1. Study uses stem cells to explore the causes of autism

    November 17, 2017 by Ashley

    From the Elsevier press release:

    Using human induced pluripotent stem cells (iPSCs) to model autism spectrum disorder (ASD), researchers at the University of São Paulo, Brazil and University of California, San Diego have revealed for the first time that abnormalities in the supporting cells of the brain, called astrocytes, may contribute to the cause of the disorder. The findings, published in Biological Psychiatry, help explain what happens at a biological level to produce ASD behavior, and may help researchers identify new treatments for patients with the disorder.

    Astrocytes play an important role in the development and function of the nervous system. But until now, iPSC models of autism have neglected their contribution. The new study, led by Dr. Patricia Beltrão-Braga and Dr. Alysson Muotri, used iPSCs to generate neurons and astrocytes to model the interaction between these brain cells and better understand how the brain forms in the disorder.

    “This new use of pluripotent stem cells suggests that neurobiological approaches to autism based solely on abnormal neuronal development may fail to account for complex interplay of neurons and astrocytes that may be an underappreciated component of the biology of this disorder,” said Dr. John Krystal, Editor of Biological Psychiatry.

    Induced pluripotent stem cell technology allows researchers to reprogram human cells into any cell in the body. In the study, first authors Dr. Fabiele Russo and Beatriz Freitas and colleagues used cells from three patients diagnosed with ASD and three healthy individuals to generate neurons and astrocytes. Neurons derived from ASD patients had less complex structure than healthy neurons, but adding healthy astrocytes to the ASD neurons improved their poorly developed structure. In reverse, pairing ASD astrocytes with healthy neurons interfered with their development, making them look more like the neurons from ASD patients.

    “The article highlights for the first time the influence of astrocytes in ASD, revealing that astrocytes play a fundamental role in neuronal structure and function,” said Beltrão-Braga.

    The researchers further investigated how the astrocytes exert their influence, and pegged a substance that astrocytes produce called IL-6, already suggested as a player in ASD, as the culprit for the defects. Astrocytes from the patients with ASD appeared to be producing too much of the substance, and the findings suggest that reducing IL-6 could be a beneficial treatment for neurons in ASD.

    Importantly, ASD has been a challenging disease to model using iPSCs because of its complexity. Several genes have been linked to ASD, but their contributions remain unknown, and genetic differences between patients have made it difficult to understand the cause and develop treatments for the disorder. But in this study, the ASD subjects were selected because they shared similar behaviors, rather than similar genes. According to Beltrão-Braga, this means the findings could provide a new alternative strategy for treating ASD symptoms, independent of the patient’s genotype.


  2. Twin study finds genetics affects where children look, shaping mental development

    November 16, 2017 by Ashley

    From the Indiana University press release:

    A new study co-led by Indiana University that tracked the eye movement of twins finds that genetics plays a strong role in how people attend to their environment.

    Conducted in collaboration with researchers from the Karolinska Institute in Sweden, the study offers a new angle on the emergence of differences between individuals and the integration of genetic and environmental factors in social, emotional and cognitive development. This is significant because visual exploration is also one of the first ways infants interact with the environment, before they can reach or crawl.

    “The majority of work on eye movement has asked ‘What are the common features that drive our attention?'” said Daniel P. Kennedy, an assistant professor in the IU Bloomington College of Arts and Sciences’ Department of Psychological and Brain Sciences. “This study is different. We wanted to understand differences among individuals and whether they are influenced by genetics.”

    Kennedy and co-author Brian M. D’Onofrio, a professor in the department, study neurodevelopmental problems from different perspectives. This work brings together their contrasting experimental methods: Kennedy’s use of eye tracking for individual behavioral assessment and D’Onofrio’s use of genetically informed designs, which draw on data from large population samples to trace the genetic and environmental contributions to various traits. As such, it is one of the largest-ever eye-tracking studies.

    In this particular experiment, the researchers compared the eye movements of 466 children — 233 pairs of twins (119 identical and 114 fraternal) — between ages 9 and 14 as each child looked at 80 snapshots of scenes people might encounter in daily life, half of which included people. Using an eye tracker, the researchers then measured the sequence of eye movements in both space and time as each child looked at the scene. They also examined general “tendencies of exploration”; for example, if a child looked at only one or two features of a scene or at many different ones.

    Published Nov. 9 in the journal Current Biology, the study found a strong similarity in gaze patterns within sets of identical twins, who tended to look at the same features of a scene in the same order. It found a weaker but still pronounced similarity between fraternal twins.

    This suggests a strong genetic component to the way individuals visually explore their environments: Insofar as both identical and fraternal twins each share a common environment with their twin, the researchers can infer that the more robust similarity in the eye movements of identical twins is likely due to their shared genetic makeup. The researchers also found that they could reliably identify a twin with their sibling from among a pool of unrelated individuals based on their shared gaze patterns — a novel method they termed “gaze fingerprinting.”

    “People recognize that gaze is important,” Kennedy said. “Our eyes are moving constantly, roughly three times per second. We are always seeking out information and actively engaged with our environment, and ultimately where you look affects your development.”

    After early childhood, the study suggests that genes influence at the micro-level — through the immediate, moment-to-moment selection of visual information — the environments individuals create for themselves.

    “This is not a subtle statistical finding,” Kennedy said. “How people look at images is diagnostic of their genetics. Eye movements allow individuals to obtain specific information from a space that is vast and largely unconstrained. It’s through this selection process that we end up shaping our visual experiences.

    “Less known are the biological underpinnings of this process,” he added. “From this work, we now know that our biology affects how we seek out visual information from complex scenes. It gives us a new instance of how biology and environment are integrated in our development.”

    “This finding is quite novel in the field,” D’Onofrio said. “It is going to surprise people in a number of fields, who do not typically think about the role of genetic factors in regulating such processes as where people look.”


  3. Study suggests malfunctions in communication between brain cells could be at root of autism

    November 11, 2017 by Ashley

    From the Washington University School of Medicine press release:

    A defective gene linked to autism influences how neurons connect and communicate with each other in the brain, according to a study from Washington University School of Medicine in St. Louis. Rodents that lack the gene form too many connections between brain neurons and have difficulty learning.

    The findings, published Nov. 2 in Nature Communications, suggest that some of the diverse symptoms of autism may stem from a malfunction in communication among cells in the brain.

    “This study raises the possibility that there may be too many synapses in the brains of patients with autism,” said senior author Azad Bonni, MD, PhD, the Edison Professor of Neuroscience and head of the Department of Neuroscience at Washington University School of Medicine in St. Louis. “You might think that having more synapses would make the brain work better, but that doesn’t seem to be the case. An increased number of synapses creates miscommunication among neurons in the developing brain that correlates with impairments in learning, although we don’t know how.”

    Autism is a neurodevelopmental disorder affecting about one out of every 68 children. It is characterized by social and communication challenges.

    Among the many genes linked to autism in people are six genes that attach a molecular tag, called ubiquitin, to proteins. These genes, called ubiquitin ligases, function like a work order, telling the rest of the cell how to deal with the tagged proteins: This one should be discarded, that one should be rerouted to another part of the cell, a third needs to have its activity dialed up or down.

    Patients with autism may carry a mutation that prevents one of their ubiquitin genes from working properly. But how problems with tagging proteins affect how the brain is hardwired and operates, and why such problems may lead to autism, has remained poorly understood.

    To understand the role of ubiquitin genes in brain development, Bonni, first author Pamela Valnegri, PhD, and colleagues removed the ubiquitin gene RNF8 in neurons in the cerebellum of young mice. The cerebellum is one of the key brain regions affected by autism.

    The researchers found that neurons that lacked the RNF8 protein formed about 50 percent more synapses — the connections that allow neurons to send signals from one to another — than those with the gene. And the extra synapses worked. By measuring the electrical signal in the receiving cells, the researchers found that the strength of the signal was doubled in the mice that lacked the protein.

    The cerebellum is indispensable for movement and learning motor skills such as how to ride a bicycle. Some of the recognizable symptoms of autism — such as motor incoordination and a tendency to walk tippy-toed — involve control of movement.

    The animals missing the RNF8 gene in the neurons of their cerebellum did not have any obvious problems with movement: They walked normally and appeared coordinated. When the researchers tested their ability to learn motor skills, however, the mice without RNF8 failed miserably.

    The researchers trained the mice to associate a quick puff of air to the eye with the blinking of a light. Most mice learn to shut their eyes when they see the light blink, to avoid the irritation of the coming air puff. After a week of training, mice with a functioning copy of the gene closed their eyes in anticipation more than three quarters of the time, while mice without the gene shut their eyes just a third of the time.

    While it is best known for its role in movement, the cerebellum is also important in higher cognitive functions such as language and attention, both of which are affected in autism. People with autism often have language delays and pay unusually intense attention to objects or topics that interest them. The cerebellum may be involved not only in motor learning but in other features of autism as well, the researchers said.

    Of course, there is a world of difference between a mouse that can’t learn to shut its eyes and a person with autism who struggles to communicate. But the researchers said the findings suggest that changing how many connections neurons make with each other can have important implications for behavior.

    Since this paper was written, Bonni and colleagues have tested the other autism-associated ubiquitin genes. Inhibition of all genes tested cause an increase in the number of synapses in the cerebellum.

    “It’s possible that excessive connections between neurons contribute to autism,” Bonni said. “More work needs to be done to verify this hypothesis in people, but if that turns out to be true, then you can start looking at ways of controlling the number of synapses. It could potentially benefit not just people who have these rare mutations in ubiquitin genes but other patients with autism.”


  4. Study suggests gene therapy protecting against age-related cognitive, memory deficits

    November 4, 2017 by Ashley

    From the Universitat Autònoma de Barcelona press release:

    Researchers from the Institute of Neurosciences at the Universitat Autònoma de Barcelona (INc-UAB) and the Vall d’Hebron Research Institute (VHIR) are the first to demonstrate that regulation of the brain’s Klotho gene using gene therapy protects against age-related learning and memory problems in mice.

    The study, published in Molecular Psychiatry (Nature group), opens the door to advancing in the research and development of therapies based on this neuroprotective gene.

    Researchers from the UAB demonstrated in a previous study that Klotho regulates age-associated processes, increasing life expectancy when over-expressed and accelerating the development of learning and memory deficiencies when inhibited.

    Now they have demonstrated in vivo for the first time that one dose of this gene injected into the central nervous system prevents the cognitive decline associated with aging in old animals which were treated at a younger age.

    The results, which form part of the PhD thesis of Anna Massó, first author of the article, are part of a study led by INc-UAB researchers Dr Miguel Chillón, ICREA researcher at the Department of Biochemistry and Molecular Biology of the UAB and the VHIR; Dr Lydia Giménez-Llort from the Department of Psychiatry and Legal Medicine of the UAB; and with the collaboration of Dr Assumpció Bosch, also from the Department of Biochemistry and Molecular Biology.

    “The therapy is based on an increase in the levels of this protein in the brain using an adeno-associated viral vector (AAV). Taking into account that the study was conducted with animals which aged naturally, we believe this could have the therapeutic ability to treat dementia and neurodegenerative disorders such as Alzheimer’s or multiple sclerosis, among others,” Miguel Chillón points out.

    The researchers patented their therapy and have licensed it to Kogenix Therapeutics. The company includes UAB participation and is based in the United States. It was launched by Dr Miguel Chillón and Dr Assumpció Bosch, together with the entrepreneur Menachem Abraham and Dr Carmela Abraham, professor of Biochemistry and Pharmacology at the Boston University School of Medicine, a pioneering centre in the study of Klotho in the central nervous system for more than a decade.

    The objective of Kogenix is to achieve the initial capital needed to advance in the pre-clinical trials already being conducted with animal models of Alzheimer’s disease. This will give way to the development of a drug to be used in gene therapy against neurodegenerative diseases based on small molecules which enhance the expression of the gene and/or the use of fragments of the Klotho protein itself.

    “In basic research studies and clinical trials the AAVs have shown to be safe and effective in the implementation of a central nervous system gene therapy. In fact, the Food and Drug Administration made the first gene therapy available in the United States in August and additional approvals are expected,” Dr Assumpció Bosch states.


  5. Prenatal exposure to BPA at low levels can affect gene expression in developing rat brain

    November 2, 2017 by Ashley

    From the North Carolina State University press release:

    New research from North Carolina State University reveals that prenatal exposure to bisphenol A (BPA) at levels below those currently considered safe for humans affects gene expression related to sexual differentiation and neurodevelopment in the developing rat brain.

    BPA is a chemical used in a variety of consumer and household products including some food containers. Experimental data has also suggested a link between the chemical and mood or anxiety-related behaviors in children. Currently, the U.S. Food and Drug Administration (FDA) No Observed Adverse Effect Level (NOAEL) for BPA is 50 micrograms per kilogram of body weight per day.

    Heather Patisaul, professor of biology at NC State, with Ph.D. candidate Sheryl Arambula, conducted a study exposing gestating rats to levels of BPA both above and below those currently considered to have no adverse effect — including levels as low as 2.5 and 25 micrograms per kilogram of body weight per day — and looked at effects in the brains of their newborn pups.

    Arambula and Patisaul found that prenatal BPA exposure, even at the lowest levels, changed the expression of numerous hormone receptors including those for androgen, estrogen, oxytocin and vasopressin in the newborns’ amygdala, a brain structure involved in a wide range of stress and emotional behaviors. Oxytocin, for example, is important for affiliation and pair-bonding, while vasopressin is involved in stress responses. The changes varied depending upon the sex of the newborn and the amount of exposure. Significantly, disruption of genes critical for synaptic transmission and neurodevelopment were also found to be altered, with females appearing to be more sensitive than males.

    “Uniquely, we found that low level prenatal BPA exposure can change androgen receptor expression levels in the amygdala,” says Arambula. “In humans, this gene is important for forming differences between male and female brains, which suggests this could be a way by which BPA exposure might alter sex differences in the human brain.”

    Patisaul is among a consortium of researchers involved in a multi-year, multi-disciplinary project called CLARITY-BPA, a research initiative that includes the FDA, the National Toxicology Program, the National Institute of Environmental Health Sciences (NIEHS), and 13 academic labs. CLARITY-BPA seeks to understand how BPA affects multiple organ systems. Patisaul’s focus is on brain and behavior. All rats in the study were housed at the National Center for Toxicological Research and followed FDA protocols for exposure. CLARITY-BPA experiments were specifically conceived and conducted to provide the FDA with data it could use to make decisions about human health risks.

    “In our previous work, including work for this consortium, we found similar changes in other brain regions including the hypothalamus and hippocampus.” says Patisaul. “There is now a wealth of data showing that BPA can alter neurodevelopment. There is no question that prenatal BPA exposure at levels currently considered safe for humans affects hormone-sensitive gene expression in the developing rodent brain, suggesting that what we consider ‘safe’ for human brains may need to be re-evaluated.”

    The researchers’ findings appear in NeuroToxicology. Arambula is first author and Patisaul is corresponding author of the work. Dereje Jima, a specialist with NC State’s Center for Human Health and the Environment, did the bioinformatics analysis. The research was funded by the NIEHS (grants P30ES025128 and U011ES020929).


  6. Mysterious DNA modification seen in stress response

    October 25, 2017 by Ashley

    From the Emory Health Sciences press release:

    With advances in genomics, scientists are discovering additional components of the DNA alphabet in animals. Do these unusual chemical modifications of DNA have a special meaning, or are they just signs that cellular machines are making mistakes?

    Geneticists at Emory University School of Medicine led by Peng Jin, PhD have been studying a modification of DNA that is not well understood in animals: methylation of the DNA letter A (adenine). They’ve found that it appears more in the brain under conditions of stress, and may have a role in neuropsychiatric disorders.

    The results are scheduled for publication in Nature Communications.

    Methylation on the DNA letter C (cytosine) generally shuts genes off and is an important part of epigenetic regulation, a way for cells to change how the DNA code is read without altering the DNA letters themselves. Methylation describes a mark consisting of an extra carbon atom and three hydrogens: -CH3.

    What if methylation appears on adenine? In bacteria, N6-methyladenine is part of how they defend themselves against invasion by phages (viruses that infect bacteria). The same modification was recently identified as present in the DNA of insects and mammals, but this epigenetic flourish has been awaiting a full explanation of its function.

    Just to start, having that extra -CH3 jutting out of the DNA could get in the way of proteins that bind DNA and direct gene activity. For C-methylation, scientists know a lot about the enzymes that grab it, add it or erase it. For A-methylation, less is known.

    “We found that 6-methyl A is dynamic, which could suggest a functional role,” Jin says. “That said, the enzymes that recognize, add and erase this type of DNA methylation are still mysterious.”

    It does appear that the enzymes that add methyl groups to A when it is part of RNA are not involved, he adds.

    First author Bing Yao, PhD, assistant professor of human genetics, recently established his own laboratory at Emory to examine these and other emerging parts of the DNA alphabet. Jin is vice chair of research in the Department of Human Genetics.

    In the Nature Communications paper, Yao, Jin and their colleagues looked at the prefrontal cortex region of the brain in mice that were subjected to stress, in standard models for the study of depression (forced swim test and tail suspension test).

    Under these conditions, the abundance of N6-methyladenine in the brain cells’ DNA rose four-fold, the scientists found. The DNA modification was detected with two sensitive techniques: liquid chromatography/mass spectrometry and binding to an antibody against N6-methyladenine. The peak abundance is about 25 parts per million, which isn’t that high — but it appears to be confined to certain regions of the genome.

    The methyl-A modification tended to appear more in regions that were between genes and was mostly excluded from the parts of the genome that encode proteins. The loss of methyl-A correlates with genes that are upregulated with stress, suggesting that something removes it around active genes. There does seem to be some “cross talk” between A and C methylation, Jin adds.

    Genes bearing stress-induced 6mA changes overlapped with those associated with neuropsychiatric disorders; a relationship that needs more investigation. The scientists speculate that aberrant 6mA in response to stress could contribute to neuropsychiatric diseases by ectopically recruiting DNA binding proteins.

    The research was supported in part by the National Institute of Neurological Disorders and Stroke (NS051630, NS097206) and the National Institute of Mental Health (MH102690).


  7. Study suggests genetic influences on the brain’s reward, stress systems underlie co-occurring alcohol use disorder, chronic pain

    October 21, 2017 by Ashley

    From the Research Society on Alcoholism press release:

    Alcohol use disorder (AUD) often co-occurs with chronic pain (CP), yet the relationship between the two is complex — involving genetic, neurophysiological, and behavioral elements — and is poorly understood. This review addressed the genetic influences on brain reward and stress systems that neurological research suggests may contribute to the co-occurrence of AUD and CP.

    Candidate gene association studies (CGAS) and genome-wide association studies (GWAS) have provided initial evidence suggesting that a similar dysregulation of reward and stress pathways contribute to AUD and CP, and that genetic influences on these pathways may contribute to both conditions. More specifically, genetic association studies that have looked at AUD and CP independently have identified a number of single-nucleotide polymorphisms (SNPs) — DNA sequence variations — suggestively associated with AUD and CP, with several of these SNPs being located in or near a common set of genes. These common genes are either directly or indirectly related to the reward and stress systems, and are also more broadly involved with the central nervous system (CNS).

    The authors suggested that these results must be interpreted with caution until studies with sufficient statistical power are conducted and replicated. Further, the co-occurrence of AUD and CP reflect a common genetic basis that will likely involve CNS processes other than reward and stress mechanisms in AUD-CP co-occurrence. As the field of molecular genetics continues to advance, if such shared genetic contributions to AUD and CP may be identified, this knowledge can help inform understanding of the underlying mechanisms that contribute to the etiologies of each disorder and their co-occurrence. This would refine and improve the diagnosis and treatment of AUD and CP.


  8. Study suggests signaling pathway may be key to why autism is more common in boys

    October 17, 2017 by Ashley

    From the University of Iowa Health Care press release:

    Researchers aiming to understand why autism spectrum disorders (ASD) are more common in boys have discovered differences in a brain signaling pathway involved in reward learning and motivation that make male mice more vulnerable to an autism-causing genetic glitch.

    “One intriguing aspect of autism is that it predominantly affects males; four boys are affected for every one girl,” says senior study author Ted Abel, PhD, director of the Iowa Neuroscience Institute at the University of Iowa Carver College of Medicine. “We don’t understand what it is about this disorder that predisposes boys as compared to girls to develop autism.”

    This male bias is also seen in other neurodevelopmental disorders, like attention deficit hyperactivity disorder (ADHD) and specific language impairments.

    Nearly one in every 200 cases of autism is caused by the deletion of a section of DNA on a particular chromosome. This type of disorder is also known as a copy number variation (CNV). The mouse model of autism used by the research team is missing the same stretch of DNA.

    The researchers tested the mice for abnormalities in reward-learning behavior — learning to associate actions with rewarding outcomes. This type of learning is mediated by a part of the brain called the striatum and is disrupted in people with autism and other neurodevelopmental disorders.

    The study, published online Oct. 17 in Molecular Psychiatry, shows that only male mice with the autism-associated genetic deletion have abnormal reward-learning behavior. Female mice with the same genetic deletion are not affected. Moreover, these sex-specific behavioral differences are accompanied by sex differences in molecular signaling pathways in the striatum brain region.

    Problems with reward learning could explain why individuals with autism don’t interact socially — because they don’t find it rewarding in the same way. It could explain why people with autism have restricted interests — because they find only very selective things rewarding — and it could explain the differences in language acquisition — because the neural circuitry involved in reward learning is the same circuitry that mediates both language learning and production,” says Abel, who also is the Roy J. Carver Chair in Neuroscience and UI professor of molecular physiology and biophysics.

    Female protective effect

    One of the genes contained in the missing section of DNA is an important signaling protein called ERK1. Activity of this protein affects the function of the striatum — the part of the brain that’s involved in reward learning and motivation. The researchers found that male mice carrying this genetic deletion have increased activation of ERK1 in the striatum coupled with decreased amounts of another protein that reduces ERK1 activity. In contrast, the female mice carrying the genetic deletion do not have overactivated ERK1. In addition, despite the genetic deletion, the female deletion mice have higher levels of ERK1 than the male deletion mice. All of these molecular differences mean that ERK1 signaling is particularly sensitive to disruption in male mice.

    “This is some of the first evidence in a mouse model of autism of a ‘female protective effect,’ from the behavioral to the molecular level,” says Nicola Grissom, first author of the study who is now an assistant professor of psychology at the University of Minnesota. “These findings shed valuable new light on the science of neurodevelopmental disorders, many of which are more common in boys. However, they also address the broader question of how sex and gender influence the neurobiology of how we learn and behave, which may be involved in the different levels of risk between women and men for developing many other neuropsychiatric conditions, as well.”

    The study also found that male mice carrying this genetic alteration linked to autism have increased expression of a receptor for dopamine; the D2 receptor. The level of D2 expression did not increase in the female autism mice. Abel notes that risperidone, one of very few drugs that is approved by the Food and Drug Administration to treat ASD symptoms, targets D2 dopamine receptors.

    “We think we are on the right track,” Abel says. “We have begun to identify what may be an underlying reason why neurodevelopmental disorders predominantly affect boys, and that involves the function of the striatum and reward learning. This has implications for how we think about the underlying behavioral differences in autism and implications for how we develop both behavioral or pharmacological therapies to improve the lives of those with autism.”

    The new findings are part of a bigger study where Abel and his colleagues are investigating many different mouse models of autism, in which different autism-linked genes have been disrupted. The researchers are seeking commonalities among the different models. One emerging theme, supported by the new study, is that a deficit in reward learning may be a common feature of ASD, and males are specifically deficient in this type of behavior.

    Abel notes that funding from the Simons Foundation was critical to the success of the project.

    “None of this would have happened without the support of the Simons Foundation Autism Research Initiative (SFARI). The impact they have had on autism research has been tremendous,” he says.


  9. Twin study suggests nearly 80% of schizophrenia risk is heritability

    October 11, 2017 by Ashley

    From the Elsevier press release:

    In the largest study of twins in schizophrenia research to date, researchers at the University of Copenhagen, Denmark, estimate that as much as 79% of schizophrenia risk may be explained by genetic factors. The estimate indicates that genetics have a substantial influence on risk for the disorder.

    Published in Biological Psychiatry, the study used a new statistical approach to address one of the factors that contributes to inconsistencies across previous studies — usually studies of heritability require that people be classified as either having schizophrenia or not, but some people at risk could still develop the disease after the study ends. Drs. Hilker, Helenius and colleagues applied a new method to take this problem into account, making the current estimates likely the most accurate to date.

    “The new estimate of heritability of schizophrenia, 79%, is very close to the high end of prior estimates of its heritability,” said Dr. John Krystal, Editor of Biological Psychiatry, referring to previous estimates that have varied between 50% and 80%. “It supports the intensive efforts in place to try to identify the genes contributing to the risk for developing schizophrenia,” said Dr. Krystal, which have been built on the idea that schizophrenia is highly heritable based on the findings of generations of twin studies.

    The study took advantage of the nationwide Danish Twin Register — a record of all twins born in Denmark since 1870 — coupled with information from the Danish Psychiatric Central Research Register, to assess genetic liability in over 30,000 pairs of twins.

    Because the diagnosis of schizophrenia is based on a narrow definition of symptoms, the researchers also estimated heritability using a broader illness category including related disorders on the schizophrenia spectrum. They found a similar estimate of 73%, indicating the importance of genetic factors across the full illness spectrum.

    Dr. Hilker explained, “This study is now the most comprehensive and thorough estimate of the heritability of schizophrenia and its diagnostic diversity. It is interesting since it indicates that the genetic risk for disease seems to be of almost equal importance across the spectrum of schizophrenia,” even though the clinical presentation may range from severe symptoms with lifelong disability to more subtle and transient symptoms. “Hence, genetic risk seems not restricted to a narrow illness definition, but instead includes a broader diagnostic profile,” she added.


  10. Epigenetic study untangles addiction and relapse in the brain

    October 6, 2017 by Ashley

    From the Medical University of South Carolina press release:

    Why do some drug users continue to seek out drugs despite the prospect of losing family, friends, health or livelihood?

    There are notable features — cues — of the early drug-using environment that often develop into persistent and powerful triggers for relapse. Epigenetic factors — enzymes in the brain that alter the packaging and accessibility of genes without changing the genes themselves — influence this process, according to research at the Medical University of South Carolina (MUSC) appearing online on September 27, 2017 in Neuron.

    A major challenge in addiction science is to understand how transient experiences lead to long-lasting risk for relapse in users who try to quit, according to MUSC professor Christopher W. Cowan, Ph.D., William E. Murray SmartState® Endowed Chair in Neuroscience, and senior researcher on the project. “Our goal was to discover the brain mechanisms responsible for the rewarding effects of the drug and the motivation to seek it even after long periods of abstinence,” says Cowan.

    The brains of drug users who have progressed to addiction differ markedly from those of early or casual users. Long-lasting associations form between the early use of a drug and different aspects of the early drug-using environment, such as the location in which a drug was first taken or the emotions a user was experiencing at the time. This can cause addicted users who have quit to experience cravings when in a similar setting. Understanding these connections could lead to better treatments for addiction.

    Cowan’s challenge was to determine which genes were activated in the early drug-using environment. Cowan and his fellow researchers had previously found that the epigenetic enzyme histone deacetylase 5 (HDAC5) slows the rodent brain from forming associations between cocaine and simple cues in the environment, such as light and sound. HDAC5 is found in high amounts in neurons in the nucleus accumbens, part of the reward center of the brain that reacts strongly to cocaine, opioids and alcohol — both in rodents and humans. When HDACs are in the nucleus of neurons, they change the way genomic DNA is packaged in the cell nucleus and often block the ability of certain genes to be turned on.

    In the new study, rodents were trained to press a lever to receive a dose of cocaine. Each time they received a dose, a lamp went on above the lever and a brief sound was generated. These served as simple environmental cues for drug use. Next, some rodents were given a form of HDAC5 that traveled straight to the nuclei of neurons. Those rodents still pressed the lever just as many times to receive drug, meaning that HDAC5, on its own, was likely not blocking genes that promoted early drug-seeking behavior.

    Yet the next experiment proved that HDAC5 reduced drug-seeking behavior during abstinence. To simulate withdrawal and abstinence, rodents were given rest without cocaine for one week, followed by a period during which they had access to the lever again. To simulate relapse, the rodents were shown the environmental cues again, this time without having pressed the lever. The presentation of the cues triggered robust lever pressing, indicating drug seeking, in control animals, proving that the associations between drug and environment persisted in their brains. In contrast, animals who had the nuclear form of HDAC5 did not press the lever nearly as often, even after the experimenters gave the animals a small priming dose of cocaine, which often produces strong drug-seeking behaviors.

    HDAC5, the gene suppressor, did not prevent addiction-like behaviors from forming, but it did prevent later drug seeking and relapse during abstinence — at least in rodents.

    The researchers next used a cutting-edge technique that encourages epigenetic enzymes to bind to DNA, allowing them to identify all the genes inhibited by HDAC5. The gene for NPAS4 was a top hit, and significant for an important reason: it is an early-onset gene, meaning that its effects could be exerted on the brain rapidly unless HDAC5 was there to inhibit it — just the molecular event Cowan and his team were seeking.

    In similar experiments, animals with less NPAS4 in the nucleus accumbens took more time to form those early connections between environmental cues and cocaine, but they still sought the drug just as often during later simulated relapse. Apparently, NPAS4 accounts for some addiction-related learning and memory processes in the brain, but not all of them, meaning that HDAC5 must be regulating additional genes that reduce relapse events. Cowan thinks uncovering additional downstream genes could help researchers untangle the details of how the brain transitions from early drug use to addiction, and how new treatments might be developed to reduce relapse in individuals suffering from substance use disorders.

    Animals in the research setting may not mimic the full complexity of human addiction. However, abstinent patients report cravings when given reminders of their drug-associated environment or cues, and animals and humans share similar enzyme pathways and brain structures. Perhaps most exciting for addiction research is that these processes may be similar in the transition to cocaine, alcohol and opioid addictions. “We might have tapped into a mechanism with relevance to multiple substance use disorders,” says Cowan.