Nerve impulses can collide and continue unaffected

According to the traditional theory of nerves, two nerve impulses sent from opposite ends of a nerve annihilate when they collide. New research from the Niels Bohr Institute now shows that two colliding nerve impulses simply pass through each other and continue unaffected. This supports the theory that nerves function as sound pulses. The results are published in the scientific journal Physical Review X.

Nerve signals control the communication between the billions of cells in an organism and enable them to work together in neural networks. But how do nerve signals work?

Old model

In 1952, Hodgkin and Huxley introduced a model in which nerve signals were described as an electric current along the nerve produced by the flow of ions. The mechanism is produced by layers of electrically charged particles (ions of sodium and potassium) on either side of the nerve membrane that change places when stimulated. This change in charge creates an electric current.

This model has enjoyed general acceptance. For more than 60 years, all medical and biology textbooks have said that nerves function is due to an electric current along the nerve pathway. However, this model cannot explain a number of phenomena that are known about nerve function.

New model

Researchers at the Niels Bohr Institute at the University of Copenhagen have now conducted experiments that raise doubts about this well-established model of electrical impulses along the nerve pathway.

“According to the theory of this ion mechanism, the electrical signal leaves an inactive region in its wake, and the nerve can only support new signals after a short recovery period of inactivity. Therefore, two electrical impulses sent from opposite ends of the nerve should be stopped after colliding and running into these inactive regions,” explains Thomas Heimburg, Professor and head of the Membrane Biophysics Group at the Niels Bohr Institute at the University of Copenhagen.

Thomas Heimburg and his research group conducted experiment in the laboratory using nerves from earthworms and lobsters. The nerves were removed and used in an experiment which allowed the researchers to stimulate the nerve fibres with electrodes on both ends. Then they measured the signals en route. 

“Our study showed that the signals passed through each other completely unhindered and unaltered. That’s how sound waves work. A sound wave doesn’t stop when it meets another sound wave. Both waves continue on unimpeded. The nerve impulse can therefore be explained by the fact that the pulse is a mechanical wave in the form of a sound pulse, a soliton, that moves along the nerve membrane,” explains Thomas Heimburg.

The theory is confirmed

When the sound pulse moves through the nerve pathway, the membrane changes locally from a liquid to a more solid form. The membrane is compressed slightly, and this change leads to an electrical pulse as a consequence of the piezoelectric effect.

“The electrical signal is thus not based on an electric current but is caused by a mechanical force,” points out Thomas Heimburg.

Thomas Heimburg, along with Professor Andrew Jackson, first proposed the theory that nerves function by sound pulses in 2005. Their research has since provided support for this theory, and the new experiments offer additional confirmation for the theory that nerve signals are sound pulses.

Zebrafish Model of a Learning and Memory Disorder Shows Better Way to Target Treatment

Using a zebrafish model of a human genetic disease called neurofibromatosis (NF1), a team from the Perelman School of Medicine at the University of Pennsylvania has found that the learning and memory components of the disorder are distinct features that will likely need different treatment approaches. They published their results this month in Cell Reports.

NF1 is one of the most common inherited neurological disorders, affecting about one in 3,000 people. It is characterized by tumors, attention deficits, and learning problems. Most people with NF1 have symptoms before the age of 10. Therapies target Ras, a protein family that guides cell proliferation. The NF1 gene encodes neurofibromin, a very large protein with a small domain involved in Ras regulation.

Unexpectedly, the Penn team showed that some of the behavioral defects in mutant fish are not related to abnormal Ras, but can be corrected by drugs that affect another signaling pathway controlled by the small molecule cAMP. They used the zebrafish model of NF1 to show that memory defects – such as the recall of a learned task — can be corrected by drugs that target Ras, while learning deficits are corrected by modulation of the cAMP pathway. Overall, the team’s results have implications for potential therapies in people with NF1.

“We now know that learning and memory defects in NF1 are distinct and potentially amenable to drug therapy,” says co-senior author Jon Epstein, MD, chair of the department of Cell and Developmental Biology. “Our data convincingly show that memory defects in mutant fish are due to abnormal Ras activity, but learning defects are completely unaffected by modulation of these pathways. Rather these deficits are corrected with medicines that modulate cAMP.”

Over the last 20 years, zebrafish have become great models for studying development and disease. Like humans, zebrafish are vertebrates, and most of the genes required for normal embryonic development in zebrafish are also present in humans. When incorrectly regulated, these same genes often cause tumor formation and metastatic cancers.

Zebrafish have also become an ideal model for studying vertebrate neuroscience and behavior. In fact, co-senior author Michael Granato, PhD, professor of Cell and Developmental Biology, has developed the first high-throughput behavioral assays that measure learning and memory in fish. For example, Granato explains, “normal fish startle with changes in noise and light level by bending and swimming away from the annoying stimuli and do eventually habituate, that is get used to the alternations in their environment. But, NF1 fish mutants fail to habituate. However, after adding cAMP to their water, they do learn, and then behave like the non-mutant fish.”

This clearly indicates that learning deficits in the NF1 mutant fish are corrected by adding various substances that boost cAMP signaling. “Our data also indicate that learning and memory defects are reversible with acute pharmacologic treatments and are therefore not hard-wired, as might be expected for a defect in the development of nerves,” says Epstein. “This offers great hope for therapeutic intervention for NF1 patients.”

The interactive brain

Neuroscientist explores mechanism that can cause deficit in working memory

Amy Griffin, associate professor of psychological and brain sciences at the University of Delaware, has received a five-year, $1.78 million grant from the National Institute of Mental Health to support her research into the brain mechanisms of working memory.

A neuroscientist, Griffin has been interested for some time in the interaction between the prefrontal cortex, located at the front of the brain, and the hippocampus, a region in the temporal lobe of the brain. When the two areas fail to work together, that failure appears to be correlated with deficits in working memory, a condition that commonly occurs in schizophrenia, general anxiety and other psychiatric disorders.

The hippocampus is the portion of the brain responsible for memory, while the prefrontal cortex controls executive function, a term that includes such cognitive abilities as problem-solving, planning and abstract thinking.

“These are two areas of the brain that are far apart, but their oscillations [rhythmic activities] are synchronized,” Griffin said. “When one area is active, so is the other.”

Working memory, sometimes called short-term memory, is “the kind of memory that fails when you walk into a room and forget why you came there,” she said.

When the oscillations in the hippocampus and prefrontal cortex are out of sync, deficits of working memory occur. In those cases, Griffin said, “both regions are active, but they’re not talking to each other.” The mechanism that causes that lack of communication has not been well explored, and her research will seek to do that.

Griffin and her research team plan to conduct two types of experiments. One will inhibit activity in a brain region called the nucleus reuniens, a region that is hypothesized to synchronize the hippocampus and prefrontal cortex and is expected to cause impairments with working memory. In the other experiment, researchers will activate the nucleus reuniens to increase synchrony, hoping to learn if that improves working memory.

The research will employ a cutting-edge technique called optogenetics, a process that uses proteins to make neurons sensitive to light and then uses light to control them. 

“Optogenetics is becoming a common technique,” Griffin said. “It’s a way to study these processes on a millisecond timescale.” 

A 2013 article in the journal Nature Neuroscience said optogenetics “is transforming the field of neuroscience. For the first time, it is now possible to use light to both trigger and silence activity in genetically defined populations of neurons with millisecond precision.”

Griffin, using a rat model, will inject the light-sensitizing substance — a harmless virus — into the nucleus reuniens and then use a laser to inhibit or activate this brain region. The rats then perform tasks that assess their working memory. Synchronization between the hippocampus and prefrontal cortex will also be recorded, with the prediction that the degree of the working memory impairment will be correlated with reductions in synchrony.

“Our experiments will not be interfering with the activities of the hippocampus or the prefrontal cortex within themselves,” Griffin said. “We want to affect only the ability of the structures to talk to each other.”

Compound protects brain cells after traumatic brain injury

A new class of compounds has now been shown to protect brain cells from the type of damage caused by blast-mediated traumatic brain injury (TBI). Mice that were treated with these compounds 24-36 hours after experiencing TBI from a blast injury were protected from the harmful effects of TBI, including problems with learning, memory, and movement.

Traumatic brain injury caused by blast injury has emerged as a common health problem among U.S. servicemen and women, with an estimated 10 to 20 percent of the more than 2 million U.S. soldiers deployed in Iraq or Afghanistan having experienced TBI. The condition is associated with many neurological complications, including cognitive and motor decline, as well as acquisition of psychiatric symptoms like anxiety and depression, and brain tissue abnormalities that resemble Alzheimer’s disease.

"The lack of neuroprotective treatments for traumatic brain injury is a serious problem in our society," says Andrew Pieper, senior study author and associate professor of psychiatry, neurology, and radiation oncology at the University of Iowa Carver College of Medicine. “Everyone involved in this work is motivated to find a way to offer hope for patients, which today include both military personnel and civilians, by establishing a basis for a new treatment to combat the deleterious neuropsychiatric outcomes after blast injury.”

It is known that TBI, as well as certain neurodegenerative diseases, damages axons—the tendril-like fibers that sprout from brains cells (neurons) and form the connections called synapses. In TBI, axon damage is followed by death of the neuron. The new study, published Sept. 11 in the journal Cell Reports, shows that a group of compounds, called the P7C3 series, blocks axon damage and preserves normal brain function following TBI.

Pieper led the team of scientists that discovered the P7C3 compound several years ago at UT Southwestern Medical Center. Subsequent studies showed that the root compound and its active analogs protect newborn neurons from cell death and also protect mature neurons in animal models of neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

The researchers have also previously shown efficacy of P7C3 molecules in brain injury due to concussion, and plan to investigate whether these compounds might be applicable in stroke as well, given that there appear to be common factors mediating neuronal cell death in these conditions.

By tweaking the structure of the original P7C3 compound, Pieper and his colleagues Joseph Ready and Steven McKnight, at UT Southwestern Medical Center, have further improved its potency and drug-like properties. In the latest study, Pieper’s team at the UI Carver College of Medicine, including co-first authors graduate student Terry Yin, senior technician Jeremy Britt, and graduate student Hector De Jesus-Cortes, tested the neuroprotective effects of the newest version, (-)-P7C3-S243, which can be given orally, in mice with blast-induced TBI.

In the study, blast-induced TBI caused learning, memory, and movement problems in the mice, which resemble the problems experienced by people affected by TBI. The researchers found that (-)-P7C3-S243 prevented acute memory and learning impairment caused by TBI. The compound also prevented TBI-associated balance and coordination problems in mice exposed to blast-injury. By examining the brain tissue at a cellular level, the team also found that the protection afforded to brain functions after injury was matched by preservation of normal neuronal axon structure and synaptic neurotransmission.

Importantly, the compound still produced its protective effects even when treatment was delayed until 24 to 36 hours after the blast injury.

"Seeing protection even when the compound was given this long after injury was important because it represents a liberal window of time within which almost all patients would be expected to be able to access treatment after injury," Pieper says.

The team also found that learning, memory, and coordination problems caused by the TBI persisted in untreated mice at least eight months after the single injury occurred, suggesting that the compound actually prevented these problems rather simply speeding up a normal recovery process.

In a separate study led by Pieper’s colleagues McKnight and Ready at UT Southwestern, and also published on Sept. 11 in the journal Cell, the team has identified the biological mechanism by which P7C3 compounds act in the brain. The compounds activate the molecular pathway that preserves neuronal levels of an energy molecule known as nicotinamide adenine dinucleotide (NAD).

"Based on the well-established role of NAD in axonal degeneration, the ability of (-)-P7C3-S243 to protect mice after blast-mediated traumatic brain injury is likely related to preservation of NAD levels," Pieper explains. "Now that we understand the mechanism of action of the P7C3 class of compounds, we can see why they should have therapeutic utility in an unusually broad spectrum of neurodegenerative conditions, without impeding any of a number of other normal forms of cell death.

"Our ultimate goal is to facilitate development of a new class of neuroprotective drugs with wide applicability to treating patients with TBI and other currently untreatable forms of neurodegeneration," he adds.

Tipping the Balance of Behavior

Humans with autism often show a reduced frequency of social interactions and an increased tendency to engage in repetitive solitary behaviors. Autism has also been linked to dysfunction of the amygdala, a brain structure involved in processing emotions. Now Caltech researchers have discovered antagonistic neuron populations in the mouse amygdala that control whether the animal engages in social behaviors or asocial repetitive self-grooming. This discovery may have implications for understanding neural circuit dysfunctions that underlie autism in humans.

This discovery, which is like a “seesaw circuit,” was led by postdoctoral scholar Weizhe Hong in the laboratory of David J. Anderson, the Seymour Benzer Professor of Biology at Caltech and an investigator with the Howard Hughes Medical Institute. The work was published online on September 11 in the journal Cell. 

"We know that there is some hierarchy of behaviors, and they interact with each other because the animal can’t exhibit both social and asocial behaviors at the same time. In this study, we wanted to figure out how the brain does that," Anderson says.

Anderson and his colleagues discovered two intermingled but distinct populations of neurons in the amygdala, a part of the brain that is involved in innate social behaviors. One population promotes social behaviors, such as mating, fighting, or social grooming, while the other population controls repetitive self-grooming—an asocial behavior.

Interestingly, these two populations are distinguished according to the most fundamental subdivision of neuron subtypes in the brain: the “social neurons” are inhibitory neurons (which release the neurotransmitter GABA, or gamma-aminobutyric acid), while the “self-grooming neurons” are excitatory neurons (which release the neurotransmitter glutamate, an amino acid).

To study the relationship between these two cell types and their associated behaviors, the researchers used a technique called optogenetics. In optogenetics, neurons are genetically altered so that they express light-sensitive proteins from microbial organisms. Then, by shining a light on these modified neurons via a tiny fiber optic cable inserted into the brain, researchers can control the activity of the cells as well as their associated behaviors.

Using this optogenetic approach, Anderson’s team was able to selectively switch on the neurons associated with social behaviors and those linked with asocial behaviors.

With the social neurons, the behavior that was elicited depended upon the intensity of the light signal. That is, when high-intensity light was used, the mice became aggressive in the presence of an intruder mouse. When lower-intensity light was used, the mice no longer attacked, although they were still socially engaged with the intruder—either initiating mating behavior or attempting to engage in social grooming.

When the neurons associated with asocial behavior were turned on, the mouse began self-grooming behaviors such as paw licking and face grooming while completely ignoring all intruders. The self-grooming behavior was repetitive and lasted for minutes even after the light was turned off.

The researchers could also use the light-activated neurons to stop the mice from engaging in particular behaviors. For example, if a lone mouse began spontaneously self-grooming, the researchers could halt this behavior through the optogenetic activation of the social neurons. Once the light was turned off and the activation stopped, the mouse would return to its self-grooming behavior.

Surprisingly, these two groups of neurons appear to interfere with each other’s function: the activation of social neurons inhibits self-grooming behavior, while the activation of self-grooming neurons inhibits social behavior. Thus these two groups of neurons seem to function like a seesaw, one that controls whether mice interact with others or instead focus on themselves. It was completely unexpected that the two groups of neurons could be distinguished by whether they were excitatory or inhibitory. “If there was ever an experiment that ‘carves nature at its joints,’” says Anderson, “this is it.”

This seesaw circuit, Anderson and his colleagues say, may have some relevance to human behavioral disorders such as autism.

"In autism," Anderson says, "there is a decrease in social interactions, and there is often an increase in repetitive, sometimes asocial or self-oriented, behaviors"—a phenomenon known as perseveration. "Here, by stimulating a particular set of neurons, we are both inhibiting social interactions and promoting these perseverative, persistent behaviors."

Studies from other laboratories have shown that disruptions in genes implicated in autism show a similar decrease in social interaction and increase in repetitive self-grooming behavior in mice, Anderson says. However, the current study helps to provide a needed link between gene activity, brain activity, and social behaviors, “and if you don’t understand the circuitry, you are never going to understand how the gene mutation affects the behavior.” Going forward, he says, such a complete understanding will be necessary for the development of future therapies.

But could this concept ever actually be used to modify a human behavior?

"All of this is very far away, but if you found the right population of neurons, it might be possible to override the genetic component of a behavioral disorder like autism, by just changing the activity of the circuits—tipping the balance of the see-saw in the other direction," he says.

Speech processing while unconscious: Sleep inhibits action but not preparation and meaning

In a team effort between the Medical Research Council Cognition and Brain Sciences Unit (Cambridge, UK) and the Laboratory of Cognitive and Psycholinguistics Sciences, Ecole Normale Superiore (Paris), part of what we are capable of while sleeping has been unravelled.

People were asked to classify words belonging to one of two categories – animals or objects – by pressing buttons with the left or the right hand, and continued to do so until they have fallen asleep. Their brain activity indicated that they were able to decode the meaning of the words and intended to act but the unconscious state during sleep prevented them from responding (no movement of the fingers).

This result indicates that once a rule (animals press left/objects press right) is established during wakefulness it can still be implemented even during sleep. This means that the decoding networks in the brain process the spoken words and that information (if it is an animal or an object for instance) is passed to a motor plan signaling the intention and subsequent action. During sleep that action is inhibited (we do not purposefully move during sleep) but this study has found that the meaning extraction and subsequent action preparation remained but was slower and lasted longer.

To confirm this result a second study tested whether people could classify word or nonwords (like boat or foat). A similar pattern emerged, showing appropriate brain preparation activity for left or right button presses even if responses were inhibited by the sleep mechanisms.

New Study Examines Impact of Violent Media on the Brain

With the longstanding debate over whether violent movies cause real world violence as a backstop, a study published today in PLOS One found that each person’s reaction to violent images depends on that individual’s brain circuitry, and on how aggressive they were to begin with.

The study, which was led by researchers at the Icahn School of Medicine at Mount Sinai and the NIH Intramural Program, featured brain scans which revealed that both watching and not watching violent images caused different brain activity in people with different aggression levels. The findings may have implications for intervention programs that seek to reduce aggressive behavior starting in childhood.

“Our aim was to investigate what is going on in the brains of people when they watch violent movies,” said lead investigator Nelly Alia-Klein, PhD, Associate Professor of Neuroscience and Psychiatry at the Friedman Brain Institute and Icahn School of Medicine at Mount Sinai. “We hypothesized that if people have aggressive traits to begin with, they will process violent media in a very different way as compared to non-aggressive people, a theory supported by these findings.”

After answering a questionnaire, a group of 54 men were split by the research team into two groups—one with individuals possessing aggressive traits, including a history of physical assault, and a second group without these tendencies. The participants’ brains were then scanned as they watched a succession of violent scenes (shootings and street fights) on day one, emotional, but non-violent scenes (people interacting during a natural disaster) on day two, and nothing on day three.

The scans measured the subjects’ brain metabolic activity, a marker of brain function. Participants also had their blood pressure taken every 5 minutes, and were asked how they were feeling at 15 minute intervals.

Investigators discovered that during mind wandering, when no movies were presented, the participants with aggressive traits had unusually high brain activity in a network of regions that are known to be active when not doing anything in particular. This suggests that participants with aggressive traits have a different brain function map than non-aggressive participants, researchers said.

Interestingly, while watching scenes from violent movies, the aggressive group had less brain activity than the non-aggressive group in the orbitofrontal cortex, a brain region associated by past studies with emotion-related decision making and self-control. The aggressive subjects described feeling more inspired and determined and less upset or nervous than non-aggressive participants when watching violent (day 1) versus just emotional (day 2) media. In line with these responses, while watching the violent media, aggressive participants’ blood pressure went down progressively with time while the non-aggressive participants experienced a rise in blood pressure.

“How an individual responds to their environment depends on the brain of the beholder,” said Dr. Alia-Klein. “Aggression is a trait that develops together with the nervous system over time starting from childhood; patterns of behavior become solidified and the nervous system prepares to continue the behavior patterns into adulthood when they become increasingly coached in personality. This could be at the root of the differences in people who are aggressive and not aggressive, and how media motivates them to do certain things. Hopefully these results will give educators an opportunity to identify children with aggressive traits and teach them to be more aware of how aggressive material activates them specifically.”

(Image credit)