For the first time in a large study sample, the decline in brain function in normal aging is conclusively shown to be influenced by genes, say researchers from the Texas Biomedical Research Institute and Yale University.

“Identification of genes associated with brain aging should improve our understanding of the biological processes that govern normal age-related decline,” said John Blangero, Ph.D., a Texas Biomed geneticist and the senior author of the paper. The study, funded by the National Institutes of Health (NIH),  is published in the November 4, 2013 issue of the Proceedings of the National Academy of Sciences. David Glahn, Ph.D., an associate professor of psychiatry at the Yale University School of Medicine, is the first author on the paper.

In large pedigrees including 1,129 people aged 18 to 83, the scientists documented profound aging effects from young adulthood to old age, on neurocognitive ability and brain white matter measures. White matter actively affects how the brain learns and functions. Genetic material shared amongst biological relatives appears to predict the observed changes in brain function with age.

Participants were enrolled in the Genetics of Brain Structure and Function Study and drawn from large Mexican Americans families in San Antonio. Brain imaging studies were conducted at the University of Texas Health Science Center at San Antonio Research Imaging Institute  directed by  Peter Fox, M.D.

“The use of large human pedigrees provides a powerful resource for measuring how genetic factors change with age,” Blangero said.

By applying a sophisticated analysis, the scientists demonstrated a heritable basis for neurocognitive deterioration with age that could be attributed to genetic factors. Similarly, decreasing white matter integrity with age was influenced by genes., The investigators further demonstrated that different sets of genes are responsible for these two biological aging processes.

 “A key advantage of this study is that we specifically focused on large extended families and so we were able to disentangle genetic from non-genetic influences on the aging process,” said Glahn.

(Source: txbiomed.org)

50 years after valproate was first discovered, research published today in the journal Neurobiology of Disease, reports how the drug works to block seizure progression.

Valproate (variously labelled worldwide as Epilim, Depacon, Depakene, Depakote, Orlept, Episenta, Orfiril, and Convulex) is one of the world’s most highly prescribed treatments for epilepsy. It was first discovered to be an effective treatment for epilepsy, by accident, in 1963 by a group of French scientists. In thousands of subsequent experiments, animals have been used to investigate how valproate blocks seizures, without success. Scientists from Royal Holloway and University College London have now identified how valproate blocks seizures in the brain, by using a simple amoeba.

“The discovery of how valproate blocks seizures, initially using the social amoeba Dictyostelium, and then replicated using accepted seizure models, highlights the successful use of non-animal testing in biomedical research,” said Professor Robin Williams from the School of Biological Sciences at Royal Holloway.

“Sodium valproate is one of the most effective antiepileptic drugs in many people with epilepsy, but its use has been limited by side-effects, in particular its effect in pregnant women on the unborn child,” said Professor Matthew Walker from the Institute of Neurology at University College London. “Understanding valproate’s mechanism of action is a first step to developing even more effective drugs that lack many of valproate’s side-effects.

“Our study also found that the decrease of a specific chemical in the brain at the start of the seizure causes even more seizure activity. This holds important implications for identifying underlying causes,” added Professor Williams.

(Source: rhul.ac.uk)

Kessler researchers find aerobic exercise benefits memory in persons with multiple sclerosis

A research study headed by Victoria Leavitt, Ph.D. and James Sumowski, Ph.D., of Kessler Foundation, provides the first evidence for beneficial effects of aerobic exercise on brain and memory in individuals with multiple sclerosis (MS). The article, “Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: Preliminary findings,” was released as an epub ahead of print on October 4 by Neurocase: The Neural Basis of Cognition. The study was funded by Kessler Foundation.

Hippocampal atrophy seen in MS is linked to the memory deficits that affect approximately 50% of individuals with MS. Despite the prevalence of this disabling symptom, there are no effective pharmacological or behavioral treatments. “Aerobic exercise may be the first effective treatment for MS patients with memory problems,” noted Dr. Leavitt, research scientist in Neuropsychology & Neuroscience Research at Kessler Foundation. “Moreover, aerobic exercise has the advantages of being readily available, low cost, self-administered, and lacking in side effects.” No beneficial effects were seen with non-aerobic exercise. Dr. Leavitt noted that the positive effects of aerobic exercise were specific to memory; other cognitive functions such as executive functioning and processing speed were unaffected.

The study’s participants were two MS patients with memory deficits who were randomized to non-aerobic (stretching) and aerobic (stationary cycling) conditions. Baseline and follow-up measurements were recorded before and after the treatment protocol of 30-minute exercise sessions 3 times per week for 3 months. Data were collected by high-resolution MRI (neuroanatomical volumes), fMRI (functional connectivity), and memory assessment. Aerobic exercise resulted in a 16.5% increase in hippocampal volume, a 53.7% increase in memory, and increased hippocampal resting-state functional connectivity. Non-aerobic exercise resulted in minimal change in hippocampal volume and no changes in memory or functional connectivity.

“These findings clearly warrant large-scale clinical trials of aerobic exercise for the treatment of memory deficits in the MS population,” said James Sumowski„ Ph.D., research scientist in Neuropsychology & Neuroscience Research at Kessler Foundation. 

(Source: kesslerfoundation.org)

It was once thought that each cell in a person’s body possesses the same DNA code and that the particular way the genome is read imparts cell function and defines the individual. For many cell types in our bodies, however, that is an oversimplification. Studies of neuronal genomes published in the past decade have turned up extra or missing chromosomes, or pieces of DNA that can copy and paste themselves throughout the genomes.

The only way to know for sure that neurons from the same person harbor unique DNA is by profiling the genomes of single cells instead of bulk cell populations, the latter of which produce an average. Now, using single-cell sequencing, Salk Institute researchers and their collaborators have shown that the genomic structures of individual neurons differ from each other even more than expected. The findings were published November 1, 2013, in Science.

"Contrary to what we once thought, the genetic makeup of neurons in the brain aren’t identical, but are made up of a patchwork of DNA," says corresponding author Fred Gage, Salk’s Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.

In the study, led by Mike McConnell, a former junior fellow in the Crick-Jacobs Center for Theoretical and Computational Biology at the Salk, researchers isolated about 100 neurons from three people posthumously. The scientists took a high-level view of the entire genome—looking for large deletions and duplications of DNA called copy number variations or CNVs—and found that as many as 41 percent of neurons had at least one unique, massive CNV that arose spontaneously, meaning it wasn’t passed down from a parent. The CNVs are spread throughout the genome, the team found.

The miniscule amount of DNA in a single cell has to be chemically amplified many times before it can be sequenced. This process is technically challenging, so the team spent a year ruling out potential sources of error in the process.

"A good bit of our study was doing control experiments to show that this is not an artifact," says Gage. "We had to do that because this was such a surprise—finding out that individual neurons in your brain have different DNA content."

The group found a similar amount of variability in CNVs within individual neurons derived from the skin cells of three healthy people. Scientists routinely use such induced pluripotent stem cells (iPSCs) to study living neurons in a culture dish. Because iPSCs are derived from single skin cells, one might expect their genomes to be the same.

"The surprising thing is that they’re not," says Gage. "There are quite a few unique deletions and amplifications in the genomes of neurons derived from one iPSC line."

Interestingly, the skin cells themselves are genetically different, though not nearly as much as the neurons. This finding, along with the fact that the neurons had unique CNVs, suggests that the genetic changes occur later in development and are not inherited from parents or passed to offspring.

It makes sense that neurons have more diverse genomes than skin cells do, says McConnell, who is now an assistant professor of biochemistry and molecular genetics at the University of Virginia School of Medicine in Charlottesville. “The thing about neurons is that, unlike skin cells, they don’t turn over, and they interact with each other,” he says. “They form these big complex circuits, where one cell that has CNVs that make it different can potentially have network-wide influence in a brain.”

Spontaneously occurring CNVs have also been linked to risk for brain disorders such as schizophrenia and autism, but those studies usually pool many blood cells. As a result, the CNVs uncovered in those studies affect many if not all cells, which suggests that they arise early in development.

The purpose of CNVs in the healthy brain is still unclear, but researchers have some ideas. The modifications might help people adapt to new surroundings encountered over a lifetime, or they might help us survive a massive viral infection. The scientists are working out ways to alter genomic variability in iPSC-derived neurons and challenge them in specific ways in the culture dish.

Cells with different genomes probably produce unique RNA and then proteins. However, for now, only one sequencing technology can be applied to a single cell.

"If and when more than one method can be applied to a cell, we will be able to see whether cells with different genomes have different transcriptomes (the collection of all the RNA in a cell) in predictable ways," says McConnell.

In addition, it will be necessary to sequence many more cells, and in particular, more cell types, notes corresponding author Ira Hall, an associate professor of biochemistry and molecular genetics at the University of Virginia. “There’s a lot more work to do to really understand to what level we think the things we’ve found are neuron-specific or associated with different parameters like age or genotype,” he says.

(Source: salk.edu)

Excessive fear can develop after a traumatic experience, leading to anxiety disorders such as post-traumatic stress disorder and phobias. During exposure therapy, an effective and common treatment for anxiety disorders, the patient confronts a fear or memory of a traumatic event in a safe environment, which leads to a gradual loss of fear. A new study in mice, published online today in Neuron, reports that exposure therapy remodels an inhibitory junction in the amygdala, a brain region important for fear in mice and humans. The findings improve our understanding of how exposure therapy suppresses fear responses and may aid in developing more effective treatments. The study, led by researchers at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts, was partially funded by a New Innovator Award from the Office of the Director at the National Institutes of Health.

A fear-inducing situation activates a small group of neurons in the amygdala. Exposure therapy silences these fear neurons, causing them to be less active. As a result of this reduced activity, fear responses are alleviated. The research team sought to understand how exactly exposure therapy silences fear neurons.

The researchers found that exposure therapy not only silences fear neurons but also induces remodeling of a specific type of inhibitory junction, called the perisomatic synapse. Perisomatic inhibitory synapses are connections between neurons that enable one group of neurons to silence another group of neurons. Exposure therapy increases the number of perisomatic inhibitory synapses around fear neurons in the amygdala. This increase provides an explanation for how exposure therapy silences fear neurons.

“The increase in number of perisomatic inhibitory synapses is a form of remodeling in the brain. Interestingly, this form of remodeling does not seem to erase the memory of the fear-inducing event, but suppresses it,” said senior author, Leon Reijmers, Ph.D., assistant professor of neuroscience at Tufts University School of Medicine and member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

Reijmers and his team discovered the increase in perisomatic inhibitory synapses by imaging neurons activated by fear in genetically manipulated mice. Connections in the human brain responsible for suppressing fear and storing fear memories are similar to those found in the mouse brain, making the mouse an appropriate model organism for studying fear circuits.

Mice were placed in a box and experienced a fear-inducing situation to create a fear response to the box. One group of mice, the control group, did not receive exposure therapy. Another group of mice, the comparison group, received exposure therapy to alleviate the fear response. For exposure therapy, the comparison group was repeatedly placed in the box without experiencing the fear-inducing situation, which led to a decreased fear response in these mice. This is also referred to as fear extinction.

The researchers found that mice subjected to exposure therapy had more perisomatic inhibitory synapses in the amygdala than mice who did not receive exposure therapy. Interestingly, this increase was found around fear neurons that became silent after exposure therapy.

“We showed that the remodeling of perisomatic inhibitory synapses is closely linked to the activity state of fear neurons. Our findings shed new light on the precise location where mechanisms of fear regulation might act. We hope that this will lead to new drug targets for improving exposure therapy,” said first author, Stéphanie Trouche, Ph.D., a former postdoctoral fellow in Reijmers’ lab at Tufts and now a medical research council investigator scientist at the University of Oxford in the United Kingdom.

“Exposure therapy in humans does not work for every patient, and in patients that do respond to the treatment, it rarely leads to a complete and permanent suppression of fear. For this reason, there is a need for treatments that can make exposure therapy more effective,” Reijmers added.

(Source: now.tufts.edu)

It doesn’t take a Watson to realize that even the world’s best supercomputers are staggeringly inefficient and energy-intensive machines.

Our brains have upwards of 86 billion neurons, connected by synapses that not only complete myriad logic circuits; they continuously adapt to stimuli, strengthening some connections while weakening others. We call that process learning, and it enables the kind of rapid, highly efficient computational processes that put Siri and Blue Gene to shame.

Materials scientists at the Harvard School of Engineering and Applied Sciences (SEAS) have now created a new type of transistor that mimics the behavior of a synapse. The novel device simultaneously modulates the flow of information in a circuit and physically adapts to changing signals.

Exploiting unusual properties in modern materials, the synaptic transistor could mark the beginning of a new kind of artificial intelligence: one embedded not in smart algorithms but in the very architecture of a computer. The findings appear in Nature Communications.

“There’s extraordinary interest in building energy-efficient electronics these days,” says principal investigator Shriram Ramanathan, associate professor of materials science at Harvard SEAS. “Historically, people have been focused on speed, but with speed comes the penalty of power dissipation. With electronics becoming more and more powerful and ubiquitous, you could have a huge impact by cutting down the amount of energy they consume.”

The human mind, for all its phenomenal computing power, runs on roughly 20 Watts of energy (less than a household light bulb), so it offers a natural model for engineers.

“The transistor we’ve demonstrated is really an analog to the synapse in our brains,” says co-lead author Jian Shi, a postdoctoral fellow at SEAS. “Each time a neuron initiates an action and another neuron reacts, the synapse between them increases the strength of its connection. And the faster the neurons spike each time, the stronger the synaptic connection. Essentially, it memorizes the action between the neurons.”

In principle, a system integrating millions of tiny synaptic transistors and neuron terminals could take parallel computing into a new era of ultra-efficient high performance.

While calcium ions and receptors effect a change in a biological synapse, the artificial version achieves the same plasticity with oxygen ions. When a voltage is applied, these ions slip in and out of the crystal lattice of a very thin (80-nanometer) film of samarium nickelate, which acts as the synapse channel between two platinum “axon” and “dendrite” terminals. The varying concentration of ions in the nickelate raises or lowers its conductance—that is, its ability to carry information on an electrical current—and, just as in a natural synapse, the strength of the connection depends on the time delay in the electrical signal.

Structurally, the device consists of the nickelate semiconductor sandwiched between two platinum electrodes and adjacent to a small pocket of ionic liquid. An external circuit multiplexer converts the time delay into a magnitude of voltage which it applies to the ionic liquid, creating an electric field that either drives ions into the nickelate or removes them. The entire device, just a few hundred microns long, is embedded in a silicon chip.

The synaptic transistor offers several immediate advantages over traditional silicon transistors. For a start, it is not restricted to the binary system of ones and zeros.

“This system changes its conductance in an analog way, continuously, as the composition of the material changes,” explains Shi. “It would be rather challenging to use CMOS, the traditional circuit technology, to imitate a synapse, because real biological synapses have a practically unlimited number of possible states—not just ‘on’ or ‘off.’”

The synaptic transistor offers another advantage: non-volatile memory, which means even when power is interrupted, the device remembers its state.

Additionally, the new transistor is inherently energy efficient. The nickelate belongs to an unusual class of materials, called correlated electron systems, that can undergo an insulator-metal transition. At a certain temperature—or, in this case, when exposed to an external field—the conductance of the material suddenly changes.

“We exploit the extreme sensitivity of this material,” says Ramanathan. “A very small excitation allows you to get a large signal, so the input energy required to drive this switching is potentially very small. That could translate into a large boost for energy efficiency.”

The nickelate system is also well positioned for seamless integration into existing silicon-based systems.

“In this paper, we demonstrate high-temperature operation, but the beauty of this type of a device is that the ‘learning’ behavior is more or less temperature insensitive, and that’s a big advantage,” says Ramanathan. “We can operate this anywhere from about room temperature up to at least 160 degrees Celsius.”

For now, the limitations relate to the challenges of synthesizing a relatively unexplored material system, and to the size of the device, which affects its speed.

“In our proof-of-concept device, the time constant is really set by our experimental geometry,” says Ramanathan. “In other words, to really make a super-fast device, all you’d have to do is confine the liquid and position the gate electrode closer to it.”

In fact, Ramanathan and his research team are already planning, with microfluidics experts at SEAS, to investigate the possibilities and limits for this “ultimate fluidic transistor.”

He also has a seed grant from the National Academy of Sciences to explore the integration of synaptic transistors into bioinspired circuits, with L. Mahadevan, Lola England de Valpine Professor of Applied Mathematics, professor of organismic and evolutionary biology, and professor of physics.

“In the SEAS setting it’s very exciting; we’re able to collaborate easily with people from very diverse interests,” Ramanathan says.

For the materials scientist, as much curiosity derives from exploring the capabilities of correlated oxides (like the nickelate used in this study) as from the possible applications.

“You have to build new instrumentation to be able to synthesize these new materials, but once you’re able to do that, you really have a completely new material system whose properties are virtually unexplored,” Ramanathan says. “It’s very exciting to have such materials to work with, where very little is known about them and you have an opportunity to build knowledge from scratch.”

“This kind of proof-of-concept demonstration carries that work into the ‘applied’ world,” he adds, “where you can really translate these exotic electronic properties into compelling, state-of-the-art devices.”

(Source: seas.harvard.edu)

Many animals have highly developed senses, such as vision in carnivores, touch in mice, and hearing in bats. New research from the RIKEN Brain Science Institute has uncovered a brain molecule that can explain the existence of such finely-tuned sensory capabilities, revealing how brain cells responsible for specific senses are positioned to receive incoming sensory information.

(Source: riken.jp)