Vast gene-expression map yields neurological and environmental stress insights

A consortium led by scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) has conducted the largest survey yet of how information encoded in an animal genome is processed in different organs, stages of development, and environmental conditions. Their findings paint a new picture of how genes function in the nervous system and in response to environmental stress.

They report their research this week in the Advance Online Publication of the journal Nature.

The scientists studied the fruit fly, an important model organism in genetics research. Seventy percent of known human disease genes have closely related genes in the fly, yet the fly genome is one-thirtieth the size of ours. Previous fruit fly research has provided insights on cancer, birth defects, addictive behavior, and neurological diseases. It has also advanced our understanding of processes common to all animals such as body patterning and synaptic transmission.

In the latest scientific fruit from the fruit fly, the consortium, led by Susan Celniker of Berkeley Lab’s Life Sciences Division, generated the most comprehensive map of gene expression in any animal to date. Scientists from the University of California at Berkeley, Indiana University at Bloomington, the University of Connecticut Health Center, and several other institutions contributed to the research.

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Physics-minded crows bring Aesop’s fable to life

Eureka! Like Archimedes in his bath, crows know how to displace water, showing that Aesop’s fable The Crow and the Pitcher isn’t purely fictional.

To see if New Caledonian crows could handle some of the basic principles of volume displacement, Sarah Jelbert at the University of Auckland in New Zealand and her colleagues placed scraps of meat just out of a crow’s reach, floating in a series of tubes that were part-filled with water. Objects potentially useful for bringing up the water level, like stones or heavy rubber erasers, were left nearby.

The crows successfully figured out that heavy and solid objects would help them get a treat faster. They also preferred to drop objects in tubes where they could access a reward more easily, picking out tubes with higher water levels and choosing tubes of water over sand-filled ones.

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Brain scans link concern for justice with reason, not emotion

People who care about justice are swayed more by reason than emotion, according to new brain scan research from the Department of Psychology and Center for Cognitive and Social Neuroscience.

Psychologists have found that some individuals react more strongly than others to situations that invoke a sense of justice—for example, seeing a person being treated unfairly or mercifully. The new study used brain scans to analyze the thought processes of people with high “justice sensitivity.”

“We were interested to examine how individual differences about justice and fairness are represented in the brain to better understand the contribution of emotion and cognition in moral judgment,” explained lead author Jean Decety, the Irving B. Harris Professor of Psychology and Psychiatry.    

Using a functional magnetic resonance imaging (fMRI) brain-scanning device, the team studied what happened in the participants’ brains as they judged videos depicting behavior that was morally good or bad. For example, they saw a person put money in a beggar’s cup or kick the beggar’s cup away. The participants were asked to rate on a scale how much they would blame or praise the actor seen in the video. People in the study also completed questionnaires that assessed cognitive and emotional empathy, as well as their justice sensitivity.

As expected, study participants who scored high on the justice sensitivity questionnaire assigned significantly more blame when they were evaluating scenes of harm, Decety said. They also registered more praise for scenes showing a person helping another individual.

But the brain imaging also yielded surprises. During the behavior-evaluation exercise, people with high justice sensitivity showed more activity than average participants in parts of the brain associated with higher-order cognition. Brain areas commonly linked with emotional processing were not affected.

The conclusion was clear, Decety said: “Individuals who are sensitive to justice and fairness do not seem to be emotionally driven. Rather, they are cognitively driven.” 

According to Decety, one implication is that the search for justice and the moral missions of human rights organizations and others do not come primarily from sentimental motivations, as they are often portrayed. Instead, that drive may have more to do with sophisticated analysis and mental calculation.

Decety adds that evaluating good actions elicited relatively high activity in the region of the brain involved in decision-making, motivation and rewards. This finding suggests that perhaps individuals make judgments about behavior based on how they process the reward value of good actions as compared to bad actions.

“Our results provide some of the first evidence for the role of justice sensitivity in enhancing neural processing of moral information in specific components of the brain network involved in moral judgment,” Decety said.

Scientists find potential target for treating mitochondrial disorders

Mitochondria, long known as “cellular power plants” for their generation of the key energy source adenosine triphosphate (ATP), are essential for proper cellular functions. Mitochondrial defects are often observed in a variety of diseases, including cancer, Alzheimer’s disease, and Parkinson’s disease, and are the hallmarks of a number of genetic mitochondrial disorders whose manifestations range from muscle weakness to organ failure. Despite a fairly strong understanding of the pathology of such genetic mitochondrial disorders, efforts to treat them have been largely ineffective.

But now, graduate student Walter Chen and postdoctoral researcher Kivanc Birsoy, both part of Whitehead Institute Member David Sabatini’s lab, have unraveled how to rescue cells suffering from mitochondrial dysfunction, a finding that may lead to new therapies for this condition.

To find genetic mutations that would rescue the cells, Chen and Birsoy mimicked mitochondrial dysfunction in a haploid genetic system developed by former Whitehead Fellow Thijn Brummelkamp. After suppressing mitochondrial function using the drug antimycin, Chen and Birsoy saw that cells with mutations inactivating the gene ATPIF1 were protected against loss of mitochondrial function.

The protein ATPIF1 is part of a backup system to save starving cells. When cells are deprived of oxygen and sugars, a mitochondrial complex that usually produces ATP, called ATP synthase, switches to consuming it, a state that can be harmful to an already starving cell. ATPIF1 interacts with ATP synthase to shut it down and prevent it from consuming the mitochondrion’s dwindling ATP supply but, in the process, also worsens the mitochondrion’s membrane potential.

“In these diseases of mitochondrial dysfunction, in a sense, it’s a false starvation situation for the cell—there are plenty of nutrients, but because there’s a block in the mitochondria’s normal function, the mitochondria behave as if there’s not enough oxygen,” says Chen, who with Birsoy, authored a paper in the journal Cell Reports describing this work. “So in these situations, activation of ATPIF1 is not good, because there are still many nutrients around to provide ATP. Instead, blocking ATPIF1 is therapeutic because it allows for maintenance of the membrane potential.”

Liver cells are frequently affected in patients with severe mitochondrial disease, so Chen and Birsoy tested the effects of mitochondrial dysfunction in the liver cells of control mice and mice with ATPIF1 genetically knocked out. Again, the liver cells with suppressed ATPIF1 function dealt better with mitochondrial dysfunction than liver cells with normal ATPIF1 activity.

“It’s very simple—if you get rid of ATPIF1, you survive in the presence of mitochondrial dysfunction,” says Birsoy. “From what we see so far, there are no major side effects from blocking ATPIF1 in mice.”

For Chen and Birsoy, the next step in this line of research is to test the effects of ATPIF1 suppression in mouse models of mitochondrial dysfunction. Then they will try to identify therapeutics that effectively block ATPIF1 function.

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Gulf War Illness Not in Veterans’ Heads, But in Their Mitochondria

Researchers at the UC San Diego School of Medicine have demonstrated for the first time that veterans of the 1990-91 Persian Gulf War who suffer from “Gulf War illness” have impaired function of mitochondria – the energy powerhouses of cells.

The findings, published in the March 27, 2014 issue of PLOS ONE, could help lead to new treatments benefitting affected individuals – and to new ways of protecting servicepersons (and civilians) from similar problems in the future, said principal investigator Beatrice A. Golomb MD, PhD, professor of medicine.

Golomb, with associate Hayley Koslik and Gavin Hamilton, PhD, a research scientist and magnetic resonance physicist, used the imaging technology to compare Gulf War veterans with diagnosed Gulf War illness to healthy controls. Cases were matched by age, sex and ethnicity.

The technique used – 31-phosphorus magnetic resonance spectroscopy or 31P-MRS – reveals amounts of phosphorus-containing compounds in cells. Such compounds are important for cell energy production, in particular phosphocreatine or PCr, which declines in muscle cells during exercise. PCr recovery takes longer when mitochondrial function is impaired, and delayed recovery is recognized as a robust marker of mitochondrial dysfunction.

Affected Gulf War veterans displayed significantly delayed PCr recovery after an exercise challenge. In fact, said Golomb, there was almost no overlap in the recovery times of Gulf War illness veterans compared to controls: All but one control participant had a recovery time-constant clustered under 31 seconds. In contrast, all but one Gulf Illness veteran had a recovery time-constant exceeding 35 seconds, with times ranging as high as 70 seconds.

There were 14 participants in the study: seven Gulf War illness cases and seven matching controls. Golomb notes that the use of 1:1 matching markedly improves statistical “power,” allowing a smaller sample size. The separation between the two groups was “visibly striking, and the large average difference was statistically significant,” she said.

Golomb noted that impaired mitochondrial function accounts for numerous features of Gulf War illness, including symptoms that have been viewed as perplexing or paradoxical.

“The classic presentation for mitochondrial illness involves multiple symptoms spanning many domains, similar to what we see in Gulf War illness. These classically include fatigue, cognitive and other brain-related challenges, muscle problems and exercise intolerance, with neurological and gastrointestinal problems also common.”

There are other similarities between patients with mitochondrial dysfunction and those suffering from Gulf War illness: Additional symptoms appear in smaller subsets of patients; varying patterns of symptoms and severity among individuals; different latency periods across symptoms, or times when symptoms first appear; routine blood tests that appear normal.

“Some have sought to ascribe Gulf War illness to stress,” said Golomb, “but stress has proven not to be an independent predictor of the condition. On the other hand, Gulf veterans are known to have been widely exposed to acetylcholinesterase inhibitors, a chemical class found in organophosphate and carbamate pesticides, nerve gas and nerve gas pre-treatment pills given to troops.

“These inhibitors have known mitochondrial toxicity and generally show the strongest and most consistent relationship to predicting Gulf War illness. Mitochondrial problems account for which exposures relate to Gulf War illness, which symptoms predominate, how Gulf War illness symptoms manifest themselves, what objective tests have been altered, and why routine blood tests have not been useful.”

Pictured: mitochondria, false colored.

Neurobiologists find chronic stress in early life causes anxiety, aggression in adulthood

In recent years, behavioral neuroscientists have debated the meaning and significance of a plethora of independently conducted experiments seeking to establish the impact of chronic, early-life stress upon behavior – both at the time that stress is experienced, and upon the same individuals later in life, during adulthood.

These experiments, typically conducted in rodents, have on the one hand clearly indicated a link between certain kinds of early stress and dysfunction in the neuroendocrine system, particularly in the so-called HPA axis (hypothalamic-pituitary-adrenal), which regulates the endocrine glands and stress hormones including corticotropin and glucocorticoid.

Yet the evidence is by no means unequivocal. Stress studies in rodents have also clearly identified a native capacity, stronger in some individuals than others, and seemingly weak or absent in still others, to bounce back from chronic early-life stress. Some rodents subjected to early-life stress have no apparent behavioral consequences in adulthood – they are disposed neither to anxiety nor depression, the classic pathologies understood to be induced by stress in certain individuals.

This week, a research team led by Associate Professor Grigori Enikolopov of Cold Spring Harbor Laboratory (CSHL) reports online in the journal Plos One the results of experiments designed to assess the impacts of social stress upon adolescent mice, both at the time they are experienced and during adulthood. Involving many different kinds of stress tests and means of measuring their impacts, the research indicates that a “hostile environment in adolescence disturbs psychoemotional state and social behaviors of animals in adult life,” the team says.

The tests began with 1-month-old male mice – the equivalent, in human terms of adolescents – each placed for 2 weeks in a cage shared with an aggressive adult male. The animals were separated by a transparent perforated partition, but the young males were exposed daily to short attacks by the adult males. This kind of chronic activity produces what neurobiologists call social-defeat stress in the young mice. These mice were then studied in a range of behavioral tests.

“The tests assessed levels of anxiety, depression, and capacity to socialize and communicate with an unfamiliar partner,” explains Enikolopov. They showed that in young mice, chronic social defeat induced high levels of anxiety and helplessness, and less social interaction, including diminished ability to communicate with other young animals. Stressed mice also had less new nerve-cell growth (neurogenesis) in a portion of the hippocampus known to be affected in depression: the subgranular zone of the dentate gyrus.

Another group of young mice was also exposed to social stress, but was then placed for several weeks in an unstressful environment. Following this “rest” period, these mice, now old enough to be considered adults, were tested in the same manner as the other cohort. 

In this second, now-adult group, most of the behaviors impacted by social defeat returned to normal, as did neurogenesis, which retuned to a level seen in healthy controls. “This shows that young mice, exposed to adult aggressors, were largely resilient biologically and behaviorally,” says Enikolopov.

However, in these resilient mice, the team measured two latent impacts on behavior. As adults they were abnormally anxious, and were observed to be more aggressive in their social interactions. “The exposure to a hostile environment during their adolescence had profound consequences in terms of emotional state and the ability to interact with peers,” Enikolopov observes.