Neuroscientists discover new ‘mini-neural computer’ in the brain

Dendrites, the branch-like projections of neurons, were once thought to be passive wiring in the brain. But now researchers at the University of North Carolina at Chapel Hill have shown that these dendrites do more than relay information from one neuron to the next. They actively process information, multiplying the brain’s computing power.

“Suddenly, it’s as if the processing power of the brain is much greater than we had originally thought,” said Spencer Smith, PhD, an assistant professor in the UNC School of Medicine.

His team’s findings, published October 27 in the journal Nature, could change the way scientists think about long-standing scientific models of how neural circuitry functions in the brain, while also helping researchers better understand neurological disorders.

Axons are where neurons conventionally generate electrical spikes, but many of the same molecules that support axonal spikes are also present in the dendrites. Previous research using dissected brain tissue had demonstrated that dendrites can use those molecules to generate electrical spikes themselves, but it was unclear whether normal brain activity uses those dendritic spikes. For example, could dendritic spikes be involved in how we see?

The answer, Smith’s team found, is yes. Dendrites effectively act as mini-neural computers, actively processing neuronal input signals themselves.

Directly demonstrating this required a series of intricate experiments that took years and spanned two continents, beginning in senior author Michael Hausser’s lab at University College London, and being completed after Smith and Ikuko Smith, PhD, DVM, set up their own lab at the University of North Carolina. They used patch-clamp electrophysiology to attach a microscopic glass pipette electrode, filled with a physiological solution, to a neuronal dendrite in the brain of a mouse. The idea was to directly “listen” in on the electrical signaling process.

“Attaching the pipette to a dendrite is tremendously technically challenging,” Smith said. “You can’t approach the dendrite from any direction. And you can’t see the dendrite. So you have to do this blind. It’s like fishing but all you can see is the electrical trace of a fish.” And you can’t use bait. “You just go for it and see if you can hit a dendrite,” he said. “Most of the time you can’t.”

But Smith built his own two-photon microscope system to make things easier.

Once the pipette was attached to a dendrite, Smith’s team took electrical recordings from individual dendrites within the brains of anesthetized and awake mice. As the mice viewed visual stimuli on a computer screen, the researchers saw an unusual pattern of electrical signals – bursts of spikes – in the dendrite.

Smith’s team then found that the dendritic spikes occurred selectively, depending on the visual stimulus, indicating that the dendrites processed information about what the animal was seeing.

To provide visual evidence of their finding, Smith’s team filled neurons with calcium dye, which provided an optical readout of spiking. This revealed that dendrites fired spikes while other parts of the neuron did not, meaning that the spikes were the result of local processing within the dendrites.

Study co-author Tiago Branco, PhD, created a biophysical, mathematical model of neurons and found that known mechanisms could support the dendritic spiking recorded electrically, further validating the interpretation of the data.

“All the data pointed to the same conclusion,” Smith said. “The dendrites are not passive integrators of sensory-driven input; they seem to be a computational unit as well.”

His team plans to explore what this newly discovered dendritic role may play in brain circuitry and particularly in conditions like Timothy syndrome, in which the integration of dendritic signals may go awry.

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Traumatic Brain Injury Research Advances with $18.8M NIH Award

The National Institutes of Health is awarding $18.8 million over five years to support worldwide research on concussion and traumatic brain injury.

The NIH award, part of one of the largest international research collaborations ever coordinated by funding agencies, will be administered through UC San Francisco.

The award supports a team of U.S. researchers at more than 20 institutions throughout the country who are participating in the International Traumatic Brain Injury (InTBIR) Initiative, a collaborative effort of the European Commission, the Canadian Institutes of Health Research (CIHR), the National Institutes of Health (NIH) and the U.S. Department of Defense (DOD).

Although the potential long-term harms due to concussions and blows to the head have gained more attention recently – due in part to media coverage of the experiences of athletes and of soldiers returning from the Middle East – traumatic brain injuries, or TBI, that results from automobile crashes or other common accidents impacts many more people.

Many of those who are affected by TBI are never diagnosed, according to UCSF neurosurgeon Geoffrey Manley, MD, PhD, a principal investigator for the grant who will serve as the U.S. research team’s primary liaison to the NIH, and the chief of neurosurgery at the UCSF-affiliated San Francisco General Hospital, a Level-1 trauma center. SFGH was the first medical center in the nation to achieve certification from the Joint Commission for the treatment of TBI.

The U.S. Centers for Disease Control and Prevention estimates that 2 percent of the U.S. population now lives with TBI-caused disabilities, at an annual cost of about $77 billion.

“Each year in the United States, at least 1.7 million people seek medical attention for TBI,” Manley said. “It is a contributing factor in a third of all injury-related deaths.”

In the work funded by the NIH grant – which also is supported by contributions from the private sector and from the nonprofit One Mind for Research – the researchers aim to refine and improve diagnosis and treatment of TBI, which often has insidious health effects, but which frequently is undiagnosed, misdiagnosed, inadequately understood and undertreated, according to Manley.

New Approach to Lead to Patient-Specific Treatments

“After three decades of failed clinical trials, a new approach is needed,” Manley said. “We expect that our approach will permit researchers to better characterize and stratify patients, will allow meaningful comparisons of treatments and outcomes, and will improve the next generation of clinical trials. The work will advance our understanding of TBI and lead to more effective, patient-specific treatments.”

Since 2009, Manley and Pratik Mukherjee, MD, PhD, a professor of radiology and biomedical imaging at UCSF, have helped lay the groundwork for the continuing TBI research by leading the NIH-funded TRACK-TBI project, through which they and their research collaborators have demonstrated the value of gathering common data across research sites, including a standardized approach to imaging, clinical data, bio-specimens, and tracking outcomes.

Already, TRACK-TBI researchers have made progress toward more useful classification and prognosis of TBI.

Earlier this year, they reported that cases of concussion, or TBI that are classified as “mild” by standard criteria but that show abnormalities on early magnetic resonance imaging (MRI) scans, are much more likely to have worse outcomes three months after the scan in comparison to cases in which scans reveal no abnormalities. Furthermore, the researchers found that elevated blood levels of a protein released during brain injury was associated with the likelihood of an abnormal CT scan.

The new NIH award funds a continuation and expansion of TRACK-TBI. Among the goals is the creation of a widely accessible, comprehensive “TBI information commons” to integrate clinical, imaging, proteomic, genomic and outcome biomarkers from subjects across the age and injury spectra. Another goal is to establish the value of biomarkers that will improve classification of TBI and better optimize selection and assignment of patients for clinical trials.

The researchers also aim to evaluate measures to assess patient outcomes across all phases of recovery and at all levels of TBI severity, to determine which tests, treatments, and services are effective and appropriate – depending on the nature of TBI in particular patients.

In addition to Manley and Mukherjee, principal investigators for the newly funded project include Claudia Robertson, MD, Baylor College of Medicine; Joseph Giacino, PhD, Harvard University; Ramon Diaz-Arrastia, MD, PhD, Uniformed Services University of the Health Sciences; David Okonkwo, MD, PhD, University of Pittsburgh; and Nancy Temkin, PhD, University of Washington. Each of these leading experts has worked in the TBI field for two decades or more.

“The principal investigators bring expertise in neurosurgery, neurology, neuroradiology, critical care medicine, rehabilitation medicine, neuropsychology and biostatistics, all of which are essential and do not reside in any single individual,” Manley said.

International Funding and Collaboration

TRACK-TBI clinical enrollment sites throughout the United States will enroll 3,000 patients across the spectrum of mild to severe brain injuries. Clinical, imaging, proteomic, genomic and clinical outcome databases will be linked into a shared platform that will promote a model for collaboration among scientists within InTBIR and elsewhere.

In addition to the U.S. award, the European Commission, the executive body of the European Union, has awarded €35.2 million to fund the Collaborative European NeuroTrauma Effectiveness-TBI (CENTER-TBI) consortium, also part of the InTBIR. This project will collect data in over 5,000 patients across Europe, where 38 scientific institutes and more than 60 hospitals will participate.

In Canada, CIHR and its national partners also have made a multimillion dollar investment in TBI research, the details of which will be formally announced in the near future.

The InTBIR Scientific Advisory Committee met in Vancouver, British Columbia, on Oct. 17-18, and awardees from all three jurisdictions (EU, USA, Canada) now are aligning efforts to share resources and collaborate on strategies for achieving the InTBIR goals.

Study points to possible treatment for brain disorders

Clemson University scientists are working to determine how neurons are generated, which is vital to providing treatment for neurological disorders like Tuberous Sclerosis Complex (TSC).

TSC is a rare genetic disease that causes the growth of tumors in the brain and other vital organs and may indicate such disorders as autism, epilepsy and cognitive impairment that may arise from the abnormal generation of neurons.

“Current medicine is directed at inhibiting the mammalian target of rapamycin (mTOR), a common feature within these tumors that have abnormally high activity,” said David M. Feliciano, assistant professor of biological sciences. “However, current treatments have severe side effects, likely due to mTOR’s many functions and playing an important role in cell survival, growth and migration.”

Feliciano and colleagues published their findings in journal Cell Reports.

“Neural stem cells generate the primary communicating cells of the brain called neurons through the process of neurogenesis, yet how this is orchestrated is unknown,” said Feliciano.

The stem cells lie at the core of brain development and repair, and alterations in the cells’ self-renewal and differentiation can have major consequences for brain function at any stage of life, according to researchers.

To better understand the process of neurogenesis, the researchers used a genetic approach known as neonatal electroporation to deliver pieces of DNA into neural stem cells in young mice, which allowed them to express and control specific components of the mTOR pathway.

The researchers found that when they increase activity of the mTOR pathway, neural stem cells make neurons at the expense of making more stem cells. They also found that this phenomenon is linked to a specific mTOR target known as 4E-BP2, which regulates the production of proteins. 

Ultimately, this study points to a possible new treatment, 4E-BP2, for neurodevelopmental disorders like TSC and may have fewer side effects.

Future experiments are aimed at identifying which proteins are synthesized due to this pathway in neurological disorders.

Learning dialects shapes brain areas that process spoken language

Using advanced imaging to visualize brain areas used for understanding language in native Japanese speakers, a new study from the RIKEN Brain Science Institute finds that the pitch-accent in words pronounced in standard Japanese activates different brain hemispheres depending on whether the listener speaks standard Japanese or one of the regional dialects.

Psychologists report new insights on human brain, consciousness

UCLA psychologists have used brain-imaging techniques to study what happens to the human brain when it slips into unconsciousness. Their research, published Oct. 17 in the online journal PLOS Computational Biology, is an initial step toward developing a scientific definition of consciousness.

"In terms of brain function, the difference between being conscious and unconscious is a bit like the difference between driving from Los Angeles to New York in a straight line versus having to cover the same route hopping on and off several buses that force you to take a ‘zig-zag’ route and stop in several places," said lead study author Martin Monti, an assistant professor of psychology and neurosurgery at UCLA.

Monti and his colleagues used functional magnetic resonance imaging (fMRI) to study how the flow of information in the brains of 12 healthy volunteers changed as they lost consciousness under anesthesia with propofol. The participants ranged in age from 18 to 31 and were evenly divided between men and women.

The psychologists analyzed the “network properties” of the subjects’ brains using a branch of mathematics known as graph theory, which is often used to study air-traffic patterns, information on the Internet and social groups, among other topics.

"It turns out that when we lose consciousness, the communication among areas of the brain becomes extremely inefficient, as if suddenly each area of the brain became very distant from every other, making it difficult for information to travel from one place to another," Monti said.

The finding shows that consciousness does not “live” in a particular place in our brain but rather “arises from the mode in which billions of neurons communicate with one another,” he said.

When patients suffer severe brain damage and enter a coma or a vegetative state, Monti said, it is very possible that the sustained damage impairs their normal brain function and the emergence of consciousness in the same manner as was seen by the life scientists in the healthy volunteers under anesthesia.

"If this were indeed the case, we could imagine in the future using our technique to monitor whether interventions are helping patients recover consciousness," he said.

"It could, however, also be the case that losing consciousness because of brain injury affects brain function through different mechanisms," said Monti, whose research team is currently addressing this question in another study.

"As profoundly defining of our mind as consciousness is, without having a scientific definition of this phenomenon, it is extremely difficult to study," Monti noted. This study, he said, marks an initial step toward conducting neuroscience research on consciousness.

The research was conducted at Belgium’s University Hospital of Liege.

Monti’s expertise includes cognitive neuroscience, the relationship between language and thought, and how consciousness is lost and recovered after severe brain injury. He was part of a team of American and Israeli brain scientists who used fMRI on former Israeli Prime Minister Ariel Sharon in January 2013 to assess his brain responses.

Surprisingly, Sharon, who was presumed to be in a vegetative state since suffering a brain hemorrhage in 2006, showed significant brain activity, Monti and his colleagues reported.

The former prime minister was scanned to assess the extent and quality of his brain processing, using methods recently developed by Monti and his colleagues. The scientists found subtle but encouraging signs of consciousness.

Keep your friends close, but …

Counterintuitive findings from a new USC study show that the part of the brain that is associated with empathizing with the pain of others is activated more strongly by watching the suffering of hateful people as opposed to likable people.

Scientists expand the genetic code of mammals to control protein activity in neurons with light

With the flick of a light switch, researchers at the Salk Institute for Biological Studies can change the shape of a protein in the brain of a mouse, turning on the protein at the precise moment they want. This allows the scientists to observe the exact effect of the protein’s activation. The new method, described in the Oct. 16, 2013, issue of the journal Neuron, relies on specially engineered amino acids—the molecules that make up proteins—and light from an LED. Now that it has been shown to work, the technique can be adapted to give researchers control of a wide variety of other proteins in the brain to study their functions.

"What we are now able to do is not only control neuronal activity, but control a specific protein within a neuron," says senior study author Lei Wang, an associate professor in Salk’s Jack H. Skirball Center for Chemical Biology and Proteomics and holder of the Frederick B. Rentschler Developmental Chair.

If a scientist wants to know what set of neurons in the brain is responsible for a particular action or behavior, being able to turn the neurons on and off at will gives the researcher a targeted way to test the neurons’ effects. Likewise, if they want to know the role of a certain protein inside the cells, the ability to activate or inactivate the protein of interest is key to studying its biology.

Over the past decade, researchers have developed a handful of ways of activating or inactivating neurons using light, as part of the burgeoning field of so-called optogenetics. In optogenetic experiments, mice are genetically engineered to have a light-sensitive channel from algae integrated into their neurons. When exposed to light, the channel opens or closes, changing the flow of molecules into the neuron and altering its ability to pass an electrochemical message through the brain. Using such optogenetic approaches, scientists can pick and choose which neurons in the brain they want turned on or off at any given time and observe the resulting change in the engineered mice.

"There’s no question that this is a great way to control neuronal activity, by borrowing light-responsive channels or pumps from other organisms and putting them in neurons," says Wang. "But rather than put a stranger into neurons, we wanted to control the activity of proteins native to neurons."

To make proteins respond to light, Wang’s team harnessed a photo-responsive amino acid, called Cmn, which has a large chemical structure. When a pulse of light shines on the molecule, Cmn’s bulky side chain breaks off, leaving cysteine, a smaller amino acid. Wang’s group realized that if a single Cmn was integrated into the right place in the structure of a protein, the drastic change in the amino acid’s size could activate or inactivate the entire protein.

To test their idea, Wang and his colleagues engineered new versions of a potassium channel in neurons, adding Cmn to their sequence.

"Basically the idea was that when you put this amino acid in the pore of the channel, the bulky side chain entirely blocks the passage of ions through the channel," explains Ji-Yong Kang, a graduate student who works in Wang’s group, and first author of the new paper. "Then, when the bond in the amino acid breaks in response to light, the channel is opened up."

The method worked in isolated cells: after trial and error, the scientists found the ideal spot in the channel to put Cmn, so that the channel was initially blocked, but opened when light shone on it. They were able to measure the change to the channel’s properties by recording the electrical current that flowed through the cells before and after exposure to light.

But to apply the technique to living mice, Wang and his colleagues needed to change the animals’ genetic code—the built-in instructions that cells use to produce proteins based on gene sequences. The normal genetic code doesn’t contain information on Cmn, so simply injecting Cmn amino acids into mice wouldn’t lead to the molecules being integrated into proteins. In the past, the Wang group and others have expanded the genetic codes of isolated cells of simple organisms like bacteria, or yeast, inserting instructions for a new amino acid. But the approach had never been successful in mammals. Through a combination of techniques and new tricks, however, Wang’s team was able to provide embryonic mice with the instructions for the new amino acid, Cmn. With the help from Salk Professor Dennis O’Leary and his research associate Daichi Kawaguchi, they then integrated the new Cmn-containing channel into the brains of the developing mice, and showed that by shining light on the brain tissue they could force the channel open, altering patterns of neuron activity. It was not only a first for expanding the genetic code of mammals, but also for protein control.

At the surface, the new approach has the same result as optogenetic approaches to studying the brain—neurons are silenced at a precise time in response to light. But Wang’s method can now be used to study a whole cadre of different proteins in neurons. Aside from being used to open and close channels or pores that let ions flow in and out of brain cells, Cmn could be used to optically regulate protein modifications and protein-protein interactions.

"We can pinpoint exactly which protein, or even which part of a protein, is crucial for the functioning of targeted neurons," says Wang. "If you want to study something like the mechanism of memory formation, it’s not always just a matter of finding what neurons are responsible, but what molecules within those neurons are critical."

Earlier this year, President Obama announced the multi-billion dollar Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, a ten-year project to map the activity of the human brain. Creating new ways to study the molecules in the brain, such as using light-responsive amino acids to study neuronal proteins, will be key to moving forward on this initiative and similar efforts to understand the brain, says Wang. His lab is now working to develop ways to not only activate proteins, but inactive them using light-sensitive amino acids, and applying the technique to proteins other than Kir2.1.