity state in response to reduced metabolic energy. A mathematical model developed by a Massachusetts General Hospital (MGH)-based research team accurately predicts and explains for the first time how the condition called burst suppression is elicited when brain cells’ energy supply becomes insufficient. Their report has been released online in PNAS Early Edition.

"The seemingly unrelated brain states that lead to burst suppression — deep anesthesia, coma, hypothermia and some developmental brain disorders — all represent a depressed metabolic state," says Emery Brown, MD, PhD, of the MGH Department of Anesthesia, Critical Care and Pain Medicine, senior author of the report. "We believe we have identified something fundamental about brain neurochemistry, neuroanatomy and neurophysiology that may help us plan better therapies for brain protection and design future anesthetics."

Burst suppression is an electroencephalogram (EEG) pattern in which periods of normal, high brain activity — the bursts — are interrupted by stretches of greatly reduced activity that can last 10 seconds or longer. Burst suppression has been observed in deep general anesthesia, in induced hypothermia — used to protect the brain or other structures from damage caused by trauma or reduced blood flow — in coma, and in infants with serious neurodevelopmental disorders. It also has transiently been observed in some premature infants. Previous investigations of burst suppression focused on characterizing the structure of the EEG patterns and understanding the brain’s responsiveness to external stimuli while in this state, not on the underlying mechanism.

Lead author ShiNung Ching, PhD, a postdoctoral fellow in Brown’s lab, had been working with Nancy Kopell, PhD, a professor of Mathematics at Boston University and co-author of the PNAS article, to develop mathematical models of different brain states under general anesthesia. In developing a model for burst suppression, they focused on what the associated conditions have in common — a significant reduction in the brain’s metabolic state. In order for a signal to pass from one nerve cell to another, the balance between sodium ions outside the cell and potassium ions within the cell needs to be correct. Maintaining that balance requires that structures called ion pumps, fueled by the cellular energy molecule ATP, function correctly. The model developed by Ching and his colleagues revealed that, when brain energy supplies drop too low and cause a deficiency in ATP, potassium leaks from the nerve cells and signal transmission halts.

"It looks like burst suppression shifts the brain into an altered physiologic state to allow for the regeneration of ATP, which is the essential metabolic substrate," Ching explains. "During suppression, the brain is trying to recover enough ATP to restart. If the substrate doesn’t regenerate quickly enough, the system will have these brief bursts of activity, stop and then need to recover again. The length of suppression is governed by how quickly ATP regenerates, which matches the observation that the deeper someone is anesthetized, the longer the periods of suppression."

Brown adds, “When we use general anesthesia to place patients with serious neurologic injuries into induced comas to allow their brains to heal, we take them down to a level of burst suppression. But there are a lot of questions regarding how deeply anesthetized an individual patient should be — how often the bursts should occur — and how long we should maintain that state. By elucidating what appears to be a fundamental energy-preserving mechanism within the brain, this model may help us think about using burst suppression to guide induced coma and track recovery from brain injuries. This is also a great example of how studying anesthesia can help us learn something very basic about the brain.”

Brown is the Warren Zapol Professor of Anesthesia at Harvard Medical School. He also is a professor of Computational Neuroscience and Health Sciences and Technology at Massachusetts Institute of Technology. Additional co-authors of the PNAS report are Patrick Purdon, PhD, MGH Anesthesia, and Sujith Vijayan, PhD, Boston University Mathematics. The study was supported by grants from the National Institutes of Health and the National Science Foundation.

Source: Science Daily

 February 9th, 2012

New technique holds promise for better understanding of brain disorders.

Quantum dot film. Optically excited quantum dots in close proximity to a cell control the opening of ion channels. Credit: Lugo et al., University of Washington.

Source: Neuroscience News

February 9, 2012

Neuroscientists at Case Western Reserve University School of Medicine have made a dramatic breakthrough in their efforts to find a cure for Alzheimer’s disease. The researchers’ findings, published in the journal Science, show that use of a drug in mice appears to quickly reverse the pathological, cognitive and memory deficits caused by the onset of Alzheimer’s. The results point to the significant potential that the medication, bexarotene, has to help the roughly 5.4 million Americans suffering from the progressive brain disease.

Bexarotene has been approved for the treatment of cancer by the U.S. Food and Drug Administration for more than a decade. These experiments explored whether the medication might also be used to help patients with Alzheimer’s disease, and the results were more than promising.

Alzheimer’s disease arises in large part from the body’s inability to clear naturally-occurring amyloid beta from the brain. In 2008 Case Western Reserve researcher Gary Landreth, PhD, professor of neurosciences, discovered that the main cholesterol carrier in the brain, Apolipoprotein E (ApoE), facilitated the clearance of the amyloid beta proteins. Landreth, a professor of neurosciences in the university’s medical school, is the senior author of this study as well.

Landreth and his colleagues chose to explore the effectiveness of bexarotene for increasing ApoE expression. The elevation of brain ApoE levels, in turn, speeds the clearance of amyloid beta from the brain. Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced.

In particular, the researchers were struck by the speed with which bexarotene improved memory deficits and behavior even as it also acted to reverse the pathology of Alzheimer’s disease. The present view of the scientific community is that small soluble forms of amyloid beta cause the memory impairments seen in animal models and humans with the disease. Within six hours of administering bexarotene, however, soluble amyloid levels fell by 25 percent; even more impressive, the effect lasted as long as three days. Finally, this shift was correlated with rapid improvement in a broad range of behaviors in three different mouse models of Alzheimer’s.

One example of the improved behaviors involved the typical nesting instinct of the mice. When Alzheimer’s-diseased mice encountered material suited for nesting – in this case, tissue paper – they did nothing to create a space to nest. This reaction demonstrated that they had lost the ability to associate the tissue paper with the opportunity to nest. Just 72 hours after the bexarotene treatment, however, the mice began to use the paper to make nests. Administration of the drug also improved the ability of the mice to sense and respond to odors.

Bexarotene treatment also worked quickly to stimulate the removal of amyloid plaques from the brain. The plaques are compacted aggregates of amyloid that form in the brain and are the pathological hallmark of Alzheimer’s disease. Researchers found that more than half of the plaques had been cleared within 72 hours. Ultimately, the reduction totaled 75 percent. It appears that the bexarotene reprogrammed the brain’s immune cells to “eat” or phagocytose the amyloid deposits. This observation demonstrated that the drug addresses the amount of both soluble and deposited forms of amyloid beta within the brain and reverses the pathological features of the disease in mice.

This study identifies a link between the primary genetic risk factor for Alzheimer’s disease and a potential therapy to address it. Humans have three forms of ApoE: ApoE2, ApoE3, and ApoE4. Possession of the ApoE4 gene greatly increases the likelihood of developing Alzheimer’s disease. Previously, the Landreth laboratory had shown that this form of ApoE was impaired in its ability of clear amyloid. The new work suggests that elevation of ApoE levels in the brain may be an effective therapeutic strategy to clear the forms of amyloid associated with impaired memory and cognition.

"This is an unprecedented finding," says Paige Cramer, PhD candidate at Case Western Reserve School of Medicine and first author of the study. "Previously, the best existing treatment for Alzheimer’s disease in mice required several months to reduce plaque in the brain."

Added Professor Landreth: “This is a particularly exciting and rewarding study because of the new science we have discovered and the potential promise of a therapy for Alzheimer’s disease. We need to be clear; the drug works quite well in mouse models of the disease. Our next objective is to ascertain if it acts similarly in humans. We are at an early stage in translating this basic science discovery into a treatment.”

Daniel Wesson, PhD, assistant professor of neurosciences at Case Western Reserve School of Medicine and co-author of the study agreed.

"Many often think of Alzheimer’s as a problem of remembering and learning, but the prevalent reality is this disease spreads throughout the brain, resulting in serious insults to numerous functions," he said. "The results of this study, showing the preservation of behaviors across a wide spectrum, and accompanying brain function, are tremendously exciting and suggest great promise in the utility of this approach in treatment of Alzheimer’s disease."

Bexarotene has a good safety and side-effect profile. The Case Western Reserve researchers hope these attributes will help speed the transition to clinical trials of the drug.

Professor Landreth said modest resources funded this self-described “far-fetched idea.” Crucial support came from the Blanchette Hooker Rockefeller Foundation, the Thome Foundation, and the National Institutes of Health.

Provided by Case Western Reserve University

Source: medicalxpress.com

February 8, 2012

"Explorers," whose decision-making style embraces the possibilities of uncertainty, use specific parts (red) of the right rostrolateral prefrontal cortex to make calculations based on relative uncertainty. Credit: Badre-Frank Lab/Brown University

Life shrouds most choices in mystery. Some people inch toward a comfortable enough spot and stick close to that rewarding status quo. Out to dinner, they order the usual. Others consider their options systematically or randomly. But many choose to grapple with the uncertainty head on. “Explorers” order the special because they aren’t sure they’ll like it. It’s a strategy of maximizing rewards by discovering whether as yet unexplored options might yield better returns. In a new study, Brown University researchers show that such explorers use a specific part of their brain to calculate the relative uncertainty of their choices, while non-explorers do not.

The study, published in the journal Neuron, newly exposes an aspect of the brain’s architecture for producing decisions and learning, said co-author David Badre, assistant professor of cognitive, linguistic, and psychological sciences at Brown. There was no consensus that a precise area of theprefrontal cortex, in this case the right rostrolateral prefrontal cortex, would be so clearly associated with a specific operation, such as performing the requisite uncertainty comparison for supporting a decision-making strategy.

"There has long been a debate about the functional organization of the frontal cortex," Badre said. "There has been a notion that the frontal lobe lacks specialization when exercising cognitive control, that it’s undifferentiated. This study provides evidence that there is a kind of organization. This is an example of how higher-order functions such as decision-making may relate to the frontal lobe’s more general functional architecture."

Stop the clock

To spot explorer behavior among their 15 participants, Badre and Michael Frank, associate professor of cognitive, linguistic, and psychological sciences, slid them into an MRI scanner and presented them with a game to play. Participants had to stop the sweeping hand of a virtual clock to win points in different rounds. They were told that they could maximize their rewards by responding quickly in some rounds, and slowly in others. The trick is they did not know round-to-round which response prevailed, and the number of points they could win was highly variable. They therefore had to employ a strategy to discover how to maximize their rewards among uncertain options, keeping track of the current expected value of fast and slow responses in each round.

While the MRI scanner tracked the blood flow in the brains of the subjects — a proxy for neural activity — the game’s software tracked their response times in each round. The computer then fed the game’s data into mathematical models devised to determine whether participants adapted their response times by taking relative uncertainty into account or adapted in another manner.

Over dozens of rounds a clear pattern emerged. Regardless of which version of the model they used, the researchers found that about half the subjects were engaging in exploratory behavior based on uncertainty: Their choices of response times correlated strongly with the choices that had the greatest outcome uncertainty.

Badre, Frank, and their team then looked at the MRI scans, reasoning that if decision-making is based on relative uncertainty, then the subjects’ brains must somehow represent this uncertainty. Sure enough, as relative uncertainty between choice options increased, so did activation in the right rostrolateral prefrontal cortex. This effect was substantially stronger in the explorers than the nonexplorers.

The result is the first to show that this region of the brain keeps track of relative uncertainty to guide exploration, but is consistent with previous studies that have shown an association between the right rostrolateral prefrontal cortex and relative comparisons. It also provides a potential explanation for Frank’s previous findings that explorers were more likely to have a variation in a gene called COMT that affects dopamine levels in the prefrontal cortex.

From cortex to choice

Frank said researchers still don’t know why some people employ the explorer strategy while others do not, but they might not be so different. According to one hypothesis, they all have an aversion to uncertainty and ambiguity.

"The difference could be that some people are averse to ambiguity in the time point where they make a single decision and other people are averse to ambiguity about their strategy over the long run," Frank said.

In other words, explorers may seek to reduce uncertainty by confronting it, rather than avoiding it.

Badre said that while the study has no direct clinical implications, the findings may still inform efforts to understand a broad set of disorders that affect frontal lobe function.

"There are a lot of diseases and disorders that affect the frontal lobes," Badre said. "They affect the ability to live independently, to carry out the day and make good decisions that get you where you want to go. The more we know about the specificity of these systems, the better that you can diagnose and suggest treatments."

Provided by Brown University

Source: medicalxpress.com

February 8, 2012

Synaptic plasticity – the ability of the synaptic connections between the brain’s neurons to change and modify over time — has been shown to be a key to memory formation and the acquisition of new learning behaviors. Now research led by a scientific team at Beth Israel Deaconess Medical Center (BIDMC) reveals that the neural circuits controlling hunger and eating behaviors are also controlled by plasticity.

Described in the February 9, 2012 issue of the journal Neuron, the findings show that during fasting, the AgRP neurons that drive feeding behaviors actually undergo anatomical changes that cause them to become more active, which results in their “learning” to be more responsive to hunger-promoting neural stimuli.

"The role of plasticity has generally not been evaluated in neuronal circuits that control feeding behavior and with this new discovery we can start to unravel the basic mechanisms underpinning hunger and gain a greater understanding of the factors that influence weight gain and obesity," explains senior author Bradford Lowell, MD, PhD, an investigator in BIDMC’s Division of Endocrinology, Diabetes and Metabolism and Professor of Medicine at Harvard Medical School (HMS).

Adds BIDMC Chairman of Neurology Clifford Saper, MD, PhD, “For most animals, finding enough food to survive is their biggest daily challenge, and so the brain’s increase in feeding drive may be adaptive. But, for humans who are overweight, reducing this drive to the AgRP neurons may prove to be a path to future weight loss therapies.”

The roots of hunger, eating, and weight are based in the brain’s complex and rapid-fire neurocircuitry. Over the years, nerve cells containing agouti-related peptide (AgRP) protein and pro-opiomelanocortin (POMC) protein have emerged as critical players in feeding behaviors. Located in the hypothalamus, the brain area that controls automatic body functions, AgRP neurons have been shown to drive eating and weight gain while POMC neurons inhibit feeding behaviors, causing satiety and weight loss.

Previous work by the Lowell lab and others had demonstrated that when AgRP neurons in mice are artificially switched on, the animals eat voraciously, consuming four times more than control animals. “The ‘switched-on’ animals search in an unrelenting fashion for food, and when given a task to obtain pellets, will work five times harder to get them,” Lowell explains.

Given the important role played by AgRP neurons, the scientists had a great interest in understanding the factors that regulate their activity. While much focus had centered on hormones, including leptin, insulin and ghrelin, as the possible mechanisms directly affecting neuronal activity, the Lowell team hypothesized that other nerve cells might be behind the regulation.

Neurons communicate with one another via neurotransmitters, chemical messengers that traverse synapses, the specialized junctions between upstream and downstream neurons. Glutamate is one such excitatory neurotransmitter.

"Studies in other regions of the brain [for example those controlling learning and reward and addiction behaviors] have demonstrated that glutamate synapses are highly plastic, changing in their strength and sometimes even in their number," explains Lowell. Shown to exert powerful control over behavior, synaptic plasticity is brought about when glutamate binds to NMDA receptors on downstream neurons.

"NMDA receptors are unusual and really interesting," he adds. "When glutamate gets released by upstream neurons and binds to NMDA receptors, calcium enters the downstream neuron. This, in turn, engages signal transduction pathways that cause synaptic plasticity. In other parts of the brain, such as the hippocampus, NMDA receptors drive plasticity which serves to encode memories."

Led by co-first authors Tiemin Liu, PhD, Dong Kong, PhD, Bhavik P. Shah, PhD, and Chianping Ye, PhD, the investigators created and studied mice genetically engineered to lack glutamate-binding NMDA receptors on the AgRP neurons. For the sake of comparison, they also created mice genetically engineered to lack NMDA receptors on POMC neurons.

They found that while mice lacking NMDA receptors on POMC neurons showed no change in feeding behavior, the situation was dramatically different in the mice lacking NMDA receptors on AgRP neurons.

"These mice ate a lot less and were much skinnier than a group of control mice," explains Lowell. Furthermore, the scientists found that a 24-hour period of fasting – which causes intense hunger in the control mice – was associated with a 67 percent increase in the number of dendritic spines on the AgRP neurons.

"Dendritic spines are tiny structures attached to the neuron’s dendrites, the tree-like branches that receive incoming signals from upstream neurons," explains Lowell. "These structures are the physical site, the subcellular communication hub, where synaptic input from upstream glutamate-releasing neurons is received, typically one synaptic input per spine."

"I’ve been studying spines for a long time and I’ve never before seen a manipulation that triggered such rapid and robust changes in spine number," says coauthor Bernardo Sabatini, MD, PhD, a Howard Hughes Medical Institute investigator in the Department of Neurobiology at Harvard Medical School. "Clearly, feeding is plugging in to the most basic mechanisms that control synapse and spine number in these cells. This may be a great system to understand not only feeding behavior, but also to understand the cell biology behind dynamic synapse formation and retraction."

When the control mice were refed – and their hunger alleviated – the number of spines dropped back to normal. (In contrast, fasting had no effect on spine number in the mutant mice lacking NMDA receptors on AgRP neurons.) These dramatic changes in spine number and their tight association with states of hunger and satiety in control mice – and the absence of changes in spine number in mice lacking NMDA receptors on the downstream AgRP neurons– strongly suggests that structural plasticity of excitatory glutamate synapses on AgRP neurons is an important regulator of feeding behavior, says Lowell.

"Obesity is a major risk factor for type 2 diabetes, cardiovascular disease, and certain types of cancer," he adds. "By understanding the neurobiological mechanisms underlying feeding behaviors, we can work on treatments for a problem that has now become a global epidemic. These findings move us closer to a mechanistic understanding of how various factors controlling hunger might work."

Provided by Beth Israel Deaconess Medical Center

Source: medicalxpress.com

February 8, 2012 by Anne Trafton

Emery Brown, an MIT professor of brain and cognitive sciences and health sciences and technology, left, and ShiNung Ching, a postdoc in Brown’s lab. Photo: M. Scott Brauer

Different brain states produce different waves of electrical activity, with the alert brain, relaxed brain and sleeping brain producing easily distinguishable electroencephalogram (EEG) patterns. These patterns change even more dramatically when the brain goes into certain deeply quiescent states during general anesthesia or a coma. 

MIT and Harvard University researchers have now figured out how one such quiescent state, known as burst suppression, arises. The finding, reported in the online edition of the Proceedings of the National Academy of Sciences the week of Feb. 6, could help researchers better monitor other states in which burst suppression occurs. For example, it is also seen in the brains of heart attack victims who are cooled to prevent brain damage due to oxygen deprivation, and in the brains of patients deliberately placed into a medical coma to treat a traumatic brain injury or intractable seizures.

During burst suppression, the brain is quiet for up to several seconds at a time, punctuated by short bursts of activity. Emery Brown, an MIT professor of brain and cognitive sciences and health sciences and technology and an anesthesiologist at Massachusetts General Hospital, set out to study burst suppression in the anesthetized brain and other brain states in hopes of discovering a fundamental mechanism for how the pattern arises. Such knowledge could help scientists figure out how much burst suppression is needed for optimal brain protection during induced hypothermia, when this state is created deliberately. 

“You might be able to develop a much more principled way to guide therapy for using burst suppression in cases of medical coma,” says Brown, senior author of the PNASpaper. “The question is, how do you know that patients are sufficiently brain-protected? Should they have one burst every second? Or one every five seconds?”

Modeling electrical activity

ShiNung Ching, a postdoc in Brown’s lab and lead author of the PNAS paper, developed a model to describe how burst suppression arises, based on the behavior of neurons in the brain. Neuron firing is controlled by the activity of channels that allow ions such as potassium and sodium to flow in and out of the cell, altering its voltage.

For each neuron, “we’re able to mathematically model the flow of ions into and out of the cell body, through the membrane,” Ching says. In this study, the team combined many neurons to create a model of a large brain network. By showing how both cooling and certain anesthetic drugs reduce the brain’s use of ATP (the cell’s energy currency), the researchers were able to generate burst-suppression patterns consistent with those actually seen in human patients. 

This is the first time that reductions in metabolic activity at the neuron level have been linked to burst suppression, and suggests that the brain likely uses burst suppression to conserve vital energy during times of trauma.

“What’s really exciting about this is the idea that the metabolic regulation of cell energy stores plays a role in the observed dynamics of EEG. That’s a different way to think about the determinants of EEG,” says Nicholas Schiff, a professor of neurology and neuroscience at Weill Cornell Medical College who was not involved in this research. 

The developing brain

Burst suppression is also seen in babies born prematurely. As these babies get older, their brain patterns move into the normal continuous pattern. Brown speculates that in premature infants, the brain may be protecting itself by conserving energy.

“When you’re looking at these kids develop, we can easily start to suggest ways of tracking their improvement quantitatively. So the same algorithms we use to track burst suppression in the operating room could be used to track the disappearance of burst suppression in these kids,” Brown says.

Such tracking could help doctors determine whether premature infants are moving toward normal development or have an underlying brain disorder that might otherwise go undiagnosed, Ching says. 

In future studies, the researchers plan to study premature infants as well as patients whose brains are cooled and those in induced comas. Such studies could reveal just how much burst suppression is enough to protect the brain in those vulnerable situations.

Provided by Massachusetts Institute of Technology

Source: medicalxpress.com