How the Brain Remembers Pleasure: Implications for Addiction

How the Brain Remembers Pleasure: Implications for Addiction

  8:46:00 PM    Science Lover

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Key details of the way nerve cells in the brain remember pleasure are revealed in a study by University of Alabama at Birmingham (UAB) researchers published today in the journal Nature Neuroscience. The molecular events that form such "reward memories" appear to differ from those created by drug addiction, despite the popular theory that addiction hijacks normal reward pathways.

Brain activity (artist's rendering). 
(Credit: © James Steidl / Fotolia)

Brain circuits have evolved to encourage behaviors proven to help our species survive by attaching pleasure to them. Eating rich food tastes good because it delivers energy and sex is desirable because it creates offspring. The same systems also connect in our mind's environmental cues with actual pleasures to form reward memories.

This study in rats supports the idea that the mammalian brain features several memory types, each using different circuits, with memories accessed and integrated as needed. Ancient memory types include those that remind us what to fear, what to seek out (reward), how to move (motor memory) and navigate (place memory). More recent developments enable us to remember the year Columbus sailed and our wedding day.

"We believe reward memory may serve as a good model for understanding the molecular mechanisms behind many types of learning and memory," said David Sweatt, Ph.D., chair of the UAB Department of Neurobiology, director of the Evelyn F. McKnight Brain Institute at UAB and corresponding author for the study. "Our results provide a leap in the field's understanding of reward-learning mechanisms and promise to guide future attempts to solve related problems such as addiction and criminal behavior."

The study is the first to illustrate that reward memories are created by chemical changes that influence known memory-related genes in nerve cells within a brain region called the ventral tegmental area, or VTA. Experiments that blocked those chemical changes -- a mix of DNA methylation and demethylation -- in the VTA prevented rats from forming new reward memories.

Methylation is the attachment of a methyl group (one carbon and three hydrogens) to a DNA chain at certain spots (cytosine bases). When methylation occurs near a gene or inside a gene sequence, it generally is thought to turn the gene off and its removal is thought to turn the gene on. This back-and-forth change affects gene expression without changing the code we inherit from our parents. Operating outside the genetic machinery proper, epigenetic changes enable each cell type to do its unique job and to react to its environment.

Furthermore, a stem cell in the womb that becomes bone or liver cells must "remember" its specialized nature and pass that identity to its descendants as they divide and multiply to form organs. This process requires genetic memory, which largely is driven by methylation. Note, most nerve cells do not divide and multiply as do other cells. They can't, according to one theory, because they put their epigenetic mechanisms to work making actual memories.

Natural pleasure versus addiction

The brain's pleasure center is known to proceed through nerve cells that signal using the neurochemical dopamine and generally is located in the VTA. Dopaminergic neurons exhibit a "remarkable capacity" to pass on pleasure signals. Unfortunately, the evolutionary processes that attached pleasure to advantageous behaviors also accidentally reinforced bad ones.

Addiction to all four major classes of abused drugs -- psychostimulants, opiates, ethanol and nicotine -- has been linked to increased dopamine transmission in the same parts of the brain associated with normal reward processing. Cues that predict both normal reward and effects of cocaine or alcohol also make dopamine nerve cells fire as do the experiences they recall. That had led to idea that drug addiction must take over normal reward-memory nerve pathways.

Along those lines, past research has argued that dopamine-producing neurons in the VTA -- and in a region that receives downstream dopamine signals from the VTA called the nucleus accumbens (NAC) -- both were involved in natural reward and drug-addiction-based memory formation. While that may true to some extent, this study revealed that blocking methylation in the VTA with a drug stopped the ability of rats to attach rewarding experiences to remembered cues but doing so in the NAC did not.

"We observed an important distinction, not in circuitry, but instead in the epigenetic regulation of that circuitry between natural reward responses and those that occur downstream with drugs of abuse or psychiatric illness," said Jeremy Day, Ph.D., a post-doctoral scholar in Sweatt's lab and first author for this study. "Although drug experiences may co-opt normal reward mechanisms to some extent, our results suggest they also may engage entirely separate epigenetic mechanisms that contribute only to addiction and that may explain its strength."

To investigate the molecular and epigenetic changes in the VTA, researchers took their cue from 19th century Russian physiologist Ivan Pavlov, who was the first to study the phenomenon of conditioning. By ringing a bell each day before giving his dogs food, Pavlov soon found that the dogs would salivate at the sound of the bell.

In this study, rats were trained to associate a sound tone with the availability of sugar pellets in their feed ports. This same animal model has been used to make most discoveries about how human dopamine neurons work since the 1990s, and most approved drugs that affect the dopamine system (e.g. L-Dopa for Parkinson's) were tested in it before being cleared for human trials.

To separate the effects of memory-related brain changes from those arising from the pleasure of the eating itself, the rats were separated into three groups. Rats in the "CS+" rats got sugar pellets each time they heard a sound cue. The "CS-" group heard the sound the same number of times and received as many sugar pellets -- but never together. A third tone-only group heard the sounds but never received sugar rewards.

Rats that always received sugar with the sound cue were found to poke their feed ports with their noses at least twice as often during this cue as control rats after three, 25-sound-cue sessions. Nose pokes are an established measure of the degree to which a rat has come to associate a cue with the memory of a tasty treat.

The team found that those CS+ rats (sugar paired with sound) that were better at forming reward memories had significantly higher expression of the genes Egr1 and Fos than control rats These genes are known to regulate memory in other brain regions by fine-tuning the signaling capacity of the connections between nerve cells. In a series of experiments, the team next revealed the methylation and demethylation pattern that drove the changes in gene expression seen as memories formed.

The study demonstrated that reward-related experiences caused both types of DNA methylation known to regulate gene expression.

One type involves attaching methyl groups to pieces of DNA called promoters, which reside immediately upstream of individual gene sequences (between genes), that tell the machinery that follows genetic instructions to "start reading here." The attachment of a methyl group to a promoter generally interferes with this and silences a nearby gene. However, ancient organisms such as plants and insects have less methylation between their genes, and more of it within the coding regions of the genes themselves (within gene bodies). Such gene-body methylation has been shown to encourage rather than silence gene expression.

Specifically, the team reported that two sites in the promoter for Egr1 gene were demethylated during reward experiences and, to a greater degree, in rats that associated the sugar with the sound cue. Conversely, spots within the gene body of both Egr1 and Fos underwent methylation as reward memories formed.

"When designing therapeutic treatments for psychiatric illness, addictions or memory disorders, you must profoundly understand the function of the biological systems you're working with," Day said. "Our field has learned from experience that attempts to treat addiction with something that globally impairs normal reward perception or reward memories do not succeed. Our study suggests the possibility that future treatments could dial down drug addiction or mental illness without affecting normal rewards."

Along with Sweatt and Day, authors for the study were Daniel Childs, Mikael Guzman-Karlsson, Mercy Kibe, Jerome Moulden, Esther Song and Absar Tahir within the Department of Neurobiology and the Evelyn F. McKnight Brain Institute at University of Alabama at Birmingham. This work is supported by the National Institute on Drug Abuse (DA029419), the National Institute on Mental Health (MH091122 and MH057014), and the Evelyn F. McKnight Brain Research Foundation.

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Mimicking the Brain -- In Silicon: New Computer Chip Models How Neurons Communicate With Each Other at Synapses

Mimicking the Brain -- In Silicon: New Computer Chip Models How Neurons Communicate With Each Other at Synapses

  1:39:00 PM    Science Lover

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For decades, scientists have dreamed of building computer systems that could replicate the human BRAIN's talent for learning new tasks.

Researchers have taken a major step toward that goal by designing a computer chip that mimics how the brain's neurons adapt in response to new information. (Credit: MIT)

MIT researchers have now taken a major step toward that goal by designing a computer chip that mimics how the brain's neurons adapt in response to new information. This phenomenon, known as plasticity, is believed to underlie many brain functions, including learning and memory.

With about 400 transistors, the silicon chip can simulate the activity of a single brain synapse -- a connection between two neurons that allows information to flow from one to the other. The researchers anticipate this chip will help neuroscientists learn much more about how the brain works, and could also be used in neural prosthetic devices such as artificial retinas, says Chi-Sang Poon, a principal research scientist in the Harvard-MIT Division of Health Sciences and Technology.

Poon is the senior author of a paper describing the chip in the Proceedings of the National Academy of Sciences the week of Nov. 14. Guy Rachmuth, a former postdoc in Poon's lab, is lead author of the paper. Other authors are Mark Bear, the Picower Professor of Neuroscience at MIT, and Harel Shouval of the University of Texas Medical School.

Modeling synapses

There are about 100 billion neurons in the brain, each of which forms synapses with many other neurons. A synapse is the gap between two neurons (known as the presynaptic and postsynaptic neurons). The presynaptic neuron releases neurotransmitters, such as glutamate and GABA, which bind to receptors on the postsynaptic cell membrane, activating ion channels. Opening and closing those channels changes the cell's electrical potential. If the potential changes dramatically enough, the cell fires an electrical impulse called an action potential.

All of this synaptic activity depends on the ion channels, which control the flow of charged atoms such as sodium, potassium and calcium. Those channels are also key to two processes known as long-term potentiation (LTP) and long-term depression (LTD), which strengthen and weaken synapses, respectively.

The MIT researchers designed their computer chip so that the transistors could mimic the activity of different ion channels. While most chips operate in a binary, on/off mode, current flows through the transistors on the new brain chip in analog, not digital, fashion. A gradient of electrical potential drives current to flow through the transistors just as ions flow through ion channels in a cell.

"We can tweak the parameters of the circuit to match specific ion channels," Poon says. "We now have a way to capture each and every ionic process that's going on in a neuron."

Previously, researchers had built circuits that could simulate the firing of an action potential, but not all of the circumstances that produce the potentials. "If you really want to mimic brain function realistically, you have to do more than just spiking. You have to capture the intracellular processes that are ion channel-based," Poon says.

The new chip represents a "significant advance in the efforts to incorporate what we know about the biology of neurons and synaptic plasticity onto CMOS [complementary metal-oxide-semiconductor] chips," says Dean Buonomano, a professor of neurobiology at the University of California at Los Angeles, adding that "the level of biological realism is impressive.

The MIT researchers plan to use their chip to build systems to model specific neural functions, such as the visual processing system. Such systems could be much faster than digital computers. Even on high-capacity computer systems, it takes hours or days to simulate a simple brain circuit. With the analog chip system, the simulation is even faster than the biological system itself.

Another potential application is building chips that can interface with biological systems. This could be useful in enabling communication between neural prosthetic devices such as artificial retinas and the brain. Further down the road, these chips could also become building blocks for artificial intelligence devices, Poon says.

Debate resolved

The MIT researchers have already used their chip to propose a resolution to a longstanding debate over how LTD occurs.

One theory holds that LTD and LTP depend on the frequency of action potentials stimulated in the postsynaptic cell, while a more recent theory suggests that they depend on the timing of the action potentials' arrival at the synapse.

Both require the involvement of ion channels known as NMDA receptors, which detect postsynaptic activation. Recently, it has been theorized that both models could be unified if there were a second type of receptor involved in detecting that activity. One candidate for that second receptor is the endo-cannabinoid receptor.

Endo-cannabinoids, similar in structure to marijuana, are produced in the brain and are involved in many functions, including appetite, pain sensation and memory. Some neuroscientists had theorized that endo-cannabinoids produced in the postsynaptic cell are released into the synapse, where they activate presynaptic endo-cannabinoid receptors. If NMDA receptors are active at the same time, LTD occurs.

When the researchers included on their chip transistors that model endo-cannabinoid receptors, they were able to accurately simulate both LTD and LTP. Although previous experiments supported this theory, until now, "nobody had put all this together and demonstrated computationally that indeed this works, and this is how it works," Poon says.

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Holograms Reveal Brain's Inner Workings: Microscopy Technique Used to Observe Activity of Neurons Like Never Before

Holograms Reveal Brain's Inner Workings: Microscopy Technique Used to Observe Activity of Neurons Like Never Before

  9:36:00 AM    Science Lover

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Like far away galaxies, powerful tools are required to bring the minute inner workings of neurons into focus. Borrowing a technique from materials science, a team of neurobiologists, psychiatrists, and advanced imaging specialists from Switzerland's EPLF and CHUV report in The Journal of Neuroscience how Digital Holographic Microscopy (DHM) can now be used to observe neuronal activity in real-time and in three dimensions -- with up to 50 times greater resolution than ever before. The application has immense potential for testing out new drugs to fight neurodegenerative diseases such as Alzheimer's and Parkinson's.

This is a 3-D image of living neuron taken by DHM 
technology. (Credit: Courtesy of Lyncée Tec)

Neurons come in various shapes and are transparent. To observe them in a Petri dish, scientists use florescent dyes that change the chemical composition and can skew results. Additionally, this technique is time consuming, often damages the cells, and only allows researchers to examine a few neurons at a time. But these newly published results show how DHM can bypass the limitations of existing techniques.

"DHM is a fundamentally novel application for studying neurons with a slew of advantages over traditional microscopes," explains Pierre Magistretti of EPFL's Brain Mind Institute and a lead author of the paper. "It is non-invasive, allowing for extended observation of neural processes without the need for electrodes or dyes that damage cells."

Senior team member Pierre Marquet adds, "DHM gives precious information not only about the shape of neurons, but also about their dynamics and activity, and the technique creates 3D navigable images and increases the precision from 500 nanometers in traditional microscopes to a scale of 10 nanometers."

A good way to understand how DHM works is to imagine a large rock in an ocean of perfectly regular waves. As the waves deform around the rock and come out the other side, they carry information about the rock's shape. This information can be extracted by comparing it to waves that did not smash up against the rock, and an image of the rock can be reconstructed. DHM does this with a laser beam by pointing a single wavelength at an object, collecting the distorted wave on the other side, and comparing it to a reference beam. A computer then numerically reconstructs a 3D image of the object -- in this case neurons -- using an algorithm developed by the authors. In addition, the laser beam travels through the transparent cells and important information about their internal composition is obtained.



Normally applied to detect minute defects in materials, Magistretti, along with DHM pioneer and EPFL professor in the Advanced Photonics Laboratory, Christian Depeursinge, decided to use DHM for neurobiological applications. In the study, their group induced an electric charge in a culture of neurons using glutamate, the main neurotransmitter in the brain. This charge transfer carries water inside the neurons and changes their optical properties in a way that can be detected only by DHM. Thus, the technique accurately visualizes the electrical activities of hundreds of neurons simultaneously, in real-time, without damaging them with electrodes, which can only record activity from a few neurons at a time.

A major advance for pharmaceutical research

Without the need to introduce dyes or electrodes, DHM can be applied to High Content Screening -- the screening of thousands of new pharmacological molecules. This advance has important ramifications for the discovery of new drugs that combat or prevent neurodegenerative diseases such as Parkinson's and Alzheimer's, since new molecules can be tested more quickly and in greater numbers.

"Due to the technique's precision, speed, and lack of invasiveness, it is possible to track minute changes in neuron properties in relation to an applied test drug and allow for a better understanding of what is happening, especially in predicting neuronal death," Magistretti says. "What normally would take 12 hours in the lab can now be done in 15 to 30 minutes, greatly decreasing the time it takes for researchers to know if a drug is effective or not."

The promise of this technique for High Content Screening has already resulted in a start-up company at EPFL called LynceeTec (www.lynceetec.com).

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Scientists Have New Help Finding Their Way Around Brain's Nooks and Crannies

Scientists Have New Help Finding Their Way Around Brain's Nooks and Crannies

  12:53:00 AM    Science Lover

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Like explorers mapping a new planet, scientists probing the brain need every type of landmark they can get. Each mountain, river or forest helps scientists find their way through the intricacies of the human brain.

Scientists have found a way to use MRI scanning data 
to map myelin, a white sheath that covers some brain 
cell branches. Such maps, previously only available via 
dissection, help scientists determine precisely where they 
are at in the brain. Red and yellow indicate regions with 
high myelin levels; blue, purple and black areas have low 
myelin levels. (Credit: David Van Essen)

Researchers at Washington University School of Medicine in St. Louis have developed a new technique that provides rapid access to brain landmarks formerly only available at autopsy. Better brain maps will result, speeding efforts to understand how the healthy brain works and potentially aiding in future diagnosis and treatment of brain disorders, the researchers report in the Journal of Neuroscience Aug. 10.

The technique makes it possible for scientists to map myelination, or the degree to which branches of brain cells are covered by a white sheath known as myelin in order to speed up long-distance signaling. It was developed in part through the Human Connectome Project, a $30 million, five-year effort to map the brain's wiring. That project is headed by Washington University in St. Louis and the University of Minnesota.

"The brain is among the most complex structures known, with approximately 90 billion neurons transmitting information across 150 trillion connections," says David Van Essen, PhD, Edison Professor and head of the Department of Anatomy and Neurobiology at Washington University. "New perspectives are very helpful for understanding this complexity, and myelin maps will give us important insights into where certain parts of the brain end and others begin."

Easy access to detailed maps of myelination in humans and animals also will aid efforts to understand how the brain evolved and how it works, according to Van Essen.

Neuroscientists have known for more than a century that myelination levels differ throughout the cerebral cortex, the gray outer layer of the brain where most higher mental functions take place. Until now, though, the only way they could map these differences in detail was to remove the brain after death, slice it and stain it for myelin.

Washington University graduate student Matthew Glasser developed the new technique, which combines data from two types of magnetic resonance imaging (MRI) scans that have been available for years.



"These are standard ways of imaging brain anatomy that scientists and clinicians have used for a long time," Glasser says. "After developing the new technique, we applied it in a detailed analysis of archived brain scans from healthy adults."

As in prior studies, Glasser's results show highest myelination levels in areas involved with early processing of information from the eyes and other sensory organs and control of movement. Many brain cells are packed into these regions, but the connections among the cells are less complex. Scientists suspect that these brain regions rely heavily on what computer scientists call parallel processing: Instead of every cell in the region working together on a single complex problem, multiple separate teams of cells work simultaneously on different parts of the problem.

Areas with less myelin include brain regions linked to speech, reasoning and use of tools. These regions have brain cells that are packed less densely, because individual cells are larger and have more complex connections with neighboring cells.

"It's been widely hypothesized that each chunk of the cerebral cortex is made up of very uniform information-processing machinery," Van Essen says. "But we're now adding to a picture of striking regional differences that are important for understanding how the brain works."

According to Van Essen, the technique will make it possible for the Connectome project to rapidly map myelination in many different research participants. Data on many subjects, acquired through many different analytical techniques including myelination mapping, will help the resulting maps cover the range of anatomic variation present in humans.

"Our colleagues are clamoring to make use of this approach because it's so helpful for figuring out where you are in the cortex, and the data are either already there or can be obtained in less than 10 minutes of MRI scanning," Glasser says.

This research was funded by the National Institutes of Health (NIH).

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New Genetic Technique Converts Skin Cells Into Brain Cells

New Genetic Technique Converts Skin Cells Into Brain Cells

  6:16:00 PM    Science Lover

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A research breakthrough has proven that it is possible to reprogram mature cells from human skin directly into brain cells, without passing through the stem cell stage. The unexpectedly simple technique involves activating three genes in the skin cells; genes which are already known to be active in the formation of brain cells at the fetal stage.

Photomicrograph of fibroblast cells in tissue culture. 
(Credit: iStockphoto/Torsten Wittmann)

The new technique avoids many of the ethical dilemmas that stem cell research has faced.

For the first time, a research group at Lund University in Sweden has succeeded in creating specific types of nerve cells from human skin. By reprogramming connective tissue cells, called fibroblasts, directly into nerve cells, a new field has been opened up with the potential to take research on cell transplants to the next level. The discovery represents a fundamental change in the view of the function and capacity of mature cells. By taking mature cells as their starting point instead of stem cells, the Lund researchers also avoid the ethical issues linked to research on embryonic stem cells.

Head of the research group Malin Parmar was surprised at how receptive the fibroblasts were to new instructions.

"We didn't really believe this would work, to begin with it was mostly just an interesting experiment to try. However, we soon saw that the cells were surprisingly receptive to instructions." The study, which was published in the latest issue of the Proceedings of the National Academy of Sciences, also shows that the skin cells can be directed to become certain types of nerve cells.

In experiments where a further two genes were activated, the researchers have been able to produce dopamine brain cells, the type of cell which dies in Parkinson's disease. The research findings are therefore an important step towards the goal of producing nerve cells for transplant which originate from the patients themselves. The cells could also be used as disease models in research on various neurodegenerative diseases.



Unlike older reprogramming methods, where skin cells are turned into pluripotent stem cells, known as IPS cells, direct reprogramming means that the skin cells do not pass through the stem cell stage when they are converted into nerve cells. Skipping the stem cell stage probably eliminates the risk of tumours forming when the cells are transplanted. Stem cell research has long been hampered by the propensity of certain stem cells to continue to divide and form tumours after being transplanted.

Before the direct conversion technique can be used in clinical practice, more research is needed on how the new nerve cells survive and function in the brain. The vision for the future is that doctors will be able to produce the brain cells that a patient needs from a simple skin or hair sample. In addition, it is presumed that specifically designed cells originating from the patient would be accepted better by the body's immune system than transplanted cells from donor tissue.

"This is the big idea in the long run. We hope to be able to do a biopsy on a patient, make dopamine cells, for example, and then transplant them as a treatment for Parkinson's disease," says Malin Parmar, who is now continuing the research to develop more types of brain cells using the new technique.

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New genetic technique converts skin cells into brain cells

New genetic technique converts skin cells into brain cells

  12:34:00 AM    Science Lover

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A research breakthrough has proven that it is possible to reprogram mature cells from human skin directly into brain cells, without passing through the stem cell stage. The unexpectedly simple technique involves activating three genes in the skin cells; genes which are already known to be active in the formation of brain cells at the foetal stage.

converts skin cells into brain cells

The new technique avoids many of the ethical dilemmas that stem cell research has faced.

For the first time, a research group at Lund University in Sweden has succeeded in creating specific types of nerve cells from human skin. By reprogramming connective tissue cells, called fibroblasts, directly into nerve cells, a new field has been opened up with the potential to take research on cell transplants to the next level. The discovery represents a fundamental change in the view of the function and capacity of mature cells. By taking mature cells as their starting point instead of stem cells, the Lund researchers also avoid the ethical issues linked to research on embryonic stem cells.

Head of the research group Malin Parmar was surprised at how receptive the fibroblasts were to new instructions.

"We didn't really believe this would work, to begin with it was mostly just an interesting experiment to try. However, we soon saw that the cells were surprisingly receptive to instructions."

The study, which was published in the latest issue of the scientific journal PNAS, also shows that the skin cells can be directed to become certain types of nerve cells.

In experiments where a further two genes were activated, the researchers have been able to produce dopamine brain cells, the type of cell which dies in Parkinson's disease. The research findings are therefore an important step towards the goal of producing nerve cells for transplant which originate from the patients themselves. The cells could also be used as disease models in research on various neurodegenerative diseases.

Unlike older reprogramming methods, where skin cells are turned into pluripotent stem cells, known as IPS cells, direct reprogramming means that the skin cells do not pass through the stem cell stage when they are converted into nerve cells. Skipping the stem cell stage probably eliminates the risk of tumours forming when the cells are transplanted. Stem cell research has long been hampered by the propensity of certain stem cells to continue to divide and form tumours after being transplanted.

Before the direct conversion technique can be used in clinical practice, more research is needed on how the new nerve cells survive and function in the brain. The vision for the future is that doctors will be able to produce the brain cells that a patient needs from a simple skin or hair sample. In addition, it is presumed that specifically designed cells originating from the patient would be accepted better by the body's immune system than transplanted cells from donor tissue.

"This is the big idea in the long run. We hope to be able to do a biopsy on a patient, make dopamine cells, for example, and then transplant them as a treatment for Parkinson's disease", says Malin Parmar, who is now continuing the research to develop more types of brain cells using the new technique.

More information: 'Direct conversion of human fibroblasts to dopaminergic neurons', publ. PNAS 2011; 6 June 2011: http://www.pnas.or … 108.abstract

Provided by Lund University

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Sense of Smell: Single Giant Interneuron in Locusts Controls Activity in 50,000 Neurons, Enabling Sparse Codes for Odours

Sense of Smell: Single Giant Interneuron in Locusts Controls Activity in 50,000 Neurons, Enabling Sparse Codes for Odours

  8:09:00 PM    Science Lover

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The brain is a coding machine: it translates physical inputs from the world into visual, olfactory, auditory, tactile perceptions via the mysterious language of its nerve cells and the networks which they form. Neural codes could in principle take many forms, but in regions forming bottlenecks for information flow (e.g., the optic nerve) or in areas important for memory, sparse codes are highly desirable.

A single "giant", non-spiking, GABAergic interneuron
(right, labelled by intracellular injection of fluorescent dye)
forms an all-to-all negative feedback loop with a population
of about 50,000 Kenyon cells, principal neurons of the
mushroom bodies, a structure involved in olfactory
memory in the insect brain. This normalizing feedback
loop serves to ensure relatively constant sparseness
of mushroom body output across varying input
strengths. Sparseness is an important feature of
sensory representations in areas involved in
memory formation. (Credit: © MPI for Brain Research)

Scientists at the Max Planck Institute for Brain Research in Frankfurt have now discovered a single neuron in the brain of locusts that enables the adaptive regulation of sparseness in olfactory codes. This single giant interneuron tracks in real time the activity of several tens of thousands of neurons in an olfactory centre and feeds inhibition back onto all of them, so as to maintain their collective output within an appropriately sparse regime. In this way, representation sparseness remains steady as input intensity or complexity varies.

Signals from the world (electromagnetic waves, pressure, chemicals etc) are converted to electrical activity in sensory neurons and processed by neuronal networks in the brain. Insects sense smells via their antennae. Odours are detected by sensory neurons there, and olfactory data are then sent to and processed by the antennal lobes and a region of the brain known as the mushroom bodies. Neurons in the antennal lobes tend to be "promiscuous": odours are thus represented by specific combinations of neuronal activity. Neurons in the mushroom bodies -- they are called Kenyon cells -- , however, respond with great specificity and thus extremely rarely. In addition, they generally respond with fewer than three electrical impulses when stimulated with the right odour. This "sparse coding" strategy has the advantage that it simplifies the task of storing odour representations in memory.

Surprisingly, each Kenyon cell is connected on average to half of all possible presynaptic neurons in the antennal lobes. So how do the Kenyon cells manage to respond only extremely rarely, and with a sparseness that varies little over large ranges of stimulation conditions? Gilles Laurent of the Max Planck Institute for Brain Research and his group found that a single giant interneuron plays a key role. Along with colleagues in his lab (formerly at Caltech) and Great Britain, he has discovered that this neuron, with its extensive arbour, is activated by the entire Kenyon cell population and in turn inhibits them all back. "The giant interneuron and the Kenyon cells form a simple negative feed-back loop: the more strongly it is activated by the Kenyon cell population, the more strongly it curtails their activity in return," explains Laurent. The interneuron itself does not generate any action potentials, but inhibits Kenyon cells via nonspiking and graded release of the neurotransmitter GABA (gamma aminobutyric acid). This smooth, graded property enables this giant interneuron to do a kind of real-time, population averaging, thus carrying out an operation that might otherwise require the involvement of hundreds or thousands of individual spiking neurons.

The effectiveness of the giant interneuron is such that it can actually turn off the Kenyon cell population completely. But the research team also discovered that the giant interneuron is, in turn, controlled by another inhibitory neuron. "This allows the network activity to be potentiated or attenuated, and the sensitivity of this feedback loop to be adjusted," says Gilles Laurent. This is an important feature for brain regions such as the mushroom bodies, which are responsible not only for olfactory processing, but also for learning and memory. Mushroom bodies are where smells can be associated with other sensory modalities, enabling the formation of complex representations.

The scientists' findings show how massive negative feed-back loops can be formed in neuronal networks and what roles they can play. In vertebrates, the piriform cortex, part of the olfactory cortical complex, sits in a position equivalent to the mushroom bodies. "It is very likely that mammals have similar all-to-all control mechanisms in cortical and other circuits. They might not consist of single interneurons, however, but rather of populations of inhibitory neurons with means to couple their responses and actions," surmises Laurent. "Insect brains never cease to give us insights about neural computation, and to put elegant solutions right on our laps, if we know where to look and are a bit lucky."

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Microsleep: Brain Regions Can Take Short Naps During Wakefulness, Leading to Errors

Microsleep: Brain Regions Can Take Short Naps During Wakefulness, Leading to Errors

  10:28:00 AM    Science Lover

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If you've ever lost your keys or stuck the milk in the cupboard and the cereal in the refrigerator, you may have been the victim of a tired brain region that was taking a quick nap.

A photo of rats with objects introduced into their 
cages to keep them awake. (Credit: Giulio Tononi,
M.D., Ph.D., University of Wisconsin-Madison)

Researchers at the University of Wisconsin-Madison have a new explanation. They've found that some nerve cells in a sleep-deprived yet awake brain can briefly go "off line," into a sleep-like state, while the rest of the brain appears awake.

"Even before you feel fatigued, there are signs in the brain that you should stop certain activities that may require alertness," says Dr. Chiara Cirelli, professor of psychiatry at the School of Medicine and Public Health. "Specific groups of neurons may be falling asleep, with negative consequences on performance."

Until now, scientists thought that sleep deprivation generally affected the entire brain. Electroencephalograms (EEGs) show network brain-wave patterns typical of either being asleep or awake.

"We know that when we are sleepy, we make mistakes, our attention wanders and our vigilance goes down," says Cirelli. "We have seen with EEGs that even while we are awake, we can experience shorts periods of 'micro sleep.' "

Periods of micro sleep were thought to be the most likely cause of people falling asleep at the wheel while driving, Cirelli says.

But the new research found that even before that stage, brains are already showing sleep-like activity that impairs them, she says.

As reported in the current issue of Nature, the researchers inserted probes into specific groups of neurons in the brains of freely-behaving rats. After the rats were kept awake for prolonged periods, the probes showed areas of "local sleep" despite the animals' appearance of being awake and active.

"Even when some neurons went off line, the overall EEG measurements of the brain indicated wakefulness in the rats," Cirelli says.

And there were behavioral consequences to the local sleep episodes.

"When we prolonged the awake period, we saw the rats start to make mistakes," Cirelli says.

When animals were challenged to do a tricky task, such as reaching with one paw to get a sugar pellet, they began to drop the pellets or miss in reaching for them, indicating that a few neurons might have gone off line.

"This activity happened in few cells," Cirelli adds. "For instance, out of 20 neurons we monitored in one experiment, 18 stayed awake. From the other two, there were signs of sleep -- brief periods of activity alternating with periods of silence."

The researchers tested only motor tasks, so they concluded from this study that neurons affected by local sleep are in the motor cortex.

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Functioning Synapse Created Using Carbon Nanotubes: Devices Might Be Used in Brain Prostheses or Synthetic Brains

Functioning Synapse Created Using Carbon Nanotubes: Devices Might Be Used in Brain Prostheses or Synthetic Brains

  1:38:00 AM    Science Lover

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Engineering researchers the University of Southern California have made a significant breakthrough in the use of nanotechnologies for the construction of a synthetic brain. They have built a carbon nanotube synapse circuit whose behavior in tests reproduces the function of a neuron, the building block of the brain.

This image shows nanotubes used in synthetic 
synapse and apparatus used to create them. 
(Credit: USC Viterbi School of Engineering)

The team, which was led by Professor Alice Parker and Professor Chongwu Zhou in the USC Viterbi School of Engineering Ming Hsieh Department of Electrical Engineering, used an interdisciplinary approach combining circuit design with nanotechnology to address the complex problem of capturing brain function.

In a paper published in the proceedings of the IEEE/NIH 2011 Life Science Systems and Applications Workshop in April 2011, the Viterbi team detailed how they were able to use carbon nanotubes to create a synapse.

Carbon nanotubes are molecular carbon structures that are extremely small, with a diameter a million times smaller than a pencil point. These nanotubes can be used in electronic circuits, acting as metallic conductors or semiconductors.

"This is a necessary first step in the process," said Parker, who began the looking at the possibility of developing a synthetic brain in 2006. "We wanted to answer the question: Can you build a circuit that would act like a neuron? The next step is even more complex. How can we build structures out of these circuits that mimic the function of the brain, which has 100 billion neurons and 10,000 synapses per neuron?"

Parker emphasized that the actual development of a synthetic brain, or even a functional brain area is decades away, and she said the next hurdle for the research centers on reproducing brain plasticity in the circuits.

The human brain continually produces new neurons, makes new connections and adapts throughout life, and creating this process through analog circuits will be a monumental task, according to Parker.

She believes the ongoing research of understanding the process of human intelligence could have long-term implications for everything from developing prosthetic nanotechnology that would heal traumatic brain injuries to developing intelligent, safe cars that would protect drivers in bold new ways.

For Jonathan Joshi, a USC Viterbi Ph.D. student who is a co-author of the paper, the interdisciplinary approach to the problem was key to the initial progress. Joshi said that working with Zhou and his group of nanotechnology researchers provided the ideal dynamic of circuit technology and nanotechnology.

"The interdisciplinary approach is the only approach that will lead to a solution. We need more than one type of engineer working on this solution," said Joshi. "We should constantly be in search of new technologies to solve this problem."

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Mechanism of Long-Term Memory Identified

Mechanism of Long-Term Memory Identified

  12:59:00 AM    Science Lover

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Using advanced imaging technology, scientists from the Florida campus of The Scripps Research Institute have identified a change in chemical influx into a specific set of neurons in the common fruit fly that is fundamental to long-term memory.

Researchers have identified a change in chemical influx 
into a specific set of neurons in the common fruit fly that 
is fundamental to long-term memory. 
(Credit: © Sebastian Kaulitzki / Fotolia)

The study was published in the April 13, 2011 issue of The Journal of Neuroscience.

"In studying fruit flies' learning and long-term memory storage, we observed an increase in calcium influx into a specific set of brain neurons in normal fruit flies that was absent in 26 different mutants known to impair long-term memory,," said Ron Davis, chair of the Scripps Research Department of Neuroscience, who led the study. "This logical conclusion is that this increase, which we call a memory trace, is a signature component of long-term memory."

The memory trace in question is an increased influx of calcium into a set of neurons after long-term memory forms in a part of the insect brain known as mushroom bodies, a pair of oversized lobes known to mediate learning and memory, particularly the memories of smell. They have been compared to the hippocampus, a site of memory formation in humans.

Increases in calcium influx also occur with learning in other animal models, Davis said, and it seems highly likely a similar correlation exists in humans.

Measuring Memory Traces


To measure the changes in the Drosophila neurons, Davis and his colleagues used functional optical imaging, an advanced technology that his laboratory helped pioneer for the study of learning and memory. Using protein sensors that become fluorescent when calcium levels are increased, the team was able to highlight changes in the levels of calcium influx into the mushroom body neurons in response to odor learning. These observed memory traces occur in parallel with behavioral changes.

Interestingly, these memory traces occur only with spaced conditioning -- where the insects receive multiple episodes of learning but with periods of rest between each episode. Spaced conditioning is required for long-term memories to form.

In an earlier study last December, also published in The Journal of Neuroscience, Davis found not only that fruit flies receiving spaced conditioning exhibited a long-term memory trace, but also that their memories lasted between four and seven days. In flies that were given a single episode of learning, memory formation lasted only a day and the long-term memory trace failed to form. These two studies are the newest in a series of six studies on the topic, including those published in the journal Neuron in 2004 and 2006, Cell in 2005, and Nature Neuroscience in 2008. Davis reviewed all of his studies of memory traces in the most recent issue of Neuron.

"The phenomenon of spaced conditioning is conserved across all species," Davis said. "No one really knows why it's important to long-term memory formation but there appears to be something magical about that rest period during learning."

The study was supported by the National Institutes of Health.

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Masked Fears: Are Fears That Are Seemingly Overcome Only Hidden?

Masked Fears: Are Fears That Are Seemingly Overcome Only Hidden?

  8:34:00 AM    Science Lover

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Fear is a natural part of our emotional life and acts as a necessary protection mechanism. However, fears sometimes grow beyond proportions and become difficult to shed. Scientists from Freiburg, Basel and Bordeaux have used computer simulations to understand the processes within the brain during the formation and extinction of fears.

One group of nerve cells in the brain controls the fear 
behaviour (right). This can be suppressed by a second 
group of nerve cells (left) -- but the fear is only masked, 
and has not disappeared completely. (Credit: Carlos 
Toledo/Bernstein Center Freiburg)

In the current issue of the scientific journal PLoS Computational Biology, Ioannis Vlachos from the Bernstein Center Freiburg and colleagues propose for the first time an explanation for how fears that were seemingly overcome are in reality only hidden.

The reason for the persistency of fears is that, literally, their roots run deep: Far below the cerebral cortex lies the "amygdala," which plays a crucial role in fear processes. Fear is commonly investigated in mice by exposing them simultaneously to a neutral stimulus -- a certain sound, for example -- and an unpleasant one. This leads to the animals being frightened of the sound as well. Context plays an important role in this case: If the scaring sound is played repeatedly in a new context without anything bad happening, the mice shed their fear again. It returns immediately, however, if the sound is presented in the original, or even a completely novel context. Had the mice not unlearned to be frightened after all?

The fact that fears can be "masked" has been known for some time. Recently, two co-authors of the present study discovered that two groups of nerve cells within the amygdala are involved in this process. By creating a model of the amygdala's neuronal network, Ioannis Vlachos and colleagues were now able to find an explanation for how such a masking of fears is implemented in the brain: One group of cells is responsible for the fear response, the second for its suppression. Activity of the latter inhibits the former and, thus, prevents fear signals to be transmitted to other parts of the brain. Nevertheless, the change in their connections that resulted in an increased activity in the fear-coding neurons in the first place, is still present. As soon as the masking by the fear-suppressing neurons disappears, for example by changing the context, these connections come into action again -- the fear returns.

According to the scientists, these insights can be transferred to us humans, helping to treat fears more successfully in the future.

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Depression Drugs-SSRIs-May Reorganize Brain Plasticity, New Research Suggests

Depression Drugs-SSRIs-May Reorganize Brain Plasticity, New Research Suggests

  9:19:00 AM    Science Lover

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Selective serotonin reuptake inhibitors (SSRI) such as Prozac are regularly used to treat severe anxiety and depression. They work by immediately increasing the amount of serotonin in the brain and by causing long term changes in brain function. However it can take weeks of treatment before a patient feels any effect and both beneficial effects and side effects can persist after treatment is stopped.

New research investigates physiological changes within the brain that may be caused by selective serotonin reuptake inhibitors. (Credit: iStockphoto/Sebastian Kaulitzki)

New research published by BioMed Central's open access journal Molecular Brain investigates physiological changes within the brain that may be caused by SSRI treatment.

The hippocampus is an area of the brain involved in long term memory and spatial awareness, and is involved in symptoms afflicting people with Alzheimer's disease, such as loss of memory and disorientation. Neuronal cells in the hippocampus can change their activity and strength of connections throughout life, a process known as plasticity, which thought to be one of the ways new memories are formed. Altered plasticity is often associated with depression and stress.

Researchers from the Department of Pharmacology, Nippon Medical School, showed that chronic treatment of adult mice with fluoxetine (Prozac) caused changes to granule cells, one of the main types of neuronal cells inside the hippocampus, and to their connections with other neuronal cells. The granule cells appeared to undergo serotonin-dependent 'dematuration', which increased their activity and reversed adult-type plasticity into an immature state. These changes to the cell's plasticity were associated with increased anxiety and in alternating between periods of hyper or hypo activity.

Katsunori Kobayashi explained, "Some of the side effects associated with Prozac in humans, such as anxiety and behavioral switching patterns, may be due to excessive dematuration of granule cells in the hippocampus."

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New Light-Sensing Mechanism Found in Neurons

New Light-Sensing Mechanism Found in Neurons

  1:06:00 AM    Science Lover

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A UC Irvine research team led by Todd C. Holmes has discovered a second form of phototransduction light sensing in cells that is derived from vitamin B2. This discovery may reveal new information about cellular processes controlled by light.

This image shows blue-light sensing arousal neurons. (Credit: UCI)

For more than 100 years, it had been believed that the phototransduction process was solely based on a chemical derived from vitamin A called retinal. Phototransduction is the conversion of light signals into electrical signals in photoreceptive neurons and underlies both image-forming and non-image-forming light sensing.
In discovering this new light-sensing phototransduction mechanism, the UCI scientists found that phototransduction can also be mediated by a protein called cryptochrome, which uses a B2 vitamin chemical derivative for light sensing. Cryptochromes are blue-light photoreceptors found in circadian and arousal neurons that regulate slow biochemical processes, but this is the first time they have been linked to rapid phototransduction.

Their work appears March 3 on online Express site for the journal Science.

"This is totally novel mechanism that does not depend on retinal," said Holmes, a professor of physiology & biophysics. "This discovery opens whole new technology opportunities for adapting light-sensing proteins to drive medically relevant cellular activities."

This basic science breakthrough -- "which literally and figuratively came 'out of the blue,'" Holmes said -- has implications in the fast-growing field of optogenetics. Optogenetics combines optical and genetic research techniques to probe neural circuits at the high speeds needed to understand brain information processing. In one area, it is being used to understand how treatments such as deep brain massage can aid people with neurodegenerative diseases.

Holmes' team found that cryptochrome mediates phototransduction directly in fruit fly circadian and arousal neurons in response to blue-light wavelengths. The researchers also found that they could genetically express cryptochrome in neurons that are not ordinarily electrically responsive to light to make them light responsive.

Keri Fogel, Kelly Parson and Nicole Dahm of UCI contributed to the study, which received National Institutes of Health support.

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Brain Cell Communication: Why It's So Fast

Brain Cell Communication: Why It's So Fast

  11:55:00 PM    Science Lover

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Billions of brain cells are communicating at any given moment. Like an organic supercomputer they keep everything going, from breathing to solving riddles, and "programming errors" can lead to serious conditions such as schizophrenia, Parkinson's Disease and attention-deficit hyperactivity disorder.

Vesicle with three "linking bridges". (Credit: Image courtesy of University of Copenhagen)

The brain uses biochemical signal molecules

Today, the biochemical language of the nerve cells is the subject of intensive research right down at the molecular level, and for the first time researchers, some from the University of Copenhagen, have described just how nerve cells are capable of transmitting signals practically simultaneously.

The cells of the nervous system communicate using small molecule neurotransmitters such as dopamine, serotonin and noradrenalin. Dopamine is associated with cognitive functions such as memory, serotonin with mood control, and noradrenaline with attention and arousal.

The brain cell communication network, the synapses, transmit messages via chemical neurotransmitters packaged in small containers (vesicles) waiting at the nerve ends of the synapses. An electrical signal causes the containers and membrane to fuse and the neurotransmitters flow from the nerve ending to be captured by other nerve cells. This occurs with immense rapidity in a faction of a millisecond.

The vesicle uses three copies of the "linking bridge"

Researchers from the Universities of Copenhagen, Göttingen and Amsterdam have been studying the complex organic protein complexes that link vesicles and membrane prior to fusion, in order to find an explanation for the rapidity of these transmissions. They have discovered that the vesicle contains no fewer than three copies of the linking bridge or "SNARE complex."

With only one SNARE complex the vesicle takes longer to fuse with the membrane and the neurotransmitter is therefore secreted more slowly.

"The precursors for the SNARE complexes are present in the vesicles before they reach the target membrane," said Professor Jakob Balsev Sørensen from the Department of Neuroscience and Pharmacology at the University of Copenhagen. "Fast (synchronous) fusion is enabled when at least three of them work in tandem. If the vesicle only has one SNARE complex it can still fuse with the target membrane, but it takes much longer."

The discovery has just been published in Science.

"Our next step will be to investigate the factors that influence and regulate the number of SNARE complexes in the vesicles. Is this a way for the nerve cells to choose to communicate more or less rapidly, and is this regulation altered when the brain is diseased?", professor Sørensen says.

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