Researchers Discover Link Between Fear and Sound Perception

Anyone who’s ever heard a Beethoven sonata or a Beatles song knows how powerfully sound can affect our emotions. But it can work the other way as well – our emotions can actually affect how we hear and process sound. When certain types of sounds become associated in our brains with strong emotions, hearing similar sounds can evoke those same feelings, even far removed from their original context. It’s a phenomenon commonly seen in combat veterans suffering from posttraumatic stress disorder (PTSD), in whom harrowing memories of the battlefield can be triggered by something as common as the sound of thunder. But the brain mechanisms responsible for creating those troubling associations remain unknown. Now, a pair of researchers from the Perelman School of Medicine at the University of Pennsylvania has discovered how fear can actually increase or decrease the ability to discriminate among sounds depending on context, providing new insight into the distorted perceptions of victims of PTSD. Their study is published in Nature Neuroscience.

“Emotions are closely linked to perception and very often our emotional response really helps us deal with reality,” says senior study author Maria N. Geffen, PhD, assistant professor of Otorhinolaryngology: Head and Neck Surgery and Neuroscience at Penn. “For example, a fear response helps you escape potentially dangerous situations and react quickly. But there are also situations where things can go wrong in the way the fear response develops. That’s what happens in anxiety and also in PTSD — the emotional response to the events is generalized to the point where the fear response starts getting developed to a very broad range of stimuli.”

Geffen and the first author of the study, Mark Aizenberg, PhD, a postdoctoral researcher in her laboratory, used emotional conditioning in mice to investigate how hearing acuity (the ability to distinguish between tones of different frequencies) can change following a traumatic event, known as emotional learning. In these experiments, which are based on classical (Pavlovian) conditioning, animals learn to distinguish between potentially dangerous and safe sounds — called “emotional discrimination learning.” This type of conditioning tends to result in relatively poor learning, but Aizenberg and Geffen designed a series of learning tasks intended to create progressively greater emotional discrimination in the mice, varying the difficulty of the task. What really interested them was how different levels of emotional discrimination would affect hearing acuity – in other words, how emotional responses affect perception and discrimination of sounds. This study established the link between emotions and perception of the world – something that has not been understood before.

The researchers found that, as expected, fine emotional learning tasks produced greater learning specificity than tests in which the tones were farther apart in frequency. As Geffen explains, “The animals presented with sounds that were very far apart generalize the fear that they developed to the danger tone over a whole range of frequencies, whereas the animals presented with the two sounds that were very similar exhibited specialization of their emotional response. Following the fine conditioning task, they figured out that it’s a very narrow range of pitches that are potentially dangerous.”

When pitch discrimination abilities were measured in the animals, the mice with more specific responses displayed much finer auditory acuity than the mice who were frightened by a broader range of frequencies.  “There was a relationship between how much their emotional response generalized and how well they could tell different tones apart,” says Geffen. “In the animals that specialized their emotional response, pitch discrimination actually became sharper. They could discriminate two tones that they previously could not tell apart.”

Another interesting finding of this study is that the effects of emotional learning on hearing perception were mediated by a specific brain region, the auditory cortex. The auditory cortex has been known as an important area responsible for auditory plasticity. Surprisingly, Aizenberg and Geffen found that the auditory cortex did not play a role in emotional learning. Likely, the specificity of emotional learning is controlled by the amygdala and sub-cortical auditory areas. “We know the auditory cortex is involved, we know that the emotional response is important so the amygdala is involved, but how do the amygdala and cortex interact together?” says Geffen. “Our hypothesis is that the amygdala and cortex are modifying subcortical auditory processing areas. The sensory cortex is responsible for the changes in frequency discrimination, but it’s not necessary for developing specialized or generalized emotional responses. So it’s kind of a puzzle.”

Solving that puzzle promises new insight into the causes and possible treatment of PTSD, and the question of why some individuals develop it and others subjected to the same events do not. “We think there’s a strong link between mechanisms that control emotional learning, including fear generalization, and the brain mechanisms responsible for PTSD, where generalization of fear is abnormal,” Geffen notes. Future research will focus on defining and studying that link.

Past Brain Activation Revealed in Scans

Weizmann Institute scientists discover that spontaneously emerging brain activity patterns preserve traces of previous cognitive activity

What if experts could dig into the brain, like archaeologists, and uncover the history of past experiences? This ability might reveal what makes each of us a unique individual, and it could enable the objective diagnosis of a wide range of neuropsychological diseases. New research at the Weizmann Institute hints that such a scenario is within the realm of possibility: It shows that spontaneous waves of neuronal activity in the brain bear the imprints of earlier events for at least 24 hours after the experience has taken place.

The new research stems from earlier findings in the lab of Prof. Rafi Malach of the Institute’s Neurobiology Department and others that the brain never rests, even when its owner is resting. When a person is resting with closed eyes – that is, no visual stimulus is entering the brain – the normal bursts of nerve cell activity associated with incoming information are replaced by ultra-slow patterns of neuronal activity. Such spontaneous or “resting” waves travel in a highly organized and reproducible manner through the brain’s outer layer – the cortex – and the patterns they create are complex, yet periodic and symmetrical.

Like hieroglyphics, it seemed that these patterns might have some meaning, and research student Tal Harmelech, under the guidance of Malach and Dr. Son Preminger, set out to uncover their significance. Their idea was that the patterns of resting brain waves may constitute “archives” for earlier experiences. As we add new experiences, the activation of our brain’s networks lead to long-term changes in the links between brain cells, a facility referred to as plasticity. As our experiences become embedded in these connections, they create “expectations” that come into play before we perform any type of mental task, enabling us to anticipate the result. The researchers hypothesized that information about earlier experiences would thus be incorporated into the links between networks of nerve cells in the cortex, and these would show up in the brain’s spontaneously emerging wave patterns.

In the experiment, the researchers had volunteers undertake a training exercise that would strongly activate a well-defined network of nerve cells in the frontal lobes. While undergoing scans of their brain activity in the Institute’s functional magnetic resonance imaging (fMRI) scanner, the subjects were asked to imagine a situation in which they had to make rapid decisions. The subjects received auditory feedback in real time, based on the information obtained directly from their frontal lobe, which indicated the level of neuronal activity in the trained network. This “neurofeedback” strategy proved highly successful in activating the frontal network – a part of the brain that is notoriously difficult to activate under controlled conditions.

To test whether the connections created in the brain during this exercise would leave their traces in the patterns formed by the resting brain waves, the researchers performed fMRI scans on the resting subjects before the exercise, immediately afterward, and 24 hours later. Their findings, which appeared in the Journal of Neuroscience, showed that the activation of the specific areas in the cortex did indeed remodel the resting brain wave patterns. Surprisingly, the new patterns not only remained the next day, they were significantly strengthened. These observations fit in with the classic learning principles proposed by Donald Hebb in the mid-20th century, in which the co-activation of two linked nerve cells leads to long term strengthening of their link, while activity that is not coordinated weakens this link. The fMRI images of the resting brain waves showed that brain areas that were activated together during the training sessions exhibited an increase in their functional link a day after the training, while those areas that were deactivated by the training showed a weakened functional connectivity.

This research suggests a number of future possibilities for exploring the brain. For example, spontaneously emerging brain patterns could be used as a “mapping tool” for unearthing cognitive events from an individual’s recent past. Or, on a wider scale, each person’s unique spontaneously emerging activity patterns might eventually reveal a sort of personal profile – highlighting each individual’s abilities, shortcomings, biases, learning skills, etc. “Today, we are discovering more and more of the common principles of brain activity, but we have not been able to account for the differences between individuals,” says Malach. “In the future, spontaneous brain patterns could be the key to obtaining unbiased individual profiles.” Such profiles could be especially useful in diagnosing or learning the brain pathologies associated with a wide array of cognitive disabilities.

Researchers Discover How Brain Circuits Can Become Miswired During Development

Researchers at Weill Cornell Medical College have uncovered a mechanism that guides the exquisite wiring of neural circuits in a developing brain — gaining unprecedented insight into the faulty circuits that may lead to brain disorders ranging from autism to mental retardation.

In the journal Cell, the researchers describe, for the first time, that faulty wiring occurs when RNA molecules embedded in a growing axon are not degraded after they give instructions that help steer the nerve cell. So, for example, the signal that tells the axon to turn — which should disappear after the turn is made — remains active, interfering with new signals meant to guide the axon in other directions.

The scientists say that there may be a way to use this new knowledge to fix the circuits.

"Understanding the basis of brain miswiring can help scientists come up with new therapies and strategies to correct the problem," says the study’s senior author, Dr. Samie Jaffrey, a professor in the Department of Pharmacology.

"The brain is quite ‘plastic’ and changeable in the very young, and if we know why circuits are miswired, it may be possible to correct those pathways, allowing the brain to build new, functional wiring," he says.

Disorders associated with faulty neuronal circuits include epilepsy, autism, schizophrenia, mental retardation and spasticity and movement disorders, among others.

In their study, the scientists describe a process of brain wiring that is much more dynamic than was previously known — and thus more prone to error.

Proteins Sense the Environment to Steer the Axon

During brain development, neurons have to connect to each other, which they do by extending their long axons to touch one another. Ultimately, these neurons form a circuit between the brain and the target tissue through which chemical and electrical signals are relayed. In this study, researchers investigated neurons that travel up the spinal cord into the brain. “It is very critical that axons are precisely positioned in the spinal cord,” Dr. Jaffrey says. “If they are improperly positioned, they will form the wrong connections, which can lead to signals being sent to the wrong target cells in the brain.”

The way that an axon guides and finds its proper target is through so-called growth cones located at the tips of axons. “These growth cones have the ability to sense the environment, determine where the targets are and navigate toward them. The question has always been — how do they know how to do this? Where do the instructions come from that tell them how to find their proper target?” Dr. Jaffrey says. The team found that RNA molecules embedded in the growth cone are responsible for instructing the axon to move left or right, up or down. These RNAs are translated in growth cones to produce antenna-like proteins that steer the axon like a self-guided missile.

"As a circuit is being built, RNAs in the neuron’s growth cones are mostly silent. We found that specific RNAs are only read at precise stages in order to produce the right protein needed to steer the axon at the right time. After the protein is produced, we saw that the RNA instruction is degraded and disappears," he says.

"If these RNAs do not disappear when they should, the axon does not position itself properly — it may go right instead of left — and the wiring will be incorrect and the circuit may be faulty," Dr. Jaffrey says.

RNAs have Tremendous Power over Brain Development

The research finding answers a long-standing puzzle in the quest to understand brain wiring, says Dr. Dilek Colak, a postdoctoral associate in Dr. Jaffrey’s laboratory.

"There have been a series of discoveries over the last five years showing that proteins that control RNA degradation are very important for brain development and, when they are mutated, you can have spasticity or other movement disorders," Dr. Colak says. "That has raised a major question — why would RNA degradation pathways be so critical for properly creating brain circuits?

"What we show here is that not only does RNA need to be present in growth cones to give instructions, it then also needs to be removed from the growth cones to take away those instructions at the right time," she says. "Both those processes are critical and it may explain why there are so many different brain disorders associated with ineffective RNA regulation."

"The idea that control of brain wiring is located in these RNA molecules that are constantly being dynamically turned over is something that we didn’t anticipate," Dr. Jaffrey adds. "This tells us that regulating these RNA degradation pathways could have a tremendous impact on brain development. Now we know where to look to tease apart this process when it goes awry, and to think about how we can repair it."

(Image: Chad Baker)

Neuroscientists Discover New Phase of Synaptic Development

Breakthrough Could Lead to Better Understanding of Learning and Memory

Students preparing for final exams might want to wait before pulling an all-night cram session — at least as far as their neurons are concerned. Carnegie Mellon University neuroscientists have discovered a new intermediate phase in neuronal development during which repeated exposure to a stimulus shrinks synapses. The findings are published in the May 8 issue of the Journal of Neuroscience.

It’s well known that synapses in the brain, the connections between neurons and other cells that allow for the transmission of information, grow when they’re exposed to a stimulus. New research from the lab of Carnegie Mellon Associate Professor of Biological Sciences Alison L. Barth has shown that in the short term, synapses get even stronger than previously thought, but then quickly go through a transitional phase where they weaken.

"When you think of learning, you think that it’s cumulative. We thought that synapses started small and then got bigger and bigger. This isn’t the case," said Barth, who also is a member of the joint Carnegie Mellon/University of Pittsburgh Center for the Neural Basis of Cognition. "Based on our data, it seems like synapses that have recently been strengthened are peculiarly vulnerable — more stimulation can actually wipe out the effects of learning.

"Psychologists know that for long-lasting memory, spaced training - like studying for your classes after very lecture, all semester long — is superior to cramming all night before the exam," Barth said. "This study shows why. Right after plasticity, synapses are almost fragile — more training during this labile phases is actually counterproductive."

Previous research from Barth’s lab established the biochemical mechanisms responsible for the strengthening of synapses in the neocortex, the part of the brain responsible for thought and language, but only measured the synapses after 24 hours. In the current study, post-doctoral student Jing A. Wen investigated how the synapses developed throughout the first 24 hours of exposure to a stimulus using a specialized transgenic mouse model created by Barth. The model senses its surroundings using only one whisker, which alters its ability to sense its environment and creates a sensory imbalance that increases plasticity in the brain. Since each whisker is linked to a specific area of the cortex, researchers can easily track neuronal changes.

Wen found that during this first day of learning, synapses go through three distinct phases. In the initiation phase, synaptic plasticity is spurred on by NMDA receptors. Over the next 12 hours or so, the synapses get stronger and stronger. As the stimulus is repeated, the NDMA receptors change their function and start to weaken the synapses in what the researchers have called the labile phase. After a few hours of weakening, another receptor, mGluR5, initiates a stabilization phase during which the synapses maintain their residual strength.

Furthermore, the researchers found that they could maintain the super-activated state found at the beginning of the labile phase by stopping the stimulus altogether or by injecting a glutamate receptor antagonist drug at an optimal time point. The findings are analogous to those seen in many psychological studies that use space training to improve memory.

"While synaptic changes can be long lasting, we’ve found that in this initial period there are a number of different things we could play with," Barth said. "The discovery of this labile phase suggests there are ways to control learning through the manipulation of the biochemical pathways that maintain memory."

Brain rewires itself after damage or injury

When the brain’s primary “learning center” is damaged, complex new neural circuits arise to compensate for the lost function, say life scientists from UCLA and Australia who have pinpointed the regions of the brain involved in creating those alternate pathways — often far from the damaged site.

The research, conducted by UCLA’s Michael Fanselow and Moriel Zelikowsky in collaboration with Bryce Vissel, a group leader of the neuroscience research program at Sydney’s Garvan Institute of Medical Research, appears this week in the early online edition of the journal Proceedings of the National Academy of Sciences.

The researchers found that parts of the prefrontal cortex take over when the hippocampus, the brain’s key center of learning and memory formation, is disabled. Their breakthrough discovery, the first demonstration of such neural-circuit plasticity, could potentially help scientists develop new treatments for Alzheimer’s disease, stroke and other conditions involving damage to the brain.

For the study, Fanselow and Zelikowsky conducted laboratory experiments with rats showing that the rodents were able to learn new tasks even after damage to the hippocampus. While the rats needed more training than they would have normally, they nonetheless learned from their experiences — a surprising finding.

"I expect that the brain probably has to be trained through experience," said Fanselow, a professor of psychology and member of the UCLA Brain Research Institute, who was the study’s senior author. "In this case, we gave animals a problem to solve."

After discovering the rats could, in fact, learn to solve problems, Zelikowsky, a graduate student in Fanselow’s laboratory, traveled to Australia, where she worked with Vissel to analyze the anatomy of the changes that had taken place in the rats’ brains. Their analysis identified significant functional changes in two specific regions of the prefrontal cortex.

"Interestingly, previous studies had shown that these prefrontal cortex regions also light up in the brains of Alzheimer’s patients, suggesting that similar compensatory circuits develop in people," Vissel said. "While it’s probable that the brains of Alzheimer’s sufferers are already compensating for damage, this discovery has significant potential for extending that compensation and improving the lives of many."

The hippocampus, a seahorse-shaped structure where memories are formed in the brain, plays critical roles in processing, storing and recalling information. The hippocampus is highly susceptible to damage through stroke or lack of oxygen and is critically inolved in Alzheimer’s disease, Fanselow said.

"Until now, we’ve been trying to figure out how to stimulate repair within the hippocampus," he said. "Now we can see other structures stepping in and whole new brain circuits coming into being."

Zelikowsky said she found it interesting that sub-regions in the prefrontal cortex compensated in different ways, with one sub-region — the infralimbic cortex — silencing its activity and another sub-region — the prelimbic cortex — increasing its activity.

"If we’re going to harness this kind of plasticity to help stroke victims or people with Alzheimer’s," she said, "we first have to understand exactly how to differentially enhance and silence function, either behaviorally or pharmacologically. It’s clearly important not to enhance all areas. The brain works by silencing and activating different populations of neurons. To form memories, you have to filter out what’s important and what’s not."

Complex behavior always involves multiple parts of the brain communicating with one another, with one region’s message affecting how another region will respond, Fanselow noted. These molecular changes produce our memories, feelings and actions.

"The brain is heavily interconnected — you can get from any neuron in the brain to any other neuron via about six synaptic connections," he said. "So there are many alternate pathways the brain can use, but it normally doesn’t use them unless it’s forced to. Once we understand how the brain makes these decisions, then we’re in a position to encourage pathways to take over when they need to, especially in the case of brain damage.

"Behavior creates molecular changes in the brain; if we know the molecular changes we want to bring about, then we can try to facilitate those changes to occur through behavior and drug therapy," he added. I think that’s the best alternative we have. Future treatments are not going to be all behavioral or all pharmacological, but a combination of both."

Flip of a single molecular switch makes an old brain young

The flip of a single molecular switch helps create the mature neuronal connections that allow the brain to bridge the gap between adolescent impressionability and adult stability. Now Yale School of Medicine researchers have reversed the process, recreating a youthful brain that facilitated both learning and healing in the adult mouse.

Scientists have long known that the young and old brains are very different. Adolescent brains are more malleable or plastic, which allows them to learn languages more quickly than adults and speeds recovery from brain injuries. The comparative rigidity of the adult brain results in part from the function of a single gene that slows the rapid change in synaptic connections between neurons.

By monitoring the synapses in living mice over weeks and months, Yale researchers have identified the key genetic switch for brain maturation a study released March 6 in the journal Neuron. The Nogo Receptor 1 gene is required to suppress high levels of plasticity in the adolescent brain and create the relatively quiescent levels of plasticity in adulthood.  In mice without this gene, juvenile levels of brain plasticity persist throughout adulthood. When researchers blocked the function of this gene in old mice, they reset the old brain to adolescent levels of plasticity.

“These are the molecules the brain needs for the transition from adolescence to adulthood,” said Dr. Stephen Strittmatter. Vincent Coates Professor of Neurology, Professor of Neurobiology and senior author of the paper. “It suggests we can turn back the clock in the adult brain and recover from trauma the way kids recover.”

Rehabilitation after brain injuries like strokes requires that patients re-learn tasks such as moving a hand. Researchers found that adult mice lacking Nogo Receptor recovered from injury as quickly as adolescent mice and mastered new, complex motor tasks more quickly than adults with the receptor.

“This raises the potential that manipulating Nogo Receptor in humans might accelerate and magnify rehabilitation after brain injuries like strokes,” said Feras Akbik, Yale doctoral student who is first author of the study.

Researchers also showed that Nogo Receptor slows loss of memories.  Mice without Nogo receptor lost stressful memories more quickly, suggesting that manipulating the receptor could help treat post-traumatic stress disorder.

“We know a lot about the early development of the brain,” Strittmatter said, “But we know amazingly little about what happens in the brain during late adolescence.”

Ectopic Eyes Function Without Connection to Brain

For the first time, scientists have shown that transplanted eyes located far outside the head in a vertebrate animal model can confer vision without a direct neural connection to the brain.

Biologists at Tufts University School of Arts and Sciences used a frog model to shed new light – literally – on one of the major questions in regenerative medicine, bioengineering, and sensory augmentation research.

"One of the big challenges is to understand how the brain and body adapt to large changes in organization," says Douglas J. Blackiston, Ph.D., first author of the paper "Ectopic Eyes Outside the Head in Xenopus Tadpoles Provide Sensory Data For Light-Mediated Learning," in the February 27 issue of the Journal of Experimental Biology. “Here, our research reveals the brain’s remarkable ability, or plasticity, to process visual data coming from misplaced eyes, even when they are located far from the head.”

Blackiston is a post-doctoral associate in the laboratory of co-author Michael Levin, Ph.D., professor of biology and director of the Center for Regenerative and Developmental Biology at Tufts University.

Levin notes, “A primary goal in medicine is to one day be able to restore the function of damaged or missing sensory structures through the use of biological or artificial replacement components. There are many implications of this study, but the primary one from a medical standpoint is that we may not need to make specific connections to the brain when treating sensory disorders such as blindness.”

In this experiment, the team surgically removed donor embryo eye primordia, marked with fluorescent proteins, and grafted them into the posterior region of recipient embryos. This induced the growth of ectopic eyes. The recipients’ natural eyes were removed, leaving only the ectopic eyes.

Fluorescence microscopy revealed various innervation patterns but none of the animals developed nerves that connected the ectopic eyes to the brain or cranial region.

To determine if the ectopic eyes conveyed visual information, the team developed a computer-controlled visual training system in which quadrants of water were illuminated by either red or blue LED lights. The system could administer a mild electric shock to tadpoles swimming in a particular quadrant. A motion tracking system outfitted with a camera and a computer program allowed the scientists to monitor and record the tadpoles’ motion and speed.

Eyes See Without Wiring to Brain

The team made exciting discoveries: Just over 19 percent of the animals with optic nerves that connected to the spine demonstrated learned responses to the lights. They swam away from the red light while the blue light stimulated natural movement.

Their response to the lights elicited during the experiments was no different from that of a control group of tadpoles with natural eyes intact. Furthermore, this response was not demonstrated by eyeless tadpoles or tadpoles that did not receive any electrical shock.

"This has never been shown before," says Levin. "No one would have guessed that eyes on the flank of a tadpole could see, especially when wired only to the spinal cord and not the brain."
The findings suggest a remarkable plasticity in the brain’s ability to incorporate signals from various body regions into behavioral programs that had evolved with a specific and different body plan.

"Ectopic eyes performed visual function," says Blackiston. "The brain recognized visual data from eyes that impinged on the spinal cord. We still need to determine if this plasticity in vertebrate brains extends to different ectopic organs or organs appropriate in different species."

One of the most fascinating areas for future investigation, according to Blackiston and Levin, is the question of exactly how the brain recognizes that the electrical signals coming from tissue near the gut is to be interpreted as visual data.

In computer engineering, notes Levin, who majored in computer science and biology as a Tufts undergraduate, this problem is usually solved by a “header”—a piece of metadata attached to a packet of information that indicates its source and type. Whether electric signals from eyes impinging on the spinal cord carry such an identifier of their origin remains a hypothesis to be tested.

Brain plasticity

Babies’ brains are highly plastic, meaning they’re constantly adapting as they learn and respond to the world and people around them.

Daphne Maurer, director of the Visual Development Laboratory at McMaster University in Hamilton, Ontario, has found clues as to when plasticity might be locked off in babies and how in some adults it actually may persist unbeknown to them.

Hypothalamic control of energy balance: insights into the role of synaptic plasticity

The past 20 years witnessed an enormous leap in understanding of the central regulation of whole-body energy metabolism. Genetic tools have enabled identification of the region-specific expression of peripheral metabolic hormone receptors and have identified neuronal circuits that mediate the action of these hormones on behavior and peripheral tissue functions. One of the surprising findings of recent years is the observation that brain circuits involved in metabolism regulation remain plastic through adulthood. In this review, we discuss these findings and focus on the role of neurons and glial cells in the dynamic process of plasticity, which is fundamental to the regulation of physiological and pathological metabolic events.