Category Archives: Research

Feeling pleasure at the misfortune of those you envy is biological (The Annals of the New York Academy of Sciences)

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Abstract image courtesy of Shutterstock. By measuring the electrical activity of cheek muscles and associated neural responses, Princeton University researchers show that people are actually biologically responsive to taking pleasure in the pain of others, a reaction known as “Schadenfreude.”

By B. Rose Huber, Woodrow Wilson School of Public and International Affairs

A new study by Princeton University researchers shows that people are actually biologically responsive to taking pleasure in the pain of others, a reaction known as “Schadenfreude.”

Ph.D student Mina Cikara took up the topic of Schadenfreude after she wore a Boston Red Sox hat to a New York Yankees baseball game. Nicknames and vulgarities were among the souvenirs she took home. And, after hearing about the name-calling and heckling her then-PhD student endured, Princeton professor Susan Fiske was compelled to join her in pursuing the phenomenon further, exploring why people fail to empathize with others based on stereotypes.

Through a series of four experiments – one involving the aforementioned sports rivalry – the researchers found that people are actually biologically responsive to taking pleasure in the pain of others, a reaction known as “Schadenfreude.” By measuring the electrical activity of cheek muscles, the researchers show that people smile more when someone they envy experiences misfortune or discomfort. While these findings hold significance for interpersonal relationships, the researchers also cite associated policy implications, such as how other countries view and stereotype the United States especially given that many countries envy the U.S., Fiske said. Their findings were reported in The Annals of the New York Academy of Sciences.

“Jealousy and envy are highly correlated,” said Fiske, coauthor of the study and the Eugene Higgins Professor of Psychology and Public Affairs in the Woodrow Wilson School. “When we ask people on surveys who is envied in American society, they report the same groups: objects of jealousy. This is all very much based on stereotypes. And so, in this study, we sought to better understand who is among these envied groups and whether that envy and jealousy elicits a harmful response.”

“We were interested in the conditions under which people fail to empathize with one another and how, for some of those people, they experience happiness at another’s expense,” said lead author Cikara, now an assistant professor at Carnegie Mellon University. “We wanted to start in a place where people would be willing to express their opinions and willingness to harm more freely, like we see in sports. We asked ourselves: what is it about rivalries that elicit a harmful response? And can we predict who will have this response?”

In the first experiment, the researchers examined participants’ physical responses by monitoring their cheek movements with an electromyogram (EMG), which captures the electrical activity of facial movements when an individual smiles. Participants were shown photographs of individuals associated with different stereotypes: the elderly (pity), students or Americans (pride), drug addicts (disgust) and rich professionals (envy). These images were then paired with everyday events such as: “Won five dollars” (positive) or “Got soaked by a taxi” (negative) or “Went to the bathroom” (neutral). Participants were asked how this would make them feel, and their facial movements were recorded.

“Because people don’t like to report envy of Schadenfreude, this was the best method for gathering such responses. And, in this experiment, we were able to viscerally capture malicious glee,” Fiske said. “We found that people did smile more in response to negative than positive events, but only for groups they envied.”

In their second experiment, the researchers used self-reporting and functional magnetic resonance imaging (fMRI) – which measures blood flow changes associated with brain activity – to determine whether participants were willing to harm certain groups. Participants viewed the same photographs and events as the first study and were asked to rate how they felt on a scale of one to nine (from extremely bad to extremely good). Similar results emerged: Participants felt the worst about positive events and the best about negative events in regards to the rich professionals. Two weeks later, the researchers followed up with an online survey in which the participants were presented a scenario-based game that involved the option to hurt another person, such as through electric shocks in order to spare several others.

“People were willing to hurt an envy target, saying, ‘Yes, let’s shock her,’” Cikara said. “We found that surprising because we weren’t certain participants would self report that. While it’s true that people are generally averse to harming others, the bottom line is that people don’t feel this way all the time.”

Manipulating stereotypes was the goal of the third experiment. Using various scenarios regarding an investment banker as an example, the researchers threw counter-stereotypic information at participants. In one article, the banker was himself, employed and status quo. In another, he was advising clients pro-bono (eliciting pride). In the next, he was using his work bonuses to buy drugs (disgust) and, finally, he was unemployed but still dressing to go to work (pity). Again, the findings matched earlier experiments – participants rated the articles associated with disgust and envy with less warmth than the pride or pity scenarios.

“This experiment shows that the dimensions predicting envy are high status and competition, and, when you move those around, the envy goes away. This is consistent with the story about who gets envied and why. A lot of it is tied into money because that’s an easy thing to look at,” said Fiske.

In the final experiment, the researchers used Cikara’s experience – a game between the Boston Red Sox and New York Yankees. Both groups of fans were prescreened for “intense fandom.” Participants were again monitored through fMRI and self-reports after watching a series of plays in which opponents struck out, scored runs or made fantastic plays. As predicted, participants reported experiencing more pleasure during positive outcomes for their team.

When a third neutral team – the Baltimore Orioles – was thrown into the mix, the fans reported little to no reaction to positive or negative events and did not wish to cause Orioles fans harm. But they were happy when their rival team lost to the Orioles, showing pure Schadenfreude, said Fiske. An online survey completed by participants two weeks later showed that both groups of fans were more likely to heckle, insult, threaten or hit a rival fan while watching the plays.

“We used a sporting event because it’s something you can bottle,” said Fiske. “Rabid fans are passionate about it, and we were looking for an intergroup phenomenon that reaches people where they live. This is certainly it. But it’s important to remember that this study isn’t just about sports teams. It’s about intergroup rivals of more consequence.”

Fiske thinks of the study as a simulation or model of group envy or harm.

“In our larger model of stereotypes, we find that when things go smoothly, people go along to get along with these envied groups. It’s when the chips are down that these groups become real targets of Schadenfreude.”

In terms of policy implications, Fiske and Cikara agree there are many.

“Around the world, the American government is seen as high status and competent but not necessarily as a group sharing other people’s or countries’ goals. So, as far as other people are concerned, we’re the world’s bullies, and we have data that show that,” said Fiske. “And so, if we want to work with another country, it’s not the respect we’re lacking; it’s the trust. We need to remember that these stereotypes really affect how we enter other settings.”

“A lack of empathy is not always pathological. It’s a human response, and not everyone experiences this, but a significant portion does,” Cikara said. “We need to remember this in terms of everyday situations. If you think about the way workplaces and organizations are set up, for example, it raises an interesting question: Is competition the best way to get your employees to produce? It’s possible, in some circumstances, that competition is good. In other ways, people might be preoccupied with bringing other people down, and that’s not what an organization wants.”

Funding for the work was provided by the Russell Sage Foundation, the Princeton Neuroscience Institute, Princeton’s Center for Human Values, WWS’s Joint Degree Program in Social Policy and the Charlotte Elizabeth Procter Fellowship (awarded to Cikara by Princeton University).

Read the abstract.

Mina Cikara and Susan T. Fiske. Their pain, our pleasure: stereotype content and schadenfreude. Annals of the New York Academy of Sciences. 2013. Vol. 1299 Sociability, Responsibility, and Criminality: From Lab to Law. Pages v–x, 1–100. Article first published online: 24 SEP 2013. DOI: 10.1111/nyas.12179

When scaling the quantum slopes, veer for the straight path (Physical Review A)

Research image

Princeton University researchers found that the “landscape” for quantum control (above) — a representation of quantum mechanics that allows the dynamics of atoms and molecules to be manipulated — can be unexpectedly simple, which could help scientists realize the next generation of technology by harnessing atoms and molecules to create small but incredibly powerful devices. Scientists achieve quantum control by finding the ideal radiation field (top of the graphic) that leads to the desired response from the system. Like a mountain hiker, a scientist can take a difficult, twisting path that requires frequent stops to evaluate the next step (right path). Or, they can opt for a straighter trail that cuts directly to the summit (left path). The researchers provide in their paper an algorithm that scientists can use to identify the starting point of the straight path to their desired quantum field. (Image courtesy of Arun Nanduri)

By Morgan Kelly, Office of Communications

Like any task, there is an easy and a hard way to control atoms and molecules as quantum systems, which are driven by tailored radiation fields. More efficient methods for manipulating quantum systems could help scientists realize the next generation of technology by harnessing atoms and molecules to create small but incredibly powerful devices such as molecular electronics or quantum computers.

Of course, controlling quantum systems is as painstaking as it sounds, and requires scientists to discover the ideal radiation field that leads to the desired response from the system. Scientists know that reaching that state of quantum nirvana can be a long and expensive slog, but Princeton University researchers have found that the process might be more straightforward than previously thought.

The researchers report in the journal Physical Review A that quantum-control “landscapes” — the path of a system’s response from the initial field to the final desired field — appears to be unexpectedly simple. Although still a mountain of a task, finding a good control radiation field turns out to be very much like climbing a mountain, and scientists need only choose the right path. Like a hiker, a scientist can take a difficult, twisting path that requires frequent stops to evaluate which step to take next. Or, as the Princeton researchers show, they can opt for a straighter trail that cuts directly to the summit.

The researchers observe in their paper that these fast tracks toward the desired control field actually exist, and are scattered all over the landscape. They provide an algorithm that scientists can use to identify the starting point of the straight path to their desired quantum field.

The existence of nearly straight paths to reach the best quantum control was surprising because the landscapes were assumed to be serpentine, explained first author Arun Nanduri, who received his bachelor’s degree in physics from Princeton in 2013 and is working in the laboratory of Herschel Rabitz, Princeton’s Charles Phelps Smyth ’16 *17 Professor of Chemistry.

“We found that not only can you always climb to the top, but you can climb along a simple path to the top,” Nanduri said. “If we could consistently identify where these paths are located, a scientist could efficiently climb the landscape. Looking around for the next good step along an unknown path takes great effort. However, starting along a straight path requires you to look around once, and you can keep walking forward with your eyes closed, as it were.”

Following a straighter path could be a far more efficient way of achieving control of atoms and molecules for a host of applications, including manipulating chemical reactions and operating quantum computers, Nanduri said. The source of much scientific excitement, quantum computers would use “qubits” that can be entangled to potentially give them enormous storage and computational capacities far beyond the capabilities of today’s digital computers.

If the Princeton research helps scientists quickly and easily find the control fields they need, it could also allow them to carry out improved measurements of quantum systems and design new ones, Nanduri said.

“We don’t know if our discovery will directly lead to futuristic quantum devices, but this finding should spur renewed research,” Nanduri said. “If straight paths to good quantum control solutions can be routinely found, it would be remarkable.”

Read the abstract.

Nanduri, Arun, Ashley Donovan, Tak-San Ho, Herschel Rabitz. 2013. Exploring quantum control landscape structure. Physical Review A. Article published: Sept. 30, 2013. DOI: 10.1103/PhysRevA.88.033425

The work was funded by the Program in Plasma Science and Technology at Princeton University, the Army Research Office, and the U.S. Department of Energy.

Small declines in agility, facial features may predict risk of dying (Epidemiology)

Photo source: Shutter Stock

Photo source: Shutter Stock

By B. Rose Huber, Woodrow Wilson School of Public and International Affairs

A new study from Princeton University shows that health assessments made by medically untrained interviewers may predict the mortality of individuals better than those made by physicians or the individuals themselves.

Features like forehead wrinkles and lack of agility may reflect a person’s overall health and risk of dying, according to recent health research. But do physicians consider such details when assessing patients’ overall health and functioning?

In a survey of approximately 1,200 Taiwanese participants, Princeton University researchers found that interviewers — who were not health professionals but were trained to administer the survey — provided health assessments that were related to a survey participant’s risk of dying, in part because they were attuned to facial expressions, responsiveness and overall agility.

The researchers report in the journal Epidemiology that these assessments were even more accurate predictors of dying than assessments made by physicians or even the individuals themselves. The findings show that survey interviewers, who typically spend a fair amount of time observing participants, can glean important information regarding participants’ health through thorough observations.

“Your face and body reveal a lot about your life. We speculate that a lot of information about a person’s health is reflected in their face, movements, speech and functioning, as well as in the information explicitly collected during interviews,” said Noreen Goldman, Hughes-Rogers Professor of Demography and Public Affairs in the Woodrow Wilson School.

Together with lead author of the paper, Princeton Ph.D. candidate Megan Todd, Goldman analyzed data collected by the Social Environment and Biomarkers of Aging Study (SEBAS). This study was designed by Goldman and co-investigator Maxine Weinstein at Georgetown University to evaluate the linkages among the social environment, stress and health. Beginning in 2000, SEBAS conducted extensive home interviews, collected biological specimens and administered medical examinations with middle-aged and older adults in Taiwan. Goldman and Todd used the 2006 wave of this study, which included both interviewer and physician assessments, for their analysis. They also included death registration data through 2011 to ascertain the survival status of those interviewed.

The survey used in the study included detailed questions regarding participants’ health conditions and social environment. Participants’ physical functioning was evaluated through tasks that determined, for example, their walking speed and grip strength. Health assessments were elicited from participants, interviewers and physicians on identical five-point scales by asking “Regarding your/the respondent’s current state of health, do you feel it is excellent (5), good (4), average (3), not so good (2) or poor (1)?”

Participants answered this question near the beginning of the interview, before other health questions were asked. Interviewers assessed the participants’ health at the end of the survey, after administering the questionnaire and evaluating participants’ performance on a set of tasks, such as walking a short distance and getting up and down from a chair. And physicians — who were hired by the study and were not the participants’ primary care physicians — provided their assessments after physical exams and reviews of the participants’ medical histories. (Study investigators did not provide special guidance about how to rate overall health to any group.)

In order to understand the many variables that go into predicting mortality, Goldman and Todd factored into their statistical models such socio-demographic variables as gender, place of residence, education, marital status, and participation in social activities. They also considered chronic conditions, psychological wellbeing (such as depressive symptoms) and physical functioning to account for a fuller picture of health.

“Mortality is easy to measure because we have death records indicating when a person has died,” Goldman said. “Overall health, on the other hand, is very complicated to measure but obviously very important for addressing health policy issues.”

Two unexpected results emerged from Goldman and Todd’s analysis. The first: physicians’ ratings proved to be weak predictors of survival. “The physicians performed a medical exam equivalent to an annual physical exam, plus an abdominal ultrasound; they have specialized knowledge regarding health conditions,” Goldman explained. “Given access to such information, we anticipated stronger, more accurate predictions of death,” she said. “These results call into question previous studies’ assumptions that physicians’ ‘objective health’ ratings are superior to ‘subjective’ ratings provided by the survey participants themselves.”

In a second surprising finding, the team found that interviewers’ ratings were considerably more powerful for predicting mortality than self-ratings. This is likely, Goldman said, because interviewers considered respondents’ movements, appearance and responsiveness in addition to the detailed health information gathered during the interviews. Also, Goldman posits, interviewer ratings are probably less affected by bias than self-reports.

“The ‘self-rated health’ question is religiously used by health researchers and social scientists, and, although it has been shown to predict mortality, it suffers from many biases. People use it because it’s easy and simple,” Goldman continued. “But the problem with self-rated health is that we have no idea what reference group the respondent is using when evaluating his or her own health. Different ethnic and racial groups respond differently as do varying socioeconomic groups. We need other simple ways to rate individual health instead of relying so heavily on self-rated health.”

One way, Goldman suggests, is by including interviewer ratings in surveys along with self-ratings: “This is a straightforward and cost-free addition to a questionnaire that is likely to improve our measurement of health in any population,” Goldman said.

The paper, “Do Interviewer and Physician Health Ratings Predict Mortality? A Comparison with Self-Rated Health,” first appeared online in Epidemology in August 2013. The article also will be featured in the November print edition. The research was conducted with the assistance of colleagues at Princeton’s Office of Population Research, Georgetown University and the Bureau of Health Promotion in the Taiwan Department of Health.

Read the abstract.

Todd MA, Goldman N. Do interviewer and physician health ratings predict mortality?: a comparison with self-rated health. Epidemiology. 2013 Nov;24(6):913-20. doi: 10.1097/EDE.0b013e3182a713a8.

 

Contaminated water linked to low-weight babies, prematurity (Canadian Journal of Economics)

By B. Rose Huber, Woodrow Wilson School of Public and International Affairs

Image: Shutter Stock

Image: Shutterstock.

Pregnant women living in areas with contaminated drinking water may be more likely to have babies that are premature or have low birth weights (less than 5.5 pounds), according to a study based at Princeton University’s Woodrow Wilson School of Public and International Affairs.

Published in the Canadian Journal of Economics, the study shows that the effects of contaminated water—such as cognitive and developmental impairments—are particularly significant for babies born to less-educated mothers. These mothers also are less likely to uproot from areas with contaminated water, which, the authors note, suggests a need for serious improvement in terms of communicating with people living in such environs.

“Fetuses are vulnerable to all types of pollution, including water contamination caused by chemicals and bacteria,” said Janet Currie, the Henry Putnam Professor of Economics and Public Affairs at the Wilson School and director of the Center for Health and Wellbeing. “This contamination can lead to a host of problems, including low-birth-weight babies who can have lifelong cognitive struggles. It’s a particular problem for less-educated women who also presumably have fewer options in terms of housing.”

While other studies have focused on the effects of air pollution on infant health, Currie’s is one of the first to evaluate the effects of water pollution on infants. Together with researchers from Columbia University and the University of California-San Diego, Currie examined ten years of New Jersey birth records and data on drinking-water quality collected from 1997 to 2007. All birth records contained information regarding the date of birth, the infant’s health at birth, and maternal characteristics such as race, education and marital status. To determine whether mothers relocated due to water contamination, the researchers studied sets of siblings and whether mothers moved between births.

Using data from the New Jersey Department of Environmental Protection (DEP), Currie and her team looked at violation records across 488 water districts in New Jersey and found that more than a quarter of districts had water contamination violations affecting more than 30,000 people. These violations included both chemical and bacterial contamination caused by such contaminants as dichloroethane — a solvent often used for plastics or as degreasers — as well as radon and coliform.

The researchers matched the birth records to the water systems that serve the infants’ residences. Because weather can dictate the amount of water a person consumes, they also incorporated daily temperatures into their data set.

“We found that infants exposed to contamination in utero tend to have mothers who are younger, less educated and less likely to be married than other mothers. They are also more likely to be African-American or Hispanic,” Currie said. “The results also suggest that mothers who are less educated are less likely than other mothers to move in response to contamination, while older mothers are more likely to drink bottled water or move.”

Currie notes that when a water district is affected, the DEP is required to send a notice to all residences. However, for renters, there may be routing difficulties.

“If someone puts something in your mailbox, do you even see it? Does your landlord pick it up?” said Currie. “Notices are being sent that people don’t receive. There’s an undercurrent here that the way information is sent isn’t adequate. We need to get this information to people directly.”

Currie suggests that health-care workers include literature about water contamination risks and hazards in clinics and exam rooms to reach more pregnant women.

“If it’s going to be harmful for some groups, we need to at least let those groups know about them, so they can avoid it,” said Currie.

In the future, Currie plans to continue studying environmental impacts on child health while also pursuing the relationship between home foreclosures and health.

Other collaborators for the study include: from Columbia University, Katherine Meckel, Matthew Neidell, and Wolfram Schlenker; and from the University of California, San Diego, Joshua Graff Zivin.

Read the abstract.

Currie, Janet, Joshua Graff Zivin, Katherine Meckel, Matthew Neidell, and Wolfram Schlenker. August 2013.  Something in the water: contaminated drinking water and infant health. Canadian Journal of Economics. Vol. 46, No. 3, pages 791-810.

Funding was provided by the John D. and Catherine T. MacArthur Foundation, the Environmental Protection Agency and the National Science Foundation.

Nano-dissection identifies genes involved in kidney disease (Genome Research)

Scanning electron microscope (SEM) micrograph of podocytes

Researchers at Princeton and the University of Michigan have created a computer-based method for separating and identifying genes from diseased kidney cells known as podocytes, pictured above. (Image courtesy of Matthias Kretzler)

By Catherine Zandonella, Office of the Dean for Research

Understanding how genes act in specific tissues is critical to our ability to combat many human diseases, from heart disease to kidney failure to cancer.  Yet isolating individual cell types for study is impossible for most human tissues.

A new method developed by researchers at Princeton University and the University of Michigan called “in silico nano-dissection” uses computers rather than scalpels to separate and identify genes from specific cell types, enabling the systematic study of genes involved in diseases.

The team used the new method to successfully identify genes expressed in cells known as podocytes — the “work-horses” of the kidney — that malfunction in kidney disease. The investigators showed that certain patterns of activity of these genes were correlated with the severity of kidney impairment in patients, and that the computer-based approach was significantly more accurate than existing experimental methods in mice at identifying cell-lineage-specific genes. The study was published in the journal Genome Research.

Using this technique, researchers can now examine the genes from a section of whole tissue, such as a biopsied section of the kidney, for specific signatures associated with certain cell types. By evaluating patterns of gene expression under different conditions in these cells, a computer can use machine-learning techniques to deduce which types of cells are present. The system can then identify which genes are expressed in the cell type in which they are interested.  This information is critical both in defining novel disease biomarkers and in selecting potential new drug targets.

By applying the new method to kidney biopsy samples, the researchers identified at least 136 genes as expressed specifically in podocytes. Two of these genes were experimentally shown to be able to cause kidney disease. The authors also demonstrated that in silico nano-dissection can be used for cells other than those found in the kidney, suggesting that the method is useful for the study of a range of diseases.

The computational method was significantly more accurate than another commonly used technique that involves isolating specific cell types in mice. The nano-dissection method’s accuracy was 65% versus 23% for the mouse method, as evaluated by a time-consuming process known as immunohistochemistry which involves staining each gene of interest to study its expression pattern.

The research was co-led by Olga Troyanskaya, a professor of computer science and the Lewis-Sigler Institute for Integrative Genomics at Princeton, and Matthias Kretzler, a professor of computational medicine and biology at the University of Michigan. The first authors on the study were Wenjun Ju, a research assistant professor at the University of Michigan, and Casey Greene, now at the Geisel School of Medicine at Dartmouth and a former postdoctoral fellow at Princeton.

The research was supported in part by National Institutes of Health (NIH) R01 grant GM071966 to OGT and MK, by NIH grants RO1 HG005998 and DBI0546275 to OGT, by NIH center grant P50 GM071508, and by NIH R01 grant DK079912 and P30 DK081943 to MK. OGT also receives support from the Canadian Institute for Advanced Research.

Read the abstract.

Wenjun Ju, Casey S Greene, Felix Eichinger, Viji Nair, Jeffery B Hodgin, Markus Bitzer, Young-suk Lee, Qian Zhu, Masami Kehata, Min Li, Song Jiang, Maria Pia Rastaldi, Clemens D Cohen, Olga G Troyanskaya and Matthias Kretzler. 2013. Defining cell-type specificity at the transcriptional level in human disease. Genome Research. Published in Advance August 15, 2013, doi: 10.1101/gr.155697.113.

New mouse model for hepatitis C (Nature)

By Catherine Zandonella, Office of the Dean for Research

Hepatitis C affects about three million people in the U.S. and is a leading cause of chronic liver disease, so creating a vaccine and new treatments is an important public health goal. Most research to date has been done in chimpanzees because they are one of a handful of species that become infected and spread the virus.

Now researchers led by Alexander Ploss of Princeton University and Charles Rice of the Rockefeller University have generated a mouse that can become infected with hepatitis C virus (HCV).  They reported the advance in the Sept 12 issue of the journal Nature. “The entire life cycle of the virus — from infection of liver cells to viral replication, assembly of new particles, and release from the infected cell — occurs in these mice,” said Ploss, who joined the Princeton faculty in July 2013 as assistant professor of molecular biology.

Ploss and his colleagues have been working for some time on the challenge of creating a small animal model for studying the disease. Four years ago, while at the Rockefeller University in New York, Ploss and Rice identified two human proteins, known as CD81 and occludin, that enable mouse cells to become infected with HCV (Nature 2009). In a follow up study Ploss and colleagues showed that a mouse engineered to express these human proteins could become infected with HCV, although the animals could not spread the virus (Nature 2011).

In the present study, which included colleagues at Osaka University and the Scripps Research Institute, the researchers bred the human-protein-containing mice with another strain that had a defective immune system – one that could not easily rid the body of viruses. The resulting mice not only become infected, but could potentially pass the virus to other susceptible mice.

The availability of this new way to study HCV could help researchers discover new vaccines and treatments, although Ploss cautioned that more work needs to be done to refine the model.

The study was supported in part by award number RC1DK087193 from the National Institute of Diabetes and Digestive and Kidney Diseases; R01AI072613, R01AI099284, and R01AI079031 from the National Institute for Allergy and Infectious Disease; R01CA057973 from the National Cancer Institute; and several foundations and contributors, as well as the Infectious Disease Society of America and the American Liver Foundation.

Read the abstract

Marcus Dorner, Joshua A. Horwitz, Bridget M. Donovan, Rachael N. Labitt, William C. Budell, Tamar Friling, Alexander Vogt, Maria Teresa Catanese, Takashi Satoh, Taro Kawai, Shizuo Akira, Mansun Law, Charles Rice & Alexander Ploss. 2013. Completion of the entire hepatitis C virus life cycle in genetically humanized mice. Nature 501, 237–241 (First published online on 31 July 2013)  doi:10.1038/nature12427.

 

Shingles symptoms may be caused by neuronal short circuit (Proceedings of the National Academy of Sciences)

By Catherine Zandonella, Office of the Dean for Research

Neurons firing in synchrony could be responsible for pain, itch in shingles and herpes infection. Click to view movie. (Source: PNAS)

The pain and itching associated with shingles and herpes may be due to the virus causing a “short circuit” in the nerve cells that reach the skin, Princeton researchers have found.

This short circuit appears to cause repetitive, synchronized firing of nerve cells, the researchers reported in the journal Proceedings of the National Academy of Sciences. This cyclical firing may be the cause of the persistent itching and pain that are symptoms of oral and genital herpes as well as shingles and chicken pox, according to the researchers.

These diseases are all caused by viruses of the herpes family. Understanding how these viruses cause discomfort could lead to better strategies for treating symptoms.

The team studied what happens when a herpes virus infects neurons. For research purposes the investigators used a member of the herpes family called pseudorabies virus. Previous research indicated that these viruses can drill tiny holes in neurons, which pass messages in the form of electrical signals along long conduits known as axons.

The researchers’ findings indicate that electrical current can leak through these holes, or fusion pores, and spread to nearby neurons that were similarly damaged, causing the neurons to fire all at once rather than as needed. The pores were likely created for the purpose of infecting new cells, the researchers said.

Researchers at Princeton University imaged the synchronized, repetitive firing of herpes-infected neurons in a region known as the submandibular ganglia (SMG) between the salivary glands and the brain in mice. Image source: PNAS.

Researchers at Princeton University imaged the synchronized, repetitive firing of herpes-infected neurons in a region known as the submandibular ganglia (SMG) between the salivary glands and the brain in mice. (Source: PNAS)

The investigators observed the cyclical firing of neurons in a region called the submandibular ganglia between the salivary glands and the brain in mice using a technique called 2-photon microscopy and dyes that flash brightly when neurons fire. (Movie of synchronized firing of herpes-infected neurons.)

The team found that two viral proteins appear to work together to cause the simultaneous firing, according to Andréa Granstedt, who received her Ph.D. in molecular biology at Princeton in 2013 and is the first author on the article.  The team was led by Lynn Enquist, Princeton’s Henry L. Hillman Professor in Molecular Biology and a member of the Princeton Neuroscience Institute.

Each colored line and number on the right represents an individual neuron. The overlapping peaks indicate synchronized firing of neurons, which occurs when electrical current is able to leak from one neuron to the next. (Source: PNAS)

The first of these two proteins is called glycoprotein B, a fusion protein that drills the holes in the axon wall. A second protein, called Us9, acts as a shuttle that sends glycoprotein B into axons, according to the researchers. “The localization of glycoprotein B is crucial,” Granstedt said. “If glycoprotein B is present but not in the axons, the synchronized flashing won’t happen.”

The researchers succeeded in stopping the short circuit from occurring in engineered viruses that lacked the gene for either glycoprotein B or Us9. Such genetically altered viruses are important as research tools, Enquist said.

Finding a way to block the activity of the proteins could be a useful strategy for treating the pain and itching associated with herpes viral diseases, Enquist said. “If you could block fusion pore formation, you could stop the generation of the signal that is causing pain and discomfort,” he said.

Granstedt conducted the experiments with Jens-Bernhard Bosse, a postdoctoral research associate in molecular biology. Assistance with 2-photon microscopy was provided by Stephan Thiberge, director of the Bezos Center for Neural Circuit Dynamics at the Princeton Neuroscience Institute.

The team previously observed the synchronized firing in laboratory-grown neurons (PLoS Pathogens, 2009), but the new study expands on the previous work by observing the process in live mice and including the contribution of Us9, Granstedt said.

Shingles, which is caused by the virus herpes zoster and results in a painful rash, will afflict almost one out of three people in the United States over their lifetime. Genital herpes, which is caused by herpes simplex virus-2, affects about one out of six people ages 14 to 49 years in the United States, according the Centers for Disease Control and Prevention.

This research was funded by National Institutes of Health (NIH) Grants NS033506 and NS060699. The Imaging Core Facility at the Lewis-Sigler Institute is funded by NIH National Institute of General Medical Sciences Center Grant PM50 GM071508.

Read the abstract

Granstedt, Andréa E., Jens B. Bosse, Stephan Y. Thiberge, and Lynn W. Enquist. 2013. In vivo imaging of alphaherpesvirus infection reveals synchronized activity dependent on axonal sorting of viral proteins. PNAS 2013 ; published ahead of print August 26, 2013, doi:10.1073/pnas.1311062110