1. Researchers implicate genetic locus on chromosome 12 in anorexia nervosa

    May 21, 2017 by Ashley

    From the University of North Carolina Health Care press release:

    A landmark study led by UNC School of Medicine researchers has identified the first genetic locus for anorexia nervosa and has revealed that there may also be metabolic underpinnings to this potentially deadly illness.

    The study, which is the most powerful genetic study of anorexia nervosa conducted to date, included genome-wide analysis of DNA from 3,495 individuals with anorexia nervosa and 10,982 unaffected individuals.

    If particular genetic variations are significantly more frequent in people with a disorder compared to unaffected people, the variations are said to be “associated” with the disorder. Associated genetic variations can serve as powerful pointers to regions of the human genome where disorder-causing problems reside, according to the National Human Genome Research Institute.

    “We identified one genome-wide significant locus for anorexia nervosa on chromosome 12, in a region previously shown to be associated with type 1 diabetes and autoimmune disorders,” said lead investigator, Cynthia Bulik, PhD, FAED, founding director of the UNC Center of Excellence for Eating Disorders and a professor at Karolinska Institutet in Stockholm, Sweden.

    “We also calculated genetic correlations — the extent to which various traits and disorders are caused by the same genes,” said Bulik.

    Anorexia nervosa was significantly genetically correlated with neuroticism and schizophrenia, supporting the idea that anorexia is indeed a psychiatric illness.”

    “But, unexpectedly, we also found strong genetic correlations with various metabolic features including body composition (BMI) and insulin-glucose metabolism. This finding encourages us to look more deeply at how metabolic factors increase the risk for anorexia nervosa,” Bulik said.

    This study was conducted by the Psychiatric Genetics Consortium Eating Disorders Working Group — an international collaboration of researchers at multiple institutions worldwide.

    “In the era of team science, we brought over 220 scientists and clinicians together to achieve this large sample size. Without this collaboration we would never have been able to discover that anorexia has both psychiatric and metabolic roots,” said Gerome Breen, PhD, of King’s College London.

    “Working with large data sets allows us to make discoveries that would never be possible in smaller studies,” said Laramie Duncan, PhD, of Stanford University, who served as lead analyst on the project.

    The researchers are continuing to increase sample sizes and see this as the beginning of genomic discovery in anorexia nervosa. Viewing anorexia nervosa as both a psychiatric and metabolic condition could ignite interest in developing or repurposing medications for its treatment where currently none exist.


  2. Gene mutation may speed up memory loss in Alzheimer’s disease

    May 12, 2017 by Ashley

    From the American Academy of Neurology (AAN) press release:

    A gene mutation may accelerate the loss of memory and thinking skills in people who are at risk for Alzheimer’s disease, according to a study published in the May 3, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology. The gene mutation is called the BDNF Val66Met allele, or just the Met allele.

    Brain derived neurotrophic factor (BDNF) is a protein produced by the gene of the same name. It is one of a group of proteins called neurotrophins that help nerve cells grow, specialize and survive. Alleles are parts of genes that work in pairs on the chromosomes to determine a person’s traits.

    “We found that people with Alzheimer’s risk who have this BDNF gene mutation called the Met allele may have a more rapid decline of memory and thinking skills,” said study author Ozioma Okonkwo, PhD, of the University of Wisconsin School of Medicine in Madison, Wisc. “Because this gene can be detected before the symptoms of Alzheimer’s start, and because this presymptomatic phase is thought to be a critical period for treatments that could delay or prevent the disease, it could be a great target for early treatments.”

    For the study, researchers followed 1,023 people with an average age of 55 for up to 13 years who were at risk for Alzheimer’s disease but at the start were still healthy. Participants gave blood samples which were tested for the Met allele gene mutation. Their memory and thinking skills were evaluated at the start of the study and at each study visit, up to five visits. Of that group, 140 were also tested with neuroimaging for beta-amyloid, a sticky protein that can build up into plaques found in the brains of people with Alzheimer’s disease.

    A total of 32 percent of the participants had the Met allele. Researchers found that when compared to people without the gene mutation, those with the mutation lost memory and thinking skills more rapidly. On tests of verbal learning and memory, those with no gene mutation improved by 0.002 units per year, while the scores of people with the mutation declined by 0.021 units per year.

    The researchers also found that people with the gene mutation who also had more beta-amyloid had an even steeper rate of decline.

    “When there is no mutation, it is possible the BDNF gene and the protein it produces are better able to be protective, thereby preserving memory and thinking skills,” Okonkwo said. “This is especially interesting because previous studies have shown that exercise can increase levels of BDNF. It is critical for future studies to further investigate the role that the BDNF gene and protein have in beta-amyloid accumulation in the brain.”

    A major strength of the study is that it was one of the largest studies investigating this mutation. A limitation is that the study participants were predominantly white. Also, the number of people with beta-amyloid data was limited.


  3. How neurons and glia cells are created in the developing brain

    May 11, 2017 by Ashley

    From the Institute of Science and Technology Austria press release:

    Neurons and glia are the cells that make up our brain. In the cortex, the brain area that enables us to think, speak and be conscious, neurons and most glia are produced by a type of neural stem cell, called radial glia progenitors (RGPs). It is vital that no errors occur in this process as disruptions can lead to neurodevelopmental disorders such as microcephaly, a condition in which a baby’s head and cortex are significantly smaller than that of other babies. But how is this production of neurons and glia cells controlled? Simon Hippenmeyer and his group at the Institute of Science and Technology Austria (IST Austria), including first author Robert Beattie, as well as colleagues at North Carolina State University and the Fred Hutchinson Cancer Research Center in USA, found that a gene called Lgl1 controls the production of certain neurons in the cortex of mouse embryos, and plays a role in the production of other types of neurons and glia after birth. This is the result of a study published today in Neuron.

    The production of neurons and glia in the developing cortex is tightly regulated. RGPs produce the majority of them. In previous studies, Hippenmeyer and colleagues have shown that the division pattern of RGPs is not random. They have demonstrated that each individual RGP produces a predefined unit of neurons and glia cells in a precisely orchestrated developmental program which ensures that the brain faithfully grows to its normal size.

    In the present Neuron study, the authors asked what mechanisms control the exact output of RGPs. In particular, the researchers investigated the role of the gene Lgl1, which had been predicted to regulate RGP proliferation. The gene’s precise role was previously unknown and Hippenmeyer and colleagues now used a technique called MADM, short for Mosaic Analysis with Double Markers in order to decipher the function of Lgl1 in RGPs at unprecedented single cell resolution.

    Using MADM, Hippenmeyer and colleagues eliminated Lgl1 either in just single RGPs, or in all RGPs. At the same time, individual cells are labelled fluorescently, so that they can be studied under the microscope. The authors show that Lgl1 controls the generation of neurons and glia cells in the developing cortex in two different ways. First, for the generation of neurons in the early embryo the function of Lgl1 is simultaneously required in the entire population of RGPs. If Lgl1 function is absent in all RGPs, but not if absent in just individual RGP cells, dynamic community effects lead to malformation of the cortex resembling ‘Double Cortex Syndrome’, a severe human brain disorder. Second, for the production of glia cells and neurons in the postnatal brain, Lgl1 function is ‘only’ required in the individual stem cell which is just in the process of generating a neuron or glia cell. This type of Lgl1 gene function is called cell-autonomous or intrinsic while the requirement of Lgl1 gene function in the entire community is called non-cell-autonomous. In other words, you require the entire orchestra for a symphony (generate neurons in embryonic cortex) but only an individual soloist for a solo (produce neurons or glia cells in postnatal brain). Simon Hippenmeyer explains how this research will influence the way how the role of genes during development should be analysed in the future: “Our study emphasizes that both intrinsic gene functions and community-based environmental contributions are important for the control of radial glia progenitor cells in the cortex in particular, and for neural stem cells in general. It will thus be important in future genetic loss-of-function experiments to precisely dissect the relative contributions of cell-autonomous, intrinsic, gene functions and the influence of the stem cell niche microenvironment to the overall interpretation of a gene function.”


  4. Study links immune system, brain structure and memory

    May 8, 2017 by Ashley

    From the University of Basel press release:

    The body’s immune system performs essential functions, such as defending against bacteria and cancer cells. However, the human brain is separated from immune cells in the bloodstream by the so-called blood-brain barrier. This barrier protects the brain from pathogens and toxins circulating in the blood, while also dividing the immune cells of the human body into those that fulfill their function in the blood and those that work specifically in the brain. Until recently, it was thought that brain function was largely unaffected by the peripheral immune system.

    However, in the past few years, evidence has accumulated to indicate that the blood’s immune system could in fact have an impact on the brain. Scientists from the University of Basel’s Transfaculty Research Platform Molecular and Cognitive Neurosciences (MCN) have now carried out two independent studies that demonstrate that this link between the immune system and brain is more significant than previously believed.

    Search for regulatory patterns

    In the first study, the researchers searched for epigenetic profiles, i.e. regulatory patterns, in the blood of 533 young, healthy people. In their genome-wide search, they identified an epigenetic profile that is strongly correlated with the thickness of the cerebral cortex, in particular in a region of the brain that is important for memory functions. This finding was confirmed in an independent examination of a further 596 people. It also showed that it is specifically those genes that are responsible for the regulation of important immune functions in the blood that explain the link between the epigenetic profile and the properties of the brain.

    Gene variant intensifies traumatic memories

    In the second study, the researchers investigated the genomes of healthy participants who remembered negative images particularly well or particularly poorly. A variant of the TROVE2 gene, whose role in immunological diseases is currently being investigated, was linked to participants’ ability to remember a particularly high number of negative images, while their general memory remained unaffected.

    This gene variant also led to increased activity in specific regions of the brain that are important for the memory of emotional experiences. The researchers also discovered that the gene is linked to the strength of traumatic memories in people who have experienced traumatic events.

    The results of the two studies show that both brain structure and memory are linked to the activity of genes that also perform important immune regulatory functions in the blood. “Although the precise mechanisms behind the links we discovered still need to be clarified, we hope that this will ultimately lead to new treatment possibilities,” says Professor Andreas Papassotiropoulos, Co-Director of the University of Basel’s MCN research platform. The immune system can be precisely affected by certain medications, and such medications could also have a positive effect on impaired brain functions.

    Innovative research methods

    These groundbreaking findings were made possible thanks to cutting edge neuroscientific and genetic methods at the University of Basel’s MCN research platform. Under the leadership of Professor Andreas Papassotiropoulos and Professor Dominique de Quervain, the research platform aims to help us better understand human brain functions and to develop new treatments for psychiatric disorders.


  5. Study suggests social media use attributable to genetic traits

    May 7, 2017 by Ashley

    From the International Communication Association press release:

    It’s easy to think in terms of linking genetics to behavior in simple ways. Are you calm or do you have a temper? Are you creative or analytical? Are you sociable or shy? But can heritable traits actually influence a person to frequently use social media? A recent study by a researcher at the Kent State University found that genetics outweighed environment in social media use using twin study survey data.

    Chance York (Kent State University) will present his findings at the 67th Annual Conference of the International Communication Association in San Diego, CA. Using a behavior genetics framework and twin study data from the 2013 Midlife in the United States (MIDUS III) survey, York examined how both environmental and genetic factors contribute to social media use by applying an analytical model called Defries-Fulker (DF) Regression.

    The data analyzed revealed one- to two-thirds of variance in social media use is attributable to additive genetic traits; unique and shared environmental factors account for the remainder of variance. York also provides an analytical blueprint for using DF regression in future investigations of genetic influence on communication behaviors and media effects.

    Past behavior genetics research using twin study survey data has shown genetic influence on a wide range of communication behaviors. This is the first study to show that genetic traits also affect social media use.

    “This study doesn’t suggest that using DF regression with twin survey data, or the behavioral genetics perspective more generally, can directly assess gene-level influence on specific behaviors. There is no ‘social media gene,'” said York. “The assumption here is that known genetic variation between fraternal and identical twins can be leveraged to study how genetic variation influences patterns of observable behavior. We are still working in a ‘black box’ in that we can’t directly observe how genes impact our neuroanatomy, which in turn impacts cognitive processing, personality, and subsequent media selection and effects. However, this study — and this line of inquiry — is a starting point for studying genetic influence on communication.”


  6. Study looks at possible role of genetics in food preferences

    May 2, 2017 by Ashley

    From the Experimental Biology 2017 press release:

    Have you ever wondered why you keep eating certain foods, even if you know they are not good for you? Gene variants that affect the way our brain works may be the reason, according to a new study. The new research could lead to new strategies to empower people to enjoy and stick to their optimal diets.

    Silvia Berciano, a predoctoral fellow at the Universidad Autonoma de Madrid, will present the new findings at the American Society for Nutrition Scientific Sessions and annual meeting during the Experimental Biology 2017 meeting, to be held April 22-26 in Chicago.

    “Most people have a hard time modifying their dietary habits, even if they know it is in their best interest,” said Berciano. “This is because our food preferences and ability to work toward goals or follow plans affect what we eat and our ability to stick with diet changes. Ours is the first study describing how brain genes affect food intake and dietary preferences in a group of healthy people.”

    Although previous research has identified genes involved with behaviors seen in eating disorders such as anorexia or bulimia, little is known about how natural variation in these genes could affect eating behaviors in healthy people. Gene variation is a result of subtle DNA differences among individuals that make each person unique.

    For the new study, the researchers analyzed the genetics of 818 men and women of European ancestry and gathered information about their diet using a questionnaire. The researchers found that the genes they studied did play a significant role in a person’s food choices and dietary habits. For example, higher chocolate intake and a larger waist size was associated with certain forms of the oxytocin receptor gene, and an obesity-associated gene played a role in vegetable and fiber intake. They also observed that certain genes were involved in salt and fat intake.

    The new findings could be used to inform precision-medicine approaches that help minimize a person’s risk for common diseases — such as diabetes, cardiovascular disease and cancer — by tailoring diet-based prevention and therapy to the specific needs of an individual.

    “The knowledge gained through our study will pave the way to better understanding of eating behavior and facilitate the design of personalized dietary advice that will be more amenable to the individual, resulting in better compliance and more successful outcomes,” said Berciano.

    The researchers plan to perform similar investigations in other groups of people with different characteristics and ethnicities to better understand the applicability and potential impact of these findings. They also want to investigate whether the identified genetic variants associated with food intake are linked to increased risks for disease or health problems.


  7. Neurons’ faulty wiring leads to serotonin imbalance, depression-like behavior in mice

    by Ashley

    From the Zuckerman Institute at Columbia University press release:

    Columbia scientists have identified a gene that allows neurons that release serotonin — a neurotransmitter that regulates mood and emotions — to evenly spread their branches throughout the brain. Without this gene, these neuronal branches become entangled, leading to haphazard distribution of serotonin, and signs of depression in mice. These observations shed light on how precise neuronal wiring is critical to overall brain health, while also revealing a promising new area of focus for studying psychiatric disorders associated with serotonin imbalance — such as depression, bipolar disorder, schizophrenia and autism.

    The findings were published in Science.

    “By pinpointing the genes that guide the organization of neurons, we can draw a line between changes to those genes, and the cellular, circuitry and behavioral deficiencies that can occur as a result,” said Tom Maniatis, PhD, a principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, the Isidore S. Edelman Professor and Chair of department of Biochemistry & Molecular Biophysics at Columbia University Medical Center and the studys’ senior author.

    Today’s research is the result of parallel efforts by Dr. Maniatis, his lab and collaborators across Columbia to understand how individual neurons in the brain ‘see’ each other — and how each of their hundreds, or even thousands, of branches wind through the brain without getting tangled up along the way.

    To investigate this problem, Dr. Maniatis and his team focused on a group of genes called clustered protocadherins, or Pcdhs. More than a decade ago, Dr. Maniatis’ lab discovered the human Pcdh gene cluster, and later studies by Maniatis and others revealed that these genes encode a cell surface “barcode” by which individual neurons can distinguish themselves from other neurons.

    Subsequently, collaborative studies with fellow Zuckerman Institute structural biologists Barry Honig, PhD, and Larry Shapiro, PhD, revealed the precise mechanism by which the Pcdh code is assembled at the cell surface, and how this code is “read” when neurons come in contact with each other. This allows neurons to prevent entanglements by recognizing — and steering clear of — their own branches, a process known as self-avoidance.

    In the two papers published in Science, Dr. Maniatis and his team examined the function of Pcdhs in the wiring of olfactory sensory neurons (which impart a sense of smell), and serotonergic neurons (which produce and release serotonin). The olfactory sensory neuron (OSN) study revealed that the diversity of Pcdhs, working together, produced the necessary combinations of cell-coating molecules to provide each neuron its unique identity. In the absence of diversity, OSNs fail to wire properly in the brain, and the mice fail to distinguish between different odors.

    The serotonergic neuron study revealed another important function of Pcdhs.

    “The main job of these neurons is to distribute serotonin uniformly throughout the brain, which is responsible for maintaining mood balance,” said Dr. Maniatis, who is also director of Columbia’s Precision Medicine Initiative. “To do this, the neurons lay their branches out in a precise, evenly-spaced pattern — a process called axonal tiling. However, the exact mechanism that allows them to do this remained elusive.”

    In a series of experiments in mice, Dr. Maniatis’ team pinpointed a single gene within the Pcdh cluster, called Pcdh-alpha-c2, that was responsible for the ability of serotonergic neurons to assemble into a tiled pattern throughout the brain, and thus evenly distribute serotonin.

    “We were surprised to find that, unlike other neurons that displays distinct barcodes of diverse Pcdhs, all serotonergic neurons display a single functional recognition protein,” said Dr. Maniatis. “Thus, serotonergic axonal branches can recognize and repel one another, leading to their even spacing.”

    “We found that deleting the Pcdh-alpha-c2 caused serotonergic neuron branches to become tangled and clumped together,” Dr. Maniatis continued. “Serotonin was released, but it wasn’t distributed evenly throughout the brain.”

    Silencing Pcdh-alpha-c2 also resulted in striking behavioral changes. Compared to normal, healthy mice, Pcdh-alpha-c2-deficient mice showed behavioral despair (reduced desire to escape) and enhanced fear memory (increased freezing when frightened) — both classic signs indicative of depression.

    “Serotonin imbalance has long been linked to a variety of psychiatric disorders, including depression, bipolar disorder and schizophrenia, but most studies focus on problems with the production or uptake of serotonin, not on problems with the brain’s wiring itself,” said Dr. Maniatis. “Wiring anomalies are clearly a new place to look.”

    Today’s results may also inform studies of autism. After an exhaustive genetic analysis of autistic individuals and their families by an international consortium of investigators, several hundred genes have been identified that are associated with the disorder, as documented by the Simons Foundation Autism Research Initiative (SFARI) human gene module. Among these genes is the Pcdh gene cluster — including Pcdh-alpha-c2.

    “For this pair of studies published today, we focused on two types of neurons that are well understood and have been deeply explored, but this is only the starting point,” said Dr. Maniatis. “If we are to truly understand how the brain is wired both in health and in disease, then the rest of the brain is where we have to go next.”


  8. Closer look at brain circuits reveals important role of genetics

    April 28, 2017 by Ashley

    From the Scripps Research Institute press release:

    Scientists at The Scripps Research Institute (TSRI) in La Jolla have revealed new clues to the wiring of the brain. A team led by Associate Professor Anton Maximov found that neurons in brain regions that store memory can form networks in the absence of synaptic activity.

    “Our results imply that assembly of neural circuits in areas required for cognition is largely controlled by intrinsic genetic programs that operate independently of the external world,” Maximov explained.

    A similar phenomenon was observed by the group of Professor Nils Brose at the Max Planck Institute for Experimental Medicine in Germany. The two complementary studies were co-published as cover stories in the April 19, 2017, issue of the journal Neuron.

    The “Nature vs. Nurture” Question

    Experience makes every brain unique by changing the patterns and properties of neuronal connections. Vision, hearing, smell, taste and touch play particularly important roles during early postnatal life when the majority of synapses is formed. New synapses also appear in the adult brain during learning. These activity-dependent changes in neuronal wiring are driven by chemical neurotransmitters that relay signals from one neuron to another. Yet, animals and humans have innate behaviors whose features are consistent across generations, suggesting that some synaptic connections are genetically predetermined.

    The notion that neurons do not need to communicate to develop networks has also been supported by earlier discoveries of synapses in mice that lacked transmitter secretion in the entire brain. These studies were performed in the laboratory of Professor Thomas Südhof, who won the 2013 Nobel Prize in Physiology or Medicine.

    “We thought these experiments were quite intriguing,” Maximov said, “but they also had a major limitation: mice with completely disabled nervous systems became paralyzed and died shortly after birth, when circuitry in the brain is still rudimental.”

    The TSRI team set out to investigate if neurons can form and maintain connections with appropriate partners in genetically engineered animals that live into adulthood with virtually no synaptic activity in the hippocampus, a brain region that is critical for learning and memory storage. “While the idea may sound crazy at the first glance,” Maximov continued, “several observations hinted that this task is technically feasible.” Indeed, mammals can survive with injuries and developmental abnormalities that result in a massive loss of brain tissue.

    Inspired by these examples, Richard Sando, a graduate student in the Maximov lab, generated mice whose hippocampus permanently lacked secretion of glutamate, a neurotransmitter that activates neurons when a memory is formed. Despite apparent inability to learn and remember, these animals could eat, walk around, groom, and even engage in rudimental social interactions.

    Working closely with Professor Mark Ellisman, who directs the National Center for Microscopy and Imaging Research at the University of California, San Diego, Sando and his co-workers then examined the connectivity in permanently inactive areas. Combining contemporary genetic and imaging tools was fruitful: the collaborative team found that several key stages of neural circuit development widely believed to require synaptic activity were remarkably unaffected in their mouse model.

    The outcomes of ultra-structural analyses were particularly surprising: it turns out that neurotransmission is unnecessary for assembly of basic building blocks of single synaptic connections, including so-called dendritic spines that recruit signaling complexes that enable neurons to sense glutamate.

    Maximov emphasized that the mice could not function normally. In a way, their hippocampus can be compared to a computer that goes though the assembly line, but never gets plugged to a power source and loaded with software. As the next step, the team aims to exploit new chemical-genetic approaches to test if intrinsically-formed networks can support learning.


  9. Study examines links between genes and parenting behaviour

    April 27, 2017 by Ashley

    From the Harvard University press release:

    Why is it that some species seem to be particularly attentive parents while others leave their young to fend for themselves? For years, scientists have believed one of the major drivers was experience – an animal raised by an attentive parent, the argument went, was likely to be an attentive parent itself.

    A new Harvard study is challenging that idea, and – for the first time – is uncovering links between the activity of specific genes and parenting differences across species.

    Led by Professor of Organismic and Evolutionary Biology and Molecular and Cellular Biology Hopi Hoekstra and Andres Bendesky, a post-doctoral researcher in Hoekstra’s lab, a team of researchers exploring the genetics underpinning parenting behaviors, found not only that different genes may influence behaviors in males and females, but that the gene for the hormone vasopressin appears to be closely tied to nest-building behavior in parenting mice. The study is described in an April 19 paper published in Nature.

    “This is one of the first cases in which a gene has been implicated in parental care in a mammal,” Hoekstra said. “In fact, it’s one of the few genes that has been implicated in the evolution of behavior in general…but what I think is particularly exciting about this is the idea that, while in many systems we know that parenting behavior can be affected by your environment, we now have evidence that genetics can play an important role as well.”

    “We know there is variation between species in how much parental behavior they provide for their young,” Bendesky said. “It’s not that one is better or worse, they’re just different strategies…but before our study we had no idea how these parental behaviors evolved, whether there was one gene that mediates all of the differences inbehavior, or if it was 10 or 20.”

    The idea for the study grew out of the differences in mating systems researchers had observed between two sister mouse species – Peromyscus maniculatus, also known as the deer mouse, and Peromyscus polionotus, or the oldfield mouse.

    “Like many rodents, the deer mouse is what we refer to as promiscuous, meaning both males and females mate with multiple individuals,” Hoekstra said. “Often when you genotype a litter, you will find pups from multiple fathers.”

    The oldfield mouse, by comparison, is monogamous, so all the pups in a litter are related to only one father.

    “It’s been widely documented that these mice have different mating systems,” Hoekstra said. “When Andres joined the lab, he was interested in asking the question of do those differences translate into differences in parental care?”

    To understand those differences, Bendesky first created a behavioral assay that tracked the behavior of both males and females of each species and measured how often they engaged in parental behavior like building nests and licking and huddling their pups.

    In general, the data showed that females of both species were attentive mothers. The major differences, Hoekstra said, were in the fathers. Oldfield mice fathers are relatively involved in raising pups, as much as oldfield mothers, but deer mice fathers participate relatively little.

    To test what impact those different parenting styles have, Bendesky then performed a cross-fostering experiment, allowing oldfield mice parents to raise deer mouse pups, and vice versa, and then observe the parenting behavior of the pups when they became parents themselves.

    “What we found was there’s no measurable effect based on who raises them,” Hoekstra said. “It’s all about who they are genetically.”

    To get at those genetics, researchers then cross-bred the two species, then cross-bred the resulting mice, creating second-generation hybrid mice that had regions of the genome from each species.

    When the team began to identify regions in the genome that were associated with differences in behavior between the two species, they not only found that some effects were sex-specific, but that some regions appeared to influence a handful of behaviors.

    “What I find very interesting is that we found different genes may explain the evolution of paternal and maternal care,” Bendesky said. “That’s interesting because it tells us that if some mutation in a population increases maternal care, it may not affect the behavior of males. So these behaviors may be evolving independently.”

    “The other significant result here is that there are some regions that affect multiple traits, and others that have very specific effects,” Hoekstra added. “For example, we found one region that affects licking, huddling, handling and retrieving, but another that affected only nest-building.”

    Armed with those genomic regions, Bendesky set about locating individual genes that might be linked with parental behaviors.

    “We looked at expression in a region of the brain called the hypothalamus, which is known to be important in social behavior,” Hoekstra said. “Specifically, we were looking at which genes showed differences in expression between the two species. While each region might contain hundreds of candidate genes, there were only a handful that fit those criteria. ”

    Almost immediately, she said, one gene – for the production of vasopressin, which was part of a pathway that had earlier been associated with social behavior in voles, jumped out at them.

    To test whether vasopressin actually affected parental behavior, Bendesky administered doses of the hormone to male and female oldfield mice, and found that nest-building behavior in both dropped. A similar experiment, in collaboration with Catherine Dulac’s lab, which used genetic tools to manipulate the activity of vasopressin neurons in lab mice, confirmed these results.

    The study also opens the door to researchers getting a new insight into the neurological circuitry involved in parental behavior by allowing for the targeting of specific genes.

    “This gives us molecular handles to start understanding the circuitry much better,” he said. “We can see what is happening in the brain not in the abstract…but we can say vasopressin is going from this part of the hypothalamus to this other part of the brain, so we can see how the brain is organized.”


  10. 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.