In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth.
The results were published in the journal Cell Reports.
“The beauty of using organoids is that they allow us to Read more
Why do people with cystic fibrosis (CF) have such trouble with lung infections? The conventional view is that people with CF are at greater risk for lung infections because thick, sticky mucus builds up in their lungs, allowing bacteria to thrive. CF is caused by a mutation that affects the composition of the mucus.
Rabindra Tirouvanziam, an immunologist at Emory, says a better question is: what type of cell is supposed to be fighting the Read more
The amygdala is a region of the brain known for its connections to emotional responses and fear memories, and hyperreactivity of the amygdala is associated with symptoms of PTSD (post-traumatic stress disorder). That said, it’s quite a leap to design neurosurgical ablation of the amygdala to address someone’s PTSD. This type of irreversible intervention could only be considered because of the presence of another brain disorder: epilepsy.
In a case series published in Neurosurgery, Emory investigators describe how for their first patient with both refractory epilepsy and PTSD, observations of PTSD symptom reduction were fortuitous. However, in a second patient, before-and-after studies could be planned. In both, neurosurgical ablation of the amygdala significantly reduced PTSD symptoms as well as reducing seizure frequency.
Supported by a $8 million, five-year grant, an Emory-led team of scientists plans to investigate new therapeutic approaches to fragile X syndrome, the most common inherited intellectual disability and a major single-gene cause of autism.
Fragile X research represents a doorway to a better understanding of autism, and learning and memory. The field has made strides in recent years. Researchers have a good understanding of the functions of the FMR1 gene, which is silenced in fragile X syndrome.
Still, clinical trials based on that understanding have been unsuccessful, highlighting limitations of current mouse models. Researchers say the answer is to use “organoid” cultures that mimic the developing human brain.
The new grant continues support for the Emory Fragile X Center, first funded by the National Institutes of Health in 1997. The Center’s research program includes scientists from Emory as well as Stanford, New York University, Penn and the University of Southern California. The Emory Center will be one of three funded by the National Institutes of Health; the others are at Baylor College of Medicine and Cincinnati Children’s Hospital Medical Center.
The co-directors for the Emory Fragile X Center are Peng Jin, PhD, chair of human genetics, and Stephen Warren, PhD, William Patterson Timmie professor and chair emeritus of human genetics. In the 1980s and 1990s, Warren led an international team that discovered the FMR1 gene and the mechanism of trinucleotide repeat expansion that silences the gene. This explained fragile X syndrome’s distinctive inheritance pattern, first identified by Emory geneticist Stephanie Sherman, PhD.
“Fragile X research is a consistent strength for Emory, stretching across several departments, based on groundbreaking work from Steve and Stephanie,” Jin says. “Now we have an opportunity to apply the knowledge we and our colleagues have gained to test the next generation of treatments.”
Looking ahead, a key element of the Center’s research will involve studying the human brain in “disease in a dish” models, says Gary Bassell, PhD, chair of cell biology. Nisha Raj, PhD, a postdoctoral fellow in Bassell’s lab, has been studying how FMR1 regulates localized protein synthesis at the brain’s synapses.
“What we’re learning is that there may be different RNA targets in human and mouse cells,” he says. “There’s a clear need to regroup and incorporate human cells into the research.”
Center investigator Zhexing Wen, PhD, has developed techniques for culturing brain organoids (image above), which reproduce features of human brain development in miniature. Wen, assistant professor of psychiatry and behavioral sciences, cell biology and neurology at Emory, has used organoids to model other disorders, such as schizophrenia and Alzheimer’s disease.
The organoids are formed from human brain cells, coming from induced pluripotent stem cells, which are in turn derived from patient-donated tissues. Emory’s Laboratory of Translational Cell Biology, directed by Bassell, has developed several lines of induced pluripotent stem cells from fragile X syndrome patients.
“All of the investigators are sharing these valuable resources and collaborating on multiple projects,” Bassell says.
Principal investigators in the Emory Fragile X Center are Jin, Warren, Bassell, and Wen, along with Eric Klann, PhD at New York University, Lu Chen, PhD, and 2013 Nobel Prize winner Thomas Südhof, MD. Chen and Südhof are neuroscientists at Stanford.
Co-investigators include biostatistician Hao Wu, PhD and geneticist Emily Allen, PhD at Emory, neuroscientist Guo-li Ming, MD, PhD, at University of Pennsylvania, and biomedical engineer Dong Song, PhD, at University of Southern California.
Allen, Warren and Jin are part of an additional grant to Baylor, Emory and University of Michigan investigators, who are focusing on FXTAS (fragile X-associated tremor-ataxia syndrome) and FXPOI (fragile X-associated primary ovarian insufficiency). These are conditions that affect people with fragile X premutations.
Fragile X syndrome is caused by a genetic duplication on the X chromosome, a “triplet repeat” in which a portion of the gene (CGG) gets repeated again and again. Fragile X syndrome affects about one child in 5,000, and is more common and more severe in boys. It often causes mild to moderate intellectual disabilities as well as behavioral and learning challenges. About a third of children affected have characteristics of autism, such as problems with eye contact, social anxiety, and delayed speech.
The award for the Emory Fragile X Center is administered by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with funding from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.
Parents around the world can relax, knowing that their kids won’t inherit all of their stresses — at least at the DNA or epigenetic level. In an animal model, neuroscientists at Yerkes National Primate Research Center have shown they can reverse influences of parental stress by exposing parents to behavioral interventions following their own exposure to stress.
“These results in our mouse model are an important public health contribution because they provide optimism for applying similar interventional approaches in humans and breaking intergenerational cycles of stress,” says lead author Brian Dias. More information here.
The research was published in Biological Psychiatry, and is a continuation of Dias’ work with Kerry Ressler on this topic, which earned some attention in 2013. Note: the mice weren’t inheriting a fear as much as a sensitivity to a smell. Even so, it remains an intriguing example of how transgenerational (um, since the word “epigenetic” is so stretchy now) influences can be studied in a precise molecular way.
Editor’s note: Guest post from Neuroscience graduate student Brendan O’Flaherty. Companion paper to the Gourley lab’s recently published work on fasudil, habit modification and neuronal pruning.
An Emory study has discovered why teenager’s brains may be especially vulnerable to cocaine. Exposure to small amounts of cocaine in adolescence can disrupt brain development and impair the brain’s ability to change its own habits, the study suggests.
Guest post from Brendan O’Flaherty
The results were published in the April 1, 2017 issue of Biological Psychiatry, by researchers at Yerkes National Primate Research Center.
Drug seeking habits play a major role in drug addiction, says senior author Shannon Gourley, PhD, assistant professor of pediatrics, psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center. The first author of the paper is former Emory graduate student Lauren DePoy, PhD.
When it comes to habits, cocaine is especially sneaky. Bad habits like drug use are already very difficult to change, but cocaine physically changes the brain, potentially weakening its ability to “override” bad habits. Although adults are susceptible to cocaine’s effects on habits, adolescent brains are especially vulnerable.
“Generally speaking, the younger you are exposed to cocaine in life, the more likely you are to have impaired decision making,” Gourley says.
Shannon Gourley, PhD, in lab
To understand why adolescent brains are especially vulnerable to cocaine, the researchers studied the effects of cocaine exposure on how the mice make decisions about food.
“I think it’s pretty amazing that we can actually talk to mice in a way that allows them to talk back,” Gourley says. “And then we can utilize a pretty tremendous biological toolkit to understand how the brain works.”
Researchers injected adolescent mice five times with either saline or cocaine. Both groups of animals then grew up without access to cocaine. Researchers then trained the mice to press two buttons, both of which caused food to drop into the cage. Since both buttons rewarded the mice equally, the mice pushed each button half the time.
Over time, pushing the two buttons equally could become a habit. To test this, the researchers then played a trick on the mice. When one of the buttons was exposed, the researchers starting giving the mice food pellets for free, instead of rewarding them for button-pressing.
“What the mouse should be learning is: ‘Ah hah, wait a minute, when I have access to this button I shouldn’t respond, because my responding doesn’t get me anything,‘” Gourley says. Read more
The placebo effect plays a big role in clinical trials for mood disorders such as depression. Emory psychiatrist Andy Miller hit upon something several years ago that could clear a path around the placebo effect.
A recent paper in Psychotherapy and Psychosomatics from Miller and psychiatry chair Mark Rapaport looks at clinical trials testing an anti-inflammatory drug against psoriasis, to see whether participants’ depressive symptoms improved. This sidesteps a situation where doctors’ main targets are the patients’ moods.
“These studies emphasize how difficult it is to interpret findings when these drugs are treating more than one problem,” Miller says. “Better to have a simpler study with just depression.”
Still, this line of research could clarify who could benefit from anti-inflammatory treatments and illuminate viable biomarkers and pathways. Two studies now underway at Emory specifically recruit patients with high levels of the inflammatory marker CRP, which Miller’s previous study showed was helpful in predicting response to infliximab.
The new paper results from a collaboration with Eli Lilly. Lilly’s ixekizumab (commercial name: Taltz) is an antibody against the cytokine IL-17A, used to treat moderate to severe psoriasis. Taltz was approved by the FDA in 2016, after clinical trials published in the New England Journal of Medicine. Read more
Low estrogen levels may make women more susceptible to the development of post-traumatic stress disorder (PTSD) at some points in their menstrual cycles or lifetimes, while high estrogen levels may be protective.
New research from Emory University School of Medicine and Harvard Medical School provides insight into how estrogen changes gene activity in the brain to achieve its protective effects.
The findings, published in Molecular Psychiatry, could inform the design of preventive treatments aimed at reducing the risk of PTSD after someone is traumatized.
The scientists examined blood samples from 278 women from the Grady Trauma Project, a study of low-income Atlanta residents with high levels of exposure to violence and abuse. They analyzed maps of DNA methylation, a modification to the shape of DNA that is usually a sign of genes that are turned off.
The group included adult women of child-bearing age, in which estrogen rises and falls with the menstrual cycle, and women that had gone through menopause and had much lower estrogen levels.
“We knew that estrogen affects the activity of many genes throughout the genome,” says Alicia Smith, PhD, associate professor and vice chair of research in the Department of Gynecology and Obstetrics at Emory University School of Medicine. “But if you look at the estrogen-modulated sites that are also associated with PTSD, just one pops out.”
That site is located in a gene called HDAC4, known to be critical for learning and memory in mice. Genetic variation in HDAC4 among the women was linked to a lower level of HDAC4 gene activity and differences in their ability to respond to and recover from fear, and also differences in “resting state” brain imaging. Women with the same variation also showed stronger connections in activation between the amygdala and the cingulate cortex, two regions of the brain involved in fear learning. Read more
Editorial note: Although the research team here is careful and confirms the findings in independent groups and in brain imaging and fear discrimination experiments, this is a preliminary result. More needs to be explored about how these genetic variants and others affect positive emotions.
“With relatively few studies on genetic underpinnings of positive emotions, we face the challenges of a nascent research area,” the authors write.
“Resilience is a multidimensional phenomenon, and we were looking at just one aspect of it,” says first author Aliza Wingo. She worked with Kerry Ressler , now at Harvard, and Tanja Jovanovic and other members of the Grady Trauma Project team.
“Positive affect” is what the team was measuring, through responses on questionnaires. And the questions are asking for the extent that respondents feel a particular positive emotion in general, rather than that day or that week. Read more
Emory researchers have identified molecular mechanisms that regulate motivation and persistence in mice. Their findings could have implications for intervention in conditions characterized by behavioral inflexibility, such as drug abuse and depression.
Scientists showedÂ that by manipulating a particular growth factor in one region of the brain, they couldÂ tune up or down a mouseâ€™s tendency to persist in seeking a reward. In humans, this region of the brain is located just behind the eyes and is called the medial orbitofrontal cortex or mOFC.
â€œWhen we make decisions, we often need to gauge the value of a reward before we can see it — for example, will lunch at a certain restaurant be better than lunch at another, or worth the cost,â€ says Shannon Gourley, PhD, assistant professor of pediatrics and psychiatry at Emory University School of Medicine. â€œWe think the mOFC is important for calculating value, particularly when we have to imagine the reward, as opposed to having it right in front of us.â€
Being able to appropriately determine the value of a perceived reward is critical in goal-directed decision making, a component of drug-seeking and addiction-related behaviors. While scientists already suspected that the medial orbitofrontal cortex was important for this type of learning and decision-making, the specific genes and growth factors were not as well-understood.
The researchers focused on brain-derived neurotrophic factor (BDNF), a protein that supports the survival and growth of neurons in the brain. BDNF is known to play key roles in long-term potentiation and neuronal remodeling, both important in learning and memory tasks. Variations in the human gene that encodes BDNF have been linked with several psychiatric disorders.
Emory psychiatrist Andrew Miller and his team have been developing a different approach over the last few years: studying symptoms of depression in people who are being treated for something else. This allows them to sidestep, at least partially, the cultural construct of depression, from William Styron to Peter Kramer to direct-to-consumer television ads.
Interferon alpha, a treatment used against hepatitis C virus infection and some forms of cancer, is a protein produced by the immune system that spurs inflammation. It also can induce symptoms of depression, such as fatigue and malaise. There are some slight differences with psychiatric depression, which Millerâ€™s team describes here (less guilt!), but they conclude that there is a â€œhigh degree of overlap.â€
Miller and his colleagues, including Jennifer Felger and Ebrahim Haroon, have documented how interferon-alpha-induced inflammation affects the brains of hepatitis C and cancer patients in several papers. That research, in turn, informs their more recent fruitfulinvestigations of inflammation in the context of major depression. More on that soon.
The focus on PTSD co-occurring with depression. As the authors note, several studies looking at traumatized individuals found PTSD and depression together more often than they were present separately. This was true of Atlanta inner city residents in the Grady Trauma Project, veterans and survivors of the 2001 World Trade Center attack.
DICER: the gene whose activity is turned down in blood samples from people with PTSD plus depression. Its name evokes one of the three Fates in Greek mythology, Atropos, who cuts the thread of life. DICER is at the center of a cellular network of regulation, because it is part of the machinery that generates regulatory micro-RNAs.
The findings recapitulate work in mouse models of stress and its effects on the brain, with a connection to the many-tentacled Wnt signaling/adhesion protein beta-catenin.
Some past posts on the Grady Trauma Projectâ€™s scientific fruits follow. Read more