SINGLE NEURON HUB ORCHESTRATES ACTIVITY OF AN ENTIRE BRAIN CIRCUIT

The idea of mapping the brain is not new. Researchers have known for years that the key to treating, curing, and even preventing brain disorders such as Alzheimer's disease, epilepsy, and traumatic brain injury, is to understand how the brain records, processes, stores, and retrieves information

New Tel Aviv University research published in PLOS Computational Biology makes a major contribution to efforts to navigate the brain. The study, by Prof. Eshel Ben-Jacob and Dr. Paolo Bonifazi of TAU's School of Physics and Astronomy and Sagol School of Neuroscience, and Prof. Alessandro Torcini and Dr. Stefano Luccioli of the Instituto dei Sistemi Complessi, under the auspices of TAU's Joint Italian-Israeli Laboratory on Integrative Network Neuroscience, offers a precise model of the organization of developing neuronal circuits.

In an earlier study of the hippocampi of newborn mice, Dr. Bonifazi discovered that a few "hub neurons" orchestrated the behavior of entire circuits. In the new study, the researchers harnessed cutting-edge technology to reproduce these findings in a computer-simulated model of neuronal circuits. "If we are able to identify the cellular type of hub neurons, we could try to reproduce them in vitro out of stem cells and transplant these into aged or damaged brain circuitries in order to recover functionality," said Dr. Bonifazi.

Flight dynamics and brain neurons

"Imagine that only a few airports in the world are responsible for all flight dynamics on the planet," said Dr. Bonifazi. "We found this to be true of hub neurons in their orchestration of circuits' synchronizations during development. We have reproduced these findings in a new computer model."

According to this model, one stimulated hub neuron impacts an entire circuit dynamic; similarly, just one muted neuron suppresses all coordinated activity of the circuit. "We are contributing to efforts to identify which neurons are more important to specific neuronal circuits," said Dr. Bonifazi. "If we can identify which cells play a major role in controlling circuit dynamics, we know how to communicate with an entire circuit, as in the case of the communication between the brain and prosthetic devices."

Conducting the orchestra of the brain

In the course of their research, the team found that the timely activation of cells is fundamental for the proper operation of hub neurons, which, in turn, orchestrate the entire network dynamic. In other words, a clique of hubs works in a kind of temporally-organized fashion, according to which "everyone has to be active at the right time," according to Dr. Bonifazi.

Coordinated activation impacts the entire network. Just by alternating the timing of the activity of one neuron, researchers were able to affect the operation of a small clique of neurons, and finally that of the entire network.

"Our study fits within framework of the 'complex network theory,' an emerging discipline that explores similar trends and properties among all kinds of networks -- i.e., social networks, biological networks, even power plants," said Dr. Bonifazi. "This theoretical approach offers key insights into many systems, including the neuronal circuit network in our brains."

Parallel to their theoretical study, the researchers are conducting experiments on in vitro cultured systems to better identify electrophysiological and chemical properties of hub neurons. The joint Italy-Israel laboratory is also involved in a European project aimed at linking biological and artificial neuronal circuitries to restore lost brain functions.

EARTHQUAKES PROVE TO BE AN UNEXPECTED HELP IN INTERPRETING BRAIN ACTIVITY OF VERY PREMATURE BABIES

University of Helsinki researchers have partnered with Swedish and Australian researchers to create a "brainstorm barometer," which allows computers to calculate the brain functions of very premature babies during their first hours of life. The new research method is based on the hypothesis that the brainstorms generated by the billions of neurons inside a baby's head are governed by the same rules as other massive natural phenomena, such as earthquakes, forest fires or snow avalanches.

Giant strides have been taken in the early care of very premature infants in postnatal intensive care units during the past two decades. Doctors can now support the function of especially the lungs, heart and the circulatory system so as to guarantee the survival of most of even extremely premature infants. Despite a good start, many of these may still have lifelong problems with brain function, such as attention deficit disorders or difficulty with visual function. For this reason, the primary focus of developing care for premature infants has been on securing brain development.

The biggest risks in the development of a very premature baby are concentrated on the first days of life, when intensive care seeks to find the care balance suitable for each individual child.

"At this stage it would be vitally important to be able to track the child's brain function and to identify the babies whose brains are at particular risk," says Sampsa Vanhatalo, PhD, who leads the University of Helsinki's Baby Brain Activity (BABA) research group based at the HUS Children's Hospital.

The brains of very premature babies being treated in intensive care have been tracked with continuous electroencephalography (EEG) monitoring, but evaluating the EEG results has proven to be a challenge:

"The brain function of very premature babies is completely different from that of older children or adults, meaning that the currently used methods of EEG interpretation are poorly suited for use on premature babies," Vanhatalo explains.

Storms help the brain mature

Researchers have found that certain episodes, brainstorms of a kind, occur in the brains of very premature babies and are critical for the maturation of the baby's brain. Together with Swedish and Australian researchers, Vanhatalo has now developed a completely new way of evaluating such brainstorms in newborn very premature infants.

"Our research was published in the journal Brain, and it is the result of exceptionally broad-based international cooperation. It involved specialists of different medical fields, physicists, mathematicians and engineers," Vanhatalo says.

The patient material for the research came from Dr. Lena Hellström-Westas' research on premature babies in Sweden. Hellström-Westas is a professor in neonatology at Uppsala University. Vanhatalo contributed the neurophysiological expertise of his research group. Finally, Professor Michael Breakspear's computational neuroscience research group in Australia developed a new kind of analysis method for the EEG signal.

The laws of nature hold true in the brain

Breakspear's research group began to develop mathematical methods used in geology and basic physics research after it was found that the brainstorms in very premature babies were astonishingly similar to the "crackling noise" that occurs on small scales in weakly magnetised metals and large-scales during earthquakes.

Ultimately, the research groups worked together to generate a clear instrument, a brainstorm barometer if you will, which can be used by a computer to calculate the state of a very premature baby's brain during the first hours of life. Of greatest clinical interest was the observation that the results from this barometer correlated significantly with the child's cognitive development at age two.

"In terms of science, this has already revolutionised the idea of what we can observe of the brain function in very premature babies. This method is the first source of objective data on the messages the brain of a very premature baby may be sending to the doctors taking care of the child during the first hours of life," Vanhatalo describes. "It's still too early to say how the brainstorm measurements we have discovered will impact the care given to each premature baby. Our discovery helps doctors identify which children are in need of special attention, and which ones have brains that are fine on their own. This is crucial information that opens the door for new targeted care studies."

The EEG instrument created in the study is a collection of sophisticated mathematical functions, combined ingeniously to create a software component for analysing the EEG signal. This component can be added to the software of existing brain monitors. In terms of technology, the adoption of the method is no more difficult than downloading new apps onto our smartphones.

"The interest of EEG monitor manufacturers to engage in product development will be the bottleneck. Luckily the market is very competitive, and new manufacturers need to introduce innovations that are necessary for hospital work," Vanhatalo points out.

TARANTULA VENOM ILLUMINATES ELECTRICAL ACTIVITY IN LIVE CELLS

Researchers at the University of California, Davis, Lawrence Berkeley National Laboratory and Marine Biological Laboratory in Woods Hole, Massachusetts, have created a cellular probe that combines a tarantula toxin with a fluorescent compound to help scientists observe electrical activity in neurons and other cells. The probe binds to a voltage-activated potassium ion channel subtype, lighting up when the channel is turned off and dimming when it is activated.

This is the first time researchers have been able to visually observe these electrical signaling proteins turn on without genetic modification. These visualization tools are prototypes of probes that could some day help researchers better understand the ion channel dysfunctions that lead to epilepsy, cardiac arrhythmias and other conditions. The study appears in the Proceedings of the National Academy of Sciences (PNAS)on October 20.

"Ion channels have been called life's transistors because they act like switches, generating electrical feedback" said senior author Jon Sack, assistant professor of physiology and membrane biology at UC Davis. "To understand how neural systems or the heart works, we need to know which switches are activated. These probes tell us when certain switches turn on."

Voltage-gated channels are proteins that allow specific ions, such as potassium or calcium, to flow in and out of cells. They perform a critical function, generating an electrical current in neurons, muscles and other cells. There are many different types, including more than 40 potassium channels. Though other methods can very precisely measure electrical activity in a cell, it has been difficult to differentiate which specific channels are turning on.

"There are about 40 voltage-gated potassium channel genes that are basically doing the same thing, and it's been shockingly hard to figure out which ones are doing something that's physiologically relevant," Sack said.

The tarantula toxin, guangxitoxin-1E, was an ideal choice because it naturally binds to the Kv2 channels. These channels are expressed in most, if not all, neurons, yet their regulation and activity are complex and actively debated. Sack and his laboratory worked closely with Bruce Cohen, a scientist in the Lawrence Berkeley Lab's Molecular Foundry, who has been studying how fluorescent molecules and nanoparticles can be used to image live cells.s

To study the channels, the team engineered variants of tarantula toxin that could be fluorescently labeled and retain function. These probes were designed to bind to the potassium channels when they were at rest and let go when they became active. The researchers then tested them on living cells. To their surprise, the probes worked right away.

"A lot of times you see ambiguous results, but when we added the probes to living cells there was a very clear signal," Sack said. "When we added potassium to stimulate the cells, the probes fell right off."

While this is just a first step towards imaging the activity of potassium and possibly other ion channels, this approach holds vast potential to help scientists understand the underlying mechanisms behind cardiac arrhythmias, muscle defects and other channelopathies.

"There are dozens of known channelopathies, and more being uncovered at an increasing pace" Sack said. "If you have electrical signaling, you have to have a potassium channel, and when that channel goes bad, the cell doesn't work the same anymore. For example, the Kv2.1 channel that this probe binds to leads to epilepsy when it's not functioning properly."

In addition, the ability to better observe electrical signaling could help researchers map the brain at its most basic levels.

"Understanding the molecular mechanisms of neuronal firing is a fundamental problem in unraveling the complexities of brain function," Cohen said.

While creating a probe that can read whether the Kv2.1 channel is firing or at rest is an important proof-of-concept, there's still a lot of work to be done. Sack and Cohen will continue to collaborate, testing other types of spider venoms that bind to different potassium channels.

"The beauty of this is the potential," Sack said. "This is a toehold into a new way of visualizing electrical activity, and there's a huge family of spider toxins that target different ion channels. We've tagged a Ford, we should be able to tag a Chevy."

MOTHERS SOOTHING PRESENCE MAKES PAIN GO AWAY CHANGES GENE ACTIVITY IN INFANTS BRAIN

A mother's "TLC" not only can help soothe pain in infants, but it may also impact early brain development by altering gene activity in a part of the brain involved in emotions, according to new study from NYU Langone Medical Center.

By carefully analyzing what genes were active in infant rat brains when the mother was present or not present, the NYU researchers found that several hundred genes were more, or less, active in rat infants experiencing pain than in those that were not. With their mothers present, however, fewer than 100 genes were similarly expressed.

According to senior study investigator and neurobiologist Regina Sullivan, PhD, who is scheduled to present her team's findings at the Society for Neuroscience annual meeting in Washington, D.C., on Nov. 18, the research is believed to be the first to show the short-term effects of maternal caregiving in a distressed infant pup's brain. The study was also designed to support her research into the long-term consequences of differences in how mammals, including humans, are nurtured from birth.

"Our study shows that a mother comforting her infant in pain does not just elicit a behavioral response, but also the comforting itself modifies -- for better or worse -- critical neural circuitry during early brain development," says Sullivan, a professor at the NYU School of Medicine and its affiliated Nathan S. Kline Institute for Psychiatric Research.

For the study, researchers performed genetic analyses on tissue from the almond-sized amygdala region of the infant rat pups' brains that is responsible for processing emotions, such as fear and pleasure.

Sullivan, whose earlier research showed how the mother's presence controlled electrical signaling in the infant pup's brain, says her latest findings shed insight on the complexity of treating pain in newborns.

"Nobody wants to see an infant suffer, in rats or any other species," says Sullivan. "But if opiate drugs are too dangerous to use in human infants because of their addictive properties, then the challenge remains for researchers to find alternative environmental stimuli, including maternal presence, coddling, or other cues, such as a mother's scent, that could relieve the pain."

Sullivan cautions, however, that the long-term consequences of these genetic modifications must also be compared to the short-term benefits for tying pain stimuli during infancy to such a powerful symbol of safety and security as the infant's mother.

"The more we learn about nurturing the infant brain during infancy, the better prepared we are to deal long-term with treating problems that arise from pain, and physical and mental abuse experienced during infancy," says Sullivan.