Researchers Identify “Switch” for Long-term Memory

Calcium signal in neuronal cell nuclei initiates the formation of lasting memories

Neurobiologists at Heidelberg University have identified calcium in the cell nucleus to be a cellular “switch” responsible for the formation of long-term memory. Using the fruit fly “Drosophila melanogaster” as a model, the team led by Prof. Dr. Christoph Schuster and Prof. Dr. Hilmar Bading investigates how the brain learns. The researchers wanted to know which signals in the brain were responsible for building long-term memory and for forming the special proteins involved. The results of the research were published in the journal “Science Signaling”.

The team from the Interdisciplinary Center for Neurosciences (IZN) measured nuclear calcium levels with a fluorescent protein in the association and learning centres of the insect’s brain to investigate any changes that might occur during the learning process. Their work on the fruit fly revealed brief surges in calcium levels in the cell nuclei of certain neurons during learning. It was this calcium signal that researchers identified as the trigger of a genetic programme that controls the production of “memory proteins”. If this nuclear calcium switch is blocked, the flies are unable to form long-term memory.

Prof. Schuster explains that insects and mammals separated evolutionary paths approximately 600 million years ago. In spite of this sizable gap, certain vitally important processes such as memory formation use similar cellular mechanisms in humans, mice and flies, as the researchers’ experiments were able to prove. “These commonalities indicate that the formation of long-term memory is an ancient phenomenon already present in the shared ancestors of insects and vertebrates. Both species probably use similar cellular mechanisms for forming long-term memory, including the nuclear calcium switch”, Schuster continues.

The IZN researchers assume that similar switches based on nuclear calcium signals may have applications in other areas – presumably whenever organisms need to adapt to new conditions over the long term. “Pain memory, for example, or certain protective and survival functions of neurons use this nuclear calcium switch, too”, says Prof. Bading. This cellular switch may no longer work as well in the elderly, which Bading believes may explain the decline in memory typically observed in old age. Thus, the discoveries by the Heidelberg neurobiologists open up new perspectives for the treatment of age- and illness-related changes in brain functions.

Exposure to Stress Even Before Conception Causes Genetic Changes to Offspring

A female’s exposure to distress even before she conceives causes changes in the expression of a gene linked to the stress mechanism in the body — in the ovum and later in the brains of the offspring from when they are born, according to a new study on rats conducted by the University of Haifa.

“The systemic similarity in many instances between us and mice raises questions about the transgenerational influences in humans as well, for example, the effects of the Second Lebanon War or the security situation in the South on the children of those who went through those difficult experiences,” the researchers said. “If until now we saw evidence only of behavioral effects, now we’ve found proof of effects at the genetic level.”

In previous studies in Prof. Micah Leshem’s lab, it was found that exposing rats to stress before they had even conceived (and even at their “teen” stage) influences the behavior of their offspring. This study, conducted in the lab of Dr. Inna Gaisler-Salomon by PhD student Hiba Zaidan, in cooperation with Prof. Leshem, the researchers sought to examine whether there was an influence on genetic expression.

In the study, which was recently published in the journal Biological Psychiatry, the researchers focused on the gene known as CRF-1, a gene linked to the body’s stress-control system that expresses itself in many places in the brain under stress.

The researchers took female rats that were 45 days old, which is parallel to human adolescence. Some of the rats were exposed to “minor” stress, which included changes in temperature and daily routine for seven days, and compared them to a control group that was not exposed to stress at all. The rats were mated and conceived two weeks later.

In the first part of the study, the researchers examined the ova of the rats that were exposed to stress even before they conceived, and they found that at that stage there was enhanced expression of the CRF-1 gene. For the second part, the researchers examined the brains of newborn rats immediately after birth, before the mother could have any influence on them, and found that even at the neonatal stage, there was enhanced expression of the CRF-1 gene in the brains of the rats born to mothers who had been exposed to stress.

During the third stage, the researchers exposed the offspring – both those whose mothers had been exposed to stress and those whose mothers were not – to stress when they reached adulthood. It emerged that the expression of CRF-1 among the offspring was dependent on three factors: The sex of the offspring, the stress undergone by the mother and the stress to which the offspring were exposed. The female rats whose mothers had been exposed to stress and who themselves underwent a “stressful” behavioral test showed higher levels of CRF-1 than other groups.

“This is the first time that we showed that the genetic response to stress in rats is linked to the experiences their mothers underwent long before they even got pregnant with them,” the researchers said. “We are learning more and more about intergenerational genetic transfer and in light of the findings, and in light of the fact that in today’s reality many women are exposed to stress even before they get pregnant, it’s important to research the degree to which such phenomenon take place in humans.”

(Image: iStockphoto)

Clues about autism may come from the gut

Bacterial flora inhabiting the human gut have become one of the hottest topics in biological research. Implicated in a range of important activities including digestion, fine-tuning body weight, regulating immune response, and producing neurotransmitters that affect brain and behavior, these tiny workers form diverse communities. Hundreds of species inhabit the gut, and although most are beneficial, some can be very dangerous.

In new research appearing in the journal PLOS ONE, a team led by Rosa Krajmalnik-Brown, a researcher at Arizona State University’s Biodesign Institute, present the first comprehensive bacterial analysis focusing on commensal or beneficial bacteria in children with autism spectrum disorder (ASD).

After publishing earlier research exploring crucial links between intestinal microflora and gastric bypass, Krajmlanik-Brown convinced James Adams— director of the ASU Autism/Asperger’s Research Program—that similar high throughput techniques could be used to mine the microbiome of patients with autism. (Previously, Adams had been studying the relationship between the gut microbiome and autism using traditional culturing techniques.)

“One of the reasons we started addressing this topic is the fact that autistic children have a lot of GI problems that can last into adulthood,” Krajmalnik-Brown says. “Studies have shown that when we manage these problems, their behavior improves dramatically.”

Following up on these tantalizing hints, the group hypothesized the existence of distinctive features in the intestinal microflora found in autistic subjects compared to typical children. The current study confirmed these suspicions, and found that children with autism had significantly fewer types of gut bacteria, probably making them more vulnerable to pathogenic bacteria. Autistic subjects also had significantly lower amounts of three critical bacteria, Prevotella, Coprococcus, and Veillonellaceae.

Krajmalnik-Brown, along with the paper’s lead authors Dae-Wook Kang and Jin Gyoon Park, suggest that knowledge gleaned through such research may ultimately be used both as a quantitative e diagnostic tool to pinpoint autism and as a guide to developing effective treatments for ASD-associated GI problems. The work also offers hope for new prevention and treatment methods for ASD itself, which has been on a mysterious and rapid ascent around the world.

A disquieting puzzle

Autism is defined as a spectrum disorder, due to the broad range of symptoms involved and the influence of both genetic and environmental factors, features often confounding efforts at accurate diagnosis. The diseases’ prevalence in children exceeds juvenile diabetes, childhood cancer and pediatric AIDS combined.

Controversy surrounds the apparent explosive rise in autism cases. Heightened awareness of autism spectrum disorders and more diligent efforts at diagnosis must account for some of the increase, yet many researchers believe a genuine epidemic is occurring. In addition to hereditary components, Western-style diets and overuse of antibiotics at an early age may be contributing to the problem by lowering the diversity of the gut microflora.

In terms of severe developmental ailments affecting children and young adults, autism is one of the most common, striking about 1 in 50 children. The disorder—often pitiless and perplexing—is characterized by an array of physical and behavioral symptoms including anxiety, depression, extreme rigidity, poor social functioning and an overall lack of independence.

To date, studies of the gut microbiome in autistic subjects have focused primarily on pathogenic bacteria, some of which have been implicated in alterations to brain function. One example involves gram-negative bacteria containing lipopolysaccharides in their cell walls, which can induce inflammation of the brain and lead to the accumulation of high levels of mercury in the cerebrum.

A new approach

Krajmalnik-Brown and lead author Dae-Wook Kang are researchers in the Biodesign Institute’s Swette Center for Environmental Biotechnology, which is devoted to the use of microbial communities for the benefit of human and environmental health. Their new study is the first to approach autism from a different angle, by examining the possible role of so-called commensal or beneficial bacteria.

Up to a quadrillion (10¹⁴) bacteria inhabit the human intestine, contributing to digestion, producing vitamins and promoting GI health. Genes associated with human intestinal flora are 100 times as plentiful as the body’s human genes, forming what some have referred to as a second genome. Various environmental factors can destabilize the natural microbiome of the gut, including antibiotics and specific diets.

In the current study, a cohort of 20 healthy and 20 autistic subjects between 3 and 16 years of age were selected and their gut microflora from fecal samples analyzed by means of a technique known as pyrosequencing. Pyrosequencing is a high-throughput method, allowing many DNA samples to be combined as well as many sequences per sample to be analyzed.

Lower diversity of gut microbes was positively correlated with the presence of autistic symptoms in the study. The authors stress that bacterial richness and diversity are essential for maintaining a robust and adaptable bacterial community capable of fighting off environmental challenges. “We believe that a diverse gut is a healthy gut,” Krajmalnik-Brown says.

The new study detected decreased microbial diversity in the 20 autistic subjects whose fecal samples were analyzed. Specifically, three bacterial genera—Prevotella, Coprococcus and Veillonellaceae—were diminished in subjects with autism, when compared with samples from normal children. (Surprisingly, these microbial changes did not seem directly correlated with the severity of GI symptoms.)

The three genera represent important groups of carbohydrate-degrading and/or fermenting microbes. Such bacteria could be critical for healthy microbial-gut interactions or play a supportive role for  a wide network of different microorganisms in the gut. The latter would explain the decreased diversity observed in autistic samples.

Bacteria: in sickness and in health

Among the fully classified genera in the study, Prevotella was the most conspicuously reduced in autistic subjects. Prevotella is believed to play a key role in the composition of the human gut microbiome. For this reason, the group undertook a sub-genus investigation of autistic subjects. They found that a species known as Prevotella copri occurred only in very low levels in the autistic samples. The species is a common component in normal children exhibiting more diverse and robust microbial communities.

“We think of Prevotella as a healthy, good thing to have,” Krajmalnik-Brown notes. (Michael Polan’s recent New York Times Magazine story on the microbiome points to the fact that he is proud that his gut microbiome is rich in Prevotella regarding it as a possible sign of a healthy non-Western diet. )

Jin Gyoon Park (the other lead author), who works in the Virginia G. Piper Center for Personalized Diagnostics, under Joshua LaBaer’s direction, conducted a rigorous bioinformatic and statistical analysis of the intestinal microflora. He believes that the microbiome can be mined in future work to find diagnostic biomarkers for autism and many other diseases. Quantitative diagnoses of this sort have so far been lacking for autism, a disease for which subjective behavior indices are typically used to identify the disorder.  

In describing the next steps for the research group, Kang and Park point to more detailed, gene-level analyses aimed at probing bacterial function and further illuminating relationships between human health and the complexities of the microbiome. Additionally, the group will use the current results as a guide for new treatment studies for autism aimed at modifying bacterial composition in the gut. 

Are Thoughts of Death Conducive to Humor?

A New Study Shows an Increase in Humorous Creativity when Individuals are Primed with Thoughts of Death.

Humor is an intrinsic part of human experience. It plays a role in every aspect of human existence, from day-to-day conversation to television shows. Yet little research has been conducted to date on the psychological function of humor. In human psychology, awareness of the impermanence of life is just as prevalent as humor. According to the Terror Management Theory, knowledge of one’s own impermanence creates potentially disruptive existential anxiety, which the individual brings under control with two coping mechanisms, or anxiety buffers: rigid adherence to dominant cultural values, and self-esteem bolstering.

A new article by Christopher R. Long of Ouachita Baptist University and Dara Greenwood of Vassar College is titled Joking in the Face of Death: A Terror Management Approach to Humor Production. Appearing in the journal HUMOR, it documents research on whether the activation of thoughts concerning death influences one’s ability to creatively generate humor. As humor is useful on a fundamental level for a variety of purposes, including psychological defense against anxiety, the authors hypothesized that the activation of thoughts concerning death could facilitate the production of humor.

For their study, Long and Greenwood subdivided 117 students into four experimental groups. These groups were confronted with the topics of pain and death while completing various tasks. Two of the test groups were exposed unconsciously to words flashed for 33 milliseconds on a computer while they completed tasks – the first to the word “pain,” the second to the word “death.” The remaining two groups were prompted in a writing task to express emotions concerning either their own death or a painful visit to the dentist. Afterward, all four groups were instructed to supply a caption to a cartoon from The New Yorker.

These cartoon captions were presented to an independent jury who knew nothing about the experiment. The captions written by individuals who were subconsciously primed with the word death were clearly voted as funnier by the jury. By contrast, the exact opposite result was obtained for the students who consciously wrote about death: their captions were seen as less humorous.

Based on this experiment, the researchers conclude that humor helps the individual to tolerate latent anxiety that may otherwise be destabilizing. In this connection, they point to previous studies indicating that humor is an integral component of resilience.

In light of the finding that the activation of conscious thoughts concerning death impaired the creative generation of humor, Long and Greenwood highlight the need for additional research, not only to explore the effectiveness of humor as a coping mechanism under various circumstances, but also to identify its emotional, cognitive, and/or social benefits under conditions of adversity.

How the brain creates the ‘buzz’ that helps ideas spread

How do ideas spread? What messages will go viral on social media, and can this be predicted?

UCLA psychologists have taken a significant step toward answering these questions, identifying for the first time the brain regions associated with the successful spread of ideas, often called “buzz.”

The research has a broad range of implications, the study authors say, and could lead to more effective public health campaigns, more persuasive advertisements and better ways for teachers to communicate with students.

"Our study suggests that people are regularly attuned to how the things they’re seeing will be useful and interesting, not just to themselves but to other people," said the study’s senior author, Matthew Lieberman, a UCLA professor of psychology and of psychiatry and biobehavioral sciences and author of the forthcoming book "Social: Why Our Brains Are Wired to Connect." "We always seem to be on the lookout for who else will find this helpful, amusing or interesting, and our brain data are showing evidence of that. At the first encounter with information, people are already using the brain network involved in thinking about how this can be interesting to other people. We’re wired to want to share information with other people. I think that is a profound statement about the social nature of our minds."

The study findings are published in the online edition of the journal Psychological Science, with print publication to follow later this summer.

"Before this study, we didn’t know what brain regions were associated with ideas that become contagious, and we didn’t know what regions were associated with being an effective communicator of ideas," said lead author Emily Falk, who conducted the research as a UCLA doctoral student in Lieberman’s lab and is currently a faculty member at the University of Pennsylvania’s Annenberg School for Communication. "Now we have mapped the brain regions associated with ideas that are likely to be contagious and are associated with being a good ‘idea salesperson.’ In the future, we would like to be able to use these brain maps to forecast what ideas are likely to be successful and who is likely to be effective at spreading them."

In the first part of the study, 19 UCLA students (average age 21), underwent functional magnetic resonance imaging (fMRI) brain scans at UCLA’s Ahmanson–Lovelace Brain Mapping Center as they saw and heard information about 24 potential television pilot ideas. Among the fictitious pilots — which were presented by a separate group of students — were a show about former beauty-queen mothers who want their daughters to follow in their footsteps; a Spanish soap opera about a young woman and her relationships; a reality show in which contestants travel to countries with harsh environments; a program about teenage vampires and werewolves; and a show about best friends and rivals in a crime family.

The students exposed to these TV pilot ideas were asked to envision themselves as television studio interns who would decide whether or not they would recommend each idea to their “producers.” These students made videotaped assessments of each pilot.

Another group of 79 UCLA undergraduates (average age 21) was asked to act as the “producers.” These students watched the interns’ videos assessments of the pilots and then made their own ratings about the pilot ideas based on those assessments.

Lieberman and Falk wanted to learn which brain regions were activated when the interns were first exposed to information they would later pass on to others.

"We’re constantly being exposed to information on Facebook, Twitter and so on," said Lieberman. "Some of it we pass on, and a lot of it we don’t. Is there something that happens in the moment we first see it — maybe before we even realize we might pass it on — that is different for those things that we will pass on successfully versus those that we won’t?"

It turns out, there is. The psychologists found that the interns who were especially good at persuading the producers showed significantly more activation in a brain region known as the temporoparietal junction, or TPJ, at the time they were first exposed to the pilot ideas they would later recommend. They had more activation in this region than the interns who were less persuasive and more activation than they themselves had when exposed to pilot ideas they didn’t like. The psychologists call this the “salesperson effect.”

"It was the only region in the brain that showed this effect," Lieberman said. One might have thought brain regions associated with memory would show more activation, but that was not the case, he said.

"We wanted to explore what differentiates ideas that bomb from ideas that go viral," Falk said. "We found that increased activity in the TPJ was associated with an increased ability to convince others to get on board with their favorite ideas. Nobody had looked before at which brain regions are associated with the successful spread of ideas. You might expect people to be most enthusiastic and opinionated about ideas that they themselves are excited about, but our research suggests that’s not the whole story. Thinking about what appeals to others may be even more important."

The TPJ, located on the outer surface of the brain, is part of what is known as the brain’s “mentalizing network,” which is involved in thinking about what other people think and feel. The network also includes the dorsomedial prefrontal cortex, located in the middle of the brain.

"When we read fiction or watch a movie, we’re entering the minds of the characters — that’s mentalizing," Lieberman said. "As soon as you hear a good joke, you think, ‘Who can I tell this to and who can’t I tell?’ Making this judgment will activate these two brain regions. If we’re playing poker and I’m trying to figure out if you’re bluffing, that’s going to invoke this network. And when I see someone on Capitol Hill testifying and I’m thinking whether they are lying or telling the truth, that’s going to invoke these two brain regions.

"Good ideas turn on the mentalizing system," he said. "They make us want to tell other people."

The interns who showed more activity in their mentalizing system when they saw the pilots they intended to recommend were then more successful in convincing the producers to also recommend those pilots, the psychologists found.

"As I’m looking at an idea, I might be thinking about what other people are likely to value, and that might make me a better idea salesperson later," Falk said.

By further studying the neural activity in these brain regions to see what information and ideas activate these regions more, psychologists potentially could predict which advertisements are most likely to spread and go viral and which will be most effective, Lieberman and Falk said.

Such knowledge could also benefit public health campaigns aimed at everything from reducing risky behaviors among teenagers to combating cancer, smoking and obesity.

"The explosion of new communication technologies, combined with novel analytic tools, promises to dramatically expand our understanding of how ideas spread," Falk said. "We’re laying basic science foundations to addressimportant public health questions that are difficult to answer otherwise — about what makes campaigns successful and how we can improve their impact."

As we may like particular radio DJs who play music we enjoy, the Internet has led us to act as “information DJs” who share things that we think will be of interest to people in our networks, Lieberman said.

"What is new about our study is the finding that the mentalizing network is involved when I read something and decide who else might be interested in it," he said. "This is similar to what an advertiser has to do. It’s not enough to have a product that people should like."

Researchers Create 15-Million-Year Model Of Great Ape History

Using the study of genetic variation in a large panel of humans, chimpanzees, gorillas and orangutans, researchers from the Universitat Pompeu Fabra in Barcelona, Spain, and Washington University in Seattle have created a model of great ape history over the past 15 million years.

This is the most comprehensive catalog of great ape genetic diversity. The catalog elucidates the evolution and population histories of great apes from Africa and Indonesia. The research team hopes the catalog will also help current and future conservation efforts that strive to preserve natural genetic diversity in populations.

An international group of more than 75 scientists and wildlife conservationists worked on the genetic analysis of 79 wild and captive-born great apes. The group of great apes represents all six great ape species: chimpanzee, bonobo, Sumatran orangutan, Bornean orangutan, eastern gorilla and western lowland gorilla; as well as seven subspecies. The study, published in Nature, also included nine human genomes.

“The research provided us the deepest survey to date of great ape genetic diversity with evolutionary insights into the divergence and emergence of great-ape species,” noted Evan Eichler, a UW professor of genome sciences and a Howard Hughes Medical Institute Investigator.

Due to the difficulty in obtaining genetic specimens from wild apes, genetic variation among great apes had been largely uncharted prior to this study. The research team credits the many conservationists in various countries, many of them in dangerous or isolated locations, with the success of the project.

Peter H. Sudmant, a UW graduate student in genome sciences, said, “Gathering this data is critical to understanding differences between great ape species, and separating aspects of the genetic code that distinguish humans from other primates.”

Factors that shaped primate evolution, including natural selection, population growth and collapse, geographic isolation and migration, climate and geological changes are likely to be revealed by the analysis of great ape genetic diversity.

Understanding more about great ape genetic diversity, according to Sudmant, also contributes to knowledge about disease susceptibility among various primate species. This knowledge is important to both conservation efforts and to human health. For example, the ebola virus is responsible for thousands of chimp and gorilla deaths in Africa. Also, the origin of the HIV in humans comes from simian immunodeficiency virus (SIV), which is found in non-human primates.

“Because the way we think, communicate and act is what makes us distinctively human,” Sudmant, who works in a lab that studies both primate evolutionary biology and neuropsychiatric diseases such as autism, schizophrenia, developmental delay, and cognitive and behavioral disorders, said, “we are specifically looking for the genetic differences between humans and other great apes that might confer these traits.”

The differences between species may direct scientists to portions of the human genome associated with cognition, speech or behavior. This could provide clues to which mutations might underlie neurological disease.

The research team published a companion paper in Genome Research, in which they found the first genetic evidence of a disorder in chimpanzees that resembles Smith-Magenis syndrome. Smith-Magenis is a disabling physical, mental and behavioral condition in humans. The veterinary records of Suzie-A, the chimpanzee exhibiting the disorder, match human symptoms of Smith-Magenis almost exactly. Suzie-A was overweight, rage-prone, had a curved-spine and died from kidney failure.

The discovery of Suzie-A’s syndrome came about while the scientists were exploring and comparing the accumulation of copy number variants during great ape evolution, which are differences between individuals, populations or species in the number of times specific segments of DNA appear. The genomes of humans and great apes have been restructured by the duplication and deletion of DNA segments, which are also behind many genetic diseases.

The new catalog of genetic diversity will help address the challenging plight of great ape species on the brink of extinction, in addition to offering a view of the origins of humans and their disorders. It will also provide an important tool to allow biologists to identify the origin of great apes poached for their body parts or hunted for bush meat. The study also explains why current zoo breeding programs that have tried to increase the genetic diversity of their captive great ape populations have resulted in populations that are genetically dissimilar to their wild counterparts.

“By avoiding inbreeding to produce a diverse population, zoos and conservation groups may be entirely eroding genetic signals specific to certain populations in specific geographic locations in the wild,” Sudmant said.

Donald, one of the captive-bred apes studied by the team, had a genetic makeup of two distinct chimpanzee subspecies which are located around 1,250 miles away from each other in the wild.

The variety of changes that occurred along each of the ape lineages, as they separated from each other through migration, geological change and climate events, are delineated in the study findings. Natural disturbances such as the formation of rivers and the partition of islands from the mainland have all served to isolate groups of apes. These isolated populations are exposed to a unique set of environmental pressures that result in population fluctuations and adaptations, depending on the circumstances.

The ancestors of some present day apes were present at the same time as early human-like species. The researchers found, however, the evolutionary history of the ancestral great ape populations had far more complexity than that of humans. Human history appears “almost boring,” according to Sudmant and Eicher, when compared to our closest relatives, the chimpanzees. For example, the last few million years of chimp evolution are full of population explosions followed by implosions. These rapid fluctuations in chimpanzee populations demonstrate remarkable plasticity. Scientists still don’t understand the reasons for the fluctuations in chimpanzee population size long before our own population explosion.

Sudmant’s interest in studying and preserving the great apes stems from the similarities of the great apes to humans.

“If you look at a chimpanzee or a gorilla, those guys will look right back at you,” he said. “They act just like us. We need to find ways to protect these precious species from extinction.”