1. Facial expressions: How brains process emotion

    May 6, 2017 by Ashley

    From the California Institute of Technology press release:

    Have you ever thought someone was angry at you, but it turned out you were just misreading their facial expression? Caltech researchers have now discovered that one specific region of the brain, called the amygdala, is involved in making these (sometimes inaccurate) judgments about ambiguous or intense emotions. Identifying the amygdala’s role in social cognition suggests insights into the neurological mechanisms behind autism and anxiety.

    The research was done in the laboratories of Ralph Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology, and collaborator Ueli Rutishauser (PhD ’08) of Cedars-Sinai Medical Center in Los Angeles and a visiting associate in biology and biological engineering at Caltech. It appears in the April 21 issue of Nature Communications.

    “We have long known that the amygdala is important in processing emotion from faces,” says Adolphs. “But now we are starting to understand that it incorporates a lot of complex information to make fairly sophisticated decisions that culminate in our judgments.”

    When looking at a face, brain cells in the amygdala fire electrical impulses or “spikes” in response. However, the role of such face cells in social cognition remains unclear. Adolphs and his group measured the activity of these cells, or neurons, in patients while they were shown images of faces expressing different degrees of happiness or fear. The subjects were also shown images of faces with more ambiguous or neutral emotions, such as moderate displeasure or muted happiness. For each type of image, subjects were asked to decide whether the face looked fearful or happy. The researchers then investigated how neurons reacted to different aspects of emotions, and how the activity of the face cells related to the decision made by the subjects.

    The researchers found that there are two groups of neurons in the amygdala that respond to facial emotions.

    One group, the emotion-tracking neurons, detects the intensity of a single specific emotion, such as happiness or fear. For example, a happiness-signaling neuron would fire more spikes if the emotion was extreme happiness, and fewer spikes if the emotion was mild happiness. Separate groups of neurons within the emotion-tracking neurons code specifically for fear or for happiness.

    The other group, the ambiguity-coding neurons, indicates the ambiguity of the perceived emotion, irrespective of the nature of that emotion.

    Showing patients images of emotionally ambiguous faces was the key to understanding how the specialized neurons in the amygdala contribute to decision making, the researchers say. The faces were so ambiguous that a patient would sometimes judge the same image to be fearful at times and happy at other times. The emotion-coding neurons indicated the subjective decision the patient made about the face.

    “Most people are familiar with feeling that a face just looks too ambiguous to really decide what emotion the person is having,” says first author and visitor in neuroscience Shuo Wang (PhD ’14). “The fact that amygdala neurons signal a decision made about a face, such as which emotion it shows, gives us important insight because it shows that the amygdala is involved in making decisions rather than simply representing sensory input.”

    In addition to recording single cells from the amygdala, the researchers also carried out a neuroimaging study using fMRI (in a separate group of participants), and additionally studied the emotion judgments of three rare subjects with lesions of the amygdala. The lesion subjects showed an abnormally low threshold for deciding when a face was fearful, and the fMRI study also showed the specific effect of emotion intensity and ambiguity in the amygdala. The study is the first to combine so many different sources of data.

    These findings also suggest a mechanistic basis for potential treatments involving the painless electrical stimulation of the amygdala, which are currently being studied in ongoing clinical trials. “Researchers at multiple institutions are currently evaluating whether deep-brain stimulation of the amygdala is effective in treating severe cases of autism or post-traumatic stress disorder,” says Rutishauser. “Patients with severe PTSD are thought to have a hyperactive amygdala, which electrical stimulation might be able to inhibit. Our findings that amygdala neurons carry signals about the subjective percept of emotions indicates a more specific reason for why such electrical stimulation might be beneficial.”


  2. Speech and language deficits in children with autism may not cause tantrums

    by Ashley

    From the Penn State press release:

    Speech or language impairments may not be the cause of more frequent tantrums in children with autism, according to Penn State College of Medicine researchers. The findings could help parents of children with autism seek out the best treatment for behavior problems.

    Children with autism experience more tantrums than children without, according to the researchers, and speech therapists, preschool teachers, parents and others often blame these frequent outbursts on speech and language problems. Some children with autism spectrum disorder are not able to speak or have speech that is not clear or well-understood by others.

    To investigate this correlation, the researchers studied the relationship between language and tantrum frequency in 240 children with autism between the ages of 15 and 71 months of age. The researchers, who published their results in a recent issue of the Journal of Development and Physical Disabilities, said that the children’s IQ, their ability to understand language and their ability to use words and speak clearly, explained less than 3 percent of their tantrums.

    “We had children in our sample with clear speech and enough intelligence to be able to communicate, and their tantrums were just as high in that group,” said Cheryl D. Tierney, associate professor of pediatrics, College of Medicine, and section chief, behavior and developmental pediatrics, Penn State Children’s Hospital.

    The researchers also found that children who spoke at the level of a 2-year-old with normal development had more tantrums than children with lower speech skills.

    “There is a common pervasive misbelief that children with autism have more tantrum behaviors because they have difficulty communicating their wants and their needs to caregivers and other adults,” Tierney explained. “The belief is that their inability to express themselves with speech and language is the driving force for these behaviors, and that if we can improve their speech and their language the behaviors will get better on their own. But we found that only a very tiny percentage of temper tantrums are caused by having the inability to communicate well with others or an inability to be understood by others.”

    In the study, Tierney and co-investigator Susan D. Mayes, professor of psychiatry, addressed the limitations in previous research by including a larger sample of children and capturing more measurements. They add that their study is unique because it measures IQ and it separates speech and language as different variables that might affect tantrum behavior in children with autism.

    “IQ is extremely important because a child that has the mental capacity to understand and use language may display different behaviors compared to a child who doesn’t have the mental capacity and comprehension to use language,” Tierney said.

    She also explained the difference between language and speech in the study of children with autism.

    “Language is a child’s ability to understand the purpose of words and to understand what is said,” she said. “Speech is their ability to use their mouth, tongue, lips and jaw to form the sounds of words and make those sounds intelligible to other people.”

    The study doesn’t answer the question of what causes tantrums in children with autism, but mood dysregulation and a low tolerance for frustration — two common traits — are likely factors that should be studied further, Tierney said.

    Tierney suggests enough evidence has accumulated to shift the emphasis from improving speech to improving behavior.

    “We should stop telling parents of children with autism that their child’s behavior will get better once they start talking or their language improves, because we now have enough studies to show that that is unlikely to happen without additional help,” she said.

    That help should come in the form of applied behavior analysis, and having a well-trained and certified behavior analyst on a child’s treatment team is key to improved outcomes, Tierney added.

    “This form of therapy can help children with autism become more flexible and can show them how to get their needs met when they use behaviors that are more socially acceptable than having a tantrum,” Tierney said.


  3. Study looks at influence of paternal age at conception on social development in offspring

    May 4, 2017 by Ashley

    From the Elsevier press release:

    The age of the father at the time his children are born may influence their social development, suggests a study published in the May 2017 issue of the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP). Analyzing social behaviors of children from early childhood until adolescence, researchers found that those whose father was either very young or older at conception differed in how they acquired social skills. These findings may offer insights into how paternal age influences children’s risk of autism and schizophrenia, which was shown in earlier studies.

    “Our study suggests that social skills are a key domain affected by paternal age. What was interesting is that the development of those skills was altered in the offspring of both older as well as very young fathers,” said Magdalena Janecka, PhD, a fellow at the Seaver Autism Center for Research and Treatment at Mount Sinai. “In extreme cases, these effects may contribute to clinical disorders. Our study, however, suggests that they could also be much more subtle.”

    Dr. Janecka and her co-authors used a UK-based sample of more than 15,000 twins who were followed between the ages of 4 and 16. To find out whether children’s social skills were affected by how old their father was when they were born, the team looked for differences in the developmental patterns of social skills, as well as other behaviors, including conduct and peer problems, hyperactivity, and emotionality. Separately, they investigated whether the effects of paternal age on development were more likely attributable to genetic or environmental factors.

    The researchers found that children born to very young and older fathers — below 25 and over 51 years of age, respectively — showed more prosocial behaviors in early development. However, by the time they reached adolescence, they lagged behind their peers with middle-aged fathers. These effects were specific to the social domain and were not observed in relation to maternal age.

    The genetic analyses further revealed that development of social skills was influenced predominantly by genetic rather than environmental factors, and that those genetic effects became even more important as the paternal age increased.

    “Our results reveal several important aspects of how paternal age at conception may affect offspring,” Dr. Janecka said. “We observed those effects in the general population, which suggests children born to very young or older fathers may find social situations more challenging, even if they do not meet the diagnostic criteria for autism. Further, increased importance of genetic factors observed in the offspring of older, but not very young fathers, suggests that there could be different mechanisms behind the effects at these two extremes of paternal age. Although the resulting behavioral profiles in their offspring were similar, the causes could be vastly different.”

    In the future, the researchers want to replicate those findings, as well as establish their biological correlates. “Those developmental differences, if confirmed, are likely traceable to alterations in brain maturation,” Dr. Janecka added. “Identifying neural structures that are affected by paternal age at conception, and seeing how their development differs from the typical patterns, will allow us to better understand the mechanisms behind those effects of paternal age, as well as, likely, autism and schizophrenia.”


  4. Diagnosed autism linked to maternal grandmother’s smoking in pregnancy

    April 29, 2017 by Ashley

    From the University of Bristol press release:

    Scientists from the University of Bristol have looked at all 14,500 participants in Children of the 90s and found that if a girl’s maternal grandmother smoked during pregnancy, the girl is 67% more likely to display certain traits linked to autism, such as poor social communication skills and repetitive behaviours.

    The team also found that if the maternal grandmother smoked, this increased by 53% the risk of her grandchildren having a diagnosed autism spectrum disorder (ASD).

    These discoveries suggest that if a female is exposed to cigarette smoke while she is still in the womb, it could affect the developing eggs — causing changes that may eventually affect the development of her own children. Further research is now needed to find out what these molecular changes might be, and to see whether the same associations are present in other groups of people.

    Unlike the analysis of autistic traits, which was based on over 7,000 participants, the 177 diagnosed with ASD were too few to analyse grandsons and granddaughters separately.

    The discovery, published today in Scientific Reports, is part of an ongoing, long-term study of the effects of maternal and paternal grandmother’s smoking in pregnancy on the development of their grandchildren, who are all part of Children of the 90s. By using detailed information collected over many years on multiple factors that may affect children’s health and development, the researchers were able to rule out other potential explanations for their results.

    The incidence of ASD has increased in recent years, and while some of this increase is undoubtedly down to improved diagnosis, changes in environment or lifestyle are also likely to play a role. The researchers also stress that many different factors, including genetic variation, are believed to affect an individual’s chances of developing ASD.

    Past studies of maternal smoking in pregnancy and ASD in children have been inconclusive. Going back a generation has revealed an intergenerational effect, which interestingly is most clear cut when the mother herself did not smoke in pregnancy.

    The reasons for this are not entirely clear but Professor Marcus Pembrey, one of the paper’s authors, says: ‘In terms of mechanisms, there are two broad possibilities. There is DNA damage that is transmitted to the grandchildren or there is some adaptive response to the smoking that leaves the grandchild more vulnerable to ASD. We have no explanation for the sex difference, although we have previously found that grand-maternal smoking is associated with different growth patterns in grandsons and granddaughters.

    ‘More specifically, we know smoking can damage the DNA of mitochondria — the numerous “power-packs” contained in every cell, and mitochondria are only transmitted to the next generation via the mother’s egg. The initial mitochondrial DNA mutations often have no overt effect in the mother herself, but the impact can increase when transmitted to her own children.’

    Professor Jean Golding, another author, added: ‘We already know that protecting a baby from tobacco smoke is one of the best things a woman can do to give her child a healthy start in life. Now we’ve found that not smoking during pregnancy could also give their future grandchildren a better start too. We have started studying the next generation of participants (COCO90s), so eventually we will be able to see if the effect carries down from the great-grandparents to their great-grandchildren too.’

    Dr Dheeraj Rai, another author, added: ‘We still do not know why many children develop autism and behaviours linked to it. The associations we observe raise intriguing issues on possible transgenerational influences in autism. Future research will help understand the meaning and mechanisms behind these findings. The National Autistic Society website contains a wealth of information about autism and details on how and where to seek advice.’

    Alycia Halladay, PhD, chief science officer at the Autism Science Foundation (USA), said: ‘To date, research into the causes of autism has been limited to studying maternal or paternal exposures during pregnancy. By utilizing a birth cohort in the United Kingdom [Children of the 90s], scientists are able to go back a generation to examine the role of grandparental exposures, presumably through germ line mutations and epigenetic modifications. Hopefully, grandparental exposures will continue to be investigated to better understand this mechanism.’


  5. Imbalances in neural pathways may contribute to repetitive behaviors in autism

    April 22, 2017 by Ashley

    From the JCI Journals press release:

    Genetic studies have linked a number of risk genes to autism spectrum disorder (ASD). Although the complex genetics underlying ASD likely involve interactions between many genes, some risk genes are singular drivers of autism-like behaviors in rodent models, particularly genes that guide synaptic development and function. One such ASD-associated gene encodes SHANK3, a scaffolding protein that organizes neurotransmitter receptors and their intracellular effectors in neuronal synapses. SHANK3-deficient display repetitive grooming behavior as well as social interaction deficits and are considered to be an experimental model for autism.

    Researchers in Guoping Feng’s lab at MIT hypothesized that a mutation in Shank3 differentially affects synaptic development in two neural pathways that contribute to motor control. Work published this week in the JCI demonstrates the profound changes in synaptic shape and function observed in neurons of the indirect striatal pathway in SHANK3-deficient mice. In contrast, synapses of the direct striatal pathway were less affected by SHANK deficiency. When the researchers specifically activated neurons in the indirect pathway, repetitive grooming behaviors diminished. These findings suggest that repetitive behaviors in SHANK3-deficient mice are driven by imbalances between the striatal pathways, revealing a potential mechanism and possible targets to treat some behavioral aspects of ASD.


  6. Parent-mediated therapy may help babies at risk of developing autism

    April 19, 2017 by Ashley

    From the Wiley press release:

    The earliest autism intervention study in the world that uses video to provide feedback to parents of babies at family risk of autism, has indicated a reduction in the severity of emerging signs of autism. This study, published in the Journal of Child Psychology and Psychiatry, is the first of its kind to work with babies in their first year of life who have a sibling with autism and are therefore at higher risk of developing the condition.

    Previous research has found that the earliest markers of autism; such as reduced social interest or difficulties with attention and disengagement may be present around the end of a child’s first year of life. This latest study led by Professor Jonathan Green at The University of Manchester in collaboration with Professor Mark Johnson’s MRC-funded team at Birkbeck, and teams at King’s College London’s Institute of Psychiatry, Psychology & Neuroscience and Evelina London Children’s Hospital, aimed to reduce these early symptoms and lower the likelihood of the child developing difficulties associated with autism later on in childhood.

    The intervention, delivered by teams at The University of Manchester and Evelina London Children’s Hospital, and assessed by teams at Birkbeck and King’s, was an adapted version of the already established Video Interaction for Promoting Positive Parenting Programme (iBASIS-VIPP). Of the 54 families who took part in the study, 28 were randomly allocated to receive a minimum of six home-based visits from a therapist who used video-feedback to help the parents understand and respond to their baby’s individual communication style to improve infant attention, communication, early language development, and social engagement. These infants received the intervention for 5 months, from the age of 9 months to 14 months. Assessments were made from the end of treatment at age 15 months, at 27 months and then at 39 months of age.

    Across the course of the study the families who received the video therapy showed improvement in early emerging behaviours associated with autism, compared to those who did not receive the therapy; and these improvements extended in development after the therapy-end. There was also a noticeable positive impact on parent-infant interactions.

    Although the findings are encouraging, the authors caution that because of the relatively limited number of participants, they cannot be conclusive. Larger studies will be needed before researchers can make definitive conclusions about the therapy’s long-term effect on reducing the severity of autism symptoms.

    Professor Jonathan Green who led the study says, “What is novel about this study is how early we began the intervention. We know that similar kinds of intervention later in childhood can show long term effects; here we have shown that beginning intervention of this kind in the first year of life can produce important improvements for the babies over the medium term in development, continuing after the therapy finishes. This is a very promising finding that provides an excellent basis for future larger scale trials using the intervention in very early development.”

    “If this intervention continues to show improvements in such larger studies, then the method would have real potential use for families at the point of early concern, or if their child is genetically at risk of developing autism.”

    The iBASIS study took place as part of the ongoing British Autism Study of Infant Siblings (basisnetwork.org).

    Michelle from Dudley took part in the study. Her daughter Natalie was considered at an increased risk, following the diagnosis of a sibling, an older brother, with autism. She said:

    “Fighting for my first child’s diagnosis, and learning how to support a child with autism was tough, so when our daughter was born we were determined that the same thing wouldn’t happen.”

    “We were so glad to come across this study when Natalie was just three months old. We’ve loved taking part in the iBasis project, and wish we’d had an opportunity like this when our eldest was young. I hope that this research can help develop tools for professionals and families so that children at risk of autism or waiting for a diagnosis, get the help that they need much earlier.”

    Dr Kathryn Adcock, Head of Neurosciences and Mental Health at the Medical Research Council, said, “Although this is quite a small study and therefore can’t provide a definitive answer, the work shows very promising indications of the benefits of early intervention.”

    Jon Spiers, CEO of Autistica, the UK’s leading autism research charity who provided initial funding for the study, said, “Parents often sense their child is developing differently very early on, yet getting a diagnosis of autism can take years. Being able to deliver an intervention during this uncertain period would be a promising step forward for many thousands of families. We are pleased to have provided funding for this initial study and are calling for urgent further investment in similar early intervention studies in autism.”


  7. Mechanism that regulates acoustic habituation identified

    April 18, 2017 by Ashley

    From the University of Western Ontario press release:

    Most people will startle when they hear an unexpected loud sound. The second time they hear the noise, they’ll startle significantly less; by the third time, they’ll barely startle at all. This ability is called acoustic habituation, and new Western-led research has identified the underlying molecular mechanism that controls this capability. The research opens the door to treatments, especially for people who have autism spectrum disorder or schizophrenia and who experience disruptions in this ability.

    Susanne Schmid, PhD, associate professor at Western’s Schulich School of Medicine & Dentistry, and principal investigator on the study explains that acoustic habituation is a common form of sensory filtering, which refers to the brain’s ability to block out extraneous sounds, feelings or visual information so that we are able to focus on what’s most important in our surroundings. Disruption in sensory processing was added as a diagnostic marker for autism spectrum disorders only in the most recent version of the Diagnostic and Statistical Manual of Mental Disorders (DSM5).

    Using electrophysiology and pharmacological tools, the research has shown that a potassium channel, specifically the BK channel, in the central nervous system can be regulated with drugs to increase or decrease these disruptions in animal models.

    “By doing this we are better able to understand what’s going wrong in people that do not habituate,” said Schmid. “It also means we might be able to improve habituation by targeting this mechanism and thereby improve their sensory filtering.”

    Schmid says enhancing habituation and sensory filtering in autism spectrum disorder and schizophrenia might have beneficial effects not only on hyper- and hyposensitivity, but also on cognitive function.

    The research was published in The Journal of Neuroscience.


  8. Children with autism find understanding facial expressions difficult but make similar mistakes as peers

    April 9, 2017 by Ashley

    From the University of Bristol press release:

    Young people with autism spectrum conditions (ASC) have difficulties recognising and distinguishing between different facial expressions, according to research from one of the largest studies to look at emotion recognition in children and adolescents with ASC. The University of Bristol findings are published in the Journal of Autism and Developmental Disorders.

    A team from Bristol’s School of Experimental Psychology aimed to find out whether six basic facial expressions differing in intensity are challenging for young people with autism to recognise.

    Researchers gave 63 children and adolescents with an ASC diagnosis and 64 without a diagnosis, an internet-based test of emotion recognition. The two groups, aged between 6 — 16 years-old, were presented with ‘happy’, ‘sad’, ‘surprised’, ‘disgusted’, ‘scared’ and ‘angry’ facial expressions and asked to select a label that matched the expression. Some faces had exaggerated ‘high-intensity’ expressions — which were easier to identify, while others had subtle ‘low-intensity’ expressions — which were more difficult but considered more relevant to real world interactions. The team also measured language skills and non-verbal reasoning skills in order to see if differences in these skills explained any differences in ability to recognise emotions.

    Results from this study found that young people with ASC do find it harder to recognise emotion from facial expressions. However, the types of mistake made by young people with ASC were very similar to the types of mistake made by young people without ASC. For example, young people in both groups often mistook ‘fear’ for ‘surprise’ and confused ‘disgust’ and ‘anger’.

    Interestingly, the biggest differences between the ASC and non-ASC groups was for the clearest ‘high-intensity’ expressions. The researchers think this was due to participants, including those without ASD, struggling to recognise the emotion in the ‘low-intensity’ expressions, making it hard for them to then see any clear difference between groups.

    Sarah Griffiths, one of the study’s researchers who completed the study as part of her PhD at the University of Bristol but is now based at the University of Cambridge’s Autism Research Centre, said: “This study is important as previous research provided very mixed results with some finding individuals with autism less accurate in recognising expressions on average, and others finding no difference. In this study we used an online platform to run a larger study to answer this question more conclusively and found that individuals with autism are on average a bit less accurate at recognising emotion from faces.”

    Professor Chris Jarrold, Professor in Cognitive Development in the School of Experimental Psychology at the University of Bristol, said: “These findings provide further evidence that people with ASC have a degree of difficulty in recognising basic emotions from facial expressions. For those who do struggle with recognising emotions from faces, teaching emotion recognition may be helpful for learning to navigate social situations.”

    To coincide with this research, the team have developed an iPad app to teach facial emotion recognition for people with and without Autism Spectrum Conditions. You can download the free app “About face” here. This app contains both the high and low-intensity expressions that were used in the study so the difficulty can be tailored to the ability level of the user.


  9. Study suggests autism better masked in girls than boys

    April 7, 2017 by Ashley

    From the University of Leiden press release:

    Girls with autism have relatively good social skills, which means that their autism is often not recognised. Autism manifests itself in girls differently from in boys. Psychologist Carolien Rieffe and colleagues from the Autism Centre and INTER-PSY (Groningen) report their findings in scientific journal Autism.

    Information about autism in girls is scarce. What we know about autism is mainly based on research among boys and men. That can be a problem, says Leiden Professor of Development Psychology Rieffe: ‘If we take the clinical picture for boys with autism as the standard, there’s a good chance that autism in girls won’t be picked up.’ To change this, Rieffe and her colleagues examined how autism manifests itself in girls.

    Study among teenagers

    The researchers analysed the behaviour of 68 teenagers, girls and boys, both with and without autism. As part of the test, the researcher pretended to have caught her finger in the ringbinder of a file, and exclaimed: ‘Ow, that hurt,’ while shaking her hand in pain. Two fellow researchers looked at the video afterwards to assess how empathically the participants had reacted.

    Empathising with emotion or resolving the problem

    Girls, whether or not they suffer from autism, reacted with more empathy than boys. Riefe explains: ‘We didn’t find any differences between the participants with or without autism. But we did see a qualitative difference between girls and boys. The girls more often responded to the emotion of the person conducting the test with questions such as: ‘Are you OK?’ The boys, on the other hand, looked for a solution to the problem: ‘If you do it like this, you won’t trap your finger.’

    Empathising with or properly understanding love problems

    Rieffe adds that neither boys nor girls have difficulty empathising with the emotions of another person. However, the ability to understand why the person feels as they do is often lacking in both girls and boys with autism. This is why it is more difficult for young autism sufferers to react with empathy to such situations as love problems or conflict situations with parents or peers, all of which are topics that young people spend a lot of their time talking about.

    Focusing on the request for help

    What do the outcomes of the research mean in practice for the care provider? According to Rieffe and her co-authors, girls with autism have the big advantage that they have a good understanding of many of the social rules. Nonetheless, their care providers should not be misled by this, because it does not necessarily indicate a strong capacity for empathy or the skills to actually be able to form good social relations and friendships. So does this mean that these girls still find themselves more socially isolated? It is important when treating girls with autism to look at what their specific needs are. This may call for a different approach and strategy than for boys with autism.


  10. Study tests the ‘three-hit’ theory of autism

    March 27, 2017 by Ashley

    From the Rockefeller University press release:

    Since the first case was documented in the United States in 1938, the causes of autism have remained elusive. Hundreds of genes, as well as environmental exposures, have been implicated in these brain disorders. Sex also seems to have something to do with it: About 80 percent of children diagnosed with an autism spectrum disorder are boys.

    This striking bias caught the attention of Rockefeller University’s Donald W. Pfaff. A neurobiologist who studies hormone effects and sex differences in the brain, Pfaff wondered if maleness might somehow amplify the genetic and environmental risk factors for the disease.

    In collaboration with colleagues specializing in child neurology and psychology, he has proposed a “three-hit” theory of autism, which suggests that a genetic predisposition in combination with early stress is more detrimental to boys than to girls, and more likely to produce the social avoidance that is a hallmark of autism disorders. Now, a team in his lab has found evidence in mice supporting this theory.

    “Together, these three hits — genes, environment, and sex — build on one another, such that their combined effect on behavior is much greater than the sum of the three individually,” says Pfaff, head of the Laboratory of Neurobiology and Behavior.

    A test run

    Pfaff and his colleagues formulated the three-hit theory based on studies of animals suggesting that the male hormone testosterone may sensitize the developing brain to stress in a way that can lead to social avoidance, a behavior characteristic of autism. Mice, like humans, are social animals, and in experiments, described in the Proceedings of the National Academy of Sciences, Pfaff’s team looked to see if male mice were more prone to problems with social responses than females when the other two risk factors were present.

    The theory and these experiments focus on the primary aspect of autism spectrum disorders, social problems, but there are others. In addition to social avoidance, autism is associated with difficulties in communication, as well as unusually restricted interests.

    To achieve a genetic hit, the team, led by Sara Schaafsma, a postdoc in the lab, used mice lacking a gene that is frequently mutated in people diagnosed with autism. To evoke stress in the as-yet unborn mice, the researchers prompted the immune systems of their pregnant mothers to react as though under attack from bacteria.

    Changes in brain and behavior

    The researchers later tested the social behavior of these mice in a series of experiments. The most compelling evidence for the three-hit theory came from a test of social recognition. Most of the animals, even those with two risk factors, showed signs of recognizing a once-unfamiliar mouse over multiple encounters. Only mice with all three hits — those that were male, were genetically predisposed to autism, and had experienced stress as embryos — seemed unable to recognize new acquaintances after encountering them multiple times.

    Next, the researchers looked for molecular changes within these rodents’ brains that might help to explain the differences in behavior. They found an increase in the expression of a gene that helps to kick off stress responses, in a brain region called the left hippocampus. With help from C. David Allis’s lab, they looked for chemical alterations in the packaging of DNA that might explain this uptick in gene activity. This effort revealed one particular chemical change in the nerve cell nucleus that encourages the expression of this stress-relevant gene.

    “Neurodevelopmental disorders, including autism, are often attributed to an interaction between genetic ‘nature’ and environmental ‘nurture.’ Our work indicates how male sex comes to be an important component of this dynamic, at least for one major aspect of autism,” Pfaff says. “By collecting a variety of evidence, we have begun to uncover one molecular mechanism, of many, by which these three hits alter sociability.”