1. Alzheimer’s disease risk linked to a network of genes associated with myeloid cells

    July 16, 2017 by Ashley

    From The Mount Sinai Hospital / Mount Sinai School of Medicine press release:

    Many genes linked to late-onset Alzheimer’s disease (AD) are expressed in myeloid cells and regulated by a single protein, according to research conducted at the Icahn School of Medicine at Mount Sinai and published June 19 in the journal Nature Neuroscience.

    Mount Sinai researchers led an international, genome-wide study of more than 40,000 people with and without the disease and found that innate immune cells of the myeloid lineage play an even more central role in Alzheimer’s disease pathogenesis than previously thought.

    Specifically, the research team identified a network of genes that are implicated in AD and expressed by myeloid cells, innate immune cells that include microglia and macrophages. Furthermore, researchers identified the transcription factor PU.1, a protein that regulates gene expression and, thus, cell identity and function, as a master regulator of this gene network.

    “Our findings show that a large proportion of the genetic risk for late-onset AD is explained by genes that are expressed in myeloid cells, and not other cell types,” says Alison Goate, DPhil, Professor of Neuroscience and Director of The Ronald M. Loeb Center for Alzheimer’s Disease at the Icahn School of Medicine at Mount Sinai and principal author of the study. “Dysregulation of this network is certainly a cause of Alzheimer’s, but we have more work to do to better understand this network and regulation by PU.1, to reveal promising therapeutic targets.”

    Using a combination of genetic approaches to analyze the genomes of 14,406 AD patients, and 25,849 control patients who do not have the disease, researchers found that many genes which are known to influence the age at which AD sets in, are expressed in myeloid cells. This work pinpointed SPI1, a gene that encodes the transcription factor PU.1, as a major regulator of this network of AD risk genes and demonstrated that lower levels of SPI1/PU.1 are associated with later age at onset of AD.

    To test the hypothesis that SPI1 expression levels influence expression of other AD risk genes and microglial function, the researchers used a mouse microglial cell line, BV2 cells that can be cultured in a dish. When researchers knocked down expression of SPI1, the gene that produces PU.1 in cells, they found that the cells showed lower phagocytic activity (engulfment of particles), while overexpression of SPI1 led to increased phagocytic activity. Many other AD genes expressed in microglia also showed altered expression in response to this manipulation of SPI1 expression.

    “Experimentally altering PU.1 levels correlated with phagocytic activity of mouse microglial cells and the expression of multiple AD genes involved in diverse biological processes of myeloid cells,” says Dr. Goate. “SPI1/PU.1 expression may be a master regulator capable of tipping the balance toward a neuroprotective or a neurotoxic microglial function.”

    The researchers stress that because the PU.1 transcription factor regulates many genes in myeloid cells, the protein itself may not be a good therapeutic target. Instead, further studies of PU.1’s role in microglia and AD pathogenesis are necessary, as they may reveal promising downstream targets that may be more effective in modulating AD risk without broad effects on microglial function. Increased understanding is crucial to facilitating the development of novel therapeutic targets for a disease that currently has no cure.


  2. Mice provide insight into genetics of autism spectrum disorders

    July 15, 2017 by Ashley

    From the University of California – Davis press release:

    While the definitive causes remain unclear, several genetic and environmental factors increase the likelihood of autism spectrum disorder, or ASD, a group of conditions covering a “spectrum” of symptoms, skills and levels of disability.

    Taking advantage of advances in genetic technologies, researchers led by Alex Nord, assistant professor of neurobiology, physiology and behavior with the Center for Neuroscience at the University of California, Davis, are gaining a better understanding of the role played by a specific gene involved in autism. The collaborative work appears June 26 in the journal Nature Neuroscience.

    “For years, the targets of drug discovery and treatment have been based on an unknown black box of what’s happening in the brain,” said Nord. “Now, using genetic approaches to study the impact of specific mutations found in cases, we’re trying to build a cohesive model that links genetic control of brain development with behavior and brain function.”

    The Nord laboratory studies how the genome encodes brain development and function, with a particular interest in understanding the genetic basis of neurological disorders.

    Mouse brain models

    There is no known specific genetic cause for most cases of autism, but many different genes have been linked to the disorder. In rare, specific cases of people with ASD, one copy of a gene called CHD8 is mutated and loses function. The CHD8 gene encodes a protein responsible for packaging DNA in cells throughout the body. Packaging of DNA controls how genes are turned on and off in cells during development.

    Because mice and humans share on average 85 percent of similarly coded genes, mice can be used as a model to study how genetic mutations impact brain development. Changes in mouse DNA mimic changes in human DNA and vice-versa. In addition, mice exhibit behaviors that can be used as models for exploring human behavior.

    Nord’s laboratory at UC Davis and his collaborators have been working to characterize changes in brain development and behavior of mice carrying a mutated copy of CHD8.

    “Behavioral tests with mice give us information about sociability, anxiety and cognition. From there, we can examine changes at the anatomical and cellular level to find links across dimensions,” said Nord. “This is critical to understanding the biology of disorders like autism.”

    By inducing mutation of the CHD8 gene in mice and studying their brain development, Nord and his team have established that the mice experience cognitive impairment and have increased brain volume. Both conditions are also present in individuals with a mutated CHD8 gene.

    New implications for early and lifelong brain development

    Analysis of data from mouse brains reveals that CHD8 gene expression peaks during the early stages of brain development. Mutations in CHD8 lead to excessive production of dividing cells in the brain, as well as megalencephaly, an enlarged brain condition common in individuals with ASD. These findings suggest the developmental causes of increased brain size.

    More surprisingly, Nord also discovered that the pathological changes in gene expression in the brains of mice with a mutated CHD8 continued through the lifetime of the mice. Genes involved in critical biological processes like synapse function were impacted by the CHD8 mutation. This suggests that CHD8 plays a role in brain function throughout life and may affect more than early brain development in autistic individuals.

    While Nord’s research centers on severe ASD conditions, the lessons learned may eventually help explain many cases along the autism spectrum.

    Collaborating to improve understanding

    Nord’s work bridges disciplines and has incorporated diverse collaborators. The genetic mouse model was developed at Lawrence Berkeley National Laboratory using CRISPR editing technology, and co-authors Jacqueline Crawley and Jill Silverman of the UC Davis MIND Institute evaluated mouse behavior to characterize social interactions and cognitive impairments.

    Nord also partnered with co-author Konstantinos Zarbalis of the Institute for Pediatric Regenerative Medicine at UC Davis to examine changes in cell proliferation in the brains of mice with the CHD8 mutation, and with Jason Lerch from the Mouse Imaging Centre at the Hospital for Sick Children in Toronto, Canada, to conduct magnetic resonance imaging on mouse brains.

    “It’s the act of collaboration that I find really satisfying,” Nord said. “The science gets a lot more interesting and powerful when we combine different approaches. Together we were able to show that mutation to CHD8 causes changes to brain development, which in turn alters brain anatomy, function and behavior.”

    In the future, Nord hopes to identify how CHD8 packages DNA in neural cells and to determine the specific impacts to early brain development and synaptic function. Nord hopes that deep exploration of CHD8 mutations will ultimately yield greater knowledge of the general factors contributing to ASD and intellectual disability.


  3. Alzheimer’s gene associated with failure to adapt to cognitive challenge in healthy adults

    by Ashley

    From the Society for Neuroscience press release:

    Healthy adults carrying the gene APOE4 — the strongest known genetic risk factor for Alzheimer’s disease (AD) — may struggle to adapt their brain activity to increasing cognitive demands as they get older, according to a study published in The Journal of Neuroscience. This age-related effect, which was not observed in people without the risk factor, suggests that interventions targeting cognitive decline in at-risk populations may need to begin many years before any symptoms of the disease emerge in order to be effective.

    Karen Rodrigue and colleagues assessed the performance of 31 adults (ages 20-86) with APOE4 on a distance judgment task at different levels of difficulty while measuring their brain activity. Although these at-risk participants showed similar adjustment in brain activity to the difficulty of the task as non-APOE4 carrying adults of the same age, sex, and education level, this ability declined with increasing age in the individuals with APOE4. These changes occurred in the precuneus, a part of the brain implicated in the early stages of AD, and reduced modulation of this area was associated with poorer performance on the task. These findings may help to inform the identification of individuals at increased risk of developing the disease.


  4. Anxiety study shows genes are not fixed: Experience and exposure can change them

    July 14, 2017 by Ashley

    From the Research Society on Alcoholism press release:

    Epigenetics refers to how certain life circumstances can cause genes to be silenced or expressed, become dormant or active, over time. New research shows that adolescent binge drinking can lead to epigenetic reprogramming that predisposes an individual to later psychiatric disorders such as anxiety. These data will be shared at the 40thannual scientific meeting of the Research Society on Alcoholism (RSA) in Denver June 24-28.

    “Adolescence is an important period of growth,” said Subhash C. Pandey, Ph.D., professor and director of the Alcohol Research Center at the University of Illinois at Chicago. “This is when the brain is maturing, and consistent epigenetic programing occurs. This is also a period when binge drinking is prevalent. Adolescent binge drinking can disrupt epigenetic programing in key brain regions by changing certain key molecular targets within the epigenome.”

    Pandey explained that early life exposure to alcohol can have not only long-lasting effects on brain chemistry but also induce a predisposition to psychiatric problems such as alcohol abuse and anxiety disorders. “Anxiety disorder is highly comorbid with alcoholism,” he said, “and adolescent alcohol exposure can lead to the development of high anxiety and alcohol intake in adulthood.” Pandey will elaborate on these findings at the RSA meeting on June 25.

    “More specifically, our data indicate that the enzymes histone deacetylases and demethylases — which are responsible for the regulation of histone acetylation and methylation — are altered in adulthood due to previous adolescent alcohol exposure. This alteration causes specific genes involved in regulating synaptic events to become suppressed, leading to high anxiety and high alcohol drinking behavior.” In other words, adolescent alcohol exposure can change the architecture where certain genes reside, and thus modify how the genes perform.

    “In short,” said Pandey, “epigenetic reprogramming in the brain due to early life experiences or exposure to alcohol can lead to the changes in gene functions and predispose an individual to adult psychopathology.”


  5. Study suggests tendency to trust may be inherited, but distrust is not

    July 3, 2017 by Ashley

    From the University of Arizona press release:

    Research has shown that how trusting a person is may depend, at least in part, on his or her genes. However, distrust does not appear to be inherited in the same way, according to a new study led by the University of Arizona.

    The research, published in Proceedings of the National Academy of Sciences, explores distrust as a separate and distinct quality from trust.

    “This research supports the idea that distrust is not merely the opposite of trust,” said Martin Reimann, assistant professor of marketing in the UA’s Eller College of Management and lead author of the study.

    “Both trust and distrust are strongly influenced by the individual’s unique environment, but what’s interesting is that trust seems to be significantly influenced by genetics, while distrust is not. Distrust appears to be primarily socialized,” Reimann said.

    Reimann and his colleagues — UA assistant professor of management and organizations Oliver Schilke and Stanford sociologist Karen S. Cook — studied sets of adult identical twins — who have identical genetic relatedness — and adult fraternal, or non-identical, twins — who have different genetic relatedness.

    Based on the core principles of behavioral genetics, if genetics explain variations in distrust and trust behaviors, then identical twins should behave more similarly to each other than fraternal twins, since the genes of identical twins are shared, while the genes of fraternal twins are only imperfectly correlated, Reimann said.

    Studying the two different types of twins allowed researchers to estimate the relative influence of three different factors on twins’ trust and distrust trust behaviors: heritable factors — that is, genetic influences; shared environmental factors — that is, common experiences of growing up in the same family and interacting with the same immediate peers; and unshared environmental factors — or the siblings’ unique experiences in life.

    For the research, 324 identical and 210 fraternal twins participated in a study task that asked them to decide how much money to send to another study participant — representing trust — and another task that asked them to decide how much money to take away from another participant — representing distrust.

    The researchers found that the identical twin pairs behaved more similarly than the fraternal twin pairs in their trust behaviors but not their distrust behaviors, suggesting that genetics influence trust, but not distrust.

    Overall, analyses estimated that trust is 30 percent heritable, while distrust is not at all heritable. Meanwhile, the estimated contribution of shared environment to distrust was 19 percent, while shared environment didn’t contribute at all to trust.

    Unshared environment — or the twins’ independent experiences in life — had the biggest impact on both trust and distrust, with unshared experiences contributing 81 percent to distrust and 70 percent to trust. In other words, much of a person’s propensity to trust or distrust is neither inherited nor commonly socialized. It is instead influenced by unique experiences in life.

    “We all have a stock of past experiences that we draw on to help determine how we are going to behave in different situations, and future research should look at what particular types of life experiences could be the most influential on trust or distrust,” Reimann said. “Disposition to trust, however, is not a product of experience alone; genetic influence is also significant. But we don’t see the same genetic influence with distrust.”


  6. Study suggests there are genes that up insomnia risk

    June 25, 2017 by Ashley

    From the Vrije Universiteit Amsterdam press release:

    An international team of researchers has found, for the first time, seven risk genes for insomnia. With this finding the researchers have taken an important step towards the unravelling of the biological mechanisms that cause insomnia. In addition, the finding proves that insomnia is not, as is often claimed, a purely psychological condition. Today, Nature Genetics publishes the results of this research.

    Insomnia is probably the most common health complaint. Even after treatment, poor sleep remains a persistent vulnerability for many people. By having determined the risk genes, professors Danielle Posthuma (VU and VUmc) and Eus Van Someren (Netherlands Institute for Neuroscience, VU and VUmc), the lead researchers of this international project, have come closer to unravelling the biological mechanisms that cause the predisposition for insomnia.

    Hope and recognition for insomniacs

    Professor Van Someren, specialized in sleep and insomnia, believes that the findings are the start of a path towards an understanding of insomnia at the level of communication within and between neurons, and thus towards finding new ways of treatment.

    He also hopes that the findings will help with the recognition of insomnia. “As compared to the severity, prevalence and risks of insomnia, only few studies targeted its causes. Insomnia is all too often dismissed as being ‘all in your head’. Our research brings a new perspective. Insomnia is also in the genes.”

    In a sample of 113,006 individuals, the researchers found 7 genes for insomnia. These genes play a role in the regulation of transcription, the process where DNA is read in order to make an RNA copy of it, and exocytosis, the release of molecules by cells in order to communicate with their environment. One of the identified genes, MEIS1, has previously been related to two other sleep disorders: Periodic Limb Movements of Sleep (PLMS) and Restless Legs Syndrome (RLS). By collaborating with Konrad Oexle and colleagues from the Institute of Neurogenomics at the Helmholtz Zentrum, München, Germany, the researchers could conclude that the genetic variants in the gene seem to contribute to all three disorders. Strikingly, PLMS and RLS are characterized by restless movement and sensation, respectively, whereas insomnia is characterized mainly by a restless stream of consciousness.

    Genetic overlap with other characteristics

    The researchers also found a strong genetic overlap with other traits, such as anxiety disorders, depression and neuroticism, and low subjective wellbeing. “This is an interesting finding, because these characteristics tend to go hand in hand with insomnia. We now know that this is partly due to the shared genetic basis,” says neuroscientist Anke Hammerschlag (VU), PhD student and first author of the study.

    Different genes for men and women

    The researchers also studied whether the same genetic variants were important for men and women. “Part of the genetic variants turned out to be different. This suggests that, for some part, different biological mechanisms may lead to insomnia in men and women,” says professor Posthuma. “We also found a difference between men and women in terms of prevalence: in the sample we studied, including mainly people older than fifty years, 33% of the women reported to suffer from insomnia. For men this was 24%.”

    The risk genes could be tracked down in cohorts with the DNA and diagnoses of many thousands of people. The UK Biobank — a large cohort from England that has DNA available — did not have information as such about the diagnosis of insomnia, but they had asked their participants whether they found it difficult to fall asleep or to have an uninterrupted sleep. By making good use of information from slaapregister.nl (the Dutch Sleep Registry), the UK Biobank was able, for the first time, to determine which of them met the insomnia profile. Linking the knowledge from these two cohorts is what made the difference.


  7. Epigenetic changes at birth could explain later behavior problems

    June 24, 2017 by Ashley

    From the King’s College London press release:

    Epigenetic changes present at birth — in genes related to addiction and aggression — could be linked to conduct problems in children, according to a new study by King’s College London and the University of Bristol.

    Conduct problems (CP) such as fighting, lying and stealing are the most common reason for child treatment referral in the UK, costing an estimated £22 billion per year. Children who develop conduct problems before the age of 10 (known as early-onset CP) are at a much higher risk for severe and chronic antisocial behaviour across the lifespan, resulting in further social costs related to crime, welfare dependence and health-care needs.

    Genetic factors are known to strongly influence conduct problems, explaining between 50-80 per cent of the differences between children who develop problems and those who do not. However, little is known about how genetic factors interact with environmental influences — especially during fetal development — to increase the risk for later conduct problems.

    Understanding changes in DNA methylation, an epigenetic process that regulates how genes are ‘switched on and off’, could aid the development of more effective approaches to preventing later conduct problems.

    The study, published in Development & Psychopathology, used data from Bristol’s Avon Longitudinal Study of Parents and Children (ALSPAC) to examine associations between DNA methylation at birth and conduct problems from the ages of four to 13.

    The researchers also measured the influence of environmental factors previously linked to early onset of conduct problems, including maternal diet, smoking, alcohol use and exposure to stressful life events.

    They found that at birth, epigenetic changes in seven sites across children’s DNA differentiated those who went on to develop early-onset versus those who did not. Some of these epigenetic differences were associated with prenatal exposures, such as smoking and alcohol use during pregnancy.

    One of the genes which showed the most significant epigenetic changes, called MGLL, is known to play a role in reward, addiction and pain perception. This is notable as previous research suggests conduct problems are often accompanied by substance abuse, and there is also evidence indicating that some people who engage in antisocial lifestyles show higher pain tolerance. The researchers also found smaller differences in a number of genes previously associated with aggression and antisocial behaviour, including MAOA.

    Dr Edward Barker, senior author from King’s College London, said: ‘We know that children with early-onset conduct problems are much more likely to engage in antisocial behaviour as adults, so this is clearly a very important group to look at from a societal point of view.

    ‘There is good evidence that exposure to maternal smoking and alcohol is associated with developmental problems in children, yet we don’t know how increased risk for conduct problems occurs. These results suggest that epigenetic changes taking place in the womb are a good place to start.’

    Dr Charlotte Cecil, first author from King’s College London, said: ‘Our study reveals significant epigenetic changes which differentiate children who go on to develop conduct problems and those who don’t. Although these findings do not prove causation, they do highlight the neonatal period as a potentially important window of biological vulnerability, as well as pinpointing novel genes for future investigation.

    ‘Given that the postnatal environment is also crucial for children’s development, future research should examine whether positive environmental experiences can help to modify these epigenetic changes.’


  8. Study suggests anorexia nervosa has a genetic basis

    by Ashley

    From the Medical University of Vienna press release:

    A large-scale, international whole-genome analysis has now revealed for the first time that anorexia nervosa is associated with genetic anomalies on chromosome 12. This finding might lead to new, interdisciplinary approaches to its treatment. The study was led by the University of North Carolina and has been published in the American Journal of Psychiatry. Child and adolescent psychiatrist Andreas Karwautz from MedUni Vienna’s Department of Child and Adolescent Psychiatry was responsible for the Austrian contribution.

    There are currently around 7,500 adolescents in Austria suffering from anorexia nervosa. Girls make up around 95% of those suffering from this serious and protracted disease, which leads to serious health problems due to excessive weight loss. The disease is currently curable in 80% of cases but is still associated with an annual mortality rate of 0.5%. At the present time, the Department of Child and Adolescent Psychiatry at MedUni Vienna is treating around 70 seriously ill adolescents, both as in-patients and out-patients.

    Although we already knew from genetic tests on monozygotic twins that genes are approximately 60% responsible for the development of anorexia nervosa, we did not know with any certainty which gene loci were involved. A study initiated by the US University of North Carolina has now been conducted worldwide, involving 220 researchers in international medical centres analysing the genetic material of 3,500 anorexics. It was found that, compared with the control group of 11,000 people, anorexics had a significant locus on chromosome 12 that contributes towards an elevated risk of developing anorexia nervosa.

    The researchers also explored whether there was any correlation with other disorders. This revealed that the significant locus lies on chromosome 12, in a region associated with Type I diabetes and autoimmune disorders, as well as insulin metabolism. Moreover, genetic correlations were found between anorexia nervosa, neuroticism and schizophrenia, supporting the idea that anorexia is a psychiatric illness.

    Child and adolescent psychiatrist Karwautz regards the findings of this study as significant proof that, in addition to the psychosocial component, biological factors also play an extremely important role in the onset of anorexia nervosa. This has huge implications in terms of improving treatment. Says Karwautz: “Such studies form a basis for providing patients and their relatives with a logical and realistic explanation for this persistent disorder, which is the third commonest disorder in this adolescent age group. Prevention programmes will also benefit from these new findings.”


  9. Genes influence ability to read a person’s mind from their eyes

    June 19, 2017 by Ashley

    From the University of Cambridge press release:

    Our DNA influences our ability to read a person’s thoughts and emotions from looking at their eyes, suggests a new study published in the journal Molecular Psychiatry.

    Twenty years ago, a team of scientists at the University of Cambridge developed a test of ‘cognitive empathy‘ called the ‘Reading the Mind in the Eyes’ Test (or the Eyes Test, for short). This revealed that people can rapidly interpret what another person is thinking or feeling from looking at their eyes alone. It also showed that some of us are better at this than others, and that women on average score better on this test than men.

    Now, the same team, working with the genetics company 23andMe along with scientists from France, Australia and the Netherlands, report results from a new study of performance on this test in 89,000 people across the world. The majority of these were 23andMe customers who consented to participate in research. The results confirmed that women on average do indeed score better on this test.

    More importantly, the team confirmed that our genes influence performance on the Eyes Test, and went further to identify genetic variants on chromosome 3 in women that are associated with their ability to “read the mind in the eyes.”

    The study was led by Varun Warrier, a Cambridge PhD student, and Professors Simon Baron-Cohen, Director of the Autism Research Centre at the University of Cambridge, and Thomas Bourgeron, of the University Paris Diderot and the Institut Pasteur.

    Interestingly, performance on the Eyes Test in males was not associated with genes in this particular region of chromosome 3. The team also found the same pattern of results in an independent cohort of almost 1,500 people who were part of the Brisbane Longitudinal Twin Study, suggesting the genetic association in females is a reliable finding.

    The closest genes in this tiny stretch of chromosome 3 include LRRN1 (Leucine Rich Neuronal 1) which is highly active in a part of the human brain called the striatum, and which has been shown using brain scanning to play a role in cognitive empathy. Consistent with this, genetic variants that contribute to higher scores on the Eyes Test also increase the volume of the striatum in humans, a finding that needs to be investigated further.

    Previous studies have found that people with autism and anorexia tend to score lower on the Eyes Test. The team found that genetic variants that contribute to higher scores on the Eyes Test also increase the risk for anorexia, but not autism. They speculate that this may be because autism involves both social and non-social traits, and this test only measures a social trait.

    Varun Warrier says: “This is the largest ever study of this test of cognitive empathy in the world. This is also the first study to attempt to correlate performance on this test with variation in the human genome. This is an important step forward for the field of social neuroscience and adds one more piece to the puzzle of what may cause variation in cognitive empathy.”

    Professor Bourgeron adds: “This new study demonstrates that empathy is partly genetic, but we should not lose sight of other important social factors such as early upbringing and postnatal experience.”

    Professor Baron-Cohen says: “We are excited by this new discovery, and are now testing if the results replicate, and exploring precisely what these genetic variants do in the brain, to give rise to individual differences in cognitive empathy. This new study takes us one step closer in understanding such variation in the population.”


  10. Social experience tweaks genome function to modify future behavior

    June 18, 2017 by Ashley

    From the Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign press release:

    Mice have a reputation for timidity. Yet when confronted with an unfamiliar peer, a mouse may respond by rearing, chasing, grappling, and biting — and come away with altered sensitivity toward future potential threats.

    What changes in the brain of an animal when its behavior is altered by experience? Research at the University of Illinois led by Professor of Cell and Developmental Biology Lisa Stubbs is working toward an answer to this question by focusing on the collective actions of genes. In a recent Genome Research publication (DOI: 10.1101/gr.214221.116), Stubbs and her colleagues identified and documented the activity of networks of genes involved in the response to social stress.

    “The goal of this study was to understand the downstream events in mice, and how they are conveyed across interacting brain regions . . . how they might set the stage for emotional learning in response to social threat,” said Stubbs. Answers to these questions could help scientists understand how the brains of other animals, including humans, generate social behavior, as well as what goes wrong in disorders of social behavior.

    The new results are part of a large-scale research project funded by the Simons Foundation that is headed by Stubbs and includes many of her coauthors, including first authors Michael Saul and Christopher Seward. Stubbs, Saul, Seward, and other coauthors are members of the Carl R. Woese Institute for Genomic Biology (IGB); Saul is an IGB Fellow and Seward is a graduate student.

    An aggressive encounter between two mice is just one strand of the web of interactions that connects a population of social animals. Like individuals in a community, the genes in a genome cannot be completely understood until their relationships to one another are examined in context, including how those relationships may change across different tissues and over time.

    Stubbs’ team wanted to gather information that would allow them to construct this type of comprehensive gene network to reflect how the brain of a social animal responds to an aggressive encounter. They staged a controlled encounter between pairs of mice; one mouse in its home cage, and a second, unfamiliar mouse introduced behind a screen. The presence of the intruder mouse created a social challenge for the resident mouse, while the screen prevented a physical encounter.

    The researchers then quantified the activity of genes in several different regions of the brain associated with social behaviors — the frontal cortex, hypothalamus, and amygdala — and at several time points in the two hours following the encounter. In analyses of the resulting data, they looked for groups of genes acting together. In particular, they sought to identify transcription factors, genes whose protein products help control other genes, that might be orchestrating the brain’s molecular response.

    Stubbs was excited to discover that the results mirrored and expanded upon previous work in other species by collaborators at the IGB, including work by the laboratory of Director Gene Robinson in honey bees.

    “As we examined the regulatory networks active in the mouse brain over time, we could see that some of the same pathways already explicated in honey bees… were also dysregulated similarly by social challenge in mice,” she said. “That cross-species concordance is extremely exciting, and opens new doors to experimentation that is not being pursued actively by other research groups.”

    Among the genes responding to social challenge were many related to metabolism and neurochemical signaling. In general terms, it appeared that cells in the brains of challenged mice may alter the way they consume energy and communicate with one another, changes that could adjust the neural response to future social experiences.

    The researchers looked for associations between genes’ responses to social experience and their epigenetic state. How different regions of DNA are packaged into the cell (sometimes referred to as chromatin structure) can influence the activity of genes, and so-called epigenetic modifications, changes to this structure, help to modify that activity in different situations.

    “We found that the chromatin landscape is profoundly remodeled over a very short time in the brain regions responding to social challenge,” said Stubbs. “This is surprising because chromatin profiles are thought to be relatively stable in adult tissues over time.” Because such changes are stable, they are sometimes hypothesized to reinforce long-term behavioral responses to experience.

    Stubbs and her colleagues hope that by identifying genomic mechanisms of social behavior that are basic enough to be shared even between distantly related animal species, they can discover which biological mechanisms are most central.

    “The most exciting thing in my view is using [comparisons between species] to drill through the complex response in a particular species to the ‘core’ conserved functions,” she said, “thereby providing mechanistic hypotheses that we can follow by exploiting the power of genetic models like the mouse.”