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.

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.

Lack of coronin 1 protein causes learning deficits and aggressive behavior

Learning and memory relies on the proper processing of signals that stimulate neuronal cells within the brain. Researchers at the Biozentrum of the University of Basel, together with an international team of scientists, has uncovered an important role for the protein coronin 1 in cognition and behavior. They found that a lack of coronin 1 in mouse and in man is associated with poor memory, defective learning and aggressive behavior. The results, recently published in PLOS Biology, identify a novel risk factor for neurobehavioral dysfunction and reveal a molecular pathway involved in transferring information within neurons.

Organisms must be able to sense signals from the outside and translate these into biochemical cues in order to adequately respond to their environment. This capability is also required to process information that reaches the brain. Within the brain, stimulation of neurons activates genes that are required, for example for learning and memory. In collaboration with an international and interdisciplinary team the research group led by Prof. Jean Pieters from the Biozentrum, University of Basel, has now uncovered the role of an evolutionarily conserved protein, called coronin 1, in providing a link between the extracellular stimulus and neuronal activation that ultimately results in efficient learning and memory in both mice and men.

From the immune system to the brain
In earlier work, Pieters’ team discovered the protein coronin 1 as being essential for the proper transduction of signals in immune cells. In mice lacking coronin 1 the researchers further investigated the molecular mechanism. Surprisingly, these mice showed aberrant behavior. In particular, mice lacking coronin 1 appeared to be far more aggressive and display extreme grooming activity, an indication of reduced sociability. An in-depth analysis in collaboration with scientists from the Friedrich Miescher Institute in Basel and the University of Bordeaux unveiled profound learning and behavioral problems and severe defects in the ability to activate neurons in the absence of coronin 1.

Activation of a signaling cascade
But how does coronin 1 ensure proper neurobehavioral functioning? Normally, stimulation of the cell surface results in an activation of an intracellular cascade of reactions and ultimately stimulates the production of the signaling molecule cAMP which then activates a number of processes, including the transcription of gene involved in neurobehavior. “We found that in the absence of coronin 1, cell surface stimulation leads to a defective cAMP production”, explains Pieters. “This in turn affects the signal transduction which is finally responsible for the deficits in learning and memory formation.”

Of mice and men
Furthermore, the researchers analyzed the clinical history of a patient lacking coronin 1 due to a mutation: it turned out that this patient showed learning defects and aggressive behavior. With this study, Pieters and his project collaborators not only define a crucial role for coronin 1 in cognition and behavior, but also unravel a coronin 1-dependent signaling pathway that may be explored both for potential risk factors as well as future interventions to modulate neurobehavioral dysfunction.