Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

Neuro

Why is it so hard to do good science?

Last week, Lab Land put out a Twitter poll, touching on the cognitive distortions that make it difficult to do high-quality science. Lots of people (almost 50) responded! Thank you!

We had to be vague about where all this came from, because it was before the publication of the underlying research paper. Ray Dingledine, in Emory’s Department of Pharmacology, asked us to do the Twitter poll first, to see what answers people would give. Dingledine’s paper in eNeuro is now published, so we can explain.

Raymond Dingledine, PhD

The paper is titled “Why Is It So Hard To Do Good Science?” Basically, Dingledine argues, our cognitive biases get in the way. eNeuro summarizes the take-home message this way: “Improving experimental design and statistical analyses alone will not solve the reproducibility crisis in science.”

When designing their experiments, Dingledine says, scientists need to take account of “the law of small numbers”—the distortions random variation can introduce when sample sizes are small – along with other cognitive biases.

In the 1960s and 1970s, psychologists Daniel Kahneman and Amos Tversky demonstrated that people tend to engage in “fast thinking” — relying on preconceived notions and emotions — when making decisions in the face of new information. In his update of this research, Dingledine found that scientists of all career stages are subject to the same biases as undergraduates when interpreting data.

The findings reinforce the roles that two inherent intuitions play in scientific decision-making: our drive to create a coherent narrative from new data regardless of its quality or relevance, and our inclination to seek patterns in data whether they exist or not. Moreover, we do not always consider how likely a result is regardless of its P-value. Read more

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When parents de-stress, so do offspring

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.

Read more

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Looking ahead to new opioid treatments

Stephanie Foster sees herself one day specializing in addiction psychiatry. When she started her MD/PhD studies at Emory, she sought out neuroscientist David Weinshenker to discuss research projects. She is now examining potential treatments for opiate addiction based on galanin, a neuropeptide found in the brain.

Weinshenker and his colleagues had already been studying galanin in relation to stimulants such as cocaine. If your loved one is showing signs of cocaine abuse, it is advised that you start looking for the best rehab company in your area.

Preliminary studies in animals indicate that activating galanin signals might reduce the rewarding effects of opiates, withdrawal symptoms, and relapse-like behavior.

“This was a whole new direction that looked promising,” Foster says. “But first, we have to work out the brain circuitry.”

Foster comes from a Native American background, and has a long-range plan to work in the Indian Health Service. The death rate of Native Americans from opiate overdoses is the highest of any American population group, according to the Centers for Disease Control and Prevention. She would like to establish a research lab in a region of the country where she could continue her addiction research and also work closely with Native communities.

Screenshot from NIH reporter (grant database). F31 grants for year 2018.

Last year, Foster applied for and received an individual grant from the National Institute on Drug Abuse to support her work. Emory currently leads U.S. universities in the number of graduate students holding their own active grants from the National Institutes of Health. This reflects a multi-year effort to build instruction in critical parts of scientific life: planning and communicating about one’s work.

Navigating opiate addiction can be a daunting journey, but finding support shouldn’t be. When it comes to seeking help, connecting with a professional interventionist can make all the difference. Whether you’re personally struggling or advocating for a loved one, know that assistance is just a click away. Click here to contact this professional interventionist and take the first step towards recovery.

When seeking help for opiate addiction, one can consider Moving Mountains Recovery. Rejuvenate and find tranquility at 1 Method Center in Los Angeles. Their comprehensive luxury rehab services focus on wellness and effective recovery. A Sober Living West Hollywood facility also offers effective addiction treatment and recovery programs.

“There isn’t really anything for people before they reach that stage,” Foster says. “Our idea is to look for an intervention that could be given earlier.” Read more

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Mysterious DNA modification important in fly brain

Emory scientists have identified a function for a mysterious DNA modification in fruit flies’ brain development, which may provide hints to its role in humans.

The results were published Thursday, August 2 in Molecular Cell.

Epigenetics may mean “above the genes,” but a lot of the focus in the field is on DNA methylation, a chemical modification of DNA itself. Methylation doesn’t change the actual DNA letters (A, C, G and T), but it does change how DNA is handled by the cell. Generally, it shuts genes off and is essential for cell differentiation.

The most commonly studied form of DNA methylation appears on the DNA letter C (cytosine). Drosophila, despite being a useful genetic model of development, have very little of this form of DNA methylation. What they do have is methylation on A — technically, N6-methyladenine, although little was known about what this modification did for flies.

Editor’s note: See this 2017 Nature feature from Cassandra Willyard on an “epigenetics gold rush”, which mentions the discovery of N6-methyladenine’s presence in the genomes of several organisms.

Emory geneticists Bing Yao, PhD, Peng Jin, PhD and colleagues now have shown that an enzyme that removes methylation from A is critical for neuronal development in Drosophila.

This finding is significant because the enzyme is in the same family (TET for ten-eleven translocation) of demethylases that trigger removal of DNA methylation from C in mammals. The function of TET enzymes, revealing that cells actively removed DNA methylation rather than just letting it slough off, was discovered only in 2009. Read more

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Fragile X: preclinical portfolio for PI3k drug strategy

Research in mice shows that a pharmacological strategy can alleviate multiple behavioral and cellular deficiencies in a mouse model of fragile X syndrome (FXS), the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorders.

The results were published online last week by Neuropsychopharmacology, and were presented at the NFXF International Fragile X Conference in Cincinnati.

When the compound GSK6A was given to mice lacking the Fmr1 gene, an established animal model of fragile X syndrome, it relieved symptomatic behaviors, such as impaired social interactions and inflexible decision making, which can be displayed by humans with fragile X syndrome.

The findings indicate that treatment with GSK6A or a similar compound could be a viable strategy for addressing cognitive and behavioral problems in fragile X syndrome; this would need to be tested directly in clinical trials. GSK6A inhibits one particular form of a cellular signaling enzyme: the p110β form of PI3 (phosphoinositide-3) kinase. A closely related p110β inhibitor is already in clinical trials for cancer.

Video from the iBook “Basic Science Breakthroughs: Fragile X Syndrome”. Narration by Emory genetics chair Stephen Warren, whose team identified the gene responsible for fragile X.

“Our results suggest that p110β inhibitors can be repurposed for fragile X syndrome, and they have implications for other subtypes of autism spectrum disorders that are characterized by similar alterations of this pathway,” says Gary Bassell, PhD, professor and chair of cell biology at Emory University School of Medicine.

“Right now, no proven efficient treatments are available for fragile X syndrome that are targeted to the disease mechanism,” says Christina Gross, PhD, from Cincinnati Children’s. “We think that p110β is an appropriate target because it is directly regulated by FMRP, and it is overactivated in both mouse models and patient cell lines.”

The paper represents a collaboration between three laboratories: two at Emory led by Bassell and Shannon Gourley, PhD, and one at Cincinnati Children’s, led by Gross. Gourley is based at Yerkes National Primate Research Center; see this earlier item on her collaboration with Bassell here.

While the researchers are discussing clinical trials of p110β inhibitors in fragile X syndrome, they say that long-term studies in animals are needed to ensure that undesirable side effects do not appear. More here.

With respect to clinical trials, the fragile X community has been disappointed before. Based on encouraging studies in mouse models, drugs targeting mGluR5 glutamate receptors were tested in adolescents and adults. mGluR5 drugs did not show clear benefits; recent re-evaluation suggests the choice of outcome measures, the ages of study participants and drug tolerance may have played a role.

Warren played a major role in developing the mGluR5 approach and Emory investigators were part of those studies. More recently, clinical trials for one of the mGluR5 medications were revived in younger children and Emory is a participating site. Also, see this 2016 discussion in Spectrum with Elizabeth Berry-Kravis on the fragile X mouse model; Bassell, Gross and Gourley have made some inroads on the limitations Berry-Kravis describes.

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The blue spot: where seeds of destruction begin

Neuroscientist and geneticist David Weinshenker makes a case that the locus coeruleus (LC), a small region of the brainstem and part of the pons, is among the earliest regions to show signs of degeneration in both Alzheimer’s and Parkinson’s disease. You can check it out in Trends in Neurosciences.

The LC is the main source of the neurotransmitter norepinephrine in the brain, and gets its name (Latin for “blue spot”) from the pigment neuromelanin, which is formed as a byproduct of the synthesis of norepinephrine and its related neurotransmitter dopamine. The LC has connections all over the brain, and is thought to be involved in arousal and attention, stress responses, learning and memory, and the sleep-wake cycle.

Cells in the locus coeruleus are lost in mild cognitive impairment and Alzheimer’s. From Kelly et al Acta Neuropath. Comm. (2017) via Creative Commons

The protein tau is one of the toxic proteins tied to Alzheimer’s, and it forms intracellular tangles. Pathologists have observed that precursors to tau tangles can be found in the LC in apparently healthy people before anywhere else in the brain, sometimes during the first few decades of life, Weinshenker writes. A similar bad actor in Parkinson’s, alpha-synuclein, can also be detected in the LC before other parts of the brain that are well known for damage in Parkinson’s, such as the dopamine neurons in the substantia nigra.

“The LC is the earliest site to show tau pathology in AD and one of the earliest (but not the earliest) site to show alpha-synuclein pathology in PD,” Weinshenker tells Lab Land. “The degeneration of the cells in both these diseases is more gradual. It probably starts in the terminals/fibers and eventually the cell bodies die.” Read more

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Complexity of NMDA receptor drug discovery target revealed

Know your target. Especially if your target is coming into focus for treating diseases such as schizophrenia and treatment-resistant depression.

NMDA receptors, critical for learning and memory, are sensors in the brain. Studying them in molecular detail is challenging, because they usually come in four parts, and the parts aren’t all the same.

Researchers at Emory have been probing one variety of NMDA receptor assembly found in the cerebellum, and also in the thalamus, a central gateway for sensory inputs, important for cognition, movement and sleep. This variety includes a subunit called GluN2C – together with two partners, GluN1 and GluN2A.

The results were published Thursday, June 28 in Neuron.

Outside of a living brain, NMDA receptor assemblies are typically studied with either two copies of GluN2C or two of GluN2A, but not with one of each, says senior author Stephen Traynelis, PhD, professor of pharmacology at Emory University School of Medicine

“Our data suggest that GluN2C is rarely by itself,” Traynelis says. “It’s typically paired up with another GluN2 subunit. This means we really don’t know what the properties of the main NMDA receptor in the cerebellum or the thalamus are.”

Psychiatrists have become interested in GluN2C because it appears to decline in the brains of schizophrenia patients. Mice without adequate levels of GluN2C display abnormalities in learning, memory and sensory processing, which together resemble schizophrenia in humans. In addition, GluN2C appears to be important for the mechanism of ketamine, a drug being studied for its rapid anti-depressant effects.

Using drugs that are selective for particular combinations of NMDA receptor subunits, Traynelis’ laboratory showed that an assembly of GluN2A and GluN2C is the dominant form in the mouse cerebellum. When GluN2C is introduced into cortical neurons, it prefers to pair up with GluN2A, the researchers found. This raises the question, in regions such as the thalamus, of whether GluN2C also appears with a partner GluN2 subunit. They also observed that the GluN2A-GluN2C assembly has distinct electrochemical properties. Read more

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Measuring sleepiness: alternatives to five naps

In a 2015 episode of The Simpsons, Homer is diagnosed with narcolepsy. Overwhelming sleepiness at the nuclear power plant lands him in the hospital. Sampling his spinal fluid (ouch!), Homer’s chuckling, deep-voiced doctor quickly performs a test for hypocretin, a brain chemical important for staying awake and regulating REM sleep.

Reality check: testing for hypocretin takes time, and is not currently available in the United States. Let’s talk about how sleep disorders such as narcolepsy and idiopathic hypersomnia are actually diagnosed: operationally, rather than biologically. The less flashy, but standard, way to assess patients is to ask them to take a series of five naps and see how fast they doze off, and how fast they go into REM sleep (the rapid eye movement dreaming phase).

This process, known as the Multiple Sleep Latency Test or MSLT, works pretty well for narcolepsy type 1, the more distinctive form of narcolepsy that includes cataplexy. And it’s hard to fake being sleepy enough to zonk out within a few minutes. But it has a bunch of problems, and dissatisfaction with the MSLT has been developing among sleep specialists for the last several years.

Lynn Marie Trotti, MD

At Emory, neurologists Lynn Marie Trotti and David Rye published an analysis of what I will call the “flip flop problem” in 2013, with others in the field following up more recently. The flip flop problem is: someone who takes the MSLT one day will frequently get another result if they take it again on a different day. Read more

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‘Unbiased’ approaches to Alzheimer’s

In recent news stories about Alzheimer’s disease research, we noticed a word popping up: unbiased. Allan Levey, chair of Emory’s neurology department and head of Emory’s Alzheimer’s Disease Research Center, likes to use that word too. It’s key to a “back to the drawing board” shift taking place in the Alzheimer’s field.

Last week’s announcement of a link between herpes viruses and Alzheimer’s, which Emory researchers contributed to, was part of this shift. Keep in mind: the idea that viral infection contributes to Alzheimer’s has been around a long time, and the Neuron paper doesn’t nail down causality.  

Still, here’s an example quote from National Institute on Aging director Richard Hodes: “This is the first study to provide strong evidence based on unbiased approaches and large data sets that lends support to this line of inquiry.”

What is the bias that needs to be wrung out of the science? The “amyloid hypothesis” has dominated drug development for the last several years. Amyloid is a main constituent of the plaques that appear in the brains of people with Alzheimer’s, so treatments that counteract amyloid’s accumulation should help, right? Unfortunately, antibodies against amyloid or inhibitors of enzymes that process it generally haven’t worked out in big clinical trials, although the possibility remains that they weren’t introduced early enough to have a decent effect. Read more

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Inflammation in PD hits the gut

Several groups studying Parkinson’s have had a hunch – a gut feeling, even – that intestinal inflammation is involved in driving the disease. Now Emory researchers led by Malu Tansey, PhD have some evidence from patient samples to back it up, published in the journal Movement Disorders.

IMP graduate student Madelyn Houser

German pathologist Heiko Braak has been honored by the Michael J. Fox Foundation for Parkinson’s Research for his theory, originally published in 2003, proposing that disease pathology – marked by aggregation of the toxic protein alpha-synuclein — may begin in the gastrointestinal tract and migrate from there to the central nervous system. This proposal was both provocative and influential in the Parkinson’s disease (PD) field. And Tansey herself has long been interested in the role of microglia, the immune cells resident in the brain, in PD.

The first author of the new paper, Immunology and Molecular Pathogenesis graduate student Madelyn Houser, notes that digestive problems such as constipation are frequently reported in PD patients. But what is the cause and what is effect? As neurologist Stewart Factor observed for a Emory Medicine article on PD’s non-motor symptoms: “A patient might tell me he’s had recurring constipation for 10 years, but he wouldn’t say anything to a neurologist about it until he starts having other symptoms.” Read more

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